Young woman with mild bone marrow dysplasia, GATA2 and ASXL1 mutation treated with allogeneic hematopoietic stem cell transplantation
Identifieur interne : 002340 ( Pmc/Corpus ); précédent : 002339; suivant : 002341Young woman with mild bone marrow dysplasia, GATA2 and ASXL1 mutation treated with allogeneic hematopoietic stem cell transplantation
Auteurs : Anna Lübking ; Sebastian Vosberg ; Nikola P. Konstandin ; Annika Dufour ; Alexander Graf ; Stefan Krebs ; Helmut Blum ; Axel Weber ; Stig Lenhoff ; Mats Ehinger ; Karsten Spiekermann ; Philipp A. Greif ; Jörg CammengaSource :
- Leukemia Research Reports [ 2213-0489 ] ; 2015.
Abstract
Heterozygous mutations in
We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to
Url:
DOI: 10.1016/j.lrr.2015.10.001
PubMed: 26716079
PubMed Central: 4672090
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Young woman with mild bone marrow dysplasia, <italic>GATA2</italic> and <italic>ASXL1</italic> mutation treated with allogeneic hematopoietic stem cell transplantation</title><author><name sortKey="Lubking, Anna" sort="Lubking, Anna" uniqKey="Lubking A" first="Anna" last="Lübking">Anna Lübking</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Vosberg, Sebastian" sort="Vosberg, Sebastian" uniqKey="Vosberg S" first="Sebastian" last="Vosberg">Sebastian Vosberg</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Konstandin, Nikola P" sort="Konstandin, Nikola P" uniqKey="Konstandin N" first="Nikola P." last="Konstandin">Nikola P. Konstandin</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Dufour, Annika" sort="Dufour, Annika" uniqKey="Dufour A" first="Annika" last="Dufour">Annika Dufour</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Graf, Alexander" sort="Graf, Alexander" uniqKey="Graf A" first="Alexander" last="Graf">Alexander Graf</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Krebs, Stefan" sort="Krebs, Stefan" uniqKey="Krebs S" first="Stefan" last="Krebs">Stefan Krebs</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Blum, Helmut" sort="Blum, Helmut" uniqKey="Blum H" first="Helmut" last="Blum">Helmut Blum</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Weber, Axel" sort="Weber, Axel" uniqKey="Weber A" first="Axel" last="Weber">Axel Weber</name><affiliation><nlm:aff id="aff0030">Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany</nlm:aff></affiliation></author><author><name sortKey="Lenhoff, Stig" sort="Lenhoff, Stig" uniqKey="Lenhoff S" first="Stig" last="Lenhoff">Stig Lenhoff</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ehinger, Mats" sort="Ehinger, Mats" uniqKey="Ehinger M" first="Mats" last="Ehinger">Mats Ehinger</name><affiliation><nlm:aff id="aff0040">Department of Pathology, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Spiekermann, Karsten" sort="Spiekermann, Karsten" uniqKey="Spiekermann K" first="Karsten" last="Spiekermann">Karsten Spiekermann</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Greif, Philipp A" sort="Greif, Philipp A" uniqKey="Greif P" first="Philipp A." last="Greif">Philipp A. Greif</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Cammenga, Jorg" sort="Cammenga, Jorg" uniqKey="Cammenga J" first="Jörg" last="Cammenga">Jörg Cammenga</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff0035">Department of Molecular Medicine and Gene Therapy, Sölvegatan 17, BMC A12, Lund University, 22184 Lund, Sweden</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26716079</idno><idno type="pmc">4672090</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672090</idno><idno type="RBID">PMC:4672090</idno><idno type="doi">10.1016/j.lrr.2015.10.001</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">002340</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002340</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Young woman with mild bone marrow dysplasia, <italic>GATA2</italic> and <italic>ASXL1</italic> mutation treated with allogeneic hematopoietic stem cell transplantation</title><author><name sortKey="Lubking, Anna" sort="Lubking, Anna" uniqKey="Lubking A" first="Anna" last="Lübking">Anna Lübking</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Vosberg, Sebastian" sort="Vosberg, Sebastian" uniqKey="Vosberg S" first="Sebastian" last="Vosberg">Sebastian Vosberg</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Konstandin, Nikola P" sort="Konstandin, Nikola P" uniqKey="Konstandin N" first="Nikola P." last="Konstandin">Nikola P. Konstandin</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Dufour, Annika" sort="Dufour, Annika" uniqKey="Dufour A" first="Annika" last="Dufour">Annika Dufour</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Graf, Alexander" sort="Graf, Alexander" uniqKey="Graf A" first="Alexander" last="Graf">Alexander Graf</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Krebs, Stefan" sort="Krebs, Stefan" uniqKey="Krebs S" first="Stefan" last="Krebs">Stefan Krebs</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Blum, Helmut" sort="Blum, Helmut" uniqKey="Blum H" first="Helmut" last="Blum">Helmut Blum</name><affiliation><nlm:aff id="aff0015">Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Weber, Axel" sort="Weber, Axel" uniqKey="Weber A" first="Axel" last="Weber">Axel Weber</name><affiliation><nlm:aff id="aff0030">Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany</nlm:aff></affiliation></author><author><name sortKey="Lenhoff, Stig" sort="Lenhoff, Stig" uniqKey="Lenhoff S" first="Stig" last="Lenhoff">Stig Lenhoff</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ehinger, Mats" sort="Ehinger, Mats" uniqKey="Ehinger M" first="Mats" last="Ehinger">Mats Ehinger</name><affiliation><nlm:aff id="aff0040">Department of Pathology, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Spiekermann, Karsten" sort="Spiekermann, Karsten" uniqKey="Spiekermann K" first="Karsten" last="Spiekermann">Karsten Spiekermann</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Greif, Philipp A" sort="Greif, Philipp A" uniqKey="Greif P" first="Philipp A." last="Greif">Philipp A. Greif</name><affiliation><nlm:aff id="aff0010">Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0020">German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff0025">German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Cammenga, Jorg" sort="Cammenga, Jorg" uniqKey="Cammenga J" first="Jörg" last="Cammenga">Jörg Cammenga</name><affiliation><nlm:aff id="aff0005">Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</nlm:aff></affiliation><affiliation><nlm:aff id="aff0035">Department of Molecular Medicine and Gene Therapy, Sölvegatan 17, BMC A12, Lund University, 22184 Lund, Sweden</nlm:aff></affiliation></author></analytic><series><title level="j">Leukemia Research Reports</title><idno type="eISSN">2213-0489</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Heterozygous mutations in <italic>GATA2</italic> underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present.</p><p>We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to <italic>GATA2</italic> mutation. Exome sequencing revealed a somatic <italic>ASXL1</italic> mutation and the patient underwent allogeneic stem cell transplantation successfully.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hsu, A P" uniqKey="Hsu A">A.P. Hsu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dickinson, R E" uniqKey="Dickinson R">R.E. Dickinson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hahn, C N" uniqKey="Hahn C">C.N. Hahn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spinner, M A" uniqKey="Spinner M">M.A. Spinner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holme, H" uniqKey="Holme H">H. Holme</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kazenwadel, J" uniqKey="Kazenwadel J">J. Kazenwadel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Opatz, S" uniqKey="Opatz S">S. Opatz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Greif, P A" uniqKey="Greif P">P.A. Greif</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ren, J" uniqKey="Ren J">J. Ren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thorvaldsdottir, H" uniqKey="Thorvaldsdottir H">H. Thorvaldsdottir</name></author><author><name sortKey="Robinson, J T" uniqKey="Robinson J">J.T. Robinson</name></author><author><name sortKey="Mesirov, J P" uniqKey="Mesirov J">J.P. Mesirov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dickinson, R E" uniqKey="Dickinson R">R.E. Dickinson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bodor, C" uniqKey="Bodor C">C. Bodor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="West, R R" uniqKey="West R">R.R. West</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Micol, J B" uniqKey="Micol J">J.B. Micol</name></author><author><name sortKey="Abdel Wahab, O" uniqKey="Abdel Wahab O">O. Abdel-Wahab</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="case-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Leuk Res Rep</journal-id><journal-id journal-id-type="iso-abbrev">Leuk Res Rep</journal-id><journal-title-group><journal-title>Leukemia Research Reports</journal-title></journal-title-group><issn pub-type="epub">2213-0489</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26716079</article-id><article-id pub-id-type="pmc">4672090</article-id><article-id pub-id-type="publisher-id">S2213-0489(14)20025-2</article-id><article-id pub-id-type="doi">10.1016/j.lrr.2015.10.001</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Young woman with mild bone marrow dysplasia, <italic>GATA2</italic> and <italic>ASXL1</italic> mutation treated with allogeneic hematopoietic stem cell transplantation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lübking</surname><given-names>Anna</given-names></name><xref rid="aff0005" ref-type="aff">a</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author"><name><surname>Vosberg</surname><given-names>Sebastian</given-names></name><xref rid="aff0010" ref-type="aff">b</xref><xref rid="aff0020" ref-type="aff">d</xref><xref rid="aff0025" ref-type="aff">e</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author"><name><surname>Konstandin</surname><given-names>Nikola P.</given-names></name><xref rid="aff0010" ref-type="aff">b</xref></contrib><contrib contrib-type="author"><name><surname>Dufour</surname><given-names>Annika</given-names></name><xref rid="aff0010" ref-type="aff">b</xref></contrib><contrib contrib-type="author"><name><surname>Graf</surname><given-names>Alexander</given-names></name><xref rid="aff0015" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Krebs</surname><given-names>Stefan</given-names></name><xref rid="aff0015" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Blum</surname><given-names>Helmut</given-names></name><xref rid="aff0015" ref-type="aff">c</xref><xref rid="aff0020" ref-type="aff">d</xref><xref rid="aff0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Weber</surname><given-names>Axel</given-names></name><xref rid="aff0030" ref-type="aff">f</xref></contrib><contrib contrib-type="author"><name><surname>Lenhoff</surname><given-names>Stig</given-names></name><xref rid="aff0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Ehinger</surname><given-names>Mats</given-names></name><xref rid="aff0040" ref-type="aff">h</xref></contrib><contrib contrib-type="author"><name><surname>Spiekermann</surname><given-names>Karsten</given-names></name><xref rid="aff0010" ref-type="aff">b</xref><xref rid="aff0020" ref-type="aff">d</xref><xref rid="aff0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Greif</surname><given-names>Philipp A.</given-names></name><xref rid="aff0010" ref-type="aff">b</xref><xref rid="aff0020" ref-type="aff">d</xref><xref rid="aff0025" ref-type="aff">e</xref><xref rid="fn2" ref-type="fn">2</xref></contrib><contrib contrib-type="author"><name><surname>Cammenga</surname><given-names>Jörg</given-names></name><email>jorg.cammenga@med.lu.se</email><xref rid="aff0005" ref-type="aff">a</xref><xref rid="aff0035" ref-type="aff">g</xref><xref rid="cor1" ref-type="corresp">⁎</xref><xref rid="fn2" ref-type="fn">2</xref></contrib></contrib-group><aff id="aff0005"><label>a</label>Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden</aff><aff id="aff0010"><label>b</label>Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany</aff><aff id="aff0015"><label>c</label>Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany</aff><aff id="aff0020"><label>d</label>German Cancer Consortium (DKTK), Heidelberg, Germany</aff><aff id="aff0025"><label>e</label>German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="aff0030"><label>f</label>Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany</aff><aff id="aff0035"><label>g</label>Department of Molecular Medicine and Gene Therapy, Sölvegatan 17, BMC A12, Lund University, 22184 Lund, Sweden</aff><aff id="aff0040"><label>h</label>Department of Pathology, Skåne University Hospital, 22185 Lund, Sweden</aff><author-notes><corresp id="cor1"><label>⁎</label>Corresponding author at: Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden.Department of Hematology and Vascular Disorders, Skåne University HospitalLund22185Sweden <email>jorg.cammenga@med.lu.se</email></corresp><fn id="fn1"><label>1</label><p>These authors contribute equally.</p></fn><fn id="fn2"><label>2</label><p>Joint senior authors.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>17</day><month>10</month><year>2015</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><year>2015</year></pub-date><pub-date pub-type="epub"><day>17</day><month>10</month><year>2015</year></pub-date><volume>4</volume><issue>2</issue><fpage>72</fpage><lpage>75</lpage><history><date date-type="received"><day>2</day><month>12</month><year>2014</year></date><date date-type="accepted"><day>16</day><month>10</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 Published by Elsevier Ltd.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder></copyright-holder><license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p></license></permissions><abstract><p>Heterozygous mutations in <italic>GATA2</italic> underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present.</p><p>We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to <italic>GATA2</italic> mutation. Exome sequencing revealed a somatic <italic>ASXL1</italic> mutation and the patient underwent allogeneic stem cell transplantation successfully.</p></abstract><abstract abstract-type="author-highlights"><title>Highlights</title><p><list list-type="simple"><list-item id="u0005"><label>•</label><p>Allogeneic stem cell transplantation was performed for DCML caused by <italic>GATA2</italic> mutation.</p></list-item><list-item id="u0010"><label>•</label><p>Genetic diagnostics were done by Sanger sequencing and whole exome sequencing.</p></list-item><list-item id="u0015"><label>•</label><p>We identified an <italic>ASXL1</italic> mutation associated with high risk for leukemic transformation.</p></list-item></list></p></abstract><kwd-group><title>Keywords</title><kwd>GATA2 mutation</kwd><kwd>Myelodysplastic syndrome</kwd><kwd>ASXL1 mutation</kwd><kwd>Allogeneic hematopoietic stem cell transplantation</kwd></kwd-group></article-meta></front><body><sec id="s0005"><label>1</label><title>Introduction</title><p>The transcription factor GATA2 has a complex role in the development of hematopoiesis and lymphopoiesis but even in differentiation of non-hematopoietic progenitors. Haploinsufficiency of <italic>GATA2</italic> leads to a variety of clinical and laboratory findings. It has been previously described that heterozygous mutations in <italic>GATA2</italic> underlie different syndromes defined by monocytopenia and mycobacterial avium complex infection (MonoMAC), deficiency of dendritic cells, monocytes, B- and NK lymphocytes (DCML), lymphedema, deafness and myelodysplasia (Emberger syndrome) or familiar myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) <xref rid="bib1" ref-type="bibr">[1]</xref>, <xref rid="bib2" ref-type="bibr">[2]</xref>, <xref rid="bib3" ref-type="bibr">[3]</xref>.</p><p>Different types of mutations are known to cause loss of function of the mutated allele leading to haploinsufficiency of <italic>GATA2</italic>, and a correlation with certain clinical symptoms has been described in some cases <xref rid="bib4" ref-type="bibr">[4]</xref>, <xref rid="bib5" ref-type="bibr">[5]</xref>, <xref rid="bib6" ref-type="bibr">[6]</xref>. Germline mutations of <italic>GATA2</italic> are transmitted with autosomal dominant inheritance. However, even among hereditary cases, there is a great variation of clinical findings, time of manifestation and even severity of disease in patients with <italic>GATA2</italic> mutations. Clinical characteristics in most patients include immunodeficiency with susceptibility to human papillomavirus (HPV) and non-tuberculous mycobacteria (NTM), predisposition to MDS/AML, pulmonary proteinosis (PAP) and congenital lymphedema. These symptoms might occur with or without preceding cytopenias and different medical specialties are involved in the diagnosis and management of these patients. The only curative treatment so far is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, it is crucial to diagnose patients with <italic>GATA2</italic> mutations as early as possible.</p><p>We report a case of DCML deficiency and MDS in a patient with <italic>GATA2</italic> mutation who successfully underwent allogeneic stem cell transplantation.</p></sec><sec id="s0010"><label>2</label><title>Case report</title><p>A 38-year old woman presented at the Department of Hematology, Lund University hospital in January 2011 with microcytic anemia. She was referred from the gynecology department where she has been treated for severe and recurrent condylomata. During the last 10 years, she had gone repeatedly through surgical intervention for severe condylomata, that were positive for HPV type 6. Additionally, the patient has been treated for recurrent pneumonia. Due to work related reasons, she had moved within Europe several times. Already at the age of 12, she was diagnosed with anemia in Germany, presumably caused by iron deficiency. Due to persisting anemia, a bone marrow biopsy was done in the Netherlands in 2008 and she was diagnosed with MDS refractory anemia (RA), IPSS low, normal karyotype. She has never required blood transfusions.</p><p>At presentation, she had adapted to a hemoglobin level of 79 g/l and had only occasional discrete symptoms of her anemia, as fatigue, other constitutional symptoms were absent. She described her menstruation as mostly normal, but sometimes heavy and prolonged due to known uterine myoma. She had no other history of bleeding. Platelets and WBC count were normal. Differential blood counts showed a discrete lymphopenia and complete absence of monocytes. A lymphocyte profile showed low levels of NK-cells (0.02×10<sup>9</sup>), CD4 T-cells (0.12×10<sup>9</sup>) and B-cells (0.01×10<sup>9</sup>). We performed a new bone marrow biopsy in 2012 in which the previous diagnosis of MDS RA could be confirmed even if signs of dysplasia were rather discrete with mainly dysplastic megakaryocytes. No fibrosis was found (<xref rid="f0005" ref-type="fig">Fig. 1</xref>). The bone marrow cells still showed a normal karyotype in routine cytogenetics. She did respond to oral iron substitution to some degree with Hb around 90 g/l.</p><p>Clinical findings of symptomatic severe HPV infection, recurrent pneumonia and warts/condylomata in combination with the diagnosis of MDS RA and monocytopenia/lymphopenia, led to the suspicion of DCML syndrome. The family history revealed no individuals with similar symptoms. In particular, no other family members are known to be affected by any type of hematological malignancy or immunodeficiency (<xref rid="f0010" ref-type="fig">Fig. 2</xref> A). Sequencing of material from both bone marrow and skin biopsy showed a heterozygous frameshift mutation in <italic>GATA2</italic> (NM_001145661.1:c.404dup;Gly136Argfs*49) (<xref rid="f0010" ref-type="fig">Fig. 2</xref>, B–D). The patient's parents were tested but no <italic>GATA2</italic> mutation could be detected (<xref rid="f0010" ref-type="fig">Fig. 2</xref> C), suggesting that the patients disorder was caused by a de-novo mutation. To systematically screen for additional mutations, we performed exome sequencing of matched tumor (bone-marrow) and normal (skin biopsy) samples as described previously <xref rid="bib7" ref-type="bibr">[7]</xref>, <xref rid="bib8" ref-type="bibr">[8]</xref>. Thereby, we detected a somatic <italic>ASXL1</italic> mutation (NM_015338.4:c.2077 C>T; Arg693*) (<xref rid="f0010" ref-type="fig">Fig. 2</xref> D).</p><p>Since no matched sibling donor was available, a search in the registry was initiated and a suitable unrelated donor with a HLA match 16/18 (difference in HLA-DPA- and HLA-DPB1-antigen), full blood group match and CMV match could be identified. After reduced conditioning with fludarabine 30 mg/m<sup>2</sup> for 3 days and TBI 2 Gy, she underwent allo-HSCT with peripheral blood stem cells in June 2013. As GvHD prophylaxis, cyclosporin A and mycophenolate mofetil were given.</p><p>Already 4 weeks after allo-HSCT she achieved an almost normal differential WBC count with monocytes around 1×10<sup>9</sup>, total lymphocytes of 0.6×10<sup>9</sup>. A new lymphocyte profile showed an almost normal amount of NK-cells (0.15×10<sup>9</sup>) and CD4 T-cells (0.18×10<sup>9</sup>). She showed a full donor blood chimerism in October 2013.</p><p>Eight weeks after allo-HSCT, she experienced a severe menstrual bleeding accompanied by some chest discomfort and fatigue. Clinical investigation revealed a hemoglobin level of around 70g/l and discrete ECG changes. Subsequently, coronary angiography was performed showing a subtotal stenosis of the proximal left anterior descendens (LAD) coronary artery without any other signs of atherosclerosis. Percutaneous transluminal coronary angioplasty (PTCA) was done and antiplatelet therapy with clopidogrel was initiated. She underwent hystero-salpingectomy after antiplatelet therapy was terminated. The patient has neither cardiac risk factors nor a family history of heart disease.</p><p>At 4 months she developed a mild graft-versus host disease (GvHD grade 1) with skin rashes, mild eosinophilia and musculoskeletal pain, responding to an intermediate steroid dose. Around the same time, both warts and condylomata disappeared gradually.</p></sec><sec id="s0015"><label>3</label><title>Discussion</title><p>In this case report we describe a young woman that presented with a long history of condylomata and microcytic anemia due to a combination of MDS associated with the DCML syndrome and iron deficiency demonstrating that an overlap of clinical symptoms may complicate diagnosis in patients with <italic>GATA2</italic> mutations. Genetic lesions in <italic>GATA2</italic> that lead to Emberger syndrome seem to be affecting endothelial cells of the lymphatic system, but vascular problems have not been described in patients with <italic>GATA2</italic> mutations, to our knowledge. Our patient suffered from a non-ST-elevation myocardial infarction (NSTEMI) caused by a stenosis in the LAD in the absence of cardiac risk factors or a family history of heart disease and is, thus, most likely triggered by anemia due to a massive menstrual bleeding aggravated by a uterine myoma. Some clinical findings may be associated with distinct type of mutation causing <italic>GATA2</italic> haploinsufficiency. However, in two large patient cohorts published recently, diversity of phenotype in patients with <italic>GATA2</italic> mutations was shown for the first time <xref rid="bib4" ref-type="bibr">[4]</xref>, <xref rid="bib11" ref-type="bibr">[11]</xref>. 84% of the patients in this study met the diagnostic criteria for MDS whereas bone marrow findings in patients with <italic>GATA2</italic> mutations seem to differ from those with typical MDS <xref rid="bib4" ref-type="bibr">[4]</xref>. Instead, patients with <italic>GATA2</italic> mutations present with a hypocellular bone marrow, increased reticulin fibrosis and atypical megakaryocytes in almost all cases. In addition cytogenetic abnormalities such as monosomy 7 or trisomy 8 are frequent <xref rid="bib12" ref-type="bibr">[12]</xref>, <xref rid="bib13" ref-type="bibr">[13]</xref>. In the case presented here, repeated bone marrow biopsies showed rather discrete changes and considering the absence of cytogenetic aberrations, it was challenging to diagnose MDS. Nevertheless, exome sequencing revealed the presence of a somatic <italic>ASXL1</italic> mutation. Myeloid transformation induced by acquired lesions of <italic>ASXL1</italic> in patients with constitutional <italic>GATA2</italic> mutations were previously reported <xref rid="bib12" ref-type="bibr">[12]</xref>, <xref rid="bib13" ref-type="bibr">[13]</xref>, <xref rid="bib14" ref-type="bibr">[14]</xref>. 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(A) May-Giemsa Grünwald (MGG), ×10: cellularity around 40%, considered to be normal for the patients age of 37, with normally distributed megakaryocytes. (B) MGG, ×40: some dysplastic megakaryocytes (arrow) with hypolobulated nuclei. (C) Gomori silver stain: normal content of reticulin fibers.</p></caption><alt-text id="at0005">Fig. 1</alt-text><graphic xlink:href="gr1"></graphic></fig><fig id="f0010"><label>Fig. 2</label><caption><p>Molecular diagnostic and genetic workup. (A) Pedigree of the affected family. Arrow indicates the index patient. (B) Germline mutation Gly136Argfs*49 mapped to the GATA2 protein structure using the software DOG1.0 <xref rid="bib9" ref-type="bibr">[9]</xref>. (C) Genetic testing of the affected family by Sanger sequencing. Chromatograms of the index patient and her parents show a partial sequence of <italic>GATA2</italic> exon 3 surrounding the cDNA position 404. (D) Exome sequence data from the index patient supporting the <italic>GATA2</italic> germline mutation and the somatic <italic>ASXL1</italic> mutation. Alignments of matched tumor (bone marrow) and normal (skin biopsy) samples from the index patient are shown using the Integrative Genomics Viewer (IGV) <xref rid="bib10" ref-type="bibr">[10]</xref>. Read counts of reference and variant alleles at the altered positions are indicated for each sample.</p></caption><alt-text id="at0010">Fig. 2</alt-text><graphic xlink:href="gr2"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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