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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency</title><author><name sortKey="Al Herz, Waleed" sort="Al Herz, Waleed" uniqKey="Al Herz W" first="Waleed" last="Al-Herz">Waleed Al-Herz</name><affiliation><nlm:aff id="aff1"><institution>Department of Pediatrics, Kuwait University</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></nlm:aff></affiliation></author><author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name><affiliation><nlm:aff id="aff3"><institution>Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University</institution>,<addr-line>Casablanca</addr-line>,<country>Morocco</country></nlm:aff></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="aff4"><institution>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chatila, Talal" sort="Chatila, Talal" uniqKey="Chatila T" first="Talal" last="Chatila">Talal Chatila</name><affiliation><nlm:aff id="aff6"><institution>Division of Immunology, Children’s Hospital Boston</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Conley, Mary Ellen" sort="Conley, Mary Ellen" uniqKey="Conley M" first="Mary Ellen" last="Conley">Mary Ellen Conley</name><affiliation><nlm:aff id="aff4"><institution>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Cunningham Rundles, Charlotte" sort="Cunningham Rundles, Charlotte" uniqKey="Cunningham Rundles C" first="Charlotte" last="Cunningham-Rundles">Charlotte Cunningham-Rundles</name><affiliation><nlm:aff id="aff7"><institution>Department of Medicine and Pediatrics, Mount Sinai School of Medicine</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Etzioni, Amos" sort="Etzioni, Amos" uniqKey="Etzioni A" first="Amos" last="Etzioni">Amos Etzioni</name><affiliation><nlm:aff id="aff8"><institution>Meyer Children’s Hospital-Technion</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></nlm:aff></affiliation></author><author><name sortKey="Franco, Jose Luis" sort="Franco, Jose Luis" uniqKey="Franco J" first="Jose Luis" last="Franco">Jose Luis Franco</name><affiliation><nlm:aff id="aff9"><institution>Group of Primary Immunodeficiencies, University of Antioquia</institution>,<addr-line>Medellin</addr-line>,<country>Colombia</country></nlm:aff></affiliation></author><author><name sortKey="Gaspar, H Bobby" sort="Gaspar, H Bobby" uniqKey="Gaspar H" first="H. Bobby" last="Gaspar">H. Bobby Gaspar</name><affiliation><nlm:aff id="aff10"><institution>UCL Institute of Child Health</institution>,<addr-line>London</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name><affiliation><nlm:aff id="aff11"><institution>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases</institution>,<addr-line>Bethesda, MD</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Klein, Christoph" sort="Klein, Christoph" uniqKey="Klein C" first="Christoph" last="Klein">Christoph Klein</name><affiliation><nlm:aff id="aff12"><institution>Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Nonoyama, Shigeaki" sort="Nonoyama, Shigeaki" uniqKey="Nonoyama S" first="Shigeaki" last="Nonoyama">Shigeaki Nonoyama</name><affiliation><nlm:aff id="aff13"><institution>Department of Pediatrics, National Defense Medical College</institution>,<addr-line>Saitama</addr-line>,<country>Japan</country></nlm:aff></affiliation></author><author><name sortKey="Ochs, Hans D" sort="Ochs, Hans D" uniqKey="Ochs H" first="Hans D." last="Ochs">Hans D. Ochs</name><affiliation><nlm:aff id="aff14"><institution>Department of Pediatrics, Seattle Children’s Research Institute, University of Washington</institution>,<addr-line>Seattle, WA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Oksenhendler, Erik" sort="Oksenhendler, Erik" uniqKey="Oksenhendler E" first="Erik" last="Oksenhendler">Erik Oksenhendler</name><affiliation><nlm:aff id="aff15"><institution>Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Sorbonne Paris Cité, Université Paris Diderot</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation><nlm:aff id="aff5"><institution>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Centre d’Étude des Déficits Immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Puck, Jennifer M" sort="Puck, Jennifer M" uniqKey="Puck J" first="Jennifer M." last="Puck">Jennifer M. Puck</name><affiliation><nlm:aff id="aff18"><institution>Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco</institution>,<addr-line>San Francisco, CA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Sullivan, Kate" sort="Sullivan, Kate" uniqKey="Sullivan K" first="Kate" last="Sullivan">Kate Sullivan</name><affiliation><nlm:aff id="aff19"><institution>Department of Pediatrics, Division of Allergy Immunology, The Children’s Hospital of Philadelphia</institution>,<addr-line>Philadelphia, PA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tang, Mimi L K" sort="Tang, Mimi L K" uniqKey="Tang M" first="Mimi L. K." last="Tang">Mimi L. K. Tang</name><affiliation><nlm:aff id="aff20"><institution>Murdoch Childrens Research Institute</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff21"><institution>Department of Paediatrics, University of Melbourne</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>Department of Allergy and Immunology, Royal Children’s Hospital</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24795713</idno><idno type="pmc">4001072</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001072</idno><idno type="RBID">PMC:4001072</idno><idno type="doi">10.3389/fimmu.2014.00162</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002492</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002492</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency</title><author><name sortKey="Al Herz, Waleed" sort="Al Herz, Waleed" uniqKey="Al Herz W" first="Waleed" last="Al-Herz">Waleed Al-Herz</name><affiliation><nlm:aff id="aff1"><institution>Department of Pediatrics, Kuwait University</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></nlm:aff></affiliation></author><author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name><affiliation><nlm:aff id="aff3"><institution>Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University</institution>,<addr-line>Casablanca</addr-line>,<country>Morocco</country></nlm:aff></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="aff4"><institution>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><institution>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Chatila, Talal" sort="Chatila, Talal" uniqKey="Chatila T" first="Talal" last="Chatila">Talal Chatila</name><affiliation><nlm:aff id="aff6"><institution>Division of Immunology, Children’s Hospital Boston</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Conley, Mary Ellen" sort="Conley, Mary Ellen" uniqKey="Conley M" first="Mary Ellen" last="Conley">Mary Ellen Conley</name><affiliation><nlm:aff id="aff4"><institution>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Cunningham Rundles, Charlotte" sort="Cunningham Rundles, Charlotte" uniqKey="Cunningham Rundles C" first="Charlotte" last="Cunningham-Rundles">Charlotte Cunningham-Rundles</name><affiliation><nlm:aff id="aff7"><institution>Department of Medicine and Pediatrics, Mount Sinai School of Medicine</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Etzioni, Amos" sort="Etzioni, Amos" uniqKey="Etzioni A" first="Amos" last="Etzioni">Amos Etzioni</name><affiliation><nlm:aff id="aff8"><institution>Meyer Children’s Hospital-Technion</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></nlm:aff></affiliation></author><author><name sortKey="Franco, Jose Luis" sort="Franco, Jose Luis" uniqKey="Franco J" first="Jose Luis" last="Franco">Jose Luis Franco</name><affiliation><nlm:aff id="aff9"><institution>Group of Primary Immunodeficiencies, University of Antioquia</institution>,<addr-line>Medellin</addr-line>,<country>Colombia</country></nlm:aff></affiliation></author><author><name sortKey="Gaspar, H Bobby" sort="Gaspar, H Bobby" uniqKey="Gaspar H" first="H. Bobby" last="Gaspar">H. Bobby Gaspar</name><affiliation><nlm:aff id="aff10"><institution>UCL Institute of Child Health</institution>,<addr-line>London</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name><affiliation><nlm:aff id="aff11"><institution>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases</institution>,<addr-line>Bethesda, MD</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Klein, Christoph" sort="Klein, Christoph" uniqKey="Klein C" first="Christoph" last="Klein">Christoph Klein</name><affiliation><nlm:aff id="aff12"><institution>Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Nonoyama, Shigeaki" sort="Nonoyama, Shigeaki" uniqKey="Nonoyama S" first="Shigeaki" last="Nonoyama">Shigeaki Nonoyama</name><affiliation><nlm:aff id="aff13"><institution>Department of Pediatrics, National Defense Medical College</institution>,<addr-line>Saitama</addr-line>,<country>Japan</country></nlm:aff></affiliation></author><author><name sortKey="Ochs, Hans D" sort="Ochs, Hans D" uniqKey="Ochs H" first="Hans D." last="Ochs">Hans D. Ochs</name><affiliation><nlm:aff id="aff14"><institution>Department of Pediatrics, Seattle Children’s Research Institute, University of Washington</institution>,<addr-line>Seattle, WA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Oksenhendler, Erik" sort="Oksenhendler, Erik" uniqKey="Oksenhendler E" first="Erik" last="Oksenhendler">Erik Oksenhendler</name><affiliation><nlm:aff id="aff15"><institution>Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Sorbonne Paris Cité, Université Paris Diderot</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation><nlm:aff id="aff5"><institution>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Centre d’Étude des Déficits Immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Puck, Jennifer M" sort="Puck, Jennifer M" uniqKey="Puck J" first="Jennifer M." last="Puck">Jennifer M. Puck</name><affiliation><nlm:aff id="aff18"><institution>Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco</institution>,<addr-line>San Francisco, CA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Sullivan, Kate" sort="Sullivan, Kate" uniqKey="Sullivan K" first="Kate" last="Sullivan">Kate Sullivan</name><affiliation><nlm:aff id="aff19"><institution>Department of Pediatrics, Division of Allergy Immunology, The Children’s Hospital of Philadelphia</institution>,<addr-line>Philadelphia, PA</addr-line>,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tang, Mimi L K" sort="Tang, Mimi L K" uniqKey="Tang M" first="Mimi L. K." last="Tang">Mimi L. K. Tang</name><affiliation><nlm:aff id="aff20"><institution>Murdoch Childrens Research Institute</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff21"><institution>Department of Paediatrics, University of Melbourne</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>Department of Allergy and Immunology, Royal Children’s Hospital</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></nlm:aff></affiliation></author></analytic><series><title level="j">Frontiers in Immunology</title><idno type="eISSN">1664-3224</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases.</p></div></front></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Front Immunol</journal-id><journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id><journal-title-group><journal-title>Frontiers in Immunology</journal-title></journal-title-group><issn pub-type="epub">1664-3224</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24795713</article-id><article-id pub-id-type="pmc">4001072</article-id><article-id pub-id-type="doi">10.3389/fimmu.2014.00162</article-id><article-categories><subj-group subj-group-type="heading"><subject>Immunology</subject><subj-group><subject>Classification Article</subject></subj-group></subj-group></article-categories><title-group><article-title>Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Al-Herz</surname><given-names>Waleed</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/39391"></uri></contrib><contrib contrib-type="author"><name><surname>Bousfiha</surname><given-names>Aziz</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/40763"></uri></contrib><contrib contrib-type="author"><name><surname>Casanova</surname><given-names>Jean-Laurent</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/23598"></uri></contrib><contrib contrib-type="author"><name><surname>Chatila</surname><given-names>Talal</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Conley</surname><given-names>Mary Ellen</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cunningham-Rundles</surname><given-names>Charlotte</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/42358"></uri></contrib><contrib contrib-type="author"><name><surname>Etzioni</surname><given-names>Amos</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/25288"></uri></contrib><contrib contrib-type="author"><name><surname>Franco</surname><given-names>Jose Luis</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/23962"></uri></contrib><contrib contrib-type="author"><name><surname>Gaspar</surname><given-names>H. Bobby</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref><xref ref-type="corresp" rid="cor1">*</xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/126978"></uri></contrib><contrib contrib-type="author"><name><surname>Holland</surname><given-names>Steven M.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klein</surname><given-names>Christoph</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nonoyama</surname><given-names>Shigeaki</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/39288"></uri></contrib><contrib contrib-type="author"><name><surname>Ochs</surname><given-names>Hans D.</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/25831"></uri></contrib><contrib contrib-type="author"><name><surname>Oksenhendler</surname><given-names>Erik</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Picard</surname><given-names>Capucine</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff17"><sup>17</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/135156"></uri></contrib><contrib contrib-type="author"><name><surname>Puck</surname><given-names>Jennifer M.</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/39286"></uri></contrib><contrib contrib-type="author"><name><surname>Sullivan</surname><given-names>Kate</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref><uri xlink:type="simple" xlink:href="http://frontiersin.org/people/u/133432"></uri></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Mimi L. K.</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref><xref ref-type="aff" rid="aff21"><sup>21</sup></xref><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Pediatrics, Kuwait University</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></aff><aff id="aff2"><sup>2</sup><institution>Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital</institution>,<addr-line>Kuwait City</addr-line>,<country>Kuwait</country></aff><aff id="aff3"><sup>3</sup><institution>Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University</institution>,<addr-line>Casablanca</addr-line>,<country>Morocco</country></aff><aff id="aff4"><sup>4</sup><institution>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></aff><aff id="aff5"><sup>5</sup><institution>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes</institution>,<addr-line>Paris</addr-line>,<country>France</country></aff><aff id="aff6"><sup>6</sup><institution>Division of Immunology, Children’s Hospital Boston</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country></aff><aff id="aff7"><sup>7</sup><institution>Department of Medicine and Pediatrics, Mount Sinai School of Medicine</institution>,<addr-line>New York, NY</addr-line>,<country>USA</country></aff><aff id="aff8"><sup>8</sup><institution>Meyer Children’s Hospital-Technion</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></aff><aff id="aff9"><sup>9</sup><institution>Group of Primary Immunodeficiencies, University of Antioquia</institution>,<addr-line>Medellin</addr-line>,<country>Colombia</country></aff><aff id="aff10"><sup>10</sup><institution>UCL Institute of Child Health</institution>,<addr-line>London</addr-line>,<country>UK</country></aff><aff id="aff11"><sup>11</sup><institution>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases</institution>,<addr-line>Bethesda, MD</addr-line>,<country>USA</country></aff><aff id="aff12"><sup>12</sup><institution>Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich</institution>,<addr-line>Munich</addr-line>,<country>Germany</country></aff><aff id="aff13"><sup>13</sup><institution>Department of Pediatrics, National Defense Medical College</institution>,<addr-line>Saitama</addr-line>,<country>Japan</country></aff><aff id="aff14"><sup>14</sup><institution>Department of Pediatrics, Seattle Children’s Research Institute, University of Washington</institution>,<addr-line>Seattle, WA</addr-line>,<country>USA</country></aff><aff id="aff15"><sup>15</sup><institution>Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris</institution>,<addr-line>Paris</addr-line>,<country>France</country></aff><aff id="aff16"><sup>16</sup><institution>Sorbonne Paris Cité, Université Paris Diderot</institution>,<addr-line>Paris</addr-line>,<country>France</country></aff><aff id="aff17"><sup>17</sup><institution>Centre d’Étude des Déficits Immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP</institution>,<addr-line>Paris</addr-line>,<country>France</country></aff><aff id="aff18"><sup>18</sup><institution>Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco</institution>,<addr-line>San Francisco, CA</addr-line>,<country>USA</country></aff><aff id="aff19"><sup>19</sup><institution>Department of Pediatrics, Division of Allergy Immunology, The Children’s Hospital of Philadelphia</institution>,<addr-line>Philadelphia, PA</addr-line>,<country>USA</country></aff><aff id="aff20"><sup>20</sup><institution>Murdoch Childrens Research Institute</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></aff><aff id="aff21"><sup>21</sup><institution>Department of Paediatrics, University of Melbourne</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></aff><aff id="aff22"><sup>22</sup><institution>Department of Allergy and Immunology, Royal Children’s Hospital</institution>,<addr-line>Melbourne, VIC</addr-line>,<country>Australia</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Jordan Orange, Baylor College of Medicine, USA</p></fn><fn fn-type="edited-by"><p>Reviewed by: Jordan Orange, Baylor College of Medicine, USA; Francisco A. Bonilla, Boston Children’s Hospital, USA; Thomas Arthur Fleisher, National Institutes of Health, USA; Fischer Alain, INSERM, France</p></fn><corresp content-type="corresp" id="cor1">*Correspondence: H. Bobby Gaspar, Molecular Immunology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK e-mail: <email>h.gaspar@ucl.ac.uk</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology.</p></fn></author-notes><pub-date pub-type="epub"><day>22</day><month>4</month><year>2014</year></pub-date><pub-date pub-type="collection"><year>2014</year></pub-date><volume>5</volume><elocation-id>162</elocation-id><history><date date-type="received"><day>16</day><month>12</month><year>2013</year></date><date date-type="accepted"><day>27</day><month>3</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014 Al-Herz, Bousfiha, Casanova, Chatila, Conley, Cunningham-Rundles, Etzioni, Franco, Gaspar, Holland, Klein, Nonoyama, Ochs, Oksenhendler, Picard, Puck, Sullivan and Tang.</copyright-statement><copyright-year>2014</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases.</p></abstract><kwd-group><kwd>primary immunodeficiencies</kwd><kwd>IUIS</kwd><kwd>classification</kwd><kwd>genetic defects</kwd><kwd>genotype</kwd></kwd-group><counts><fig-count count="0"></fig-count><table-count count="9"></table-count><equation-count count="0"></equation-count><ref-count count="0"></ref-count><page-count count="33"></page-count><word-count count="12720"></word-count></counts></article-meta></front><body><sec id="S1"><title>Background</title><p>The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in New York on 19th–21st April 2013 to update the classification of human primary immunodeficiencies (PIDs). This report represents the most current and complete catalog of known PIDs. It serves as a reference for these conditions and provides a framework to help in the diagnostic approach to patients suspected to have PID.</p><p>As in previous reports, we have classified the conditions into major groups of PIDs and these are now represented in nine different tables. In each table, we list the condition, its genetic defect if known, and the major immunological and in some conditions the non-immunological abnormalities associated with the disease. The classification this year differs slightly from the previous edition in that Table <xref ref-type="table" rid="T1">1</xref> lists combined immunodeficiencies without non-immunologic phenotypes, whereas Table <xref ref-type="table" rid="T2">2</xref> refers to combined immunodeficiencies with syndromic features, as increasing numbers of these are being identified. The title and classification of Tables <xref ref-type="table" rid="T3">3</xref>–<xref ref-type="table" rid="T8">8</xref> present the same major PID groups as in the previous report.</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><p><bold>Combined immunodeficiencies</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Circulating T cells</th><th align="left" rowspan="1" colspan="1">Circulating B cells</th><th align="left" rowspan="1" colspan="1">Serum Ig</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="8" rowspan="1">1. T<sup>−</sup>B<sup>+</sup> severe combined immunodeficiency (SCID)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) γc deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>IL-2RG</italic></td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal or increased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300400">300400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) JAK3 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>JAK3</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal or increased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600173">600173</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in Janus-activating kinase 3</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) IL7Rα deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>IL7RA</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal or increased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/146661">146661</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in IL-7 receptor α chain</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) CD45 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>PTPRC</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal γ/δ T cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/151460">151460</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in CD45</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) CD3δ deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD3D</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186790">186790</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in CD3δ chain of T cell antigen receptor complex</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">No γ/δ T cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) CD3ε deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD3E</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186830">186830</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in CD3ε chain of T cell antigen receptor complex</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">No γ/δ T cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) CD3ζ deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD3Z</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186740">186740</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in CD3ζ chain of T cell antigen receptor complex</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">No γ/δ T cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) Coronin-1A deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CORO1A</italic> defective thymic egress of T cells and defective T cell locomotion</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Detectable thymus EBV associated B cell lymphoproliferation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605000">605000</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">2. T<sup>−</sup>B<sup>−</sup>SCID</td></tr><tr><td align="left" colspan="8" rowspan="1">(i) DNA recombination defects</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) RAG 1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>RAG1</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601457">601457</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective VDJ recombination; defect of recombinase activating gene (RAG) 1</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(a) RAG 2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>RAG2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601457">601457</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective VDJ recombination; defect of recombinase activating gene (RAG) 2</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) DCLRE1C (artemis) deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>ARTEMIS</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Radiation sensitivity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602450">602450</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective VDJ recombination; defect in artemis DNA recombinase repair protein</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) DNA PKcs deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>PRKDC</italic>- Defective VDJ recombination; defect in DNA PKcs</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Radiation sensitivity, microcephaly, and developmental defects</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600899">600899</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Recombinase repair protein</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(ii) Reticular dysgenesis, AK2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>AK2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Decreased or normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Granulocytopenia and deafness</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/103020">103020</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective maturation of lymphoid and myeloid cells (stem cell defect)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defect in mitochondrial adenylate kinase 2</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(iii) Adenosine deaminase (ADA) deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of ADA absent <italic>ADA</italic> activity, elevated lymphotoxic metabolites (dATP, <italic>S</italic>-adenosyl homocysteine)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent from birth (null mutations) or progressive decrease</td><td align="left" rowspan="1" colspan="1">Absent from birth of progressive decrease</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Decreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/102700">102700</uri></td></tr><tr><td align="left" colspan="8" rowspan="1"><bold>Combined immunodeficiencies generally less profound than severe combined immunodeficiency</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">3. CD40 ligand deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD40LG</italic> defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signaling</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Normal; may progressively decrease</td><td align="left" rowspan="1" colspan="1">sIgM<sup>+</sup> and sIgD<sup>+</sup> B cells present, other surface isotype positive B cells absent</td><td align="left" rowspan="1" colspan="1">IgM increased or normal, other isotypes decreased</td><td align="left" rowspan="1" colspan="1">Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300386">300386</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">4. CD40 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD40</italic> (also called TNFRSF5) defects in CD40 cause defective isotype switching and impaired dendritic cell signaling</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">IgM<sup>+</sup> and IgD<sup>+</sup> B cells present, other isotypes absent</td><td align="left" rowspan="1" colspan="1">IgM increased or normal, other isotypes decreased</td><td align="left" rowspan="1" colspan="1">Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/109535">109535</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">5. Purine nucleoside phosphorylase (PNP) deficiency</td><td align="left" rowspan="1" colspan="1">Mutation of <italic>PNP</italic>, absent PNP, and T cell and neurologic defects from elevated toxic metabolites, especially dGTP</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">Autoimmune hemolytic anemia, neurological impairment</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/164050">164050</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">6. CD3γ deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD3G</italic> defect in CD3 γ – component of the T cell antigen receptor complex</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal, but reduced TCR expression</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186740">186740</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">7. CD8 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>CD8A</italic>, defects of CD8 α chain – important for maturation and function of CD8 T cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CD8, normal CD4 cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186910">186910</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">8. ZAP70 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased CD8, normal CD4 cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Autoimmunity in some cases</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/269840">269840</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">9. MHC class I deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TAP1, TAP2</italic>, or <italic>TAPBP</italic> (tapasin) genes giving MHC class I deficiency</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased CD8, normal CD4</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Vasculitis; pyoderma gangrenosum</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604571">604571</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">10. MHC class II deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in transcription factors for MHC class II proteins (<italic>CIITA, RFX5, RFXAP, RFXANK</italic> genes)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal number, decreased CD4 cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">Failure to thrive, diarrhea, respiratory tract infections, liver/biliary tract disease</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/209920">209920</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">11. ITK deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ITK</italic> encoding IL-2-inducible T cell kinase required for TCR-mediated activation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">EBV-associated B cell lymphoproliferation, lymphoma</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613011">613011</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Normal or decreased IgG</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">12. SH2D1A deficiency (XLP1)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SH2D1A</italic> encoding an adaptor protein regulating intracellular signals</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Normal or increased activated T cells</td><td align="left" rowspan="1" colspan="1">Reduced memory B cells</td><td align="left" rowspan="1" colspan="1">Partially defective NK cell and CTL cytotoxic activity</td><td align="left" rowspan="1" colspan="1">Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, aplastic anemia, lymphoma</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/308240">308240</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Absent iNKT cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">13. Cartilage hair hypoplasia</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RMRP</italic> (RNase MRP RNA) involved in processing of mitochondrial RNA and cell cycle control</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or reduced. antibodies variably decreased</td><td align="left" rowspan="1" colspan="1">Can present just as combined immunodeficiency without other features of short-limbed dwarfism</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/250250">250250</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Also see Table <xref ref-type="table" rid="T2">2</xref></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">14. MAGT1 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>MAGT1</italic>, impaired Mg<sup>++</sup> flux leading to impaired TCR signaling</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Decreased CD4 cells reduced numbers of RTE, impaired T cell proliferation in response to CD3</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">EBV infection, lymphoma; viral infections, respiratory, and GI infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300715">300715</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">15. DOCK8 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>DOCK8</italic> – regulator of intracellular actin reorganization</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased impaired T lymphocyte proliferation</td><td align="left" rowspan="1" colspan="1">Decreased, low CD27+ memory B cells</td><td align="left" rowspan="1" colspan="1">Low IgM, increased IgE</td><td align="left" rowspan="1" colspan="1">Low NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/243700">243700</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">16. RhoH deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RHOH</italic> – an atypical Rho GTPase transducing signals downstream of various membrane receptors</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">HPV infection, lymphoma, lung granulomas, molluscum contagiosum</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602037">602037</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">17. MST1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STK4</italic> – a serine/threonine kinase</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased/increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population, and impaired T cells proliferation</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">High</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; congenital heart disease, autoimmune cytopenias; HPV infection</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614868">614868</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">18. TCRα deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TRAC</italic> – essential component of the T cell receptor</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal all CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T cell deficiency), impaired T cells proliferation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Recurrent viral, bacterial, and fungal infections, immune dysregulation autoimmunity, and diarrhea</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615387">615387</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">19. LCK deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>LCK</italic> – a proximal tyrosine kinase that interacts with TCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal total numbers but CD4+ T cell lymphopenia, low Treg numbers, restricted T cell repertoire, and impaired TCR signaling</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal IgG and IgA and increased IgM</td><td align="left" rowspan="1" colspan="1">Diarrhea, recurrent infections, immune dysregulation autoimmunity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/153390">153390</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">20. MALT1 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>MALT1</italic> – a caspase-like cysteine protease that is essential for nuclear factor kappa B activation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal impaired T cells proliferation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Bacterial, fungal, and viral infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604860">604860</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Impaired antibody response</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">21. IL-21R deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>IL-21R</italic> – together with common gamma chain binds IL-21</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Abnormal T cell cytokine production; abnormal T cell proliferation to specific stimuli</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal but impaired specific responses</td><td align="left" rowspan="1" colspan="1">Susceptibility to cryptosporidium and pneumocystis and cholangitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605383">605383</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">22. UNC119 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>UNC119</italic> – an activator of src tyrosine kinases</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Low T cells</td><td align="left" rowspan="1" colspan="1">Mostly low</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial, fungal, and viral infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604011">604011</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">CD4+ T cell lymphopenia, impaired TCR signaling</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">23. CARD11 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>CARD11</italic> – acts as a scaffold for NF-κB activity in the adaptive immune response</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal predominance of naive T lymphocyte, impaired T cells proliferation</td><td align="left" rowspan="1" colspan="1">Normal predominance of transitional B lymphocytes</td><td align="left" rowspan="1" colspan="1">Absent/low</td><td align="left" rowspan="1" colspan="1"><italic>Pneumocystis jiroveci</italic> pneumonia, bacterial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615206">615206</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">24. OX40 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>OX40</italic> – a co-stimulatory molecule expressed on activated T cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal T cell numbers</td><td align="left" rowspan="1" colspan="1">Normal B cell numbers</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Kaposi’s sarcoma; impaired immunity to HHV8</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615593">615593</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Low levels of antigen-specific memory CD4+ cells</td><td align="left" rowspan="1" colspan="1">Lower frequency of memory B cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">25. IKBKB deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in <italic>IKBKB</italic> – encodes IkB kinase 2 a component of the NF-κB pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal total T cells; absent regulatory and gd T cells; impaired TCR activation</td><td align="left" rowspan="1" colspan="1">Normal B cell numbers; impaired BCR activation</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial, viral, and fungal infections; clinical phenotype of SCID</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615592">615592</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">26. Activated PI3K-δ</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>PIK3CD</italic>, PI3K-δ</td><td align="left" rowspan="1" colspan="1">AD gain-of-function</td><td align="left" rowspan="1" colspan="1">Decreased total numbers of T cells</td><td align="left" rowspan="1" colspan="1">Decreased total peripheral B cell and switched memory B cells; increased transitional B cells</td><td align="left" rowspan="1" colspan="1">Reduced IgG2 and impaired antibody to pneumococci and hemophilus</td><td align="left" rowspan="1" colspan="1">Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, and CMV infection</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602839">602839</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">27. LRBA deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>LRBA</italic> (lipopolysaccharide responsive beige-like anchor protein)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal or decreased CD4 numbers; T cell dysregulation</td><td align="left" rowspan="1" colspan="1">Low or normal numbers of B cells</td><td align="left" rowspan="1" colspan="1">Reduced I IgG and IgA in most</td><td align="left" rowspan="1" colspan="1">Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606453">606453</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">28. CD27 deficiency<xref ref-type="table-fn" rid="tfn1"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD27</italic>, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">No memory B cells</td><td align="left" rowspan="1" colspan="1">Hypogamma globulinemia following EBV infection</td><td align="left" rowspan="1" colspan="1">Clinical and immunologic features triggered by EBV infection, HLH</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615122">615122</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Aplastic anemia, lymphoma</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Low iNKT cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">29. Omenn syndrome</td><td align="left" rowspan="1" colspan="1">Hypomorphic mutations in <italic>RAG1, RAG2, artemis, IL7RA, RMRP, ADA, DNA ligase IV, IL-2RG, AK2</italic>, or associated with DiGeorge syndrome; some cases have no defined gene mutation</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Present; restricted T cell repertoire, and impaired function</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">Decreased, except increased IgE</td><td align="left" rowspan="1" colspan="1">Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/603554">603554</uri></td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; SCID, severe combined immune deficiencies; EBV, Epstein–Barr virus; Ca<sup>++</sup>, calcium; MHC, major histocompatibility complex, RTE, recent thymic emigrants, HPV, human papillomavirus</italic>.</p><fn id="tfn1"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>Infants with SCID who have maternal T cells engraftment may have T cells that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID or a less profound CID phenotype. Both OS and leaky SCID can be associated with higher numbers of T cells and reduced rather than absent activation responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, granulomas with T lymphopenia, autoimmunity, and CD4+ T lymphopenia can be found with RAG gene defects. RAC2 deficiency is a disorder of leukocyte motility and is reported in Table <xref ref-type="table" rid="T5">5</xref>; however, one patient with RAC2 deficiency was found to have absent T cell receptor excision circles (TRECs) by newborn screening, but T cell numbers and mitogen responses were not impaired. For additional syndromic conditions with T cell lymphopenia, such as DNA repair defects, cartilage hair hypoplasia, IKAROS deficiency, and NEMO syndrome, see Tables <xref ref-type="table" rid="T2">2</xref> and <xref ref-type="table" rid="T6">6</xref>; however, it should be noted that individuals with the most severe manifestations of these disorders could have clinical signs and symptoms of SCID. Severe folate deficiency (such as with malabsorption due to defects in folate carrier or transporter genes SLC10A1 or PCFT) and some metabolic disorders, such as methylmalonic aciduria, may present with reversible profound lymphopenia in addition to their characteristic presenting features</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T2" position="float"><label>Table 2</label><caption><p><bold>Combined immunodeficiencies with associated or syndromic features</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Circulating T cells</th><th align="left" rowspan="1" colspan="1">Circulating B cells</th><th align="left" rowspan="1" colspan="1">Serum Ig</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="8" rowspan="1">1. Congenital thrombocytopenia</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Wiskott– Aldrich syndrome (WAS)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>WAS</italic>; cytoskeletal, and immunologic synapse defect affecting hematopoietic stem cell derivatives</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Progressive decrease, abnormal lymphocyte responses to anti-CD3</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE</td><td align="left" rowspan="1" colspan="1">Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/301000">301000</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) WIP deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>WIPF1</italic>; cytoskeletal and immunologic synapse defect affecting hematopoietic stem cell derivatives</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Reduced, defective lymphocyte responses to anti-CD3</td><td align="left" rowspan="1" colspan="1">Low</td><td align="left" rowspan="1" colspan="1">Normal, except for increased IgE</td><td align="left" rowspan="1" colspan="1">Recurrent infections; eczema; thrombocytopenia. WAS-<italic>like</italic> phenotype</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614493">614493</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">2. DNA repair defects (other than those in Table <xref ref-type="table" rid="T1">1</xref>)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Ataxia–telangiectasia</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ATM</italic>; disorder of cell cycle checkpoint; and DNA double-strand break repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Often decreased IgA, IgE, and IgG subclasses; increased IgM monomers; antibodies variably decreased</td><td align="left" rowspan="1" colspan="1">Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/208900">208900</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Ataxia–telangiectasia-like disease (ATLD)<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Hypomorphic mutations in <italic>MRE11</italic>; disorder of cell cycle checkpoint and DNA double-strand break repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Antibodies variably decreased</td><td align="left" rowspan="1" colspan="1">Moderate ataxia; pulmonary infections; severely increased radiosensitivity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604391">604391</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Nijmegen breakage syndrome</td><td align="left" rowspan="1" colspan="1">Hypomorphic mutations in <italic>NBS1 (Nibrin)</italic>; disorder of cell cycle checkpoint and DNA double-strand break repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Variably reduced</td><td align="left" rowspan="1" colspan="1">Often decreased IgA, IgE, and IgG subclasses; increased IgM; antibodies variably decreased</td><td align="left" rowspan="1" colspan="1">Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/251260">251260</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Bloom syndrome</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>BLM</italic>; RecQ-like helicase</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Reduced</td><td align="left" rowspan="1" colspan="1">Short stature; bird-like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/210900">210900</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) Immunodeficiency with centromeric instability and facial anomalies (ICF)</td><td align="left" rowspan="1" colspan="1">Mutations in DNA methyltransferase <italic>DNMT3B</italic> (ICF1) resulting in defective DNA methylation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased or normal; responses to PHA may be decreased</td><td align="left" rowspan="1" colspan="1">Decreased or normal</td><td align="left" rowspan="1" colspan="1">Hypogamma globulinemia; variable antibody deficiency</td><td align="left" rowspan="1" colspan="1">Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/242860">242860</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) Immunodeficiency with centromeric instability and facial anomalies (ICF)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ZBTB24</italic> (ICF2)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased or normal; responses to PHA may be decreased</td><td align="left" rowspan="1" colspan="1">Decreased or normal</td><td align="left" rowspan="1" colspan="1">Hypogamma globulinemia; variable antibody deficiency</td><td align="left" rowspan="1" colspan="1">Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/242860">242860</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) PMS2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>PMS2</italic>, resulting in class switch recombination deficiency due to impaired mismatch repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Switched and non-switched B cells are reduced</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA, elevated IgM, abnormal antibody responses</td><td align="left" rowspan="1" colspan="1">Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600259">600259</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) RNF168 deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RNF168</italic>, resulting in defective DNA double-strand break repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Low IgG or low IgA</td><td align="left" rowspan="1" colspan="1">Short stature; mild motor control to ataxia and normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/611943">611943</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) MCM4 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>MCM4</italic> (minichromosome maintenance complex component 4) gene involved in DNA replication and repair</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Viral infections (EBV, HSV, VZV) Adrenal failure Short stature</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/609981">609981</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">3. Thymic defects with additional congenital anomalies</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) DiGeorge anomaly</td><td align="left" rowspan="1" colspan="1">Contiguous gene defect in 90% affecting thymic development; may also be due to heterozygous mutation in <italic>TBX1</italic> (chromosome 22q11.2 deletion or TBX1 haploinsufficient syndrome)</td><td align="left" rowspan="1" colspan="1"><italic>De novo</italic> defect (majority) or AD</td><td align="left" rowspan="1" colspan="1">Decreased or normal; 5% have <1500 CD3 T cells/μL</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">Hypoparathyroidism, conotruncal malformation; abnormal facies; large deletion (3 Mb) in 22q11.2 (or rarely a deletion in 10p)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/188400">188400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) CHARGE syndrome</td><td align="left" rowspan="1" colspan="1">Variable defects of the thymus and associated T cell abnormalities often due to deletions or mutations in <italic>CHD7, SEMA3E</italic>, or as yet unknown genes</td><td align="left" rowspan="1" colspan="1"><italic>De novo</italic> defect (majority) or AD</td><td align="left" rowspan="1" colspan="1">Decreased or normal; some have <1500 CD3 T cells/μL</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or decreased</td><td align="left" rowspan="1" colspan="1">Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/214800">214800</uri><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/608892">608892</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">4. Immune-osseous dysplasias</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Cartilage hair hypoplasia</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RMRP</italic> (RNase MRP RNA) involved in processing of mitochondrial RNA and cell cycle control</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal or reduced. Antibodies variably decreased</td><td align="left" rowspan="1" colspan="1">Short-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/250250">250250</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Schimke syndrome</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SMARCAL1</italic> involved in chromatin remodeling</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, and fungal infections; may present as SCID; bone marrow failure</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/242900">242900</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">5. Hyper-IgE syndromes (HIES)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) AD-HIES (Job’s syndrome)</td><td align="left" rowspan="1" colspan="1">Dominant-negative heterozygous mutations in <italic>STAT3</italic></td><td align="left" rowspan="1" colspan="1">AD Often <italic>de novo</italic> defect</td><td align="left" rowspan="1" colspan="1">Normal Th-17 and T follicular helper cells decreased</td><td align="left" rowspan="1" colspan="1">Normal Switched and non-switched memory B cells are reduced; BAFF level increased</td><td align="left" rowspan="1" colspan="1">Elevated IgE; specific antibody production decreased</td><td align="left" rowspan="1" colspan="1">Distinctive facial features (broad nasal bridge), eczema, osteoporosis, and fractures, scoliosis, delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses, pneumatoceles) due to <italic>Staphylococcus aureus</italic>, candidiasis, aneurysm formation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147060">147060</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) Tyk2 deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TYK2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal, but multiple cytokine signaling defect</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">(±) Elevated IgE</td><td align="left" rowspan="1" colspan="1">Susceptibility to intracellular bacteria (<italic>Mycobacteria, Salmonella</italic>), fungi, and viruses</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/611521">611521</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(ii) DOCK8 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>DOCK8</italic> – regulator of intracellular actin reorganization</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased impaired T lymphocyte proliferation</td><td align="left" rowspan="1" colspan="1">Decreased, low CD27+ memory B cells</td><td align="left" rowspan="1" colspan="1">Low IgM, increased IgE</td><td align="left" rowspan="1" colspan="1">Low NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/243700">243700</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">6. Dyskeratosis congenital (DKC)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) XL-DKC</td><td align="left" rowspan="1" colspan="1">Mutations in dyskerin <italic>(DKC1)</italic> (Hoyeraal–Hreidarsson syndrome)</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/305000">305000</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) AR-DKC due to NHP2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>NOLA2 (NHP2)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613987">613987</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) AR-DKC due to NOP10 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>NOLA3 (NOP10 PCFT)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/224230">224230</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) AR-DKC due to RTEL1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>(RTEL1)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/608833">608833</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) AD-DKC due to TERC deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TERC</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/127550">127550</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) AD-DKC due to TERT deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TERT</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614742">614742</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) AD-DKC due to TINF2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TINF2</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613990">613990</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">7. Defects of vitamin B12 and folate metabolism</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) TCN2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TCN2</italic>; encodes transcobalamin, a transporter of cobalamin into blood cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Megaloblastic anemia, pancytopenia, untreated for prolonged periods results in mental retardation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/275350">275350</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) SLC46A1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>SLC46A1</italic>; a proton coupled folate transporter</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Variable numbers and activation profile</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Megaloblastic anemia, failure to thrive untreated for prolonged periods results in mental retardation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/229050">229050</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) MTHFD1<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref> deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>MTHFD1</italic>; essential for processing of single-carbon folate derivatives</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low</td><td align="left" rowspan="1" colspan="1">Low</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Megaloblastic anemia, failure to thrive neutropenia, seizures, mental retardation</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">8. Comel–Netherton syndrome</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SPINK5</italic> resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Switched and non-switched B cells are reduced</td><td align="left" rowspan="1" colspan="1">Elevated IgE and IgA</td><td align="left" rowspan="1" colspan="1">Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/256500">256500</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Antibody variably decreased</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">9. Winged helix deficiency (Nude)<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Defects in forkhead box N1 transcription factor encoded by <italic>FOXN1</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Markedly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Alopecia, abnormal thymic epithelium, impaired T cell maturation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600838">600838</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">10. ORAI-I deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ORAI1</italic>, a Ca<sup>++</sup> release-activated channel (CRAC) modulatory component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal number, but defective TCR-mediated activation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy defective TCR-mediated activation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610277">610277</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">11. STIM1 deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STIM1</italic>, a stromal interaction molecule 1</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal number, but defective TCR-mediated activation</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy defective TCR-mediated activation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605921">605921</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">12. STAT5b deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STAT5B</italic>, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Modestly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Growth-hormone insensitive dwarfism</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/245590">245590</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Dysmorphic features</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Eczema</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Lymphocytic interstitial pneumonitis, autoimmunity</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">13. Hepatic veno-occlusive disease with immunodeficiency (VODI)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SP110</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal (decreased memory T cells)</td><td align="left" rowspan="1" colspan="1">Normal (decreased memory B cells)</td><td align="left" rowspan="1" colspan="1">Decreased IgG, IgA, IgM, absent germinal centers, absent tissue plasma cells</td><td align="left" rowspan="1" colspan="1">Hepatic veno-occlusive disease; <italic>Pneumocystis jiroveci</italic> pneumonia; susceptibility to CMV, <italic>Candida</italic>; thrombocytopenia; hepatosplenomegaly</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/235550">235550</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">14. IKAROS deficiency<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IKAROS</italic></td><td align="left" rowspan="1" colspan="1">AD <italic>de novo</italic></td><td align="left" rowspan="1" colspan="1">Normal, but impaired lymphocyte proliferation</td><td align="left" rowspan="1" colspan="1">Absent</td><td align="left" rowspan="1" colspan="1">Presumably decreased</td><td align="left" rowspan="1" colspan="1">Anemia, neutropenia, thrombocytopenia</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">15. FILS syndrome<xref ref-type="table-fn" rid="tfn2"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>POLE1</italic>; defective DNA replication</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low naïve T cells; decreased T cell proliferation</td><td align="left" rowspan="1" colspan="1">Low memory B cells</td><td align="left" rowspan="1" colspan="1">Decreased IgM and IgG; lack of antibodies to polysaccharide antigens</td><td align="left" rowspan="1" colspan="1">Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections, and recurrent meningitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615139">615139</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">16. Immunodeficiency with multiple intestinal atresias</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>TTC7A</italic> [tetratricopeptide repeat (TPR) domain 7A] protein of unknown function</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Variable, but sometimes absent</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased</td><td align="left" rowspan="1" colspan="1">Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/243150">243150</uri></td></tr></tbody></table><table-wrap-foot><p><italic>SCID, severe combined immune deficiencies; XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; MSMD, Mendelian susceptibility of mycobacterial disease</italic>.</p><fn id="tfn2"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>T and B cell number and function in these disorders exhibit a wide range of abnormality; the most severely affected cases meet diagnostic criteria for SCID or leaky SCID and require immune system restoring therapy such as allogeneic hematopoietic cell transplantation. While not all DOCK8-deficient patients have elevated serum IgE, most have recurrent viral infections and malignancies as a result of combined immunodeficiency. AR-HIES due to Tyk2 deficiency is also listed in Table <xref ref-type="table" rid="T6">6</xref>, because of its association with atypical mycobacterial disease resulting in MSMD. Riddle syndrome is caused by mutations in a gene involved in DNA double-strand break repair and is associated with hypogammaglobulinemia. Autosomal dominant and autosomal recessive forms of dyskeratosis congenita are included in this table. IKAROS-deficiency represents a single prematurely born infant who died at the age of 87 days and who had absent B and NK cells and non-functional T cells</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T3" position="float"><label>Table 3</label><caption><p><bold>Predominantly antibody deficiencies</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Serum Ig</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="6" rowspan="1">1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) BTK deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>BTK</italic>, a cytoplasmic tyrosine kinase activated by crosslinking of the BCR</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">All isotypes decreased in majority of patients; some patients have detectable immunoglobulins</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300300">300300</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) μ Heavy chain deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in μ heavy chain; essential component of the pre-BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147020">147020</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) λ5 Deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in l5; part of the surrogate light chain in the pre-BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/146770">146770</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Igα deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in Iga <italic>(CD79a)</italic>; part of the pre-BCR and BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/112205">112205</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) Igβ deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in Igb <italic>(CD79β)</italic>; part of the pre-BCR and BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147245">147245</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) BLNK deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>BLNK</italic>; a scaffold protein that binds to BTK</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; normal numbers of pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604615">604615</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) PI3 kinase deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>PIK3R1</italic>; a kinase involved in signal transduction in multiple cell types</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Severe bacterial infections; decreased or absent pro-B cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/171833">171833</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) E47 transcription factor deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TCF3</italic>; a transcription factor required for control of B cell development</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">All isotypes decreased</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147141">147141</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) Myelodysplasia with hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1">May have monosomy 7, trisomy 8, or dyskeratosis congenita</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">One or more isotypes may be decreased</td><td align="left" rowspan="1" colspan="1">Infections; decreased number of pro-B cells</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">(j) Thymoma with immunodeficiency</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">None</td><td align="left" rowspan="1" colspan="1">One or more isotypes may be decreased</td><td align="left" rowspan="1" colspan="1">Bacterial and opportunistic infections; autoimmunity; decreased number of pro-B cells</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" colspan="6" rowspan="1">2. Severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Common variable immunodeficiency disorders</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA and/or IgM</td><td align="left" rowspan="1" colspan="1">Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous disease</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">(b) ICOS deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ICOS</italic>; a co-stimulatory molecule expressed on T cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA and/or IgM</td><td align="left" rowspan="1" colspan="1">Recurrent infections; autoimmunity, gastroenteritis, granuloma in some</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604558">604558</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) CD19 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD19</italic>; transmembrane protein that amplifies signal through BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA and/or IgM</td><td align="left" rowspan="1" colspan="1">Recurrent infections; may have glomerulonephritis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/107265">107265</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) CD81 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD81</italic>; transmembrane protein that amplifies signal through BCR</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG, low or normal IgA and IgM</td><td align="left" rowspan="1" colspan="1">Recurrent infections; may have glomerulonephritis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186845">186845</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) CD20 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD20</italic>; a B cell surface receptor involved in B cell development and plasma cell differentiation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG, normal or elevated IgM and IgA</td><td align="left" rowspan="1" colspan="1">Recurrent infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/112210">112210</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) CD21 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD21</italic>; also known as complement receptor 2 and forms part of the CD19 complex</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG; impaired anti-pneumococcal response</td><td align="left" rowspan="1" colspan="1">Recurrent infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614699">614699</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) TACI deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TNFRSF13B</italic> (TACI); a TNF receptor family member found on B cells and is a receptor for BAFF and APRIL</td><td align="left" rowspan="1" colspan="1">AD or AR or complex</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA and/or IgM</td><td align="left" rowspan="1" colspan="1">Variable clinical expression</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604907">604907</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) LRBA deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>LRBA</italic> (lipopolysaccharide responsive beige-like anchor protein)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Reduced I IgG and IgA in most</td><td align="left" rowspan="1" colspan="1">Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606453">606453</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) BAFF receptor deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TNFRSF13C</italic> (BAFF-R); a TNF receptor family member found on B cells and is a receptor for BAFF</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG and IgM</td><td align="left" rowspan="1" colspan="1">Variable clinical expression</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606269">606269</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(j) TWEAK<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TWEAK</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Low IgM and IgA; lack of anti-pneumococcal antibody</td><td align="left" rowspan="1" colspan="1">Pneumonia, bacterial infections, warts; thrombocytopenia. neutropenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602695">602695</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(k) NFKB2 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>NFKB2</italic>; an essential component of the non-canonical NF-κB pathway</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA and IgM</td><td align="left" rowspan="1" colspan="1">Recurrent infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615577">615577</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(l) Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome</td><td align="left" rowspan="1" colspan="1">Gain-of-function mutations of <italic>CXCR4</italic>, the receptor for CXCL12</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Panhypogammaglobulinemia, decreased B cells</td><td align="left" rowspan="1" colspan="1">Warts/human papilloma virus (HPV) infection Neutropenia Reduced B cell number Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/193670">193670</uri></td></tr><tr><td align="left" colspan="6" rowspan="1">3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) CD40L deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD40LG</italic> (also called <italic>TNFSF5</italic> or <italic>CD154</italic>)</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increased</td><td align="left" rowspan="1" colspan="1">Bacterial and opportunistic infections, neutropenia, autoimmune disease</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300386">300386</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) CD40 deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD40</italic> (also called <italic>TNFRSF5</italic>)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG and IgA; normal or raised IgM</td><td align="left" rowspan="1" colspan="1">Bacterial and opportunistic infections, neutropenia, autoimmune disease</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/109535">109535</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) AID deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>AICDA</italic> gene</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">IgG and IgA decreased; IgM increased</td><td align="left" rowspan="1" colspan="1">Bacterial infections, enlarged lymph nodes, and germinal centers</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605257">605257</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) UNG deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>UNG</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">IgG and IgA decreased; IgM increased</td><td align="left" rowspan="1" colspan="1">Enlarged lymph nodes and germinal centers</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/191525">191525</uri></td></tr><tr><td align="left" colspan="6" rowspan="1">4. Isotype or light chain deficiencies with generally normal numbers of B cells</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Ig heavy chain mutations and deletions</td><td align="left" rowspan="1" colspan="1">Mutation or chromosomal deletion at 14q32</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">One or more IgG and/or IgA subclasses as well as IgE may be absent</td><td align="left" rowspan="1" colspan="1">May be asymptomatic</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">(b) κ Chain deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in Kappa constant gene</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">All immunoglobulins have lambda light chain</td><td align="left" rowspan="1" colspan="1">Asymptomatic</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147200">147200</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Isolated IgG subclass deficiency</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Reduction in one or more IgG subclass</td><td align="left" rowspan="1" colspan="1">Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">(d) IgA with IgG subclass deficiency</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Reduced IgA with decrease in one or more IgG subclass</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infections</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">(e) PRKC δ deficiency<xref ref-type="table-fn" rid="tfn3"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>PRKCD</italic>; encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation, and apoptosis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Low IgG levels; IgA and IgM above the normal range</td><td align="left" rowspan="1" colspan="1">Recurrent infections; EBV chronic infection Lymphoproliferation SLE-like autoimmunity (nephrotic and antiphospholipid syndromes)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615559">615559</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) Activated PI3K-δ</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>PIK3CD</italic>, PI3K-δ</td><td align="left" rowspan="1" colspan="1">AD gain-of-function</td><td align="left" rowspan="1" colspan="1">Reduced IgG2 and impaired antibody to pneumococci and hemophilus</td><td align="left" rowspan="1" colspan="1">Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602839">602839</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) Selective IgA deficiency</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">IgA decreased/absent</td><td align="left" rowspan="1" colspan="1">Usually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune disease. A very few cases progress to CVID, others coexist with CVID in the family</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/137100">137100</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">5. Specific antibody deficiency with normal Ig concen-trations and normal numbers of B cells</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Reduced ability to produce antibodies to specific antigens</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1">6. Transient hypogammaglobulinemia of infancy with normal numbers of B cells</td><td align="left" rowspan="1" colspan="1">Unknown</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">IgG and IgA decreased</td><td align="left" rowspan="1" colspan="1">Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; BTK, Bruton tyrosine kinase; BLNK, B cell linker protein; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase; ICOS, inducible costimulator; Ig(κ), immunoglobulin or κ light chain type</italic>.</p><fn id="tfn3"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>Several autosomal recessive disorders that might previously have been called CVID have been added to Table <xref ref-type="table" rid="T3">3</xref>. CD81 is normally co-expressed with CD19 on the surface of B cells. As for CD19 mutations, mutations in CD81 result in normal numbers of peripheral blood B cells, low serum IgG, and an increased incidence of glomerulonephritis. Single patient with a homozygous mutation in CD20 and CD21 has been reported</italic>.</p><p><italic>Common variable immunodeficiency disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Alterations in TNFRSF13B (TACI) and TNFRSF13C (BAFF-R) sequences may represent disease-modifying mutations rather than disease causing mutations. CD40L and CD40 deficiency are included in Table <xref ref-type="table" rid="T1">1</xref> as well as this table. A small minority of patients with XLP (Table <xref ref-type="table" rid="T4">4</xref>), WHIM syndrome (Table <xref ref-type="table" rid="T6">6</xref>), ICF (Table <xref ref-type="table" rid="T2">2</xref>), VOD1 (Table <xref ref-type="table" rid="T2">2</xref>), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells. Patients with GATA2 mutations (Table <xref ref-type="table" rid="T5">5</xref>) may have markedly reduced numbers of B cells, as well as decreased monocytes and NK cells, and a predisposition to myelodysplasia but they do not usually have an antibody deficiency</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T4" position="float"><label>Table 4</label><caption><p><bold>Diseases of immune dysregulation</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Circulating T cells</th><th align="left" rowspan="1" colspan="1">Circulating B cells</th><th align="left" rowspan="1" colspan="1">Functional defect</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="8" rowspan="1">1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes</td></tr><tr><td align="left" colspan="8" rowspan="1"> 1.1 FHL syndromes without hypopigmentation</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Perforin deficiency (FHL2)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>PRF1</italic>; perforin is a major cytolytic protein</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased activated T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased to absent NK and CTL activities (cytotoxicity)</td><td align="left" rowspan="1" colspan="1">Fever, hepatosplenomegaly (HSMG), hemophagocytic lymphohistiocytosis (HLH), cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/603553">603553</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) UNC13D/Munc13-4 deficiency (FHL3)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>UNC13D <xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></italic>; required to prime vesicles for fusion</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased activated T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Fever, HSMG, HLH, cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/608898">608898</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Syntaxin 11 deficiency (FHL4)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STX11</italic>, required for secretory vesicle fusion with the cell membrane</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased activated T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased NK activity (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Fever, HSMG, HLH, cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/603552">603552</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) STXBP2/Munc18-2 deficiency (FHL5)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STXBP2</italic>, required for secretory vesicle fusion with the cell membrane</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased activated T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Fever, HSMG, HLH, cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613101">613101</uri></td></tr><tr><td align="left" colspan="8" rowspan="1"> 1.2. FHL syndromes with hypopigmentation</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Chediak–Higashi syndrome</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>LYST</italic> Impaired lysosomal trafficking</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased activated T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Partial albinism<break></break>Recurrent infections, fever<break></break>HSMG, HLH<break></break>Giant lysosomes, neutropenia, cytopenias<break></break>Bleeding tendency<break></break>Progressive neurological dysfunction</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/214500">214500</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Griscelli syndrome, type 2</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RAB27A</italic> encoding a GTPase that promotes docking of secretory vesicles to the cell membrane</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Partial albinism, fever, HSMG, HLH, cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/607624">607624</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Hermansky–Pudlak syndrome, type 2</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>AP3B1</italic> gene, encoding for the b subunit of the AP-3 complex</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased NK and CTL activities (cytotoxicity and/or degranulation)</td><td align="left" rowspan="1" colspan="1">Partial albinism<break></break>Recurrent infections<break></break>Pulmonary fibrosis<break></break>Increased bleeding<break></break>Neutropenia<break></break>HLH</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/608233">608233</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">2. Lymphoproliferative syndromes</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) SH2D1A deficiency (XLP1)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SH2D1A</italic> encoding an adaptor protein regulating intracellular signaling</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Normal or increased activated T cells</td><td align="left" rowspan="1" colspan="1">Reduced memory B cells</td><td align="left" rowspan="1" colspan="1">Partially defective NK cell and CTL cytotoxic activity</td><td align="left" rowspan="1" colspan="1">Clinical and immunological features triggered by EBV infection: HLH<break></break>Lymphoproliferation, aplastic anemia, lymphoma<break></break>Hypogammaglobulinemia<break></break>Absent iNKT cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/308240">308240</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) XIAP deficiency (XLP2)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>XIAP/BIRC4</italic> encoding an inhibitor of apoptosis</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Normal or increased activated T cells; low/normal iNK T cells</td><td align="left" rowspan="1" colspan="1">Normal or reduced memory B cells</td><td align="left" rowspan="1" colspan="1">Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)</td><td align="left" rowspan="1" colspan="1">EBV infection, splenomegaly, lymphoproliferation HLH, colitis, IBD, hepatitis Low iNKT cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300635">300635</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) ITK deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ITK</italic> encoding IL-2 inducible T cell kinase required for TCR-mediated activation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Progressive decrease</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Decreased T cell activations</td><td align="left" rowspan="1" colspan="1">EBV-associated B cell lymphoproliferation, lymphoma<break></break>Normal or decreased IgG</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613011">613011</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) CD27 deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CD27</italic>, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">No memory B cells</td><td align="left" rowspan="1" colspan="1">Low T and NK cells functions</td><td align="left" rowspan="1" colspan="1">Clinical and immunological features triggered by EBV infection: HLH<break></break>Aplastic anemia, lymphoma, hypogammaglobulinemia<break></break>Low iNKT cells</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615122">615122</uri></td></tr><tr><td align="left" colspan="8" rowspan="1">3. Genetic defects of regulatory T cells</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>FOXP3</italic>, encoding a T cell transcription factor</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Lack of (and/or impaired function of) CD4<sup>+</sup> CD25<sup>+</sup> FOXP3<sup>+</sup> regulatory T cells (Tregs)</td><td align="left" rowspan="1" colspan="1">Autoimmune enteropathy<break></break>Early-onset diabetes<break></break>Thyroiditis, hemolytic anemia, thrombocytopenia, eczema<break></break>Elevated IgE, IgA</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/304790">304790</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) CD25 deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-2RA</italic>, encoding IL-2Rα chain</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal to decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">No CD4+ C25+ cells with impaired function of Tregs cells</td><td align="left" rowspan="1" colspan="1">Lymphoproliferation, autoimmunity. Impaired T cell proliferation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606367">606367</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) STAT5b deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>STAT5B</italic>, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Modestly decreased</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Impaired development and function of γδT cells, Tregs, and NK cells Low T cell proliferation</td><td align="left" rowspan="1" colspan="1">Growth-hormone insensitive dwarfism</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/245590">245590</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Dysmorphic features</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Eczema</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Lymphocytic interstitial pneumonitis, autoimmunity</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="8" rowspan="1">4. Autoimmunity without lymphoproliferation</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>AIRE</italic>, encoding a transcription regulator needed to establish thymic self-tolerance</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">AIRE-1 serves as checkpoint in the thymus for negative selection of autoreactive T cells and for generation of Tregs</td><td align="left" rowspan="1" colspan="1">Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction, and other endocrine abnormalities</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/240300">240300</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic mucocutaneous candidiasis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Dental enamel hypoplasia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Alopecia areata</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Enteropathy, pernicious anemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) ITCH deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ITCH</italic>, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling protein in the cell including phospholipase Cγ1 (PLCγ1)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs</td><td align="left" rowspan="1" colspan="1">Early-onset chronic lung disease (interstitial pneumonitis)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613385">613385</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Failure to thrive, developmental delay, dysmorphic facial features</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="8" rowspan="1">5. Autoimmune lymphoproliferative syndrome (ALPS)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) ALPS–FAS</td><td align="left" rowspan="1" colspan="1">Germinal mutations in <italic>TNFRSF6</italic>, encoding CD95/Fas cell surface apoptosis receptor<xref ref-type="table-fn" rid="tfn5"><sup>b</sup></xref></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Increased CD4<sup>−</sup>CD8<sup>−</sup> TCRα/β double negative (DN) T cells</td><td align="left" rowspan="1" colspan="1">Normal, low memory B cells</td><td align="left" rowspan="1" colspan="1">Apoptosis defect FAS mediated</td><td align="left" rowspan="1" colspan="1">Splenomegaly, adenopathies, autoimmune cytopenias</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601859">601859</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AR<xref ref-type="table-fn" rid="tfn6"><sup>c</sup></xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Increased lymphoma risk</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IgG and A normal or increased</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Elevated FasL and IL-10, vitamin B12</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) ALPS– FASLG</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TNFSF6</italic>, Fas ligand for CD95 apoptosis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased DN T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Apoptosis defect FAS mediated</td><td align="left" rowspan="1" colspan="1">Splenomegaly, adenopathies, autoimmune cytopenias, SLE</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/134638">134638</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Soluble FasL is not elevated</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) ALPS–caspase 10<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CASP10</italic>, intracellular apoptosis pathway</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Increased DN T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Defective lymphocyte apoptosis</td><td align="left" rowspan="1" colspan="1">Adenopathies, splenomegaly, autoimmunity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/603909">603909</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) ALPS–caspase 8<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>CASP8</italic>, intracellular apoptosis, and activation pathways</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Slightly increased DN T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Defective lymphocyte apoptosis and activation</td><td align="left" rowspan="1" colspan="1">Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/607271">607271</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) FADD deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>FADD</italic> encoding an adaptor molecule interacting with FAS, and promoting apoptosis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Increased DN T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Defective lymphocyte apoptosis</td><td align="left" rowspan="1" colspan="1">Functional hyposplenism, bacterial and viral infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613759">613759</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Recurrent episodes of encephalopathy and liver dysfunction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) CARD11 gain-of-function (GOF) mutations<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">GOF mutations in <italic>CARD11</italic>, encoding a protein required for antigen receptor–induced NF-κB activation in B and T lymphocytes</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Increased M<sup>+</sup>D<sup>+</sup>CD19<sup>+</sup> CD20<sup>+</sup> B cells</td><td align="left" rowspan="1" colspan="1">Constitutive activation of NF-κB in B & T</td><td align="left" rowspan="1" colspan="1">Lymphoproliferation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606445">606445</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Bacterial and viral infections</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">EBV chronic infection</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Autoimmune cytopenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) PRKCδ deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>PRKCD</italic>, encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation, and apoptosis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Low memory B cells and elevation of CD5 B cells</td><td align="left" rowspan="1" colspan="1">Apoptotic defect in B cells</td><td align="left" rowspan="1" colspan="1">Recurrent infections; EBV chronic infection</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615559">615559</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Lymphoproliferation</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">SLE-like autoimmunity (nephrotic and antiphospholipid syndromes)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HypoIgG</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="8" rowspan="1">6. Immune dysregulation with colitis</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IL-10 deficiency<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10</italic>, encoding IL-10</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">No functional IL-10 secretion</td><td align="left" rowspan="1" colspan="1">Inflammatory bowel disease (IBD) folliculitis</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Recurrent respiratory diseases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Arthritis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) IL-10Rα deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10RA</italic>, encoding IL-10R1</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Leukocytes, no response to IL-10</td><td align="left" rowspan="1" colspan="1">IBD, folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613148">613148</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Recurrent respiratory diseases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Arthritis, lymphoma</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) IL-10Rβ deficiency</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10RB</italic>, encoding IL-10R2</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Leukocytes, no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29</td><td align="left" rowspan="1" colspan="1">IBD, folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612567">612567</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Recurrent respiratory diseases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Arthritis, lymphoma</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="8" rowspan="1">7. Type 1 interferonopathies</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) TREX1 deficiency, Aicardi–Goutieres syndrome 1 (AGS1)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>TREX1</italic>, encoding nuclease involves in clearing cellular nucleic debris</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcifications</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606609">606609</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AD<xref ref-type="table-fn" rid="tfn8"><sup>e</sup></xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cerebral atrophy, leukodystrophy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HSMG, thrombocytopenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Elevated hepatic transaminases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic cerebrospinal fluid (CSF) lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) RNASEH2B deficiency, AGS2</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RNASEH2B</italic>, encoding nuclease subunit involves in clearing cellular nucleic debris</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcifications</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610326">610326</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cerebral atrophy, leukodystrophy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HSMG, thrombocytopenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Elevated hepatic transaminases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic CSF lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) RNASEH2C deficiency, AGS3</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RNASEH2C</italic>, encoding nuclease subunit involves in clearing cellular nucleic debris</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcifications</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610330">610330</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cerebral atrophy, leukodystrophy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HSMG, thrombocytopenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Elevated hepatic transaminases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic CSF lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) RNASEH2A deficiency, AGS4<xref ref-type="table-fn" rid="tfn4"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RNASEH2A</italic>, encoding nuclease subunit involves in clearing cellular nucleic debris</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcifications</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606034">606034</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cerebral atrophy, leukodystrophy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HSMG, thrombocytopenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Elevated hepatic transaminases</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic CSF lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) SAMHD1 deficiency, AGS5</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>SAMHD1</italic>, encoding negative regulator of the immunostimulatory DNA response</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcifications</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612952">612952</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cerebral atrophy, leukodystrophy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HSMG, thrombocytopenia, anemia elevated lactates</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Chronic CSF lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Skin vasculitis, mouth ulcers, arthropathy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) ADAR1 deficiency, AGS6</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ADAR1</italic>, encoding an RNA-specific adenosine deaminase</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Catalyzes the deamination of adenosine to inosine in dsRNA substrates markedly elevated CSF IFN-alpha</td><td align="left" rowspan="1" colspan="1">Progressive encephalopathy intracranial calcification Severe developmental delay, leukodystrophy</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615010">615010</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>ACP5</italic>, encoding tartrate-resistant acid phosphatase (TRAP)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Not assessed</td><td align="left" rowspan="1" colspan="1">Upregulation of IFN-alpha and type I IFN-stimulated genes</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial and viral infections, intracranial calcification</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/607944">607944</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; FHL, familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; HSMG, hepatosplenomegaly; DN, double negative; SLE, systemic lupus erythematous; IBD, inflammatory bowel disease; CSF, chronic cerebrospinal fluid</italic>.</p><fn id="tfn4"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><fn id="tfn5"><p><italic><sup>b</sup>Somatic mutations of TNFRSF6 cause a similar phenotype (ALPS–sFAS), see Table <xref ref-type="table" rid="T9">9</xref>. Germinal mutation and somatic mutation of TNFRSF6 can be associated in some ALPS–FAS patients</italic>.</p></fn><fn id="tfn6"><p><italic><sup>c</sup>AR ALPS–FAS patients have a most severe clinical phenotype</italic>.</p></fn><p><italic><sup>d</sup>Somatic mutations in KRAS or NRAS can give this clinical phenotype associated autoimmune leukoproliferative disease (RALD) and are now included in Table <xref ref-type="table" rid="T9">9</xref> entitled phenocopies of PID</italic>.</p><fn id="tfn8"><p><italic><sup>e</sup><italic>De novo</italic> dominant TREX1 mutations have been reported</italic>.</p></fn><p><italic>Fourteen new disorders have been added to Table <xref ref-type="table" rid="T4">4</xref>. Two new entries have been added in the table, including immune dysregulation with colitis and Type 1 interferonopathies. EBV-driven lymphoproliferation is also observed in MAGT1 deficiency (Table <xref ref-type="table" rid="T1">1</xref>)</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T5" position="float"><label>Table 5</label><caption><p><bold>Congenital defects of phagocyte number, function, or both</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Affected cells</th><th align="left" rowspan="1" colspan="1">Affected function</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="7" rowspan="1">1. Defects of neutrophil function</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Severe congenital neutropenia 1 (ELANE deficiency)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ELANE</italic>: misfolded protein response, increased apoptosis</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">Susceptibility to MDS/leukemia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/202700">202700</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) SCN2<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref> (GFI 1 deficiency)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>GFI1</italic>: loss of repression of ELANE</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">B/T lymphopenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613107">613107</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) SCN3 (Kostmann disease)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>HAX1</italic>: control of apoptosis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610738">610738</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) SCN4 (G6PC3 deficiency)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>G6PC3</italic>: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of N and F</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + F</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation, chemotaxis, O<sub>2</sub><sup>−</sup>production</td><td align="left" rowspan="1" colspan="1">Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612541">612541</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) SCN5</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>VPS45 controls vesicular trafficking</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + F</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation, migration</td><td align="left" rowspan="1" colspan="1">Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615285">615285</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) Glycogen storage disease type 1b</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>G6PT1</italic>: glucose-6-phosphate transporter 1</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation, chemotaxis, O<sub>2</sub><sup>−</sup>production</td><td align="left" rowspan="1" colspan="1">Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/232220">232220</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) Cyclic neutropenia</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ELANE</italic>: misfolded protein response</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Differentiation</td><td align="left" rowspan="1" colspan="1">Oscillations of other leukocytes and platelets</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/162800">162800</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) X-linked neutropenia/<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref>myelodysplasia</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>WAS</italic>: regulator of actin cytoskeleton (loss of auto-inhibition)</td><td align="left" rowspan="1" colspan="1">XL, gain-of-function</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Mitosis</td><td align="left" rowspan="1" colspan="1">Monocytopenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300299">300299</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) P14/LAMTOR2 deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ROBLD3/LAMTOR2</italic>: endosomal adaptor protein 14</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + L Mel</td><td align="left" rowspan="1" colspan="1">Endosome biogenesis</td><td align="left" rowspan="1" colspan="1">Neutropenia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610389">610389</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">↓CD8 cytotoxicity</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Partial albinism</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Growth failure</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(j) Barth syndrome</td><td align="left" rowspan="1" colspan="1">Mutation in tafazzin <italic>(TAZ)</italic> gene: abnormal lipid structure of mitochondrial membrane, defective carnitine metabolism</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">Cardiomyopathy, myopathy, growth retardation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/302060">302060</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(k) Cohen syndrome</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>COH1</italic> gene: Pg unknown</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">Retinopathy, developmental delay, facial dysmorphisms</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/216550">216550</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(l) Clericuzio syndrome poikiloderma with neutropenia</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C16ORF57</italic>, affects genomic integrity</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Myeloid differentiation</td><td align="left" rowspan="1" colspan="1">Poikiloderma, neutropenia, MDS</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613276">613276</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">2. Defects of motility</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Leukocyte adhesion deficiency type 1 (LAD1)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ITGB2</italic>: adhesion protein (CD18)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M + L + NK</td><td align="left" rowspan="1" colspan="1">Adherence, chemotaxis, endocytosis, T/NK cytotoxicity</td><td align="left" rowspan="1" colspan="1">Delayed cord separation, skin ulcers Periodontitis Leukocytosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/116920">116920</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Leukocyte adhesion deficiency type 2 (LAD2)<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>FUCT1</italic>: GDP-fucose transporter</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Rolling, chemotaxis</td><td align="left" rowspan="1" colspan="1">Mild LAD type 1 features plus hh-blood group plus mental and growth retardation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/266265">266265</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Leukocyte adhesion deficiency type 3 (LAD3)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>KINDLIN3</italic>: Rap1-activation of β1–3 integrins</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M + L + NK</td><td align="left" rowspan="1" colspan="1">Adherence, chemotaxis</td><td align="left" rowspan="1" colspan="1">LAD type 1 plus bleeding tendency</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612840">612840</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Rac 2 deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>RAC2</italic>: regulation of actin cytoskeleton</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Adherence, chemotaxis, O<sub>2</sub><sup>−</sup>production</td><td align="left" rowspan="1" colspan="1">Poor wound healing, leukocytosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602049">602049</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) β-Actin deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ACTB</italic>: cytoplasmic actin</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Motility</td><td align="left" rowspan="1" colspan="1">Mental retardation, short stature</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/102630">102630</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) Localized juvenile periodontitis</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>FPR1</italic>: chemokine receptor</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Formylpeptide induced chemotaxis</td><td align="left" rowspan="1" colspan="1">Periodontitis only</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/136537">136537</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) Papillon–Lefèvre syndrome</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CTSC</italic>: cathepsin C activation of serine proteases</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Chemotaxis</td><td align="left" rowspan="1" colspan="1">Periodontitis, palmoplantar hyperkeratosis in some patients</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/245000">245000</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) Specific granule deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C/EBPE</italic>: myeloid transcription factor</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Chemotaxis</td><td align="left" rowspan="1" colspan="1">Neutrophils with bilobed nuclei; absent secondary granules and defensins</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/245480">245480</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(i) Shwachman–Diamond syndrome</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>SBDS</italic>: defective ribosome synthesis</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">Chemotaxis</td><td align="left" rowspan="1" colspan="1">Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/260400">260400</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">3. Defects of respiratory burst</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) X-linked chronic granulomatous disease (CGD)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CYBB</italic>: electron transport protein (gp91phox)</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations McLeod phenotype in patients with deletions extending into the contiguous Kell locus</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/306400">306400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Autosomal recessive CGD – p22 phox deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CYBA</italic>: electron transport protein (p22phox)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/233690">233690</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Autosomal recessive CGD – p47 phox deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>NCF1</italic>: adapter protein (p47phox)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/233700">233700</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Autosomal recessive CGD – p67 phox deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>NCF2</italic>: activating protein (p67phox)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/233710">233710</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) Autosomal recessive CGD – p40 phox deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>NCF4</italic>: activating protein (p40phox)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">N + M</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Inflammatory gut manifestations only</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601488">601488</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">4. Mendelian susceptibility to mycobacterial disease (MSMD)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IL-12 and IL-23 receptor β1 chain deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IL-12RB1</italic>: IL-12 and IL-23 receptor β1 chain</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">L + NK</td><td align="left" rowspan="1" colspan="1">IFN-γ secretion</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic> and <italic>Salmonella</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/209950">209950</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) IL-12p40 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IL-12B</italic>: subunit p40 of IL-12/IL-23</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">M</td><td align="left" rowspan="1" colspan="1">IFN-γ secretion</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic> and <italic>Salmonella</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/161561">161561</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) IFN-γ receptor 1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IFNGR1</italic>: IFN-γR ligand binding chain</td><td align="left" rowspan="1" colspan="1">AR, AD</td><td align="left" rowspan="1" colspan="1">M + L</td><td align="left" rowspan="1" colspan="1">IFN-γ binding and signaling</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic> and <italic>Salmonella</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/107470">107470</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) IFN-γ receptor 2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IFNGR2</italic>: IFN-γR accessory chain</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">M + L</td><td align="left" rowspan="1" colspan="1">IFN-γ signaling</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic> and <italic>Salmonella</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/147569">147569</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) STAT1 deficiency (AD form)<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>STAT1</italic> (loss of function)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">M + L</td><td align="left" rowspan="1" colspan="1">IFN-γ signaling</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600555">600555</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(f) Macrophage gp91 phox deficiency<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CYBB</italic>: electron transport protein (gp 91 phox)</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Mf only</td><td align="left" rowspan="1" colspan="1">Killing (faulty O<sub>2</sub><sup>−</sup>production)</td><td align="left" rowspan="1" colspan="1">Isolated susceptibility to <italic>Mycobacteria</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/306400">306400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(g) IRF8-deficiency (AD form)<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IRF8</italic>: IL-12 production by CD1c<sup>+</sup> MDC</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">CD1c+ MDC</td><td align="left" rowspan="1" colspan="1">Differentiation of CD1c+ MDC subgroup</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601565">601565</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(h) ISG15</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ISG15</italic>; an interferon (IFN) α/β-inducible, ubiquitin-like intracellular protein</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">M + N + L</td><td align="left" rowspan="1" colspan="1">IFN-γ secretion</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/14751">14751</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">5. Other defects</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IRF 8-deficiency (AR form)<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IRF8</italic>: IL-12 production</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Monocytes peripheral DC</td><td align="left" rowspan="1" colspan="1">Cytopenias</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria, Candida</italic>, myeloproliferation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614893">614893</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) GATA2 deficiency (Mono MAC syndrome)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>GATA2</italic>: loss of stem cells</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Monocytes peripheral DC + NK + B</td><td align="left" rowspan="1" colspan="1">Multilineage cytopenias</td><td align="left" rowspan="1" colspan="1">Susceptibility to <italic>Mycobacteria</italic>, papilloma viruses, histoplasmosis, alveolar proteinosis, MDS/AML/CMML</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/137295">137295</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Pulmonary alveolar proteinosis<xref ref-type="table-fn" rid="tfn9"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CSF2RA</italic></td><td align="left" rowspan="1" colspan="1">Biallelic mutations in pseudo-autosomal gene</td><td align="left" rowspan="1" colspan="1">Alveolar macro-phages</td><td align="left" rowspan="1" colspan="1">GM-CSF signaling</td><td align="left" rowspan="1" colspan="1">Alveolar proteinosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/306250">306250</uri></td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; ACTB, actin beta; B, B lymphocytes; CEBPE, CCAAT/enhancer-binding protein epsilon; CMML, chronic myelomonocytic leukemia; CTSC, cathepsin C; CYBA, cytochrome <italic>b</italic> alpha subunit; CYBB, cytochrome <italic>b</italic> beta subunit; DC, dendritic cells; ELANE, elastase neutrophil-expressed; GATA2, GATA binding protein 2; IFN, interferon; IFNGR1, interferon-gamma receptor subunit 1; IFNGR2, interferon-gamma receptor subunit 2; IL-12B, interleukin-12 beta subunit; IL-12RB1, interleukin-12 receptor beta 1; IFR8, interferon regulatory factor 8; F, fibroblasts; FPR1, formylpeptide receptor 1; FUCT1, fucose transporter 1; GFI1, growth factor independent 1; HAX1, HLCS1-associated protein X1; ITGB2, integrin beta-2; L, lymphocytes; M, monocytes–macrophages; MDC, myeloid dendritic cells; MDS, myelodysplasia; Mel, melanocytes; Mϕ, macrophages; MSMD, Mendelian susceptibility to mycobacterial disease; N, neutrophils; NCF1, neutrophil cytosolic factor 1; NCF2, neutrophil cytosolic factor 2; NCF4, neutrophil cytosolic factor 4; NK, natural killer cells; ROBLD3: roadblock domain containing 3; SBDS, Shwachman–Bodian–Diamond syndrome; STAT, signal transducer and activator of transcription</italic>.</p><fn id="tfn9"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>Table <xref ref-type="table" rid="T5">5</xref> includes seven newly described genetic defects of phagocyte number and/or function including Barth syndrome, Cohen syndrome, and poikiloderma with neutropenia. In these three clinically well-known diseases, the genetic defects have been elucidated, although their molecular pathogenesis remains ill-defined. A new cause of autosomal recessive chronic granulomatous disease, namely a deficiency of the cytosolic activating protein p40 phox, has now been found in two CGD patients and is included under defects of respiratory burst. Under the heading of Mendelian susceptibility of mycobacterial disease (MSMD), two new entities were added: (a) a subgroup of X-linked gp91 phox deficiency with isolated susceptibility to mycobacteria and a defect of the respiratory burst in macrophages only; (b) an autosomal dominant form of IRF8-deficiency, resulting from a lack of CD1c+ myeloid dendritic cells that would normally secrete IL-12. The clinical phenotype of MSMD may vary, depending on the nature of the genetic defect. Finally, GATA2 deficiency was recently identified as the cause of the Mono MAC syndrome, with multilineage cytopenias (of monocytes, peripheral dendritic cells, NK- and B-lymphocytes) resulting in opportunistic infections (including mycobacteria), alveolar proteinosis, and malignancy</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T6" position="float"><label>Table 6</label><caption><p><bold>Defects in innate immunity</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Affected cell</th><th align="left" rowspan="1" colspan="1">Functional defect</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="7" rowspan="1">1. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) EDA-ID, X-linked (NEMO deficiency)</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>NEMO (IKBKG)</italic>, a modulator of NF-κB activation</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Lymphocytes + monocytes</td><td align="left" rowspan="1" colspan="1">NF-κB signaling pathway</td><td align="left" rowspan="1" colspan="1">Various infections (bacteria, <italic>Mycobacteria</italic>, viruses, and fungi)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/300248">300248</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Colitis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">EDA (not in all patients)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia to specific antibody polysaccharides deficiency</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) EDA-ID, autosomal-dominant<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Gain-of-function mutations of <italic>IKBA</italic>, resulting in impaired activation of NF-κB</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Lymphocytes + monocytes</td><td align="left" rowspan="1" colspan="1">NF-κB signaling pathway</td><td align="left" rowspan="1" colspan="1">Various infections (bacteria, viruses, and fungi)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612132">612132</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">EDA</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">T cell defect</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="7" rowspan="1">2. TIR signaling pathway deficiency</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IRAK-4 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>IRAK-4</italic>, a component of TLR- and IL-1R-signaling pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Lymphocytes + granulocytes + monocytes</td><td align="left" rowspan="1" colspan="1">TIR–IRAK signaling pathway</td><td align="left" rowspan="1" colspan="1">Bacterial infections (pyogenes)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/607676">607676</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) MyD88 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>MYD88</italic>, a component of the TLR and IL-1R signaling pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Lymphocytes + granulocytes + monocytes</td><td align="left" rowspan="1" colspan="1">TIR–MyD88 signaling pathway</td><td align="left" rowspan="1" colspan="1">Bacterial infections (pyogenes)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612260">612260</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">3. HOIL1 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation of <italic>HOIL1</italic>, a component of LUBAC</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Lymphocytes + granulocytes + monocytes</td><td align="left" rowspan="1" colspan="1">NF-κB signaling pathway</td><td align="left" rowspan="1" colspan="1">Bacterial infections (pyogenes)</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Autoinflammation</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Amylopectinosis</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">4. WHIM (Warts, hypogammaglobulinemia, infections, myelokathexis) syndrome</td><td align="left" rowspan="1" colspan="1">Gain-of-function mutations of <italic>CXCR4</italic>, the receptor for CXCL12</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Granulocytes + lymphocytes</td><td align="left" rowspan="1" colspan="1">Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)</td><td align="left" rowspan="1" colspan="1">Warts/human papilloma virus (HPV) infection</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/193670">193670</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Neutropenia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Reduced B cell number</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="7" rowspan="1">5. Epidermodysplasia verruciformis</td></tr><tr><td align="left" rowspan="1" colspan="1">EVER1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>EVER1</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Keratinocytes and leukocytes</td><td align="left" rowspan="1" colspan="1">EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes</td><td align="left" rowspan="1" colspan="1">HPV (group B1) infections and cancer of the skin (typical EV)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/226400">226400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">EVER2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>EVER2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Keratinocytes and leukocytes</td><td align="left" rowspan="1" colspan="1">EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes</td><td align="left" rowspan="1" colspan="1">HPV (group B1) infections and cancer of the skin (typical EV)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/226400">226400</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">6. Predisposition to severe viral infection</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) STAT2 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations of <italic>STAT2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">T and NK cells</td><td align="left" rowspan="1" colspan="1">STAT2-dependent</td><td align="left" rowspan="1" colspan="1">Severe viral infections (disseminated vaccine-strain measles)</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α and -β response</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) MCM4 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>MCM4</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">NK cells</td><td align="left" rowspan="1" colspan="1">DNA repair disorder</td><td align="left" rowspan="1" colspan="1">Viral infections (EBV, HSV, VZV)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/609981">609981</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Adrenal failure</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Short stature</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="7" rowspan="1">7. Herpes simplex encephalitis (HSE)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) TLR3 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(b) Mutations of <italic>TLR3</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Central nervous system (CNS) resident cells and fibroblasts</td><td align="left" rowspan="1" colspan="1">TLR3-dependent</td><td align="left" rowspan="1" colspan="1">Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613002">613002</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α, -β, and -λ induction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) UNC93B1 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(a) Mutations of <italic>UNC93B1</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">CNS resident cells and fibroblasts</td><td align="left" rowspan="1" colspan="1">UNC-93B-dependent</td><td align="left" rowspan="1" colspan="1">Herpes simplex virus 1 encephalitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610551">610551</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α, -β, and -λ induction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) TRAF3 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(c) Mutations of <italic>TRAF3</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">CNS resident cells and fibroblasts</td><td align="left" rowspan="1" colspan="1">TRAF3-dependent</td><td align="left" rowspan="1" colspan="1">Herpes simplex virus 1 encephalitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614849">614849</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α, -β, and -λ induction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) TRIF deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(c) Mutations of <italic>TRIF</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">CNS resident cells and fibroblasts</td><td align="left" rowspan="1" colspan="1">TRIF-dependent</td><td align="left" rowspan="1" colspan="1">Herpes simplex virus 1 encephalitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614850">614850</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α, -β, and -λ induction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) TBK1 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(c) Mutations of <italic>TBK1</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">CNS resident cells and fibroblasts</td><td align="left" rowspan="1" colspan="1">TBK1-dependent</td><td align="left" rowspan="1" colspan="1">Herpes simplex virus 1 encephalitis</td><td align="left" rowspan="1" colspan="1">Not assigned</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">IFN-α, -β, and -λ induction</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" colspan="7" rowspan="1">8. Predisposition to invasive fungal diseases<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td></tr><tr><td align="left" rowspan="1" colspan="1">CARD9 deficiency</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>CARD9</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Mononuclear phagocytes</td><td align="left" rowspan="1" colspan="1">CARD9 signaling pathway</td><td align="left" rowspan="1" colspan="1">Invasive candidiasis infection Deep dermatophytoses</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/212050">212050</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">9. Chronic mucocutaneous candidiasis (CMC)</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) IL-17RA deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(a) Mutations in <italic>IL-17RA</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Epithelial cells, fibroblasts, mononuclear phagocytes</td><td align="left" rowspan="1" colspan="1">IL-17RA signaling pathway</td><td align="left" rowspan="1" colspan="1">CMC Folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605461">605461</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) IL-17F deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(b) Mutations in <italic>IL-17F</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">T cells</td><td align="left" rowspan="1" colspan="1">IL-17F-containing dimers</td><td align="left" rowspan="1" colspan="1">CMC Folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/606496">606496</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) STAT1 gain-of-function</td><td align="left" rowspan="1" colspan="1">(c) Gain-of-function mutations in <italic>STAT1</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">T cells</td><td align="left" rowspan="1" colspan="1">Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells</td><td align="left" rowspan="1" colspan="1">CMC</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614162">614162</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Various fungal, bacterial, and viral (HSV) infections</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Autoimmunity (thyroiditis, diabetes, cytopenia)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Enteropathy</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) ACT1 deficiency<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">(c) Mutations in <italic>ACT1</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">T cells, fibroblasts</td><td align="left" rowspan="1" colspan="1">Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E</td><td align="left" rowspan="1" colspan="1">CMC</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/615527">615527</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Blepharitis, folliculitis, and macroglossia</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">10. Trypanosomiasis<xref ref-type="table-fn" rid="tfn10"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations in <italic>APOL-I</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">APOL-I</td><td align="left" rowspan="1" colspan="1">Trypanosomiasis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/603743">603743</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">11. Isolated congenital asplenia (ICA)</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>RPSA</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Spleen</td><td align="left" rowspan="1" colspan="1">RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome</td><td align="left" rowspan="1" colspan="1">Bacteremia (encapsulated bacteria) No spleen</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/271400">271400</uri></td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; NF-κB, nuclear factor kappa B; TIR, Toll and interleukin 1 receptor; IFN, interferon; HVP, human papilloma virus; TLR, Toll-like receptor; IL, interleukin</italic>.</p><fn id="tfn10"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>Eight new disorders have been added to Table <xref ref-type="table" rid="T6">6</xref>. Three new entries have been added in the table. One is a new PID with the association of recurrent bacterial infections, autoinflammation, and amylopectinosis caused by AR HOIL1 mutations found in two kindreds. The second is severe viral infection, for which three genetic etiologies have been discovered. AR-STAT2 deficiency and AR-CD16 deficiency have been found in one kindred each. AR MCM4 deficiency has been found in several Irish kindreds. The third is isolated congenital asplenia identified in 18 patients from 8 kindreds</italic>.</p><p><italic>XR-EDA-ID is highly heterogeneous clinically, both in terms of developmental features (some patients display osteopetrosis and lymphedema, in addition to EDA, while others do not display any developmental features) and infectious diseases (some display multiple infections, viral, fungal, and bacterial, while others display a single type of infection). The various OMIM entries correspond to these distinct clinical diseases</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T7" position="float"><label>Table 7</label><caption><p><bold>Autoinflammatory disorders</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Affected cells</th><th align="left" rowspan="1" colspan="1">Functional defects</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" colspan="7" rowspan="1">1. Defects effecting the inflammasome</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Familial Mediterranean fever</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Mature granulocytes, cytokine-activated monocytes</td><td align="left" rowspan="1" colspan="1">Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased</td><td align="left" rowspan="1" colspan="1">Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/249100">249100</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Mevalonate kinase deficiency (hyper IgD syndrome)</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>MVK (lead to a block in the mevalonate pathway). Interleukin-1beta mediates the inflammatory phenotype</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Affecting cholesterol synthesis; pathogenesis of disease is unclear</td><td align="left" rowspan="1" colspan="1">Periodic fever and leukocytosis with high IgD levels</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/260920">260920</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Muckle–Wells syndrome</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>CIAS1 (also called PYPAF1 or NALP3) lead to constitutive activation of the NLRP3 inflammasome</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">PMNs monocytes</td><td align="left" rowspan="1" colspan="1">Defect in cryopyrin, involved in leukocyte apoptosis and NF-κB signaling and IL-1 processing</td><td align="left" rowspan="1" colspan="1">Urticaria, SNHL, amyloidosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/191900">191900</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Familial cold autoinflammatory syndrome</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>CIAS1</italic> (see above) Mutations of <italic>NLRP12</italic></td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">PMNs, monocytes</td><td align="left" rowspan="1" colspan="1">Same as above</td><td align="left" rowspan="1" colspan="1">Non-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120100">120100</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">5. Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>CIAS1</italic> (see above)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">PMNs, chondrocytes</td><td align="left" rowspan="1" colspan="1">Same as above</td><td align="left" rowspan="1" colspan="1">Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/607115">607115</uri></td></tr><tr><td align="left" colspan="7" rowspan="1">2. Non inflammasome-related conditions</td></tr><tr><td align="left" rowspan="1" colspan="1">(a) TNF receptor-associated periodic syndrome (TRAPS)</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>TNFRSF1</italic> (resulting in increased TNF inflammatory signaling)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">PMNs, monocytes</td><td align="left" rowspan="1" colspan="1">Mutations of 55-kDa TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF</td><td align="left" rowspan="1" colspan="1">Recurrent fever, serositis, rash, and ocular or joint inflammation</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/142680">142680</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Early-onset inflammatory bowel disease</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10 (results in increase many proinflammatory cytokines)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Monocyte/macrophage, activated T cells</td><td align="left" rowspan="1" colspan="1">IL-10 deficiency leads to increase of TNFγ and other proinflammatory cytokines</td><td align="left" rowspan="1" colspan="1">Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/124092">124092</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Early-onset inflammatory bowel disease</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10RA (see above)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Monocyte/macrophage, activated T cells</td><td align="left" rowspan="1" colspan="1">Mutation in IL-10 receptor alpha leads to increase of TNFγ and other proinflammatory cytokines</td><td align="left" rowspan="1" colspan="1">Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/146933">146933</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Early-onset inflammatory bowel disease</td><td align="left" rowspan="1" colspan="1">Mutations in <italic>IL-10RB (see above)</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Monocyte/macrophage, activated T cells</td><td align="left" rowspan="1" colspan="1">Mutation in IL-10 receptor beta leads to increase of TNFγ and other proinflammatory cytokines</td><td align="left" rowspan="1" colspan="1">Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/123889">123889</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>PSTPIP1</italic> (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Hematopoietic tissues, upregulated in activated T cells</td><td align="left" rowspan="1" colspan="1">Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response</td><td align="left" rowspan="1" colspan="1">Destructive arthritis, inflammatory skin rash, myositis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604416">604416</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Blau syndrome</td><td align="left" rowspan="1" colspan="1">Mutations of <italic>NOD2</italic> (also called CARD15) (involved in various inflammatory processes)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Monocytes</td><td align="left" rowspan="1" colspan="1">Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling</td><td align="left" rowspan="1" colspan="1">Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies, 30% develop Crohn’s disease</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/186580">186580</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">10. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)<xref ref-type="table-fn" rid="tfn11"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations of <italic>LPIN2</italic> (increased expression of the proinflammatory genes)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Neutrophils, bone marrow cells</td><td align="left" rowspan="1" colspan="1">Undefined</td><td align="left" rowspan="1" colspan="1">Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/609628">609628</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">11. DIRA (deficiency of the interleukin 1 receptor antagonist)<xref ref-type="table-fn" rid="tfn11"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutations of <italic>IL-1RN</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">PMNs, monocytes</td><td align="left" rowspan="1" colspan="1">Mutations in the IL-1 receptor antagonist allow unopposed action of Interleukin 1</td><td align="left" rowspan="1" colspan="1">Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612852">612852</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">12. DITRA – deficiency of IL-36 receptor antagonist</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>IL-36RN</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Keratinocyte leukocytes</td><td align="left" rowspan="1" colspan="1">Mutations in IL-36RN leads to increase IL-8 production</td><td align="left" rowspan="1" colspan="1">Pustular psoriasis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614204">614204</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">13. SLC29A3 mutation</td><td align="left" rowspan="1" colspan="1">Mutation in SLC29A3 (?)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Leukocyte, bone cells</td><td align="left" rowspan="1" colspan="1">Macrophage activation?</td><td align="left" rowspan="1" colspan="1">Hyperpigmentation hypertrichosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/602782">602782</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">14. CAMPS (CARD14 mediated psoriasis)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CARD14</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Mainly in keratinocyte</td><td align="left" rowspan="1" colspan="1">Mutations in CARD14 activate the NF-κB pathway and production of IL-8</td><td align="left" rowspan="1" colspan="1">Psoriasis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/173200">173200</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">15. Cherubism</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>SH3BP2</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Stroma cells, bone cells</td><td align="left" rowspan="1" colspan="1">Hyperactivated macrophage and increased NF-κB</td><td align="left" rowspan="1" colspan="1">Bone degeneration in jaws</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/11840">11840</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">16. CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>PSMB8</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Keratinocyte, B cell adipose cells</td><td align="left" rowspan="1" colspan="1">Mutations cause increase IL-6 production</td><td align="left" rowspan="1" colspan="1">Dystrophy, panniculitis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/256040">256040</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">17. HOIL1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>HOIL1</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">PMNs, fibroblast</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>HOIL1</italic> leads to IL-1β dysfunction</td><td align="left" rowspan="1" colspan="1">Immunodeficiency autoinflammation amylopectinosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610924">610924</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">18. PLAID (PLCγ2 associated antibody deficiency and immune dysregulation)</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>PLCG2</italic> (see functional defect)</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">B cells, NK, mast cells</td><td align="left" rowspan="1" colspan="1">Mutations cause activation of IL-1 pathways</td><td align="left" rowspan="1" colspan="1">Cold urticaria hypogammaglobulinemia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/614878">614878</uri></td></tr></tbody></table><table-wrap-foot><p><italic>AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; PMN, polymorphonuclear cells; ASC, apoptosis-associated speck-like protein with a caspase recruitment domain; CARD, caspase recruitment domain; CD2BP1, CD2 binding protein 1; PSTPIP1, proline/serine/threonine phosphatase-interacting protein 1; SNHL, sensorineural hearing loss; CIAS1, cold-induced autoinflammatory syndrome 1</italic>.</p><fn id="tfn11"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>Autoinflammatory diseases are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. While the genetic defect of one of the most common autoinflammatory conditions, PFAPA, is not known, recent studies suggest that it is associated with activation of IL-1 pathway and response to IL-1beta antagonists</italic>.</p><p><italic>Muckle–Wells syndrome, familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), which is also called chronic infantile neurologic cutaneous and articular syndrome (CINCA) are caused by similar mutations in CIAS1 mutations. The disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors</italic>.</p></table-wrap-foot></table-wrap><table-wrap id="T8" position="float"><label>Table 8</label><caption><p><bold>Complement deficiencies</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect; presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Inheritance</th><th align="left" rowspan="1" colspan="1">Functional defect</th><th align="left" rowspan="1" colspan="1">Associated features</th><th align="left" rowspan="1" colspan="1">OMIM number</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">1. C1q deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C1QA, C1QB, C1QC</italic>: classical complement pathway components</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 hemolytic activity, defective activation of the classical pathway</td><td align="left" rowspan="1" colspan="1">SLE, infections with encapsulated organisms</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120550">120550</uri>; <uri xlink:type="simple" xlink:href="http://www.omim.org/entry/601269">601269</uri>; <uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120575">120575</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Diminished clearance of apoptotic cells</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">2. C1r deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C1R</italic>: classical complement pathway component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 hemolytic activity, defective activation of the classical pathway</td><td align="left" rowspan="1" colspan="1">SLE, infections with encapsulated organisms</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/216950">216950</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">3. C1s deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C1S</italic>: classical complement pathway component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 hemolytic activity, defective activation of the classical pathway</td><td align="left" rowspan="1" colspan="1">SLE, infections with encapsulated organisms</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120580">120580</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">4. C4 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C4A, C4B</italic>: classical complement pathway components</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 hemolytic activity, defective activation of the classical pathway, defective humoral immune response to carbohydrate antigens in some patients</td><td align="left" rowspan="1" colspan="1">SLE, infections with encapsulated organisms</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120810">120810</uri>; <uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120820">120820</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">5. C2 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C2</italic>: classical complement pathway component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 hemolytic activity, defective activation of the classical pathway</td><td align="left" rowspan="1" colspan="1">SLE, infections with encapsulated organisms, atherosclerosis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/217000">217000</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">6. C3 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C3</italic>: central complement component</td><td align="left" rowspan="1" colspan="1">AR, gain-of-function AD</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity defective opsonization</td><td align="left" rowspan="1" colspan="1">Infections; glomerulonephritis</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120700">120700</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective humoral immune response</td><td align="left" rowspan="1" colspan="1">Atypical hemolytic–uremic syndrome with gain-of-function mutations</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">7. C5 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C5</italic>: terminal complement component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity; defective bactericidal activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120900">120900</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">8. C6 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C6</italic>: terminal complement component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity; defective bactericidal activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/217050">217050</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">9. C7 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C7</italic>: terminal complement component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity; defective bactericidal activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/217070">217070</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">10. C8 α–γ deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C8A, C8G</italic>: terminal complement components</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity; defective bactericidal activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120950">120950</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">11. C8b deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C8B</italic>: Terminal complement component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent CH50 and AH50 hemolytic activity; defective bactericidal activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120960">120960</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">12. C9 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>C9</italic>: Terminal complement component</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Reduced CH50 and AP50 hemolytic activity; deficient bactericidal activity</td><td align="left" rowspan="1" colspan="1">Mild susceptibility to Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/613825">613825</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">13. C1 inhibitor deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>SERPING1</italic>: regulation of kinins and complement activation</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Spontaneous activation of the complement pathway with consumption of C4/C2</td><td align="left" rowspan="1" colspan="1">Hereditary angioedema</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/138470">138470</uri></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">14. Factor B<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFB</italic>: activation of the alternative pathway</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Gain-of-function mutation with increased spontaneous AH50</td><td align="left" rowspan="1" colspan="1">aHUS</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/138470">138470</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">15. Factor D deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFD</italic>: regulation of the alternative complement pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absent AH50 hemolytic activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/134350">134350</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">16. Properdin deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFP</italic>: regulation of the alternative complement pathway</td><td align="left" rowspan="1" colspan="1">XL</td><td align="left" rowspan="1" colspan="1">Absent AH50 hemolytic activity</td><td align="left" rowspan="1" colspan="1">Neisserial infections</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/312060">312060</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">17. Factor I deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFI</italic>: regulation of the alternative complement pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Spontaneous activation of the alternative complement pathway with consumption of C3</td><td align="left" rowspan="1" colspan="1">Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/610984">610984</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">18. Factor H deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFH</italic>: regulation of the alternative complement pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Spontaneous activation of the alternative complement pathway with consumption of C3</td><td align="left" rowspan="1" colspan="1">Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/609814">609814</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">19. Factor H-related protein deficiencies</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CFHR1-5</italic>: bind C3b</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Normal CH50, AH50, autoantibodies to Factor H</td><td align="left" rowspan="1" colspan="1">aHUS</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/235400">235400</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">20. Thrombomodulin<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>THBD</italic>: regulates complement and coagulant activation</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Normal CH50, AH50</td><td align="left" rowspan="1" colspan="1">aHUS</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/188040">188040</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">21. MASP1 deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>MASP1</italic>: cleaves C2 and activates MASP2</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Deficient activation of the lectin activation pathway, cell migration</td><td align="left" rowspan="1" colspan="1">Infections, 3MC syndrome</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/600521">600521</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">22. MASP2 deficiency<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1"><italic>MASP2</italic>: cleavage of C2 and C4</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Deficient activation of the lectin activation pathway</td><td align="left" rowspan="1" colspan="1">Pyogenic infections; inflammatory lung disease, autoimmunity</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/605102">605102</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">23. 3MC syndrome COLEC11 deficiency<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>COLEC11</italic>: binds MASP1, MASP3</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Loss of neural crest cell migration signals</td><td align="left" rowspan="1" colspan="1">A developmental syndrome of facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability, and genital, limb, and vesicorenal anomalies (3MC syndrome)</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/612502">612502</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">24. Complement receptor 2 (CR2) deficiency<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CD21</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">See CD21 deficiency in Table <xref ref-type="table" rid="T3">3</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120650">120650</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">25. Complement receptor 3 (CR3) deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>ITGB2</italic></td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">See LAD1 in Table <xref ref-type="table" rid="T5">5</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/116920">116920</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">Membrane cofactor protein (CD46) deficiency</td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CD46</italic>: dissociates C3b and C4b</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Inhibitor of complement alternate pathway, decreased C3b binding</td><td align="left" rowspan="1" colspan="1">aHUS, infections, preeclampsia</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/120920">120920</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">Membrane Attack Complex inhibitor (CD59) deficiency<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>CD59</italic>: regulates the membrane attack complex formation</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Erythrocytes highly susceptible to complement-mediated lysis</td><td align="left" rowspan="1" colspan="1">Hemolytic anemia, polyneuropathy</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/107271">107271</uri></td></tr><tr><td align="left" rowspan="1" colspan="1">Ficolin 3 deficiency<xref ref-type="table-fn" rid="tfn12"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">Mutation in <italic>FCN3</italic>: activates the classical complement pathway</td><td align="left" rowspan="1" colspan="1">AR</td><td align="left" rowspan="1" colspan="1">Absence of complement activation by the Ficolin 3 pathway</td><td align="left" rowspan="1" colspan="1">Respiratory infections, abscesses</td><td align="left" rowspan="1" colspan="1"><uri xlink:type="simple" xlink:href="http://www.omim.org/entry/604973">604973</uri></td></tr></tbody></table><table-wrap-foot><p><italic>XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; MAC, membrane attack complex; SLE, systemic lupus erythematosus; MBP, mannose-binding protein; MASP2, MBP-associated serine protease 2</italic>.</p><fn id="tfn12"><p><italic><sup>a</sup>Ten or fewer unrelated cases reported in the literature</italic>.</p></fn><p><italic>New entities added to Table <xref ref-type="table" rid="T8">8</xref> demonstrate the important role of complement regulators in a group of well-described inflammatory disorders. In particular, we have added mutations in membrane bound as well as surface attached soluble complement regulatory proteins recognized in hemolytic–uremic syndrome, age-related macular degeneration, and preeclampsia. The connecting theme of these otherwise unrelated clinical events is excessive activation or insufficient regulation of C3; these events lead to recruitment of leukocytes and permit secretion of inflammatory and anti-angiogenic mediators that disrupt the vascular bed of the target organ. Alterations in the genes for Factor B (CFB), Factor I (CFI), Factor H (CFH), and CD46 act as susceptibility genes rather than disease causing mutations. Population studies reveal no detectable increase in infections in MBP (also known at mannose-binding lectin – MBL) deficient adults. The 3MC syndrome, a developmental syndrome, has been variously called Carnevale, Mingarelli, Malpuech, and Michels syndrome</italic>.</p></table-wrap-foot></table-wrap><p>In this updated version, we have added a new category in Table <xref ref-type="table" rid="T9">9</xref> in which “Phenocopies of PID” are listed. This has resulted from our understanding and study of conditions that present as inherited immunodeficiencies, but which are not due to germline mutations and instead arise from acquired mechanisms. Examples include somatic mutations in specific immune cell populations that give rise to the phenotype of autoimmune lymphoproliferative syndrome (ALPS), and also autoantibodies against specific cytokines or immunological factors, with depletion of these factors leading to immunodeficiency. It is likely that increasing numbers of PID phenocopies will be identified in the future, and this may be the start of a much longer table.</p><table-wrap id="T9" position="float"><label>Table 9</label><caption><p><bold>Phenocopies of PID</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Genetic defect/presumed pathogenesis</th><th align="left" rowspan="1" colspan="1">Circulating T cells</th><th align="left" rowspan="1" colspan="1">Circulating B cells</th><th align="left" rowspan="1" colspan="1">Serum Ig</th><th align="left" rowspan="1" colspan="1">Associated features/similar PID</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Associated with somatic mutations</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Autoimmune lymphoproliferative syndrome (ALPS–SFAS)</td><td align="left" rowspan="1" colspan="1">Somatic mutation in <italic>TNFRSF6</italic></td><td align="left" rowspan="1" colspan="1">Increased CD4<sup>−</sup>CD8<sup>−</sup>double negative (DN) T alpha/beta cells</td><td align="left" rowspan="1" colspan="1">Normal, but increased number of CD5<sup>+</sup> B cells</td><td align="left" rowspan="1" colspan="1">Normal or increased</td><td align="left" rowspan="1" colspan="1">Splenomegaly, lymphadenopathy, autoimmune cytopenias</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Defective lymphocyte apoptosis/<italic>ALPS–FAS (=ALPS type Im)</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) RAS-associated autoimmune leukoproliferative disease (RALD)</td><td align="left" rowspan="1" colspan="1">Somatic mutation in <italic>KRAS</italic> (gain-of-function)</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">B cell lymphocytosis</td><td align="left" rowspan="1" colspan="1">Normal or increased</td><td align="left" rowspan="1" colspan="1">Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/<italic>ALPS-like</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) RAS-associated autoimmune leukoproliferative disease (RALD)</td><td align="left" rowspan="1" colspan="1">Somatic mutation in <italic>NRAS</italic> (gain-of-function)</td><td align="left" rowspan="1" colspan="1">Increased CD4<sup>−</sup>CD8<sup>−</sup>double negative (DN) T alpha/beta cells</td><td align="left" rowspan="1" colspan="1">Lymphocytosis</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Splenomegaly, lymphadenopathy, autoantibodies/<italic>ALPS-like</italic></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Associated with autoantibodies</bold></td></tr><tr><td align="left" rowspan="1" colspan="1">(a) Chronic mucocutaneous candidiasis (isolated or with APECED syndrome)</td><td align="left" rowspan="1" colspan="1">Germline mutation in <italic>AIRE</italic>AutoAb to IL-17 and/or IL-22</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Endocrinopathy, chronic mucocutaneous candidiasis/<italic>CMC</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(b) Adult-onset immunodeficiency</td><td align="left" rowspan="1" colspan="1">AutoAb to IFN gamma</td><td align="left" rowspan="1" colspan="1">Decreased naive T cells</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Mycobacterial, fungal, <italic>Salmonella</italic> VZV infections/<italic>MSMD, or CID</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(c) Recurrent skin infection</td><td align="left" rowspan="1" colspan="1">AutoAb to IL-6</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Staphylococcal infections/<italic>STAT3 deficiency</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(d) Pulmonary alveolar proteinosis</td><td align="left" rowspan="1" colspan="1">AutoAb to GM-CSF</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Pulmonary alveolar proteinosis, cryptococcal meningitis/<italic>CSF2RA deficiency</italic></td></tr><tr><td align="left" rowspan="1" colspan="1">(e) Acquired angioedema</td><td align="left" rowspan="1" colspan="1">AutoAb to CI inhibitor</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Normal</td><td align="left" rowspan="1" colspan="1">Angioedema/<italic>C1 INH deficiency</italic> (hereditary angioedema)</td></tr></tbody></table></table-wrap><p>As with all complex diseases, any classification cannot be strictly adhered to. Certain conditions fall into more than one category and so appear in more than one table. For example, CD40L ligand deficiency is reported in both Tables <xref ref-type="table" rid="T1">1</xref> and <xref ref-type="table" rid="T3">3</xref> as it was initially identified as a defect of B cell isotype switching but is now known to be a defect of co-stimulatory T cell help and function. Similarly, XLP1 due to defects in SH2D1A is listed in Table <xref ref-type="table" rid="T1">1</xref> – combined immunodeficiencies, due to defects of T cell cytotoxicity, T cell help, and B cell maturation, but also in Table <xref ref-type="table" rid="T4">4</xref> – diseases of immune dysregulation, due to the susceptibility to hemophagocytosis. There is a growing appreciation that there can be wide phenotypic viability within a specific genotype that is a product of varied specific mutations between different patients as well as other host and/or environmental factors. The complexities of these conditions in terms of clinical and immunological presentation and heterogeneity cannot be easily captured in the limited space of a table format. For this reason, the furthest left column contains the Online Mendelian Inheritance in Man (OMIM) reference for each condition to allow access to greater detail and updated information.</p><p>The rapid advances in gene identification technology, including the widespread use of whole exome and whole genome sequencing, has meant that the ability to identify gene defects in affected families and even single individuals with inherited diseases has grown enormously. In this report, over 30 new gene defects have been added that were identified since the previous classification in November, 2011. These defects can be found in all major groups of PIDs included in this report. In many cases, the mutations are not necessarily in genes formally implicated in immune cell function but are genes involved in essential cell processes. The more detailed analysis and functional consequences of such defects as illustrated by these PIDs will increase our understanding of the interplay between different cellular processes in the development and function of the immune system.</p><p>Among the newly identified, gene defects are many that are to date particular to a single pedigree or individual; such defects may prove exceedingly rare, or indeed may not necessarily be found to recur in other individuals. We have marked conditions for which there are 10 or fewer reported individuals with an asterisk, although historically, following the description of the first few cases, additional individuals with a similar PID phenotype and genotype have often been recognized. It is likely that we will uncover many more “personal” or very rare gene defects over time and that the spectrum of PIDs will become increasingly diverse and complex, due to contributions of both environmental exposures and genetic modifiers to each affected individual. The value of this report therefore to capture and catalog the full spectrum at any one time point becomes increasingly important.</p><p>The goal of the IUIS Expert Committee on PIDs is to increase awareness, facilitate recognition, and promote optimal treatment for patients with PIDs. In addition to the current report and previous “classification table” publications, the committee has also produced a “Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside,” which aims to lead physicians to particular groups of PIDs starting from clinical features and combining routine immunological investigations. Together, these contributions will hopefully allow a practical clinical framework for PID diagnosis. The committee also aims to establish a classification of PIDs based on other aspects and will work on publishing further guidelines in due course.</p></sec><sec id="S2"><title>Conflict of Interest Statement</title><p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec></body></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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