ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26

Thrombocytopenia 2 (THC2), a non-syndromic, autosomal dominant thrombocytopenia, is caused by mutations in the ANKRD26 gene, located on chromosome 10p12. Thus far, 12 heterozygous single nucleotide substitutions in the 5′-untranslated region of the ANKRD26 gene have been described in 21 families. Affected patients usually present with moderate thrombocytopenia with normal platelet size and normal mean platelet volumes. Many patients were reported to have an α-granule deficiency as detected by immunofluorescent labelling without consistent defects in platelet aggregation studies. Evidence for dysmegakaryopoiesis has been observed in a small number of patients who have undergone bone marrow biopsies. Surprisingly, a small subset of individuals can have elevated hemoglobin levels and leukocyte counts, without a clear explanation. Germline mutations in RUNX1 (ref. 4) and recently ETV6 (ref. 5) have been associated with familial thrombocytopenias with an inherent predisposition to myeloid neoplasms. This phenomenon has also been described in patients with germline ANKRD26 mutations. In an extended series of 118 patients with Thrombocytopenia 2 (THC2), 10 developed myeloid neoplasms: acute myeloid leukemia-4 (age at onset, 40–60 years), myelodysplastic syndrome-4 (MDS) (age at onset, 35–70 years) and chronic myeloid leukemia-2 (age at onset, 30–65 years). Two additional patients: a pregnant woman with acute myeloid leukemia and her mother with myelodysplastic syndrome-4, have also been described. We describe a 62-year-old male who had been referred to our institution for evaluation of monocytosis and chronic worsening thrombocytopenia. He had been diagnosed with idiopathic