Clinically Silent Carriers in Families with Myelodysplastic Syndrome Due to GATA2 Mutations

The proband presented at age 15 with pancytopenia, and was found to have MDS and monosomy 7; he died from post-BMT complications including aspergillosis. His brother was found to have leukopenia, neutropenia and macrocytosis at age 13 during an infection with H1N1 influenza; the leukopenia and macrocytosis persisted. Six months later, repeat bone marrow showed early refractory anemia; the next year his marrow had myeloid dyspoiesis and dysplastic megakaryocytes; FISH showed −7 in 2.3% of cells, leading to classification as MDS-RCC. In retrospect, both boys had absolute monocytopenia (<100/uL). GATA2 sequencing of samples from the surviving brother and his 51 y.o. mother identified a deleterious mutation (c.1116_1130del15, p.C373del5). The mother had breast cancer at age 50, but otherwise was asymptomatic. Closer clinical examination revealed lower limb lymphedema, while laboratory studies revealed lymphopenia (360/uL), monocytopenia (110/uL), low lymphocyte subsets, especially CD19 (3/uL) and MCV = 100fL. Her marrow did not show overt dyspoiesis in myeloid or erythroid lineages; among mostly normal megakaryocytes there were occasional atypical forms, including some with hypolobulated or separated lobes; G-banded karyotyping and interphase FISH for −7/7q- were normal. She would not have been suspected to have GATA2-related MDS based on her clinical status, and is thus a silent carrier.

Three children in this family were diagnosed with MDS. The oldest had a history of warts and pancytopenia at age 18; his marrow showed MDS with trisomy 8. His brother was a compatible transplant donor, but he had mild pancytopenia and monocytopenia; his marrow had MDS and trisomy 8. Their sister was diagnosed at age 14 with MDS and trisomy 8; she, too, had monocytopenia. All 3 were transplanted. Subsequently, a mutation - c.1187G>A, p.R396Q - was found in GATA2, in all 3 brothers and their healthy father. He had normal blood counts (monocytes 500/uL) and immunoglobulins, but low B-cells in peripheral blood (CD20 23/uL) and bone marrow. His normocellular marrow had occasional atypical megakaryocytes with separated lobes, hypolobulation, and mononuclear and micromegakaryocytes. He, too, would not have been suspected to have GATA2-related MDS, and is also a clinically silent carrier.

These two families indicate that familial GATA2-related MDS is a dominantly-inherited syndrome. In our two families, dominant inheritance was not initially considered, in part because the genetically affected parent was clinically asymptomatic. It is unclear whether GATA2 MDS shows “anticipation,” in which the younger generation is more severely affected than the parental generation. It is important that GATA2 be evaluated in families with apparently inherited childhood MDS, since the variable expression might lead inadvertently to selecting an asymptomatic GATA2 mutation carrier as a stem cell transplant donor. Genetic counseling needs to be provided with regard to risk to other family members. In addition, only long-term follow-up and surveillance of the clinically silent carriers will determine whether they remain unaffected.

No relevant conflicts of interest to declare.