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.
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 (0.02x109), CD4 T-cells (0.12x109) and B-cells (0.01x109). 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 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.
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. Thereby, we detected a somatic ASXL1 mutation (NM_015338.4:c.2077 C>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 30 mg/m2 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.
Already 4 weeks after allo-HSCT she achieved an almost normal differential WBC count with monocytes around 1x109, total lymphocytes of 0.6x109. A new lymphocyte profile showed an almost normal amount of NK-cells (0.15x109) and CD4 T-cells (0.18x109). She showed a full donor blood chimerism in October 2013.
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.
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.