Expanding the Morphologic Spectrum of ANKRD26-Related Thrombocytopenia-2: A Case Series

Familial thrombocytopenias with a predisposition to myeloid malignancies have been associated with mutations in several genes, including ankyrin repeat domain 26 (ANKRD26), which leads to ANKRD26-related thrombocytopenia-2 (ANKRD26-RT), characterized by mild to moderate thrombocytopenia and an increased risk of myeloid malignancies. ANKRD26 mutations affecting the 5'untranslated region (5'UTR) or N-terminus lead to its derepression, impacting megakaryopoiesis by modulating type I cytokine signaling through MAPK hyperactivation. Despite expanding phenotypic descriptions, the events leading to hematologic malignancies and baseline bone marrow (BM) morphology remain poorly characterized.

We identified eight patients from five families with ANKRD26-RT and characterized their BM morphologic features. All patients exhibited a similar histopathologic phenotype with dysmegakaryopoiesis and a stable elevation of myeloblasts, determined by CD34 immunohistochemical staining of the BM core biopsy, over many years without somatic cytogenetic abnormalities, mutations, or progression to malignancy.

Two siblings (patients 1.1 and 1.2) and their father (patient 1.3) had chronic moderate thrombocytopenia with platelet counts ranging from 28k to 54k cells/mm³. All carried a previously reported pathogenic germline heterozygous ANKRD26variant in the 5'UTR (c.-126T>C). Patient 1.1, a 22-year-old male, developed B-precursor acute lymphoblastic leukemia at age 17, with clinical sequencing revealing somatic CDKN2A deletion and pathogenic variants in PTPN11 and NRAS. After completing therapy, BM histopathological examination showed dysmegakaryopoiesis and a stable population of myeloblasts, making up 7.8% to 10% of total cells, which persisted for over four years. Patient 1.2, a 24-year-old male, displayed a persistent increase in BM myeloblasts at approximately 9% over 42 months without clonal abnormalities. Patient 1.3, their 57-year-old father, had stable, mildly increased BM myeloblasts (4% to 5.8%) over three years.

BM examination of a 20-year-old male (patient 2.1) with a previously unreported germline c.-125T>C ANKRD26 variant and platelet counts ranging from 85k to 108k cells/mm³ showed 5.8% myeloblasts and a variant of unknown significance (VUS) in CUX1, with no subsequent bone marrow examinations and the patient remaining clinically well with two years of follow-up.

A third family included an 18-year-old male (patient 3.1) and his father (patient 3.2), who carry a germline c.-119C>G ANKRD26 variant and have platelet counts of 80k to 90k cells/mm³. BM examination on both showed dysmegakaryopoiesis and mildly elevated myeloblasts, at 7.2% and 4.5%, respectively.

BM examination from an 18-year-old female (patient 4.1) with thrombocytopenia and a germline WAC::ANKRD26 fusion showed 6% myeloblasts and typical dysmegakaryopoiesis. Finally, BM examination of a 67-year-old female (patient 5.1) with a c.-118C>T ANKRD26 variant, platelet counts of 46k to 57k cells/mm³, and three first-degree relatives with myeloid malignancies showed 7% myeloblasts, and she has remained stable without leukemia for 10 years.

Our findings expand the phenotypic spectrum of ANKRD26-RT, documenting a stable increase in bone marrow myeloblasts without the development of somatic mutations or malignancy. Previous reports described normocellularity or hypercellularity with megakaryocytic hyperplasia and dysmegakaryopoiesis. This is the first report of a chronic elevation in myeloblasts without clonal abnormalities, suggesting a disease-specific expansion of immature cells rather than an active malignancy. The lack of additional cytopenia other than thrombocytopenia, multilineage dysplasia, or acquired clonal abnormalities supports a non-malignant process. These findings suggest that mild elevations in myeloblasts, in the absence of clonal abnormalities, may be a baseline characteristic of ANKRD26-RT, challenging the traditional diagnostic criteria for myelodysplastic syndromes (MDS) in patients with germline predisposition and complicating disease surveillance. This study provides unique clinical insights into the potential path to malignant transformation in familial myeloid malignancies and highlights the need for further research to understand disease penetrance and latency.

Drazer:Argenx: Consultancy. Shimamura:Novartis: Membership on an entity's Board of Directors or advisory committees; X4 pharma: Consultancy; Fulcrum: Consultancy. Bledsoe:X4 Pharmaceuticals: Consultancy, Other: Provides reagents (Flow cytometry antibodies).