Multiple heterozygous germline mutations have been identified in GATA2 that are associated with a range of phenotypic presentations including MonoMAC1–3/dendritic cell, monocyte, B- and NK-lymphoid deficiency (DCML deficiency),4–5 familial myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML),6 and lymphedema/Emberger syndrome.7–9 The clinical presentation of the patient in the case report by Chu et al.,10 who had a history of M. avium complex (MAC) infection with cytopenias and was diagnosed with aplastic anemia and idiopathic CD4-positive (CD4) lymphocytopenia (ICL), is not uncommon for MonoMAC patients.1–2 MonoMAC is associated with a peripheral blood flow cytometric profile of profound monocytopenia, and NK and B lymphopenia, which underlie immunodeficiency and susceptibility to infections with MAC, human papillomavirus, and other opportunistic fungal pathogens. Several MonoMAC patients have displayed CD4 lymphocytopenia,1 while others have evidence of increased CD3/CD8 large granular lymphocyte populations with clonal T-cell gene rearrangements.2 Over half of MonoMAC patients at our institution present with, or ultimately develop, additional cytopenias (anemia, neutropenia and thrombocytopenia) associated with MDS/AML. Similar to the patient reported by Chu et al., the marrows of the majority of MonoMAC patients with MDS/AML in our study2 were hypocellular with trilineage hypoplasia with morphological features often resembling aplastic anemia, in contrast to de novo MDS, which typically presents with hypercellular marrows.
GATA2 is a zinc finger transcription factor that is critical in hematopoiesis. To date, mutations identified include missense mutations, frameshift mutations, splice site mutations, and large intragenic deletions.3,5,6,8,9 Several of these GATA2 mutants result in haploinsufficiency,3,9 and presumably impair self-renewal of hematopoietic progenitors.11 Over time, haploinsufficiency of GATA2 may contribute to progressive cytopenias that develop in adolescence or adulthood, manifesting as the MonoMAC phenotype and predisposing to MDS/AML. Some mutants have been reported to have dominant negative function impairing the activity of wild-type GATA2 expressed from the non-mutated allele.6 Inheritance is consistent with autosomal dominance with variable expression. Phenotypic variation suggests that other genetic or environmental factors may impact the evolution of MDS/AML, cytopenias and immunodeficiency.
The diagnosis of hypocellular MDS in unrecognized GATA2 deficiency can be challenging since cytopenias in the presence of a hypocellular marrow can have overlapping features with aplastic anemia. In our study, several MonoMAC patients carried prior diagnoses of aplastic anemia or had family members who were diagnosed with aplastic anemia based on hypocellularity of bone marrow biopsies. However, severe immunodeficiency and opportunistic infections with MAC are not typically seen in aplastic anemia and, if present, should warrant further investigation for the possibility of MonoMAC with GATA2 mutational analysis.
For the hematologist or hematopathologist, the recognition of dysplasia in hypocellular MDS is frequently complicated by paucicellular aspirates with insufficient material for adequate morphological evaluation of erythroid and myeloid dysplasia on smears, and suboptimal material for flow cytometry and cytogenetic analyses. The large majority of MonoMAC marrows we studied have shown evidence of megakaryocytic atypia, which can help differentiate hypocellular MDS from aplastic anemia. Large osteoclast-like megakaryocytes with separated nuclear lobes are also present in many monoMAC marrows (similar to Figures I-K in Chu et al.10), in addition to hypolobulated, mononuclear and/or micromegakaryocytes (best appreciated by immunohistochemical stains for Factor VIIIvw or CD61). In cases with adequate aspirate smears, the level of dysplastic changes in MonoMAC can be subtle (e.g. 10–20% of hematopoietic precursors in a given lineage). Immunohistochemistry for CD34 on core biopsies is critical in the identification of increased blasts. When adequate material is obtained for cytogenetic analysis, the presence of a cytogenetic abnormality is useful in establishing or confirming the diagnosis of hypocellular MDS; albeit up to 40% of monoMAC patients with MDS/AML do not have detectable cytogenetic abnormalities. When present, the cytogenetic abnormalities in MonoMAC and other GATA2 deficiency phenotypes are heterogeneous and have included monosomy 7, trisomy 8, trisomy 1q, and monosomy 6.
Patients with cytopenias and hypoplastic or aplastic bone marrows who have a history of MAC infections, HPV infections, familial MDS/AML and/or lymphedema warrant further investigation for germline GATA2 mutations. MonoMAC has high morbidity and mortality, and bone marrow transplantation is a viable option for many MonoMAC/GATA2 deficient patients.12 We agree with Chu et al. that the history and bone marrow findings in their patient are compatible with MonoMAC. A positive family history for MAC or MDS/AML, along with cytogenetic abnormalities in the hypoplastic bone marrow, would support the diagnosis of MonoMAC. Mutational analysis for GATA2 is critical in confirming the diagnosis, facilitating the screening of family members, and identifying matched related donors for allogeneic hematopoietic stem cell transplantation.
- Vinh DC, Patel SY, Uzel G, Anderson VL, Freeman AF, Olivier KN. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood. 2010; 115(8):1519-29. PubMedhttps://doi.org/10.1182/blood-2009-03-208629Google Scholar
- Calvo KR, Vinh DC, Maric I, Wang W, Noel P, Stetler-Stevenson M. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica. 2011; 96(8):1221-5. PubMedhttps://doi.org/10.3324/haematol.2011.041152Google Scholar
- Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011; 118(10):2653-5. PubMedhttps://doi.org/10.1182/blood-2011-05-356352Google Scholar
- Bigley V, Haniffa M, Doulatov S, Wang XN, Dickinson R, McGovern N. The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J Exp Med. 2011; 208(2):227-34. PubMedhttps://doi.org/10.1084/jem.20101459Google Scholar
- Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011; 118(10):2656-8. PubMedhttps://doi.org/10.1182/blood-2011-06-360313Google Scholar
- Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011; 43(10):1012-7. PubMedhttps://doi.org/10.1038/ng.913Google Scholar
- Mansour S, Connell F, Steward C, Ostergaard P, Brice G, Smithson S. Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. Am J Med Genet A. 2010; 152A(9):2287-96. Google Scholar
- Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011; 43(10):929-31. PubMedhttps://doi.org/10.1038/ng.923Google Scholar
- Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 2012; 119(5):1283-91. PubMedhttps://doi.org/10.1182/blood-2011-08-374363Google Scholar
- Chu VH, Curry JL, Elghetany MT, Curry CV. MonoMAC versus Idiopathic CD4+ lymphocytopenia. Haematologica. 2012; 97(4):e9-e11. PubMedhttps://doi.org/10.3324/haematol.2011.058669Google Scholar
- Rodrigues NP, Janzen V, Forkert R, Dombkowski DM, Boyd AS, Orkin SH. Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. Blood. 2005; 106(2):477-84. PubMedhttps://doi.org/10.1182/blood-2004-08-2989Google Scholar
- Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, Hsu AP, Zerbe CS, Calvo KR. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood. 2011; 118(13):3715-20. PubMedhttps://doi.org/10.1182/blood-2011-06-365049Google Scholar