ANKRD26-related thrombocytopenia and myeloid malignancies

To the editor:

Since the discovery that mutations in the 5′ untranslated region (UTR) of ANKRD26 are responsible for an autosomal-dominant form of thrombocytopenia (ANKRD26-RT),¹  21 affected families were reported.²  A study analyzing this series of patients suggested that ANKRD26-RT is characterized by normal platelet size, moderate thrombocytopenia, and absent or mild bleeding tendency.²  The study also found that the number of hematologic malignancies in affected families was higher than expected, but the relatively small cohort of patients precluded firm conclusions.

To gain further information on this matter, we screened for mutations in the 5′ UTR of ANKRD26 215 subjects with an inherited thrombocytopenia of unknown origin and found 11 mutations (3 not previously described) in 23 cases (Table 1 ³ ). Analysis of family members identified another 52 affected subjects. Moreover, we found 43 additional subjects, first- or second-degree relatives of ANKRD26-RT patients, who were known to be thrombocytopenic from an early age but were not available for genetic investigation (they were dead or not willing to perform the analysis). Analysis of the new series of 75 patients with ANKRD26 mutations confirmed that ANKRD26-RT is characterized by moderate thrombocytopenia with normal platelet size and a mild bleeding phenotype.

In the extended series of 118 subjects certainly or very likely affected, we identified 10 patients who had developed myeloid malignancies: 4 acute myeloid leukemias (age at onset, 40-60 years), 4 myelodysplastic syndromes (MDS) (age at onset, 35-70 years), and 2 chronic myeloid leukemias (CML) (age at onset, 30-65 years). The total observation time was 4741 years, and the incidence of acute myeloid leukemia, MDS, and CML was 84 (confidence interval [CI], 23-216), 84 (CI, 23-216), and 42 (CI, 5-152) per 100 000, respectively. Putting together the 118 cases examined in this study and the 104 cases already reported, 4.9% of patients had acute leukemias, 2.2% MDS, and 1.3% CML. The total observation time was 8915 years, with an incidence of acute leukemias, MDS, and CML of 123 (CI, 62-221), 56 (CI, 18-131), and 34 (CI, 7-98) per 100 000, respectively, thus higher than expected in the general population (5.2, 4.5, and 1.6 per 100 000, respectively, according to the National Cancer Institute⁴ ). Unlike myeloid malignancies, the incidence of lymphoproliferative disorders and nonhematologic cancers in ANKRD26-RT pedigrees was not higher than expected (data not reported). Available data are therefore compatible with the hypothesis that ANKRD26-RT, as the inherited thrombocytopenia deriving from RUNX1 mutations,⁵  predisposes to myeloid malignancies, in particular acute leukemias. The observation that this unfavorable outcome occurred in a limited proportion of subjects and has been observed in only 12 of 44 families indicates that the penetrance for malignancies was incomplete and other genetic and/or environmental factors contributed to the development of these disorders. Of note, the the case series described in this paper confirmed the already reported finding of unexplained high leukocyte counts in a large proportion of subjects. Further observation is required to ascertain whether the higher leukocyte counts are related to eventual development of leukemia.

In conclusion, ANKRD26-RT is an insidious form of inherited thrombocytopenias that exposes patients to a low risk of bleeding but predisposes them to hematologic myeloid malignancies. Recognizing this disorder and its attendant risks is important for proper management of affected subjects.⁶