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  • We report a case of DCML deficiency

    2019-05-13

    We report a case of DCML deficiency and MDS in a patient with GATA2 mutation who successfully underwent allogeneic stem cell transplantation.
    Case report At presentation, she had adapted to a hemoglobin level of 79g/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 (0.02×109), CD4 T-cells (0.12×109) and B-cells (0.01×109). 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 (Fig. 1). The bone marrow ldv cost still showed a normal karyotype in routine cytogenetics. She did respond to oral iron substitution to some degree with Hb around 90g/l. 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 (Fig. 2 A). Sequencing of material from both bone marrow and skin biopsy showed a heterozygous frameshift mutation in GATA2 (NM_001145661.1:c.404dup;Gly136Argfs*49) (Fig. 2, B–D). The patient\'s parents were tested but no GATA2 mutation could be detected (Fig. 2 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 [7,8]. Thereby, we detected a somatic ASXL1 mutation (NM_015338.4:c.2077C>T; Arg693*) (Fig. 2 D). 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 30mg/m2 for 3 days and TBI 2Gy, she underwent allo-HSCT with peripheral blood stem cells in June 2013. As GvHD prophylaxis, cyclosporin A and mycophenolate mofetil were given. Already 4 weeks after allo-HSCT she achieved an almost normal differential WBC count with monocytes around 1×109, total lymphocytes of 0.6×109. A new lymphocyte profile showed an almost normal amount of NK-cells (0.15×109) and CD4 T-cells (0.18×109). She showed a full donor blood chimerism in October 2013.
    Discussion 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 GATA2 mutations. Genetic lesions in GATA2 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 GATA2 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 GATA2 haploinsufficiency. However, in two large patient cohorts published recently, diversity of phenotype in patients with GATA2 mutations was shown for the first time [4,11]. 84% of the patients in this study met the diagnostic criteria for MDS whereas bone marrow findings in patients with GATA2 mutations seem to differ from those with typical MDS [4]. Instead, patients with GATA2 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 [12,13]. 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 ASXL1 mutation. Myeloid transformation induced by acquired lesions of ASXL1 in patients with constitutional GATA2 mutations were previously reported [12–14]. This demonstrates that an early diagnosis and evaluation for allo-HSCT is crucial for patients with GATA2 mutations and genetic counseling should be offered to affected families.