Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature

Abstract

A 50-year-old woman was diagnosed with acute myeloid leukemia (AML). She has history of thrombocytopenia for 25 years and a significant family history of thrombocytopenia, affecting her mother, siblings and their children, as well as her own children. Both her mother and maternal aunt died from myelodysplastic syndrome (MDS). Additional genetic analysis was performed and identified two heterozygous missence mutations in the second zinc finger domain of GATA2 gene (p.Thr358Lys, and p.Leu359Val), occurring in cis on the same allele. Given the patient's family history and clinical manifestation, this was interpreted as an acute myeloid leukemia with heritable GATA2 mutations associated with familial AML-MDS. Germline GATA2 mutations are involved in a group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema and propensity to acute myeloid leukemia or myelodysplastic syndrome (AML-MDS). Here we reported a case of familial AML-MDS with two novel GATA2 mutations. This case illustrates the importance of recognizing the clinical features for this rare category of AML-MDS and performing the appropriate molecular testing. The diagnosis of heritable gene mutations associated familial AML-MDS has significant clinical implication for the patients and affected families. Clinical trials are available to further investigate the role of allogeneic hematopoietic stem cell transplant in managing these patients.

Figure 1

Morphological findings of familial AML-MDS with inherited GATA2 mutations. (A) Peripheral blood smear revealed increased number of blasts, occasional dysplastic neutrophils with hyposegmented nuclei and platelets with abnormal morphology (Wright-Giemsa, ×400). (B) Bone marrow aspirate smears contain occasional blasts with fine chromatin, round nuclei and scant cytoplasm (Wright-Giemsa, ×1000). (C) and (D) The bone marrow core biopsy sections showed a markedly hypercelluar bone marrow with significantly increased numbers of blasts (C: Hematoxylin and eosin, ×200, D: Hematoxylin and eosin, ×600).

Figure 2

Cytogenetic and molecular findings of familial AML-MDS with inherited GATA2 mutations. (A) Cytogenetic analysis performed on fresh bone marrow aspirate revealed all 20 cells with a deletion of long arm of chromosome 7, i.e. 46,XX,del(7)(q22q36)[20]. (B) To screen GATA2 for known mutations, PCR products were amplified by either Qiagen Taq or by Roche GC rich PCR kit using primers listed in table below. PCR products were Sanger sequencing using the same primers with Big Dye chemistry (ABI) on a 3730xl DNA Analyzer (ABI). Bidirectional Sanger sequencing revealed 2 heterozygous mutations in 2^nd zinc finger domain of GATA2 gene, p. Thr358Lys (c.1074 C > A) and p.Leu359Val (c.1076 T > G). To differentiate whether the mutations were cis or trans, PCR products were cloned into a pCI vector (Promega) and 8 clones were sequenced. Of the 8 clones, 3 failed to produce sequence information, 2 contained both wild type alleles and 3 contained both mutant alleles.