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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Spondyloenchondrodysplasia Due to Mutations in <italic>ACP5</italic>: A Comprehensive Survey</title><author><name sortKey="Briggs, Tracy A" sort="Briggs, Tracy A" uniqKey="Briggs T" first="Tracy A." last="Briggs">Tracy A. Briggs</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Rice, Gillian I" sort="Rice, Gillian I" uniqKey="Rice G" first="Gillian I." last="Rice">Gillian I. Rice</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Adib, Navid" sort="Adib, Navid" uniqKey="Adib N" first="Navid" last="Adib">Navid Adib</name><affiliation><nlm:aff id="Aff3">Department of Rheumatology, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Ades, Lesley" sort="Ades, Lesley" uniqKey="Ades L" first="Lesley" last="Ades">Lesley Ades</name><affiliation><nlm:aff id="Aff4">Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Discipline of Paedatrics and Child Health, The University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Barete, Stephane" sort="Barete, Stephane" uniqKey="Barete S" first="Stephane" last="Barete">Stephane Barete</name><affiliation><nlm:aff id="Aff6">Dermatology Department, Pitie-Salpetriere Hospital, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Baskar, Kannan" sort="Baskar, Kannan" uniqKey="Baskar K" first="Kannan" last="Baskar">Kannan Baskar</name><affiliation><nlm:aff id="Aff7">Creighton University, 2500 California Plaza, NE 68178, Omaha, USA</nlm:aff></affiliation></author><author><name sortKey="Baudouin, Veronique" sort="Baudouin, Veronique" uniqKey="Baudouin V" first="Veronique" last="Baudouin">Veronique Baudouin</name><affiliation><nlm:aff id="Aff8">Pediatric Nephrology Department, Robert Debré University Hospital – APHP, 48 boulevard Sérurier, 75019 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cebeci, Ayse N" sort="Cebeci, Ayse N" uniqKey="Cebeci A" first="Ayse N." last="Cebeci">Ayse N. Cebeci</name><affiliation><nlm:aff id="Aff9">Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye</nlm:aff></affiliation></author><author><name sortKey="Clapuyt, Philippe" sort="Clapuyt, Philippe" uniqKey="Clapuyt P" first="Philippe" last="Clapuyt">Philippe Clapuyt</name><affiliation><nlm:aff id="Aff10">Pediatric Imaging Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Coman, David" sort="Coman, David" uniqKey="Coman D" first="David" last="Coman">David Coman</name><affiliation><nlm:aff id="Aff11">Neuroscience Department, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12">School of Medicine, Griffith University, Gold Coast, Australia</nlm:aff></affiliation></author><author><name sortKey="De Somer, Lien" sort="De Somer, Lien" uniqKey="De Somer L" first="Lien" last="De Somer">Lien De Somer</name><affiliation><nlm:aff id="Aff13">Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Finezilber, Yael" sort="Finezilber, Yael" uniqKey="Finezilber Y" first="Yael" last="Finezilber">Yael Finezilber</name><affiliation><nlm:aff id="Aff14">Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel</nlm:aff></affiliation></author><author><name sortKey="Frydman, Moshe" sort="Frydman, Moshe" uniqKey="Frydman M" first="Moshe" last="Frydman">Moshe Frydman</name><affiliation><nlm:aff id="Aff14">Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff15">Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel</nlm:aff></affiliation></author><author><name sortKey="Guven, Ayla" sort="Guven, Ayla" uniqKey="Guven A" first="Ayla" last="Guven">Ayla Guven</name><affiliation><nlm:aff id="Aff9">Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye</nlm:aff></affiliation><affiliation><nlm:aff id="Aff16">Amasya University Medical Faculty, Department of Pediatric Endocrinology, Istanbul, Türkiye</nlm:aff></affiliation></author><author><name sortKey="Heritier, Sebastien" sort="Heritier, Sebastien" uniqKey="Heritier S" first="Sébastien" last="Heritier">Sébastien Heritier</name><affiliation><nlm:aff id="Aff17">Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Karall, Daniela" sort="Karall, Daniela" uniqKey="Karall D" first="Daniela" last="Karall">Daniela Karall</name><affiliation><nlm:aff id="Aff18">Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Kulkarni, Muralidhar L" sort="Kulkarni, Muralidhar L" uniqKey="Kulkarni M" first="Muralidhar L." last="Kulkarni">Muralidhar L. Kulkarni</name><affiliation><nlm:aff id="Aff19">J. J. M. Medical College, Davangere, Karnataka, 577004 India</nlm:aff></affiliation></author><author><name sortKey="Lebon, Pierre" sort="Lebon, Pierre" uniqKey="Lebon P" first="Pierre" last="Lebon">Pierre Lebon</name><affiliation><nlm:aff id="Aff20">Service de Virologie, AP-HP Hôpital Cochin, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Levitt, David" sort="Levitt, David" uniqKey="Levitt D" first="David" last="Levitt">David Levitt</name><affiliation><nlm:aff id="Aff21">Department of Paediatrics, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Le Merrer, Martine" sort="Le Merrer, Martine" uniqKey="Le Merrer M" first="Martine" last="Le Merrer">Martine Le Merrer</name><affiliation><nlm:aff id="Aff22">Centre de Référence des Maladies Osseuses Constitutionnelles et Institut Imagine, Hopital Necker 149 rue de Sevres, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnes" last="Linglart">Agnes Linglart</name><affiliation><nlm:aff id="Aff23">APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, 94270 Le Kremlin Bicêtre, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24">Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d’expertise Paris Sud Maladies Rares, APHP, 94270 Le Kremlin Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Livingston, John H" sort="Livingston, John H" uniqKey="Livingston J" first="John H." last="Livingston">John H. Livingston</name><affiliation><nlm:aff id="Aff25">Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK</nlm:aff></affiliation></author><author><name sortKey="Navarro, Vincent" sort="Navarro, Vincent" uniqKey="Navarro V" first="Vincent" last="Navarro">Vincent Navarro</name><affiliation><nlm:aff id="Aff26">Epilepsy Unit, Pitie-Salpetriere Hospital, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Okenfuss, Ericka" sort="Okenfuss, Ericka" uniqKey="Okenfuss E" first="Ericka" last="Okenfuss">Ericka Okenfuss</name><affiliation><nlm:aff id="Aff27">Kaiser Permanente – Genetics, 1650 Response Rd, Sacramento, CA 95815 USA</nlm:aff></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm:aff id="Aff28">Génétique Humaine des Maladies Infectieuses, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Pièce 421-B1, 24 boulevard du Montparnasse, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Revencu, Nicole" sort="Revencu, Nicole" uniqKey="Revencu N" first="Nicole" last="Revencu">Nicole Revencu</name><affiliation><nlm:aff id="Aff29">Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Scholl Burgi, Sabine" sort="Scholl Burgi, Sabine" uniqKey="Scholl Burgi S" first="Sabine" last="Scholl-Bürgi">Sabine Scholl-Bürgi</name><affiliation><nlm:aff id="Aff18">Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Vivarelli, Marina" sort="Vivarelli, Marina" uniqKey="Vivarelli M" first="Marina" last="Vivarelli">Marina Vivarelli</name><affiliation><nlm:aff id="Aff30">Division of Nephrology, IRCCS Bambino Gesu’ Pediatric Hospital, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Wouters, Carine" sort="Wouters, Carine" uniqKey="Wouters C" first="Carine" last="Wouters">Carine Wouters</name><affiliation><nlm:aff id="Aff31">Department of Microbiology and Immunology, Pediatric Immunology, KU Leuven, University of Leuven, Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Bader Meunier, Brigitte" sort="Bader Meunier, Brigitte" uniqKey="Bader Meunier B" first="Brigitte" last="Bader-Meunier">Brigitte Bader-Meunier</name><affiliation><nlm:aff id="Aff32">Pediatric Immunology and Rheumatology Unit, Hôpital Necker, APHP, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33">Institut Imagine, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Crow, Yanick J" sort="Crow, Yanick J" uniqKey="Crow Y" first="Yanick J." last="Crow">Yanick J. Crow</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff34">Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 24 boulevard du Montparnasse, 75015 Paris, France</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26951490</idno><idno type="pmc">4792361</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792361</idno><idno type="RBID">PMC:4792361</idno><idno type="doi">10.1007/s10875-016-0252-y</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000D47</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D47</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Spondyloenchondrodysplasia Due to Mutations in <italic>ACP5</italic>: A Comprehensive Survey</title><author><name sortKey="Briggs, Tracy A" sort="Briggs, Tracy A" uniqKey="Briggs T" first="Tracy A." last="Briggs">Tracy A. Briggs</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Rice, Gillian I" sort="Rice, Gillian I" uniqKey="Rice G" first="Gillian I." last="Rice">Gillian I. Rice</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation></author><author><name sortKey="Adib, Navid" sort="Adib, Navid" uniqKey="Adib N" first="Navid" last="Adib">Navid Adib</name><affiliation><nlm:aff id="Aff3">Department of Rheumatology, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Ades, Lesley" sort="Ades, Lesley" uniqKey="Ades L" first="Lesley" last="Ades">Lesley Ades</name><affiliation><nlm:aff id="Aff4">Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Discipline of Paedatrics and Child Health, The University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Barete, Stephane" sort="Barete, Stephane" uniqKey="Barete S" first="Stephane" last="Barete">Stephane Barete</name><affiliation><nlm:aff id="Aff6">Dermatology Department, Pitie-Salpetriere Hospital, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Baskar, Kannan" sort="Baskar, Kannan" uniqKey="Baskar K" first="Kannan" last="Baskar">Kannan Baskar</name><affiliation><nlm:aff id="Aff7">Creighton University, 2500 California Plaza, NE 68178, Omaha, USA</nlm:aff></affiliation></author><author><name sortKey="Baudouin, Veronique" sort="Baudouin, Veronique" uniqKey="Baudouin V" first="Veronique" last="Baudouin">Veronique Baudouin</name><affiliation><nlm:aff id="Aff8">Pediatric Nephrology Department, Robert Debré University Hospital – APHP, 48 boulevard Sérurier, 75019 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cebeci, Ayse N" sort="Cebeci, Ayse N" uniqKey="Cebeci A" first="Ayse N." last="Cebeci">Ayse N. Cebeci</name><affiliation><nlm:aff id="Aff9">Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye</nlm:aff></affiliation></author><author><name sortKey="Clapuyt, Philippe" sort="Clapuyt, Philippe" uniqKey="Clapuyt P" first="Philippe" last="Clapuyt">Philippe Clapuyt</name><affiliation><nlm:aff id="Aff10">Pediatric Imaging Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Coman, David" sort="Coman, David" uniqKey="Coman D" first="David" last="Coman">David Coman</name><affiliation><nlm:aff id="Aff11">Neuroscience Department, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12">School of Medicine, Griffith University, Gold Coast, Australia</nlm:aff></affiliation></author><author><name sortKey="De Somer, Lien" sort="De Somer, Lien" uniqKey="De Somer L" first="Lien" last="De Somer">Lien De Somer</name><affiliation><nlm:aff id="Aff13">Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Finezilber, Yael" sort="Finezilber, Yael" uniqKey="Finezilber Y" first="Yael" last="Finezilber">Yael Finezilber</name><affiliation><nlm:aff id="Aff14">Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel</nlm:aff></affiliation></author><author><name sortKey="Frydman, Moshe" sort="Frydman, Moshe" uniqKey="Frydman M" first="Moshe" last="Frydman">Moshe Frydman</name><affiliation><nlm:aff id="Aff14">Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel</nlm:aff></affiliation><affiliation><nlm:aff id="Aff15">Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel</nlm:aff></affiliation></author><author><name sortKey="Guven, Ayla" sort="Guven, Ayla" uniqKey="Guven A" first="Ayla" last="Guven">Ayla Guven</name><affiliation><nlm:aff id="Aff9">Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye</nlm:aff></affiliation><affiliation><nlm:aff id="Aff16">Amasya University Medical Faculty, Department of Pediatric Endocrinology, Istanbul, Türkiye</nlm:aff></affiliation></author><author><name sortKey="Heritier, Sebastien" sort="Heritier, Sebastien" uniqKey="Heritier S" first="Sébastien" last="Heritier">Sébastien Heritier</name><affiliation><nlm:aff id="Aff17">Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France</nlm:aff></affiliation></author><author><name sortKey="Karall, Daniela" sort="Karall, Daniela" uniqKey="Karall D" first="Daniela" last="Karall">Daniela Karall</name><affiliation><nlm:aff id="Aff18">Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Kulkarni, Muralidhar L" sort="Kulkarni, Muralidhar L" uniqKey="Kulkarni M" first="Muralidhar L." last="Kulkarni">Muralidhar L. Kulkarni</name><affiliation><nlm:aff id="Aff19">J. J. M. Medical College, Davangere, Karnataka, 577004 India</nlm:aff></affiliation></author><author><name sortKey="Lebon, Pierre" sort="Lebon, Pierre" uniqKey="Lebon P" first="Pierre" last="Lebon">Pierre Lebon</name><affiliation><nlm:aff id="Aff20">Service de Virologie, AP-HP Hôpital Cochin, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Levitt, David" sort="Levitt, David" uniqKey="Levitt D" first="David" last="Levitt">David Levitt</name><affiliation><nlm:aff id="Aff21">Department of Paediatrics, The Lady Cilento Children’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Le Merrer, Martine" sort="Le Merrer, Martine" uniqKey="Le Merrer M" first="Martine" last="Le Merrer">Martine Le Merrer</name><affiliation><nlm:aff id="Aff22">Centre de Référence des Maladies Osseuses Constitutionnelles et Institut Imagine, Hopital Necker 149 rue de Sevres, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Linglart, Agnes" sort="Linglart, Agnes" uniqKey="Linglart A" first="Agnes" last="Linglart">Agnes Linglart</name><affiliation><nlm:aff id="Aff23">APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, 94270 Le Kremlin Bicêtre, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff24">Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d’expertise Paris Sud Maladies Rares, APHP, 94270 Le Kremlin Bicêtre, France</nlm:aff></affiliation></author><author><name sortKey="Livingston, John H" sort="Livingston, John H" uniqKey="Livingston J" first="John H." last="Livingston">John H. Livingston</name><affiliation><nlm:aff id="Aff25">Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK</nlm:aff></affiliation></author><author><name sortKey="Navarro, Vincent" sort="Navarro, Vincent" uniqKey="Navarro V" first="Vincent" last="Navarro">Vincent Navarro</name><affiliation><nlm:aff id="Aff26">Epilepsy Unit, Pitie-Salpetriere Hospital, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Okenfuss, Ericka" sort="Okenfuss, Ericka" uniqKey="Okenfuss E" first="Ericka" last="Okenfuss">Ericka Okenfuss</name><affiliation><nlm:aff id="Aff27">Kaiser Permanente – Genetics, 1650 Response Rd, Sacramento, CA 95815 USA</nlm:aff></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm:aff id="Aff28">Génétique Humaine des Maladies Infectieuses, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Pièce 421-B1, 24 boulevard du Montparnasse, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Revencu, Nicole" sort="Revencu, Nicole" uniqKey="Revencu N" first="Nicole" last="Revencu">Nicole Revencu</name><affiliation><nlm:aff id="Aff29">Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Scholl Burgi, Sabine" sort="Scholl Burgi, Sabine" uniqKey="Scholl Burgi S" first="Sabine" last="Scholl-Bürgi">Sabine Scholl-Bürgi</name><affiliation><nlm:aff id="Aff18">Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria</nlm:aff></affiliation></author><author><name sortKey="Vivarelli, Marina" sort="Vivarelli, Marina" uniqKey="Vivarelli M" first="Marina" last="Vivarelli">Marina Vivarelli</name><affiliation><nlm:aff id="Aff30">Division of Nephrology, IRCCS Bambino Gesu’ Pediatric Hospital, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Wouters, Carine" sort="Wouters, Carine" uniqKey="Wouters C" first="Carine" last="Wouters">Carine Wouters</name><affiliation><nlm:aff id="Aff31">Department of Microbiology and Immunology, Pediatric Immunology, KU Leuven, University of Leuven, Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Bader Meunier, Brigitte" sort="Bader Meunier, Brigitte" uniqKey="Bader Meunier B" first="Brigitte" last="Bader-Meunier">Brigitte Bader-Meunier</name><affiliation><nlm:aff id="Aff32">Pediatric Immunology and Rheumatology Unit, Hôpital Necker, APHP, Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33">Institut Imagine, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Crow, Yanick J" sort="Crow, Yanick J" uniqKey="Crow Y" first="Yanick J." last="Crow">Yanick J. Crow</name><affiliation><nlm:aff id="Aff1">Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff34">Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 24 boulevard du Montparnasse, 75015 Paris, France</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Clinical Immunology</title><idno type="ISSN">0271-9142</idno><idno type="eISSN">1573-2592</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Purpose</title><p>Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in <italic>ACP5.</italic> We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.</p></sec><sec><title>Methods</title><p>We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic <italic>ACP5</italic> mutations.</p></sec><sec><title>Results</title><p>We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.</p></sec><sec><title>Conclusions</title><p>Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Schorr, S" uniqKey="Schorr S">S Schorr</name></author><author><name sortKey="Legum, C" uniqKey="Legum C">C Legum</name></author><author><name sortKey="Ochshorn, M" uniqKey="Ochshorn M">M Ochshorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Renella, R" uniqKey="Renella R">R Renella</name></author><author><name sortKey="Schaefer, E" uniqKey="Schaefer E">E Schaefer</name></author><author><name sortKey="Lemerrer, M" uniqKey="Lemerrer M">M LeMerrer</name></author><author><name sortKey="Alanay, Y" uniqKey="Alanay Y">Y Alanay</name></author><author><name sortKey="Kandemir, N" uniqKey="Kandemir N">N 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Immunol</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Immunol</journal-id><journal-title-group><journal-title>Journal of Clinical Immunology</journal-title></journal-title-group><issn pub-type="ppub">0271-9142</issn><issn pub-type="epub">1573-2592</issn><publisher><publisher-name>Springer US</publisher-name><publisher-loc>New York</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26951490</article-id><article-id pub-id-type="pmc">4792361</article-id><article-id pub-id-type="publisher-id">252</article-id><article-id pub-id-type="doi">10.1007/s10875-016-0252-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Spondyloenchondrodysplasia Due to Mutations in <italic>ACP5</italic>: A Comprehensive Survey</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Briggs</surname><given-names>Tracy 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contrib-type="author"><name><surname>Baudouin</surname><given-names>Veronique</given-names></name><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Cebeci</surname><given-names>Ayse N.</given-names></name><xref ref-type="aff" rid="Aff9"></xref></contrib><contrib contrib-type="author"><name><surname>Clapuyt</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="Aff10"></xref></contrib><contrib contrib-type="author"><name><surname>Coman</surname><given-names>David</given-names></name><xref ref-type="aff" rid="Aff11"></xref><xref ref-type="aff" rid="Aff12"></xref></contrib><contrib contrib-type="author"><name><surname>De Somer</surname><given-names>Lien</given-names></name><xref ref-type="aff" rid="Aff13"></xref></contrib><contrib contrib-type="author"><name><surname>Finezilber</surname><given-names>Yael</given-names></name><xref ref-type="aff" rid="Aff14"></xref></contrib><contrib contrib-type="author"><name><surname>Frydman</surname><given-names>Moshe</given-names></name><xref ref-type="aff" rid="Aff14"></xref><xref ref-type="aff" rid="Aff15"></xref></contrib><contrib contrib-type="author"><name><surname>Guven</surname><given-names>Ayla</given-names></name><xref ref-type="aff" rid="Aff9"></xref><xref ref-type="aff" rid="Aff16"></xref></contrib><contrib contrib-type="author"><name><surname>Heritier</surname><given-names>Sébastien</given-names></name><xref ref-type="aff" rid="Aff17"></xref></contrib><contrib contrib-type="author"><name><surname>Karall</surname><given-names>Daniela</given-names></name><xref ref-type="aff" rid="Aff18"></xref></contrib><contrib contrib-type="author"><name><surname>Kulkarni</surname><given-names>Muralidhar L.</given-names></name><xref ref-type="aff" rid="Aff19"></xref></contrib><contrib contrib-type="author"><name><surname>Lebon</surname><given-names>Pierre</given-names></name><xref ref-type="aff" rid="Aff20"></xref></contrib><contrib contrib-type="author"><name><surname>Levitt</surname><given-names>David</given-names></name><xref ref-type="aff" rid="Aff21"></xref></contrib><contrib contrib-type="author"><name><surname>Le Merrer</surname><given-names>Martine</given-names></name><xref ref-type="aff" rid="Aff22"></xref></contrib><contrib contrib-type="author"><name><surname>Linglart</surname><given-names>Agnes</given-names></name><xref ref-type="aff" rid="Aff23"></xref><xref ref-type="aff" rid="Aff24"></xref></contrib><contrib contrib-type="author"><name><surname>Livingston</surname><given-names>John H.</given-names></name><xref ref-type="aff" rid="Aff25"></xref></contrib><contrib contrib-type="author"><name><surname>Navarro</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="Aff26"></xref></contrib><contrib contrib-type="author"><name><surname>Okenfuss</surname><given-names>Ericka</given-names></name><xref ref-type="aff" rid="Aff27"></xref></contrib><contrib contrib-type="author"><name><surname>Puel</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="Aff28"></xref></contrib><contrib contrib-type="author"><name><surname>Revencu</surname><given-names>Nicole</given-names></name><xref ref-type="aff" rid="Aff29"></xref></contrib><contrib contrib-type="author"><name><surname>Scholl-Bürgi</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="Aff18"></xref></contrib><contrib contrib-type="author"><name><surname>Vivarelli</surname><given-names>Marina</given-names></name><xref ref-type="aff" rid="Aff30"></xref></contrib><contrib contrib-type="author"><name><surname>Wouters</surname><given-names>Carine</given-names></name><xref ref-type="aff" rid="Aff31"></xref></contrib><contrib contrib-type="author"><name><surname>Bader-Meunier</surname><given-names>Brigitte</given-names></name><xref ref-type="aff" rid="Aff32"></xref><xref ref-type="aff" rid="Aff33"></xref></contrib><contrib contrib-type="author"><name><surname>Crow</surname><given-names>Yanick J.</given-names></name><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff34"></xref></contrib><aff id="Aff1"><label></label>Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK</aff><aff id="Aff2"><label></label>St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK</aff><aff id="Aff3"><label></label>Department of Rheumatology, The Lady Cilento Children’s Hospital, Brisbane, Australia</aff><aff id="Aff4"><label></label>Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, Australia</aff><aff id="Aff5"><label></label>Discipline of Paedatrics and Child Health, The University of Sydney, Sydney, Australia</aff><aff id="Aff6"><label></label>Dermatology Department, Pitie-Salpetriere Hospital, Paris, France</aff><aff id="Aff7"><label></label>Creighton University, 2500 California Plaza, NE 68178, Omaha, USA</aff><aff id="Aff8"><label></label>Pediatric Nephrology Department, Robert Debré University Hospital – APHP, 48 boulevard Sérurier, 75019 Paris, France</aff><aff id="Aff9"><label></label>Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye</aff><aff id="Aff10"><label></label>Pediatric Imaging Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</aff><aff id="Aff11"><label></label>Neuroscience Department, The Lady Cilento Children’s Hospital, Brisbane, Australia</aff><aff id="Aff12"><label></label>School of Medicine, Griffith University, Gold Coast, Australia</aff><aff id="Aff13"><label></label>Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, B-3000 Leuven, Belgium</aff><aff id="Aff14"><label></label>Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel</aff><aff id="Aff15"><label></label>Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel</aff><aff id="Aff16"><label></label>Amasya University Medical Faculty, Department of Pediatric Endocrinology, Istanbul, Türkiye</aff><aff id="Aff17"><label></label>Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France</aff><aff id="Aff18"><label></label>Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria</aff><aff id="Aff19"><label></label>J. J. M. Medical College, Davangere, Karnataka, 577004 India</aff><aff id="Aff20"><label></label>Service de Virologie, AP-HP Hôpital Cochin, Paris, France</aff><aff id="Aff21"><label></label>Department of Paediatrics, The Lady Cilento Children’s Hospital, Brisbane, Australia</aff><aff id="Aff22"><label></label>Centre de Référence des Maladies Osseuses Constitutionnelles et Institut Imagine, Hopital Necker 149 rue de Sevres, 75015 Paris, France</aff><aff id="Aff23"><label></label>APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, 94270 Le Kremlin Bicêtre, France</aff><aff id="Aff24"><label></label>Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d’expertise Paris Sud Maladies Rares, APHP, 94270 Le Kremlin Bicêtre, France</aff><aff id="Aff25"><label></label>Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK</aff><aff id="Aff26"><label></label>Epilepsy Unit, Pitie-Salpetriere Hospital, Paris, France</aff><aff id="Aff27"><label></label>Kaiser Permanente – Genetics, 1650 Response Rd, Sacramento, CA 95815 USA</aff><aff id="Aff28"><label></label>Génétique Humaine des Maladies Infectieuses, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Pièce 421-B1, 24 boulevard du Montparnasse, 75015 Paris, France</aff><aff id="Aff29"><label></label>Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium</aff><aff id="Aff30"><label></label>Division of Nephrology, IRCCS Bambino Gesu’ Pediatric Hospital, Rome, Italy</aff><aff id="Aff31"><label></label>Department of Microbiology and Immunology, Pediatric Immunology, KU Leuven, University of Leuven, Leuven, Belgium</aff><aff id="Aff32"><label></label>Pediatric Immunology and Rheumatology Unit, Hôpital Necker, APHP, Paris, France</aff><aff id="Aff33"><label></label>Institut Imagine, Paris, France</aff><aff id="Aff34"><label></label>Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 24 boulevard du Montparnasse, 75015 Paris, France</aff></contrib-group><pub-date pub-type="epub"><day>8</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>8</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="ppub"><year>2016</year></pub-date><volume>36</volume><fpage>220</fpage><lpage>234</lpage><history><date date-type="received"><day>15</day><month>12</month><year>2015</year></date><date date-type="accepted"><day>22</day><month>2</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s) 2016</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.</license-p></license></permissions><abstract id="Abs1"><sec><title>Purpose</title><p>Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in <italic>ACP5.</italic> We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.</p></sec><sec><title>Methods</title><p>We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic <italic>ACP5</italic> mutations.</p></sec><sec><title>Results</title><p>We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.</p></sec><sec><title>Conclusions</title><p>Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Spondyloenchondrodysplasia</kwd><kwd>SPENCD/SPENCDI</kwd><kwd><italic>ACP5</italic></kwd><kwd>tartrate-resistant acid phosphatase (TRAP)</kwd><kwd>type I interferon</kwd><kwd>interferon signature</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000272</institution-id><institution>National Institute for Health Research</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000691</institution-id><institution>Academy of Medical Sciences</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000781</institution-id><institution>European Research Council</institution></institution-wrap></funding-source><award-id>GA 309449</award-id><principal-award-recipient><name><surname>Crow</surname><given-names>Yanick J.</given-names></name></principal-award-recipient></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100001665</institution-id><institution>Agence Nationale de la Recherche</institution></institution-wrap></funding-source><award-id>ANR-10-IAHU-01</award-id><principal-award-recipient><name><surname>Crow</surname><given-names>Yanick J.</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer Science+Business Media New York 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p>Spondyloenchondrodysplasia (SPENCD) (OMIM: 271,550) is a skeletal dysplasia, characterised by radiolucent metaphyseal and vertebral lesions [<xref ref-type="bibr" rid="CR1">1</xref>]. Enchondromas predominantly develop within long bones, but may also occur in other areas of endochondral growth [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR3">3</xref>]. The severity of the lesions varies, but slow progression during childhood is most frequently observed, resulting in significant short stature [<xref ref-type="bibr" rid="CR2">2</xref>]. The first extra-osseous manifestations reported in SPENCD were of neurological dysfunction, including developmental delay and spasticity, which may be associated with intracranial calcification [<xref ref-type="bibr" rid="CR2">2</xref>–<xref ref-type="bibr" rid="CR5">5</xref>]. It was subsequently recognised that autoimmune disease was also a prominent feature [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR6">6</xref>].</p><p>SPENCD is caused by biallelic mutations in <italic>ACP5</italic>, encoding tartrate-resistant acid phosphatase (TRAP) [<xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR8">8</xref>]. Affected individuals displayed an absence of TRAP serum expression and, in keeping with autoimmune manifestations, increased levels of serum interferon-alpha (IFNα) and an upregulation of interferon-stimulated genes (ISGs) (an interferon signature) [<xref ref-type="bibr" rid="CR7">7</xref>]. An interferon signature is also recognised in SLE [<xref ref-type="bibr" rid="CR9">9</xref>] and in monogenic disease in association with mutations in <italic>TMEM173</italic> [<xref ref-type="bibr" rid="CR10">10</xref>] and <italic>ISG15</italic> [<xref ref-type="bibr" rid="CR11">11</xref>] and any of the phenotypes recognised with mutations in <italic>TREX1</italic>, <italic>RNASEH2A</italic>/<italic>B</italic>/<italic>C</italic>, <italic>SAMHD1</italic>, <italic>ADAR1</italic> and <italic>IFIH1</italic> - including the monogenic encephalopathy Aicardi-Goutières syndrome (AGS), which can show significant overlap with SPENCD [<xref ref-type="bibr" rid="CR12">12</xref>, <xref ref-type="bibr" rid="CR13">13</xref>].</p><p>Interestingly, since the description of causative <italic>ACP5</italic> mutations [<xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR8">8</xref>] the disorder has been designated under two separate Online Mendelian Inheritance in Man (OMIM) entries, namely SPENCD (271,550) and SPENCD with immune dysregulation (SPENCDI) (607,944). SPENCD is described as a skeletal and neurological disorder of unknown aetiology. Whilst SPENCDI, refers to patients with an immune phenotype, in addition to the typical skeletal and neurological features, and is attributed to <italic>ACP5</italic> mutations.</p><p>Here, we present data from 26 patients with biallelic <italic>ACP5</italic> mutations conforming to both the SPENCD and SPENCDI phenotypes, leading us to propose that these phenotypes should be considered under the single designation of SPENCD.</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Methods</title><sec id="Sec3"><title>Subjects</title><p>Twenty-six subjects with a clinical diagnosis of SPENCD (based on bone, brain and/or immune features, i.e. per current OMIM classification of SPENCD or SPENCDI) from 18 independent pedigrees were recruited through collaborating physicians. A U.K. Multicentre Research Ethics Committee (reference number 10/H1307/132) approved the study.</p></sec><sec id="Sec4"><title>Mutation Analysis</title><p>All coding exons of <italic>ACP5</italic> were sequenced as described previously [<xref ref-type="bibr" rid="CR7">7</xref>]. Variant pathogenicity was analysed using Alumut and minor allele frequency was assessed using the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) database.</p></sec><sec id="Sec5"><title>Interferon Analysis</title><p>Type I interferon activity was determined using a cytopathic reduction assay [<xref ref-type="bibr" rid="CR7">7</xref>]. As previously described [<xref ref-type="bibr" rid="CR12">12</xref>], qPCR was performed on cDNA derived from whole blood and the median fold change of six interferon-simulated genes was compared with the median of the combined controls, to create an interferon score for each patient. Scores higher than the mean of the controls plus two SD (>2.466) were designated as a positive score.</p></sec></sec><sec id="Sec6" sec-type="results"><title>Results</title><sec id="Sec7"><title>Mutation Data</title><p>All 26 patients with a clinical diagnosis of SPENCD/SPENCDI harboured homozygous or compound heterozygous <italic>ACP5</italic> mutations (Table <xref rid="Tab1" ref-type="table">1</xref>, Fig. <xref rid="Fig1" ref-type="fig">1</xref>). These data confirm the autosomal recessive nature of the disorder and suggest that it is not a genetically heterogeneous condition. The observation that 15 out of 18 families have a history of consanguinity is in keeping with the low minor allele frequency of pathogenic heterozygous variants in control populations. Seventeen different mutations distributed throughout the gene were identified (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). Four mutations were observed in more than one pedigree, whilst the remainder were private to individual pedigrees.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Demographic, genetic and presenting complaint of <italic>ACP5</italic> mutation positive patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Patient<sup>a</sup></th><th>Gender</th><th>Country of origin</th><th>Consanguinity</th><th>Relationship to other patients in cohort</th><th>Mutation</th><th>Protein</th><th>Age at presentation (months (mo.)/years (yr.))</th><th>Features at initial presentation</th><th>Current age in years</th></tr></thead><tbody><tr><td>1</td><td>Female</td><td>France</td><td>No</td><td>None</td><td>11,544,822–11,556,767 del</td><td>p.Ex4_7 del Hom</td><td>3 yr.</td><td>Seizures</td><td>Deceased at age 30</td></tr><tr><td>2</td><td>Female</td><td>Austria</td><td>No</td><td>Sibling of 3</td><td>c.369C > A/c.721G > A</td><td>p.Tyr123X Het./p.Asp241Asn Het.</td><td>12 mo.</td><td>Delayed motor development</td><td>13</td></tr><tr><td>3</td><td>Male</td><td>Austria</td><td>No</td><td>Sibling of 2</td><td>c.369C > A/c.721G > A</td><td>p.Tyr123X Het./p.Asp241Asn Het.</td><td>3 yr.</td><td>AITP</td><td>13</td></tr><tr><td>4</td><td>Male</td><td>Turkey</td><td>Yes</td><td>Sibling of 5</td><td>c.266C > T</td><td>p.Thr89Ile Hom.</td><td>2 yr.</td><td>Spasticity & vasculitic skin rash</td><td>17</td></tr><tr><td>5</td><td>Female</td><td>Turkey</td><td>Yes</td><td>Sibling of 4</td><td>c.266C > T</td><td>p.Thr89Ile Hom.</td><td>14 yr.</td><td>Short stature</td><td>20</td></tr><tr><td>6</td><td>Male</td><td>Pakistan</td><td>Yes</td><td>None</td><td>c.667C > T</td><td>p.Gln223X Hom.</td><td>8 mo.</td><td>Short stature</td><td>17</td></tr><tr><td>7</td><td>Male</td><td>India</td><td>Yes</td><td>None</td><td>11,543,690–11,548,656 del</td><td>p.Ex5_7 del Hom</td><td>2 yr.</td><td>Recurrent infections</td><td>14</td></tr><tr><td>8</td><td>Female</td><td>Portugal</td><td>Yes</td><td>None<sup>b</sup></td><td>c.791 T > A</td><td>p.Met264Val Hom.</td><td>3 yr.</td><td>Recurrent infections</td><td>34</td></tr><tr><td>9</td><td>Female</td><td>Mali</td><td>Yes</td><td>None</td><td>c.643G > A</td><td>p.Gly215Arg Hom.</td><td>6 yr.</td><td>Lupus nephropathy</td><td>22</td></tr><tr><td>10</td><td>Female</td><td>Egypt</td><td>Yes</td><td>None</td><td>c.772-790del</td><td>p.Ser258Trpfs*39 Hom.</td><td>4 yr.</td><td>Leg pain</td><td>17</td></tr><tr><td>11</td><td>Male</td><td>France</td><td>Yes</td><td>None</td><td>c.821 T > C</td><td>p.Val274Ala Hom.</td><td>2 yr.</td><td>Dev. delay & hypothyroidism</td><td>14</td></tr><tr><td>12</td><td>Female</td><td>Senegal</td><td>Yes</td><td>Sibling of 13</td><td>c.643 g > a</td><td>p.Gly215Arg Hom.</td><td>5 yrs.</td><td>Cerebral haemorrhage (AITP)</td><td>7</td></tr><tr><td>13</td><td>Male</td><td>Senegal</td><td>Yes</td><td>Sibling of 12</td><td>c.643 g > a</td><td>p.Gly215Arg Hom.</td><td>4 mo.</td><td>Metaphyseal lesions</td><td>2</td></tr><tr><td>14</td><td>Female</td><td>Turkey</td><td>Yes</td><td>None<sup>c</sup></td><td>c.155 A > C</td><td>p.Lys52Thr Hom.</td><td>6 yrs.</td><td>Bruising & petechia (AITP)</td><td>12</td></tr><tr><td>15</td><td>Female</td><td>Mexico</td><td>Yes</td><td>None</td><td>c.725 A > G</td><td>p.His242Arg Hom.</td><td>3 yrs.</td><td>Short stature & leg bowing</td><td>16</td></tr><tr><td>16</td><td>Female</td><td>Turkey</td><td>Yes</td><td>Sibling of 17</td><td>c.155 A > C/c.790 A > G</td><td>p.Lys52Thr Hom./p.Met264Val Het.</td><td>2.5 yrs.</td><td>AIHA</td><td>15</td></tr><tr><td>17</td><td>Male</td><td>Turkey</td><td>Yes</td><td>Sibling of 16</td><td>c.155 A > C/c.790 A > G</td><td>p.Lys52Thr Hom./p.Met264Val Het.</td><td>3 mo.</td><td>Short stature & AIHA</td><td>13</td></tr><tr><td>18</td><td>Female</td><td>Iraq (Jewish)</td><td>Yes</td><td>None<sup>d</sup></td><td>c.325G > A</td><td>p.Gly109Arg Hom.</td><td>2 yrs.</td><td>Short stature</td><td>36</td></tr><tr><td>19</td><td>Female</td><td>Lebanon</td><td>Yes</td><td>Sibling of 20</td><td>c.389 + 1G > A</td><td>p.? Hom.</td><td>9 yrs.</td><td>Jaundice (Hepatitis)</td><td>10</td></tr><tr><td>20</td><td>Female</td><td>Lebanon</td><td>Yes</td><td>Sibling of 19</td><td>c.389 + 1G > A</td><td>p.? Hom.</td><td>Birth</td><td>AITP</td><td>Deceased at less than 1 year</td></tr><tr><td>21</td><td>Male</td><td>Italy</td><td>Yes</td><td>None</td><td>c.359 A > G</td><td>Gln120Arg Hom.</td><td>1 mo.</td><td>AITP</td><td>9</td></tr><tr><td>22</td><td>Male</td><td>Israel (Arabic)</td><td>Yes</td><td>None<sup>e</sup></td><td>c.325G > A</td><td>p.Gly109Arg Hom.</td><td>15 yrs.</td><td>Short stature & spasticity</td><td>35</td></tr><tr><td>23</td><td>Male</td><td>China</td><td>No</td><td>Sibling of 24, cousin of 25 & 26</td><td>c.325G > A/c.712 T > C</td><td>p.Gly109Arg Het./p.Cys238Arg Het.</td><td>5 yrs.</td><td>Short stature</td><td>12</td></tr><tr><td>24</td><td>Female</td><td>China</td><td>No</td><td>Sibling of 23, cousin of 25 & 26</td><td>c.325G > A/c.712 T > C</td><td>p.Gly109Arg Het./p.Cys238Arg Het.</td><td>7 mo.</td><td>Short stature & motor delay</td><td>7</td></tr><tr><td>25</td><td>Female</td><td>China</td><td>No</td><td>Sibling of 26, cousin of 23 & 24</td><td>c.131C > T/c.712 T > C</td><td>p.Thr44Met Het./p.Cys238Arg Het.</td><td>6 mo.</td><td>Short stature</td><td>10</td></tr><tr><td>26</td><td>Female</td><td>China</td><td>No</td><td>Sibling of 25, cousin of 23 & 24</td><td>c.131C > T/c.712 T > C</td><td>p.Thr44Met Het./p.Cys238Arg Het.</td><td>6 mo.</td><td>Short stature</td><td>15</td></tr></tbody></table><table-wrap-foot><p><italic>AITP</italic> Autoimmune thrombocytopenia, <italic>AIHA</italic> Autoimmune haemolytic anaemia, <italic>Dev.Delay</italic> Developmental delay</p><p><sup>a</sup>Patients 1 to 10 have been previously described [<xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR16">16</xref>] and additional data are added where available</p><p><sup>b</sup>Clinically affected sibling previously described (Patient 2 [<xref ref-type="bibr" rid="CR6">6</xref>])</p><p><sup>c</sup>Affected cousin (confirmed <italic>ACP5</italic> biallelic mutation) previously described [<xref ref-type="bibr" rid="CR8">8</xref>]</p><p><sup>d</sup>Clinically affected sibling previously described (Patient 1 [<xref ref-type="bibr" rid="CR4">4</xref>])</p><p><sup>e</sup>Clinically affected sibling previously described (Patient 5 [<xref ref-type="bibr" rid="CR4">4</xref>])</p></table-wrap-foot></table-wrap><fig id="Fig1"><label>Fig. 1</label><caption><p>A diagram illustrating the distribution of all reported <italic>ACP5</italic> pathogenic variants. Below the gene diagram data are shown from this study with number of alleles per variant observed in parentheses; in addition pathogenic variants not identified in this study, but previously reported by Lausch et al. [<xref ref-type="bibr" rid="CR8">8</xref>] and Girschick et al. [<xref ref-type="bibr" rid="CR17">17</xref>] are depicted above the gene diagram</p></caption><graphic xlink:href="10875_2016_252_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec8"><title>Clinical Data</title><p>The most frequent reason for first seeking medical attention, in a total of 13 patients, was due to symptoms of immune disease, particularly autoimmune thrombocytopenia (AITP), which prompted presentation in five patients (Table <xref rid="Tab1" ref-type="table">1</xref>). Skeletal manifestations, with short stature or leg pain/bowing, were the reason for initial presentation in 12 patients, whilst in six a neurological phenotype was manifest. In five individuals, complaints in more than one system prompted presentation. The age at which features first necessitated medical consultation varied from birth to 15 years.</p><p>The varied nature and severity of the disease continued throughout the disease course. For example, Patient 18 presented at two years of age with short stature. After which, she did not develop any additional features – so that at 36 years of age she was of normal intellect, in full time employment and gave birth to her first child. In contrast, Patient 1 presented at three years of age with seizures, and suffered a severe, progressive deterioration with skeletal, neurological and multi-organ autoimmune disease [<xref ref-type="bibr" rid="CR3">3</xref>]. Marked variation was evident between the seven sib-pairs within the cohort, Patient 2 and 3 for example are non-identical twins and at 13 years of age Patient 2 was 5.5 SD below the mean for height, due to spasticity was classified as level 3 on the Gross Motor Classification System and manifested hypothyroidism and SLE with Class IV nephritis. In contrast Patient 3 was 2.5 SD below the mean for height, had no neurological manifestations and was diagnosed with eczema, AITP and proteinuria and did not fulfil lupus diagnostic criteria.</p></sec><sec id="Sec9"><title>Skeletal Manifestations</title><p>Until recently the diagnosis of SPENCD was made based on the presence of characteristic radiolucent metaphyseal and vertebral lesions (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Even with molecular testing, skeletal findings remain an important diagnostic clue. Thus, although short stature did not always lead to medical referral (perhaps because autoimmune or neurological features were more problematic), in all patients where assessment was undertaken, skeletal manifestations were evident on radiographs, with features of both platyspondyly and metaphyseal dysplasia in 23, and either platyspondyly or metaphyseal dysplasia in a further two (Table <xref rid="Tab2" ref-type="table">2</xref>). We tested over 30 patients with a neurological and/or autoimmune phenotype, including AITP, SLE, intracranial calcification with seizures or spasticity, but without typical skeletal radiological changes, and did not identify biallelic <italic>ACP5</italic> mutations.<fig id="Fig2"><label>Fig. 2</label><caption><p>A skeletal survey in a patient with biallelic <italic>ACP5</italic> mutations. Imaging in Patient 14 at age seven years identified platyspondyly and lacunar lesions localized to the posterior third of the vertebral bodies (<bold>a</bold>); radiolucent lesions extending from the growth plate into the metaphysis of the long bones of the distal radius and ulna (<bold>b</bold>), proximal fibula and tibia (<bold>c</bold>) and the distal femora (<bold>d</bold>)</p></caption><graphic xlink:href="10875_2016_252_Fig2_HTML" id="MO2"></graphic></fig><table-wrap id="Tab2"><label>Table 2</label><caption><p>Key skeletal and neurological features of <italic>ACP5</italic> mutation positive patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Patient<sup>1</sup></th><th>Last recorded height as SD below the mean (age at assessment)</th><th>Metaphyseal dysplasia</th><th>Platyspondyly</th><th>Intracranial calcification</th><th>Cranial MRI manifestations</th><th>Spasticity</th><th>Developmental delay (Degree)</th></tr></thead><tbody><tr><td>1</td><td>4 (23)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Periventricular white matter changes</td><td>No</td><td>Yes (Mod.)</td></tr><tr><td>2</td><td>5.5 (12)</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>Yes</td><td>Yes (Mild)</td></tr><tr><td>3</td><td>2.5 (12)</td><td>No</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>4</td><td>4.3 (16)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>5</td><td>3.8 (19)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Nil beyond changes associated with calcification</td><td>Yes</td><td>No</td></tr><tr><td>6</td><td>5 (13)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Ischaemic lateral ventricle lesions</td><td>Yes</td><td>Yes (Mod.)</td></tr><tr><td>7</td><td>3 (8)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Subcortical parietal granuloma (TB reaction)</td><td>No</td><td>No</td></tr><tr><td>8</td><td>4 (18)</td><td>Yes</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>9</td><td>6.5 (18)</td><td>Yes</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td></tr><tr><td>10</td><td>3 (13)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>11</td><td>2 (12)</td><td>Yes</td><td>Yes</td><td>No</td><td>Ventricular dilatation</td><td>Yes</td><td>Yes (Severe)</td></tr><tr><td>12</td><td>2 (6)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Left subdural fronto-parietal subacute to chronic bleed; multiple petechial bilateral intra-parenchymal lesions</td><td>Yes</td><td>No</td></tr><tr><td>13</td><td>0 (0.5)</td><td>Yes</td><td>Yes</td><td>No</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>14</td><td>2.5 (10)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td></tr><tr><td>15</td><td>6 (12)</td><td>Yes</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>16</td><td>4 (12)</td><td>Yes</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>17</td><td>3 (10)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td></tr><tr><td>18</td><td>3.5 (36)</td><td>Yes</td><td>Yes</td><td>No</td><td>NA</td><td>Yes</td><td>No</td></tr><tr><td>19</td><td>2.5 (10)</td><td>Yes</td><td>Yes</td><td>NA</td><td>Developmental venous anomaly associated with 3 mm pontine cavernoma</td><td>No</td><td>Yes (Mild)</td></tr><tr><td>20</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>21</td><td>3 (10)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Leukodystrophy in the internal capsule of the semioval centre</td><td>Yes</td><td>Yes (Mild)</td></tr><tr><td>22</td><td>5.5 (35)</td><td>Yes</td><td>Yes</td><td>Yes</td><td>NA</td><td>Yes</td><td>Yes (Mod.)</td></tr><tr><td>23</td><td>2 (12)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td></tr><tr><td>24</td><td>3 (7)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>25</td><td>3.5 (10)</td><td>Yes</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>26</td><td>5 (15)</td><td>Yes</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>No</td></tr><tr><td>Total</td><td>0–6.5</td><td>24/25 (1 NA)</td><td>24/25 (1 NA)</td><td>9/14 (12 NA)</td><td>8/16 (10 NA)</td><td>11/25 (1 NA)</td><td>7/25 (1 NA)</td></tr><tr><td>Further cases [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR17">17</xref>]</td><td>1.8–4.2</td><td>15/15</td><td>14/15</td><td>6/8 (7 NA)</td><td>2/3 (13 NA)</td><td>4/14 (1 NA)</td><td>4/14 (1 NA)</td></tr></tbody></table><table-wrap-foot><p><italic>NA</italic> Not assessed/reported, <italic>Mod</italic> moderate developmental delay</p><p><sup>1</sup>Patients 1 to 10 have previously been described [<xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR16">16</xref>] and additional data are added where available</p></table-wrap-foot></table-wrap></p><p>The skeletal phenotype is variable, with stature from within the normal range to 6.5 SD below the mean. Exacerbation of the degree of short stature over time was evident; for example, Patient 22 progressed from 3 to 5.5 SD below the mean between 15 and 35 years of age. Short stature was due to short trunk and/or short limbs depending upon the relative degree of spinal and/or long bone dysplasia. A number of patients also manifested specific skeletal deformities, including short distal phalanges (Patient 4 and 5), kyphosis and pectus carinatum (Patient 22) [<xref ref-type="bibr" rid="CR4">4</xref>]. Bone mineral density was normal in Patient 2 and 19, whilst it was increased in Patient 4 and 5 (above superior percentile for age) and Patient 10 (1.5 SD above mean), although there was no evidence of localized osteopetrosis. Patient 17 demonstrated growth hormone (GH) deficiency and height improved with GH treatment. However, we are not aware of GH deficiency in other patients and indeed GH supplementation has been tried in at least one other patient without any effect on growth.</p></sec><sec id="Sec10"><title>Neurological Manifestations</title><p>Neurological features are frequent in <italic>ACP5</italic>-associated disease. We observed spasticity in eleven patients (44 %), and developmental delay in seven patients (28 %) (Table <xref rid="Tab2" ref-type="table">2</xref>). Delay was typically of mild to moderate severity, except in Patient 11, who presented at age two years with hypothyroidism and severe delay. Additional neurological features included ataxia, seizures, psychosis and painful multifocal neuropathy.</p><p>Intracranial calcification was demonstrated on cranial CT imaging in nine out of the thirteen patients assessed (62 %), variably involving the basal ganglia, pons, dentate nuclei of the cerebellum and white-grey matter junction. Figure <xref rid="Fig3" ref-type="fig">3</xref> demonstrates the intracerebral calcification observed in Patient 21, associated with a history of spasticity, developmental delay and autoimmune disease. Cranial MRI abnormalities were detected in 8 of 16 patients assessed with features including leukodystrophy (Table <xref rid="Tab2" ref-type="table">2</xref>), and angiography in Patient 1 demonstrated an intracranial aneurysm.<fig id="Fig3"><label>Fig. 3</label><caption><p>A cranial CT in a patient with biallelic <italic>ACP5</italic> mutations. Imaging in Patient 21 at nine years of age demonstrated intracranial calcification of the white and grey matter junction and bilateral blush and spots in the head of the caudate, putamen and globus pallidus and deep gyral matter on the right and left</p></caption><graphic xlink:href="10875_2016_252_Fig3_HTML" id="MO3"></graphic></fig></p><p>Neurological manifestations may evolve over time. Patient 5 for example, was diagnosed at age 14 years due to short stature, Raynaud’s phenomenon and a positive family history [<xref ref-type="bibr" rid="CR7">7</xref>]. At 19 years of age she developed lower limb pyramidal signs, which coincided with the detection of anti-nuclear antibodies for the first time, and a 10-fold increase in serum ISG levels compared to five years previously. CT revealed bilateral calcifications in the basal gangla and thalami.</p></sec><sec id="Sec11"><title>Immune Manifestations</title><p>Immune dysfunction was the most frequent presenting complaint in our cohort, and deterioration was observed over-time.</p><sec id="Sec12"><title>Autoimmune Manifestations</title><p>At least one autoimmune diagnosis was present in 22 patients (85 %), with many exhibiting more than three (Table <xref rid="Tab3" ref-type="table">3</xref>). The most common was AITP in a total of 12 patients (46 %), seven of whom had SLE. AITP was lethal in one patient in infancy, and the associated morbidity in other cases was significant, with cerebral haemorrhage in two patients. In many cases, AITP necessitated intensive treatment with corticosteroids, intravenous immunoglobulins, rituximab and/or splenectomy. Seven patients with renal manifestations fulfilled ACR diagnostic criteria for SLE [<xref ref-type="bibr" rid="CR14">14</xref>], whilst the other three were under follow up for proteinuria and did not fulfil criteria. In total nine (36 %) patients fulfilled SLE diagnostic criteria. Recurrent fevers of unknown origin were reported in several patients. Skin manifestations were noted, with severe eczema in four patients. Two patients had vasculitis; in Patient 1 sclerodermatous/acrocyanotic changes were evident in the hands and feet with oedema and sludging on capillaroscopy. Ultimately digital auto-amputation occurred, secondary to vasculitis. Skin biopsy in Patient 4 showed a perivascular polymorphonuclear infiltrate without evidence of deposition of complement or immunoglobulin, consistent with a non-specific leukocytoclastic vasculitis [<xref ref-type="bibr" rid="CR3">3</xref>]. Two patients had Raynaud’s phenomenon and in one (Patient 5) capillaroscopy demonstrated the disappearance of parallel loops of some dilated capillaries with slow blood flow, which was not considered reminiscent of sclerodermatous disease [<xref ref-type="bibr" rid="CR15">15</xref>]. Additional autoimmune phenotypes were reported, including in two patients: Sjögren’s syndrome and livedo reticularis; and in a single patient: post-operative macrophage activation syndrome, pancreatitis, scleroderma and polymyositis, coeliac disease, endocarditis and vitiligo. Disease progression was frequently observed; Patient 4, for example, developed renal lupus at age 15 years thus fulfilling the diagnostic criteria for SLE, and Patient 1 developed eight autoimmune diagnoses over a 27 year period.<table-wrap id="Tab3"><label>Table 3</label><caption><p>Key autoimmune features of <italic>ACP5</italic> mutation positive patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Patient<sup>1</sup></th><th>Antinuclear antibodies (fluorescence, titre)</th><th>Anti-dsDNA antibodies (titre)</th><th>Serum IFNα >2 IU/ml</th><th>ISG Score positive (>2.466)</th><th>Raynaud’s phenomenon (RP) or vasculitis</th><th>AITP (Anti-platelet abs)</th><th>AIHA</th><th>Juvenile idiopathic arthritis</th><th>SLE</th><th>Renal disease</th><th>Hypo- thyroidism</th><th>Biopsy proven autoimmune hepatitis</th></tr></thead><tbody><tr><td>1</td><td>Yes (Nuclear dots & diffuse cytoplasmic, 1:1280)</td><td>No</td><td>Yes</td><td>Yes (40.034, 49.393)</td><td>Yes (vasculitis)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>2</td><td>Yes (Homogenous,1:640)</td><td>Yes (1:320)</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>3</td><td>Yes (Homogenous,1:5120)</td><td>Yes</td><td>Yes</td><td>Yes (13.931)</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>4</td><td>Yes (1:640)</td><td>Yes (100 Farr IU/ml)</td><td>Yes</td><td>Yes (14.826, 21.388)</td><td>Yes (vasculitis)</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>5</td><td>Yes (1:160)</td><td>No</td><td>Yes</td><td>Yes (3.756, 30.404)</td><td>Yes (RP)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>6</td><td>Yes (>1:320)</td><td>Yes (1:1280)</td><td>Yes</td><td>Yes (71.094)</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>7</td><td>Yes (Strongly positive on immunoblot)</td><td>Yes (strongly positive on immunoblot)</td><td>NA</td><td>NA</td><td>No</td><td>Yes (Abs)</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>8</td><td>Yes (1:1280)</td><td>Yes (>500 Farr IU/ml)</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>9</td><td>Yes (1:1600)</td><td>Yes (121, <italic>n</italic> < 100 ELISA)</td><td>Yes</td><td>Yes (34.120)</td><td>No</td><td>Yes (Abs)</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>10</td><td>Yes (Speckled, 1:640)</td><td>Yes (33, <italic>n</italic> < 20 ELISA)</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>11</td><td>Yes (Speckled, 1/200)</td><td>NA</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>12</td><td>Yes (1/200)</td><td>No</td><td>Yes</td><td>NA</td><td>No</td><td>Yes (Abs)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>13</td><td>Yes (1/400)</td><td>Yes</td><td>Yes</td><td>NA</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>14</td><td>Yes (1:640)</td><td>Yes</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>15</td><td>Yes (Speckled, 1:80)</td><td>No</td><td>NA</td><td>NA</td><td>No</td><td>No</td><td>No</td><td>Yes (RF pos.)</td><td>No</td><td>No</td><td>No</td><td>Yes</td></tr><tr><td>16</td><td>No</td><td>No</td><td>NA</td><td>Yes (24.839)</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>17</td><td>Yes (Homogenous, 1/100)
</td><td>Yes (1.78 index, <italic>n</italic> ≥ 1.1 positive)</td><td>NA</td><td>Yes (24.815)</td><td>Yes (RP)</td><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>18</td><td>NA</td><td>NA</td><td>NA</td><td>Yes (2.77)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>19</td><td>Yes (Homogenous, 1/2560)</td><td>Yes (10 k IU/L)</td><td>NA</td><td>NA</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes</td></tr><tr><td>20</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Yes</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>21</td><td>Yes (Homogenous, 1:640)</td><td>Yes (1:640)</td><td>NA</td><td>No (0.725, 0.6)</td><td>No</td><td>Yes (No abs)</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>22</td><td>NA</td><td>NA</td><td>NA</td><td>No (0.770)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>23</td><td>Yes (Homogenous, 1:640)</td><td>Yes (>90, <italic>n</italic> < 7 IU/ml)</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>LFTs abnormal, biopsy pending</td></tr><tr><td>24</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>LFTs abnormal, biopsy pending</td></tr><tr><td>25</td><td>Yes (Homogenous, >2560, <italic>n</italic> < 40)</td><td>Yes (15, <italic>n</italic> < 7 IU/ml)</td><td>NA</td><td>NA</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>Yes</td></tr><tr><td>26</td><td>Yes (Homogenous, 640, <italic>n</italic> < 40)</td><td>No</td><td>NA</td><td>NA</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>LFTs abnormal, biopsy pending</td></tr><tr><td>Total</td><td>21/22 (4 NA)</td><td>15/21 (5 NA)</td><td>10/10 (16 NA)</td><td>9/11 (15 NA)</td><td>4/25 (1NA)</td><td>12/26</td><td>7/26</td><td>2/25 (1 NA)</td><td>9/25 (1 NA)</td><td>10/25 (1 NA)</td><td>5/25 (1 NA)</td><td>3/25 (1 NA)</td></tr><tr><td>Further cases [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR17">17</xref>]</td><td>7/14 (1 NA)</td><td>NA</td><td>5/5<break></break>10 NA</td><td>1/1<break></break>14 NA</td><td>1/14<break></break>1 NA</td><td>6/14 (1 NA)</td><td>3/14 (1 NA)</td><td>2/14 (1 NA)</td><td>5/14 (1 NA)</td><td>4/14 (1 NA)</td><td>1/14 (1 NA)</td><td>0/14 (1 LFT abnormal) (1 NA)</td></tr></tbody></table><table-wrap-foot><p><italic>NA</italic> Not assessed/reported, <italic>AITP</italic> Autoimmune thrombocytopenia, <italic>ABS</italic> antibodies, <italic>AIHA</italic> Autoimmune haemolytic anaemia, <italic>SLE</italic> Systemic lupus erythematosus, <italic>RF pos</italic> Rheumatoid Factor Positive, <italic>LFT</italic> Liver Function Test</p><p><sup>1</sup>Patients 1 to 10 have previously been described [<xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR16">16</xref>] and additional data are added where available</p></table-wrap-foot></table-wrap></p><p>Serologically, 21 of 22 patients had at least one episode of positive antinuclear antibodies, and 15 of 21 positive anti-dsDNA antibodies. Positive antiplatelet, anti-phospholipid, antigliadin, antineutrophil, anti-thyroglobulin and anti ADAMTS XII antibodies were also detected. Two autoantibodies positive patients did not have clinical evidence of autoimmune disease.</p><p>We previously reported an association between biallelic <italic>ACP5</italic> mutations and elevated levels of serum IFNα and an upregulation of ISGs in whole blood [<xref ref-type="bibr" rid="CR7">7</xref>]. In this cohort, all ten patients in whom serum IFNα activity levels were measured demonstrated elevated levels, and on serial assessment, levels were persistently high. An absence of CSF IFNα activity was observed in Patient 1, despite neurological manifestations [<xref ref-type="bibr" rid="CR3">3</xref>]. ISGs were measured in 11 patients, and in nine the interferon score was significantly higher than age and sex matched controls and remained elevated on repeat measurement (Table <xref rid="Tab3" ref-type="table">3</xref> and Fig. <xref rid="Fig4" ref-type="fig">4</xref>). In Patient 5, the initial ISG assessment undertaken at age 14 years was marginally raised, however, a 10-fold increase was observed five years later, in association with neurological deterioration. Two patients, Patient 21 and Patient 22, did not demonstrate an interferon signature.<fig id="Fig4"><label>Fig. 4</label><caption><p>Expression of interferon-stimulated genes in SPENCD patients compared to controls. The median fold change for six ISGs (IFI27, RSAD2, IFI44L, ISG15, IFIT1, SIGLEC1) as normalised to 18S/HPRT1 is calculated to derive an interferon score. The mean interferon score of the controls plus two standard deviations above the mean (+ 2 SD) is considered as positive (red). Overall, the score in SPENCD patients was significantly higher than age and sex matched controls (** <italic>p</italic> < 0.0001)</p></caption><graphic xlink:href="10875_2016_252_Fig4_HTML" id="MO4"></graphic></fig></p><p>Patient 22 did not manifest any clinical autoimmune disease to age 35 years, when ISGs were within normal range (autoantibodies were not assessed). Features of SPENCD had been present since adolescence, with typical skeletal findings, spasticity, moderate intellectual disability and basal ganglia calcification [<xref ref-type="bibr" rid="CR4">4</xref>].</p><p>Patient 21 had a history of skeletal, neurological and immune disease. He presented at one month of age with spontaneous bleeding and splenomegaly secondary to AITP. In the first year of life he suffered recurrent respiratory infections, but these resolved. He developed nephrotic syndrome at two years of age and, following the identification of class V lupus nephritis at four years of age, was treated with cyclosporine A for three years with partial remission. A subsequent relapse was managed with oral prednisone and cyclosporine A, but was then discontinued by the family. At nine years of age he developed right sigmoidal sinus thrombosis and severe hypertension, renal failure with class V lupus nephritis, serositis, (pleuritic and pericardial effusions), and dilated cardiomyopathy (ejection faction 34 %), with no sign of systemic infection. He had positive antinuclear and anti-dsDNA antibodies (1:640), low C3, C4 and thrombocytopenia. Two doses of intravenous methylprednisolone (2 mg/kg/day) and eight sessions of plasmapheresis were administered, followed by oral prednisone (2 mg/kg/day) for four weeks, which was then tapered (0.5 mg/kg/day) and given with mycophenolate mophetil (600 mg/m<sup>2</sup>/bd) and a dose of rituximab (375 mg/m<sup>2</sup>). Two months later he was switched to maintenance immunotherapy of prednisone (0.5 mg/kg/day) and mycophenolate mophetil (600 mg/m<sup>2</sup>/bd). This was continued for 12 months, and twice during this period (separated by several months) the ISG profile was assessed and an interferon signature was not detected. Follow-up during this time revealed significantly improved autoimmune disease with non-nephrotic proteinuria, low positive ANA titres and anti-dsDNA antibodies (1:80), with normal C3, C4 and white cell counts.</p></sec><sec id="Sec13"><title>Manifestation of Immunodeficiency</title><p>Recurrent bacterial and viral infections were reported in five patients, raising the suggestion that immunodeficiency is a part of <italic>ACP5</italic>-associated disease (Table <xref rid="Tab4" ref-type="table">4</xref>). Infections included recurrent pneumonia, disseminated herpes zoster, and skin and dental abscesses. Interpretation of immunological testing undertaken in the cohort was difficult, in terms of differentiating disease-related immunodeficiency from immune defects resulting from immunosuppressive therapy. Low lymphocyte count and/or hypogammaglobulinemia was evidenced in three patients who did not receive immunuppressive drugs and in nine treated patients (Table <xref rid="Tab4" ref-type="table">4</xref>). Where lymphocyte subsets were available, the low counts consisted of low T, B and NK cell counts in two cases (one not treated and one treated), low T and B cell counts in one treated case, low B and NK cell counts in one treated case, low T and NK cell counts in one treated case and low T cell counts in five cases (two not treated and three treated). Of note, Patient 6 demonstrated a persistent hypogammaglobulinemia following rituximab treatment for AITP, whilst prior to treatment he had normal serum immunoglobulins.<table-wrap id="Tab4"><label>Table 4</label><caption><p>Features of immunodeficiency and total serum immunoglobulin and lymphocyte sub-sets in <italic>ACP5</italic> mutation positive patients</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Patients<sup>1</sup></th><th>History of recurrent infection</th><th>Medication at time of assay</th><th>IgG g/L</th><th>IgM g/L</th><th>IgA g/L</th><th>Lympho-cyte count</th><th>Neutrophil count</th><th><italic>CD3</italic> (T-cells)</th><th>CD4+/CD3+</th><th>CD8+/CD3+</th><th>CD19 (total B cells)</th><th>CD56 & CD16 (NK cells)</th><th>CD3%</th><th>CD4+/CD3+ %</th><th>CD8+/CD3+ %</th><th>CD19%</th><th>CD56 & CD16%</th></tr></thead><tbody><tr><td>1</td><td>No</td><td>Methotrexate</td><td>N</td><td>N</td><td>N</td><td><bold><underline>1000</underline></bold> /mm3 (2500–7200)</td><td><bold><underline>1000</underline></bold> /mm3 (1500–8000)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>2</td><td>No</td><td>Mycophenol-ate mofetil & prednisolone</td><td><bold><underline>5.1</underline></bold> (7.2–14.8)</td><td><bold><underline>0.31</underline></bold> (0.7–2.8)</td><td>0.55 (0.5–2.6)</td><td><bold><underline>3</underline></bold> g/L (4.5–13.5)</td><td><bold><underline>1.6</underline></bold> g/L (2–7)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>3</td><td>No</td><td>Prednisolone</td><td>NA</td><td>NA</td><td>NA</td><td>5.5 g/L (4.5–13.5)</td><td>2.5 g/L (2–7)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>4</td><td>No</td><td>Azathioprine when Ig’s assayed & none for lymphocytes</td><td>19 (5.7–12.6)</td><td>1.1 (0.3–1.6)</td><td>4.56 (0.8–2.3)</td><td>4.04 X10(9)/L (1.5–7)</td><td>NA</td><td>3.10 X10(9)/L (0.66–2.41)</td><td>1.13 X10(9)/L (0.43–1.62)</td><td>1.605 X10(9)/L (0.15–1.01)</td><td>0.788 X10(9)/L (0.08–0.58)</td><td>0.376 X10(9)/L (0.05–0.52)</td><td>76.7 (52–78)</td><td>28 (25–48)</td><td>39.7 (9–35)</td><td>19.5 (8–24)</td><td>7.3 (4–17)</td></tr><tr><td>5</td><td>No</td><td>None</td><td>13.3 (5.7–12.6)</td><td>1.32 (0.3–1.6)</td><td>4.97 (0.8–2.3)</td><td>NA</td><td>NA</td><td>0.867 X10(9)/L (0.66–2.41)</td><td>0.518 X10(9)/L (0.43–1.62)</td><td>0.299 X10(9)/L (0.15–1.01)</td><td>0.245 X10(9)/L (0.08–0.58)</td><td>0.076 X10(9)/L (0.05–0.52)</td><td>72.2 (52–78)</td><td>43.2 (25–48)</td><td>24.9 (9–35)</td><td>20.4 (8–24)</td><td>6.3 (4–17)</td></tr><tr><td>6</td><td>No</td><td>Post-rituximab</td><td><bold><underline>4.23</underline></bold> (6.5–12.2)</td><td><bold><underline>0.48</underline></bold> (0.5–2.03)</td><td>2.38 (0.5–2.03)</td><td>3900/μl</td><td>NA</td><td>2769/μl (1200–1600)</td><td>1053/μl (650–1500)</td><td>1326/μl (370–1100)</td><td>780/μl (270–860)</td><td></td><td>71 (60–76)</td><td><underline>27</underline> (31–47)</td><td>34 (18–35)</td><td>20 (13–27)</td><td></td></tr><tr><td>7</td><td>Yes (3 episodes of pneum-onia; dissemin-ated herpes zoster; TB reaction)</td><td>None</td><td>20.1 (3.4–12.3)</td><td>N</td><td>N</td><td>NA</td><td>NA</td><td>NA</td><td><bold><underline>0.277</underline></bold> X10(9)/L (0.9–2.86)</td><td><bold><underline>0.384</underline></bold> X10(9)/L (0.63–1.91)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>8</td><td>Yes (2 episodes of pneum-onia)</td><td>None</td><td>20.9 (6.7–17.3)</td><td><bold><underline>0.05</underline></bold> (0.5–3.1)</td><td>1.5 (0.4–3.7)</td><td>2.7 X10(9)/L (1.5–7)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td><bold><underline>32</underline></bold> (60–85)</td><td><bold><underline>17</underline></bold> (30–60)</td><td><bold><underline>13</underline></bold> (15–35)</td><td>NA</td><td>NA</td></tr><tr><td>9</td><td>No</td><td>Prednisolone, hydroxochlo-roquine & mycophenol-ate mofetil,</td><td>19 (6.4–13.5)</td><td>6.63 (0.7–3.1)</td><td><underline>0.23</underline> (0.6–3.5)</td><td><bold><underline>736</underline></bold>/mm3 (2500–7200)</td><td><bold><underline>1056</underline></bold>/mm3 (1500–8000)</td><td><bold><underline>613</underline></bold>/mm3 (800–3500)</td><td>421/mm3 (400–2100)</td><td><bold><underline>181</underline></bold>/mm3 (200–1200)</td><td><bold><underline>26</underline></bold>/mm3 (200–600)</td><td><bold><underline>66</underline></bold>/mm3 (70–1200)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>10</td><td>No</td><td>Prednisolone,</td><td>17.7 (6.5–12.2)</td><td>1.3 (0.5–2.0)</td><td><bold><underline>0.23</underline></bold> (0.5–2.03)</td><td>NA</td><td>NA</td><td>NA</td><td>1080/μl (650–1550)</td><td>1800/μl (370–1100)</td><td>NA</td><td>N</td><td>NA</td><td><bold><underline>27</underline></bold> (31–47)</td><td>45 (18–35)</td><td>NA</td><td>NA</td></tr><tr><td>11</td><td>Yes (severe chicken-pox; skin & dental abscesses)</td><td>None</td><td>13 (6.5–12.2)</td><td><underline>0.36</underline> (0.5–2.0)</td><td>1.56 (0.5–2.03)</td><td>1000/μl (2500–7200)</td><td>NA</td><td><underline>670/</underline>μl (1200–2600)</td><td><underline>200</underline>/μl (650–1550)</td><td><underline>280</underline>/μl (370–1100)</td><td><bold><underline>210</underline></bold>/μl (270–860)</td><td><underline>60</underline>/μl (100–480)</td><td>67 (60–76)</td><td><bold><underline>20</underline></bold> (31–47)</td><td>28 (18–35)</td><td>21 (13–27)</td><td>6 (4–17)</td></tr><tr><td>12</td><td>No</td><td>Steroids</td><td>23 (6.5–12.2)</td><td>1.9 (0.5–2.0)</td><td>1.1 (0.5–2.03)</td><td><bold><underline>1000/</underline></bold>μl (2500–7200)</td><td>NA</td><td>NA</td><td><bold><underline>300</underline></bold>/μl (700–2200)</td><td><bold><underline>420</underline></bold>/μl (490–1300)</td><td><bold><underline>80</underline></bold>/μl (390–1400)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>13</td><td>No</td><td>None</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>14</td><td>No</td><td>Prednisolone</td><td>13 (6.5–14.5)</td><td>1.56 (0.5–2)</td><td>2.09 (0.45–2.5)</td><td>3.9 X10(9)/L (0.8–5)</td><td>3.49 X10(9)/L (1.6–7)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>77</td><td>35</td><td>38</td><td>11</td><td></td></tr><tr><td>15</td><td>No</td><td>Prednisolone & azathioprine</td><td>15.8 (6–16)</td><td>0.95 (0.3–1.9)</td><td>2.84 (0.4–3.75)</td><td>NA</td><td>NA</td><td>1084/μl (800–3500)</td><td>727/μl (400–2100)</td><td>333/μl (200–1200)</td><td><bold><underline>131</underline></bold>/μl (200–600)</td><td><bold><underline>13</underline></bold>/μl (70–1200)</td><td>89 (52–78)</td><td>60 (25–48)</td><td>27 (9–35)</td><td>11 (8–24)</td><td><bold><underline>1</underline></bold> (6–27)</td></tr><tr><td>16</td><td>No</td><td>Prednisolone</td><td>38.8 (5.5–16.3)</td><td>0.6 (0.6–2.9)</td><td>1.75 (0.8–4.5)</td><td>2700/mm<sup>3</sup> (2500–7200)</td><td>2200/mm<sup>3</sup> (1500–8000)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>80.6 (57–86)</td><td>29.3 (29–57)</td><td>45.8 (13–47)</td><td>11.75 (3.5–15.5)</td><td>5.75 (4.5–30)</td></tr><tr><td>17</td><td>No</td><td>Prednisolone</td><td>NA</td><td>1.1 (0.6–2.9)</td><td>3.84 (0.8–4.5)</td><td><bold><underline>1600</underline></bold>/mm<sup>3</sup> (2500–7200)</td><td>3000/mm<sup>3</sup> (1500–8000)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>63 (57–86)</td><td><bold><underline>25.6</underline></bold> (29–57)</td><td>33.4 (13–47)</td><td>27.5 (3.5–15.5)</td><td><bold><underline>4</underline></bold> (4.5–30)</td></tr><tr><td>19</td><td>Yes</td><td>Azathioprine</td><td>17 (6.2–14.4)</td><td>0.77 (0.5–2.6)</td><td>1.67 (0.7–2.9)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>20</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>21</td><td>Yes (frequent RTI <1 yr.)</td><td>Prednisolone</td><td>NA</td><td>NA</td><td>NA</td><td><bold><underline>1550</underline></bold>/mm<sup>3</sup> (2500–7200)</td><td>7660//mm<sup>3</sup> (1500–8000)</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td><bold><underline>16.8</underline></bold> (57–86)</td><td><bold><underline>4</underline></bold> (29–57)</td><td><bold><underline>12</underline></bold> (13–47)</td><td>74.3 (3.5–15.5)</td><td>8.5 (4.5–30)</td></tr><tr><td>22</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>23</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>24</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>25</td><td>No</td><td>None</td><td>12.1 (5–13)</td><td>0.8 (0.5–1.6)</td><td>1.2 (0.4–1.7)</td><td>NA</td><td>NA</td><td>3.13 X10(9)/L (0.66–2.41)</td><td>1.23 X10(9)/L (0.43–1.62)</td><td>1.82 X10(9)/L (0.15–1.01)</td><td>0.59 X10(9)/L (0.08–0.58)</td><td>0.2 X10(9)/L (0.05–0.52)</td><td>79</td><td>31</td><td>46</td><td>15</td><td>5</td></tr><tr><td>26</td><td>No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>Total</td><td>5/25 (1 NA)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Further cases [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR17">17</xref>]</td><td>1/15</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table><table-wrap-foot><p>Bold and underlined values are below the normal reference range</p><p><sup>1</sup>Immune features in Patients 7 and 8 have previously been described [<xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR16">16</xref>]</p><p><italic>NA</italic> Not assessed/reported, <italic>N</italic> Normal, <italic>RTI</italic> Respiratory tract infections</p></table-wrap-foot></table-wrap></p></sec></sec><sec id="Sec14"><title>Causes of Death and Severe Disability</title><p>Two patients died in our cohort, Patient 1 at age 30 years, following a gastrointestinal bleed and heart failure with severe arterial hypertension and Patient 20 before one year of age secondary to AITP. Disease morbidity was marked, with nine patients manifesting three or more different autoimmune diagnoses, which frequently required immunosuppressive therapy (Table <xref rid="Tab4" ref-type="table">4</xref>), or in the case of AITP splenectomy. Mental retardation was typically of mild to moderate severity, but in Patient 11 this was categorized as severe. Whilst stature was variable, when 6.5 SD below the mean at 18 years this likely impeded activities of daily living.</p></sec></sec><sec id="Sec15" sec-type="discussion"><title>Discussion</title><p>This review describes the largest cohort of patients with confirmed biallelic <italic>ACP5</italic> mutations yet reported. Our findings highlight the marked clinical variability of the associated phenotype, ranging from infantile death secondary to AITP, to isolated skeletal dysplasia in an adult woman. Lausch et al. [<xref ref-type="bibr" rid="CR8">8</xref>]. also noted variability, reporting both a 64 year old affected male and childhood mortality. The age at which features first became manifest ranged from birth to 15 years, similar to the ten month to 16-year range reported by previously [<xref ref-type="bibr" rid="CR8">8</xref>]. Clinical diversity was observed both within and between families, and means that patients may present to different medical specialists, increasing possible diagnostic delay. Disease progression was observed frequently, indicating the need for continued follow up. As all <italic>ACP5</italic> mutations assessed to date appear functionally null, with an absence of TRAP expression in the blood [<xref ref-type="bibr" rid="CR7">7</xref>], additional unidentified modifying genetic and/or environmental factors may play a role in the inter- and intra-familial variation of disease manifestations. At present, no specific genotype-phenotype correlation is evident.</p><p>Skeletal radiological findings were a consistent feature, thus serving as a key diagnostic handle. As was observed by Lausch et al. [<xref ref-type="bibr" rid="CR8">8</xref>] who identified skeletal changes in all 14 patients they reported (Table <xref rid="Tab2" ref-type="table">2</xref>). However, variability was observed, with subtle manifestations in some cases, and two patients demonstrating only metaphyseal or vertebral changes. A mild skeletal phenotype, with only ‘discrete metaphyseal changes’ at the wrist was also reported by Girschick et al. [<xref ref-type="bibr" rid="CR17">17</xref>]. In keeping with this radiological diversity, a height within the normal range, particularly at a young age, does not exclude the diagnosis. We note an increased bone mineral density in three of five patients measured, which is perhaps analogous to the ostepetrosis observed in the <italic>ACP5</italic> knock-out mouse [<xref ref-type="bibr" rid="CR18">18</xref>].</p><p>Over half of the cohort demonstrated features of neurological disease, the commonest being spasticity (44 %), with onset as early as age two years. It is noteworthy that SPENCD/SPENCDI demonstrates phenotypic overlap with the neuro-inflammatory interferonopathy AGS and patients with <italic>ISG15</italic> mutations, the hallmarks of which are intracranial calcification and neurological dysfunction [<xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR12">12</xref>]. Furthermore, an elevated IFNα in both the serum and CSF has been reported in a nine year old with confirmed biallelic <italic>ACP5</italic> mutations [<xref ref-type="bibr" rid="CR17">17</xref>]. Thus, whilst the etiology of the neurological disease is unclear, we consider it likely to be secondary to abnormal immune activation.</p><p>The prevalence of autoimmune disease in the cohort was high, with 92 % of patients demonstrating clinical or serological features of autoimmunity. The onset of autoimmune pathology was early, with cytopenia before a year of age in three patients, and with many patients developed three or more autoimmune diagnoses during childhood, demonstrating the need for careful monitoring. Cytopenia was the commonest manifestation (AITP in 46 %) and paediatric SLE was also frequent (36 %). We propose that in cases of severe autoimmune disease, particularly in a consanguineous family and/or in association with a short stature, SPENCD/SPENCDI should be considered as a potential diagnosis.</p><p>Whilst autoimmune disease was not observed in all cases of <italic>ACP5</italic> related disease, a diverse range of organ-specific and systemic autoimmune conditions were detected. Part of the explanation for these disorders likely relates to elevated type I interferon levels, which are associated autoimmune disease [<xref ref-type="bibr" rid="CR19">19</xref>]. Elevated levels of serum IFNα and/or ISGs were recorded in the majority of patients tested (Table <xref rid="Tab3" ref-type="table">3</xref> and Fig. <xref rid="Fig4" ref-type="fig">4</xref>). We hypothesize that type I interferon is elevated in TRAP deficiency because TRAP may be a negative regulator of IFNα, perhaps via its action upon osteopontin. Osteopontin, a highly phosphorylated glycoprotein, forms a signalsome with TLR9 and MyD88 in mice and appears integral to IFNα production in murine plasmacytoid dendritic cells [<xref ref-type="bibr" rid="CR20">20</xref>].</p><p>The absence of ISGs in Patient 21 during maintenance immunosuppressive therapy suggests that the treatment was effective at both a symptomatic and a biochemical level. The identification of an effective therapy, even if multimodal, is important, as SPENCD related autoimmune disease may be fatal. The normal ISG value during treatment also suggests that the assay might be used to evaluate targeted therapies.</p><p>The observation of an absence of an interferon signature in a patient without clinical autoimmune disease is of interest, and an assessment of similar cases (e.g. those in Table <xref rid="Tab5" ref-type="table">5</xref>) is needed to determine whether this is a recurrent phenomenon. As we have observed elevation of ISG expression in association with disease progression (Patient 5), we recommend a low threshold for the investigation of immune symptoms in all SPENCD patients. In addition, whilst an ISG signature is not universal in SPENCD it remains a useful screening tool when considering the diagnosis, and may serve as a biomarker of disease progression and future treatments.<table-wrap id="Tab5"><label>Table 5</label><caption><p>Literature summary of cases of SPENCD in whom genetic testing has not been undertaken to our knowledge</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Patient (Pt.)</th><th>Gender</th><th>Consanguinity (relationship to other patients)</th><th>SPENCD skeletal dysplasia</th><th>Short stature (standard Deviation (SD) below the mean)</th><th>Neurological disease</th><th>Intracranial calcification</th><th>Immune phenotype</th></tr></thead><tbody><tr><td>Schorr et al. [<xref ref-type="bibr" rid="CR1">1</xref>] Pt. 1</td><td>Male</td><td>Yes (sibling of Pt. 2 [<xref ref-type="bibr" rid="CR1">1</xref>])</td><td>Yes</td><td>Yes</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Schorr et al. [<xref ref-type="bibr" rid="CR1">1</xref>] Pt. 2</td><td>Male</td><td>Yes (sibling of Pt. 1 [<xref ref-type="bibr" rid="CR1">1</xref>])</td><td>Yes</td><td>Yes</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Gustavson et al. [<xref ref-type="bibr" rid="CR21">21</xref>] Pt. 1</td><td>Female</td><td>No (sibling of Pt. 2 [<xref ref-type="bibr" rid="CR21">21</xref>])</td><td>Yes</td><td>Yes (−7.5SD at 16 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Gustavson et al. [<xref ref-type="bibr" rid="CR21">21</xref>] Pt. 2</td><td>Male</td><td>No (sibling of Pt. 1 [<xref ref-type="bibr" rid="CR21">21</xref>])</td><td>Yes</td><td>Yes (−6.5SD at 13 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Spranger et al. [<xref ref-type="bibr" rid="CR22">22</xref>] Pt. 1</td><td>Male</td><td>No</td><td>Possibly<sup>1</sup></td><td>Yes</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Spranger et al. [<xref ref-type="bibr" rid="CR22">22</xref>] Pt. 2</td><td>Male</td><td>NR</td><td>Possibly<sup>2</sup></td><td>Yes</td><td>Dev. delay</td><td>NR</td><td>NR</td></tr><tr><td>Spranger et al. [<xref ref-type="bibr" rid="CR22">22</xref>] Pt. 3</td><td>Male</td><td>No</td><td>Possibly<sup>3</sup></td><td>Yes</td><td>Dev. delay</td><td>NR</td><td>NR</td></tr><tr><td>Sauvegrain et al. [<xref ref-type="bibr" rid="CR23">23</xref>] Pt. 1</td><td>Female</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Sauvegrain et al. [<xref ref-type="bibr" rid="CR23">23</xref>] Pt. 5</td><td>Male</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Dev. delay</td><td>NR</td><td>NR</td></tr><tr><td>Chagnon et al. [<xref ref-type="bibr" rid="CR24">24</xref>]</td><td>Male</td><td>No</td><td>Yes</td><td>Yes</td><td>Spasticity</td><td>NR</td><td>NR</td></tr><tr><td>Azouz [<xref ref-type="bibr" rid="CR25">25</xref>]</td><td>Male</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Ziv et al. [<xref ref-type="bibr" rid="CR31">31</xref>] Pt. 1</td><td>Male</td><td>No (sibling of Pt. 2 [<xref ref-type="bibr" rid="CR31">31</xref>])</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Ziv et al. [<xref ref-type="bibr" rid="CR31">31</xref>] Pt. 2</td><td>Female</td><td>No (sibling of Pt. 1 [<xref ref-type="bibr" rid="CR31">31</xref>])</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Menger et al. [<xref ref-type="bibr" rid="CR30">30</xref>] Pt. 1</td><td>Male</td><td>Yes (sibling of Pt. 2 [<xref ref-type="bibr" rid="CR30">30</xref>])</td><td>Yes</td><td>Yes (−6SD at 12 years)</td><td>Dev. delay</td><td>NR</td><td>NR</td></tr><tr><td>Menger et al. [<xref ref-type="bibr" rid="CR30">30</xref>] Pt. 2</td><td>Male</td><td>Yes (sibling of Pt. 1 [<xref ref-type="bibr" rid="CR30">30</xref>])</td><td>Yes</td><td>Yes (−6SD at 6 years)</td><td>Dev. delay</td><td>NR</td><td>NR</td></tr><tr><td>Menger et al. [<xref ref-type="bibr" rid="CR30">30</xref>] Pt. 3</td><td>Male</td><td>Yes (distant relative of Pt. 1 and 2 [<xref ref-type="bibr" rid="CR30">30</xref>])</td><td>Yes</td><td>Yes (−1.5SD at 12 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Menger et al. [<xref ref-type="bibr" rid="CR30">30</xref>] Pt. 4</td><td>Male</td><td>Yes</td><td>Yes</td><td>Yes (−2SD at 6 years)</td><td>Dev. delay & spasticity</td><td>NR</td><td>NR</td></tr><tr><td>Frydman et al. [<xref ref-type="bibr" rid="CR4">4</xref>] Pt. 1</td><td>Male</td><td>Yes (sibling of Pt. 18 in present cohort)</td><td>Yes</td><td>Yes (−3.5SD at 8 years)</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Frydman et al. [<xref ref-type="bibr" rid="CR4">4</xref>] Pt. 3</td><td>Male</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Frydman et al. [<xref ref-type="bibr" rid="CR4">4</xref>] Pt. 5</td><td>Male</td><td>Yes (sibling of Pt. 22 in present cohort)</td><td>Yes</td><td>Yes (−4.4SD at 8 years)</td><td>Dev. delay & spasticity</td><td>Yes</td><td>No</td></tr><tr><td>Frydman et al. [<xref ref-type="bibr" rid="CR4">4</xref>] Pt. 6</td><td>Male</td><td>No</td><td>Yes</td><td>Yes (−5.4SD at 8 years)</td><td>No</td><td>Yes</td><td>NR</td></tr><tr><td>Robinson et al. [<xref ref-type="bibr" rid="CR28">28</xref>] Pt. 1</td><td>Male</td><td>No (grandson of Pt. 2 [<xref ref-type="bibr" rid="CR28">28</xref>])</td><td>Yes</td><td>Yes (−3SD at 19 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Robinson et al. [<xref ref-type="bibr" rid="CR28">28</xref>] Pt. 2</td><td>Male</td><td>NR (paternal grandfather of Pt. 1 [<xref ref-type="bibr" rid="CR28">28</xref>])</td><td>Yes</td><td>Yes (−5.5SD at 86 years)</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Passwell et al. [<xref ref-type="bibr" rid="CR32">32</xref>] Pt. 1</td><td>Male</td><td>Yes (sibling with skeletal phenotype, data limited)</td><td>Yes</td><td>Yes</td><td>NR</td><td>Yes</td><td>SLE</td></tr><tr><td>Passwell et al. [<xref ref-type="bibr" rid="CR32">32</xref>] Pt. 2</td><td>Female</td><td>Yes (sibling with skeletal phenotype, data limited)</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>SLE</td></tr><tr><td>Passwell et al. [<xref ref-type="bibr" rid="CR30">30</xref>] Pt. 3</td><td>Female</td><td>Yes</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>SLE</td></tr><tr><td>Uhlmann et al. [<xref ref-type="bibr" rid="CR26">26</xref>] Pt. 1</td><td>Male</td><td>No</td><td>Yes</td><td>Yes (−4SD at 5 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Uhlmann et al. [<xref ref-type="bibr" rid="CR26">26</xref>] Pt. 2</td><td>Male</td><td>No</td><td>Yes</td><td>Yes</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Tuysuz et al. [<xref ref-type="bibr" rid="CR5">5</xref>] Pt. 1</td><td>Male</td><td>No (sibling of Pt. 2 [<xref ref-type="bibr" rid="CR5">5</xref>])</td><td>Yes</td><td>Yes (−4.5SD at 9 years)</td><td>No</td><td>No</td><td>NR</td></tr><tr><td>Tuysuz et al. [<xref ref-type="bibr" rid="CR5">5</xref>] Pt. 2</td><td>Female</td><td>No (sibling of Pt. 1 [<xref ref-type="bibr" rid="CR5">5</xref>])</td><td>Yes</td><td>Yes (−1.5SD at 21 years)<sup>4</sup></td><td>No</td><td>No</td><td>NR</td></tr><tr><td>Tuysuz et al. [<xref ref-type="bibr" rid="CR5">5</xref>] Pt. 3</td><td>Male</td><td>NR</td><td>Yes</td><td>Yes (−4.5SD at 7 years)</td><td>Dev. delay</td><td>Yes</td><td>NR</td></tr><tr><td>Bhargava et al. [<xref ref-type="bibr" rid="CR29">29</xref>] Pt. 1</td><td>Male</td><td>No (son of Pt. 2 [<xref ref-type="bibr" rid="CR29">29</xref>])</td><td>Yes</td><td>Yes (−2.5SD at 13 years)</td><td>No</td><td>NR</td><td>NR</td></tr><tr><td>Bhargava et al. [<xref ref-type="bibr" rid="CR29">29</xref>] Pt. 2</td><td>Female</td><td>No (mother of Pt. 1 [<xref ref-type="bibr" rid="CR29">29</xref>])</td><td>Yes</td><td>Yes (−2.5SD at 42 years)</td><td>No</td><td>NR</td><td>NR</td></tr></tbody></table><table-wrap-foot><p><italic>Pt</italic> Patient number from original publication, <italic>Dev Delay</italic> developmental delay, <italic>NR</italic> not recorded</p><p><sup>1</sup>Enchondromatosis with irregular vertebral lesionss</p><p><sup>2</sup>Enchondromatosis with irregular vertebral lesions</p><p><sup>3</sup>Enchondromatosis with mild platyspondyly</p><p><sup>4</sup>Two years of growth hormone therapy at 12 years</p></table-wrap-foot></table-wrap></p><p>We also note a history of recurrent bacterial and/or viral infections in five patients, in some with associated reduced lymphocyte counts (Table <xref rid="Tab4" ref-type="table">4</xref>). Additional cases of SPENCD with immunodeficiency may include some of the patients described by Roifman and Melamed [<xref ref-type="bibr" rid="CR6">6</xref>], who manifested immunodeficiency, autoimmunity and spondylometaphyseal dysplasia. One patient in the Roifman and Melamed [<xref ref-type="bibr" rid="CR6">6</xref>] series had a skeletal diagnosis of SPENCD on X-ray [<xref ref-type="bibr" rid="CR2">2</xref>] and was found to have a homozygous <italic>ACP5</italic> mutation (Patient 8 described here). Patient 8 had a younger brother with metaphyseal sclerosis, a history of recurrent infections and AITP, he died of encephalitis at age three years [<xref ref-type="bibr" rid="CR6">6</xref>]; molecular testing in this case and the other reported cases [<xref ref-type="bibr" rid="CR6">6</xref>] has not been reported. The case reported by Girschick et al. [<xref ref-type="bibr" rid="CR17">17</xref>] supports the association of concurrent autoimmunity and immunodeficiency with both autoantibodies and low CD4+, B and NK cell counts noted. The finding of recurrent infection in SPENCD is of interest given the susceptibility to <italic>Staphylococcus aureus</italic> infection noted in the <italic>ACP5</italic> knock-out mouse [<xref ref-type="bibr" rid="CR27">27</xref>]. Whilst additional data are needed, we would recommend in the interim that patients with biallelic <italic>ACP5</italic> mutations should be monitored for an infectious susceptibility and should undergo lymphocyte phenotyping and serum immunoglobulin values prior to immunosuppressive therapy.</p><p>The identification of biallelic <italic>ACP5</italic> mutations in two patients without immune dysfunction is interesting; specifically, a p.Gly109Arg homozygous mutation in Patient 18 and 22. These unrelated patients were diagnosed in childhood (Patient 2 and 4 [<xref ref-type="bibr" rid="CR4">4</xref>]), along with their similarly affected siblings (Patient 1 and 5 [<xref ref-type="bibr" rid="CR4">4</xref>], Table <xref rid="Tab5" ref-type="table">5</xref>). All four individuals were reviewed in their 30’s, and an absence of clinical autoimmune disease was observed. Mutation testing has not been undertaken in either sibling [<xref ref-type="bibr" rid="CR4">4</xref>]. According to the OMIM classification, these patients satisfy SPENCD, rather than SPENCDI criteria. However, our data suggest that this separation is inappropriate, since we observed this same mutation, in the compound heterozygote state, in two individuals, both of whom had skeletal and autoimmune manifestations and one neurological sequelae (Patient 22 and 23), and this mutation was reported previously in four patients (two in the homozygous state) who demonstrated variable skeletal, neurological and autoimmune features [<xref ref-type="bibr" rid="CR8">8</xref>]. Furthermore, Lausch et al., [<xref ref-type="bibr" rid="CR8">8</xref>] described a 10 year old patient with a p.Gly215Arg homozygous <italic>ACP5</italic> mutation in whom the only extra-skeletal feature was of intracranial calcification, i.e. a patient with ‘SPENCD’, whilst, we and Lausch et al., [<xref ref-type="bibr" rid="CR8">8</xref>] observed the same mutation in three unrelated patients, from two families, all of whom had autoimmune disease.</p><p>The suggestion that SPENCD and SPENCDI appear to be a continuum has implications for our understanding of the disease spectrum and thus patient management. A review of the literature since 1976 identified 33 cases (beyond those with <italic>ACP5</italic> mutations [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR8">8</xref>] or those reported by Roifman and Melamed [<xref ref-type="bibr" rid="CR6">6</xref>]) with skeletal features consistent with a diagnosis of SPENCD. Nine of the 33 cases also manifested a neurological phenotype, and three were diagnosed with SLE (see Table <xref rid="Tab5" ref-type="table">5</xref>). Of the 33 cases, from 25 families, there were seven sibling-pairs and ten consanguineous parental relationships, in keeping with autosomal recessive inheritance in at 29 cases. Biallelic <italic>ACP5</italic> mutations may be present in these 29 cases, although genetic testing is required and genetic heterogeneity cannot be excluded. Four further cases demonstrate possible autosomal dominant transmission [<xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR29">29</xref>] and different genes may explain the aetiology in these cases. However, the possibility of a causative heterozygous <italic>ACP5</italic> mutation, due to haploinsufficiency, also requires consideration. Most parents heterozygous for an <italic>ACP5</italic> mutation in our cohort appear healthy; however, two parents had short stature, two had a history of neuropsychiatric illness, and one psoriasis. Before conclusions can be made, genetic testing is needed in these cases, and further assessment is required of heterozygote <italic>ACP5</italic> carriers.</p><p>Twelve of the 25 families reported in Table <xref rid="Tab5" ref-type="table">5</xref> are Jewish families of Iraqi origin [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR30">30</xref>–<xref ref-type="bibr" rid="CR32">32</xref>]. Patient 18 and Patient 22 are both from Israel and both harbor the same homozygous point mutation, and this same variant was previously reported in a case of Jewish ancestry [<xref ref-type="bibr" rid="CR8">8</xref>]. This suggests both an increased prevalence of SPENCD in Israel, as noted previously [<xref ref-type="bibr" rid="CR28">28</xref>], and raises the possibility of a common founder mutation.</p></sec><sec id="Sec16" sec-type="conclusion"><title>Conclusions</title><p>Biallelic <italic>ACP5</italic> mutations are primarily associated with skeletal, neurological and immune features, which can be highly variable in their manifestation and severity. Our data show that this diversity may include an absence of autoimmune disease, and indicate that SPENCD and SPENCDI are a continuum of the same condition. The majority of patients demonstrate elevated expression of ISGs, which therefore represents a useful diagnostic tool. SPENCD is a rare condition, but may be associated with significant childhood morbidity and mortality. Thus, there is a need for improved understanding of the underlying disease mechanism to facilitate the development of targeted therapies. In the interim, multimodal immunosuppression may be of benefit in certain cases.</p><sec id="FPar1"><title>Authorship Contributions</title><p>TAB and GIR performed genetic and ISG analysis. TAB and YJC designed the project, TAB wrote the manuscript and YJC and BBM reviewed the manuscript. BBM provided clinical samples and data. PL performed the type I IFN cytopathic assays. JHL interpreted patient cranial imaging. 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