Insights into the clinical, platelet and genetic landscape of inherited thrombocytopenia with malignancy risk

Abstract

Inherited thrombocytopenia (IT) with germline variants in RUNX1, ETV6 or ANKRD26 carries a high risk (10%-45%) of developing haematological malignancy (IT-HM). We evaluated the clinical, platelet and molecular characteristics in 37 patients with RUNX1-related thrombocytopenia (RT), 9 with ETV6-RT and 20 with ANRKD26-RT. Genetic diagnosis was delayed by about 20 years from the identification of thrombocytopenia. Bleeding tendency was present in 25%-30% of RUNX1-RT and ANKRD26-RT patients. Platelet aggregation was impaired in 90% of all patients, while reduced activation and granule secretion were heterogeneous. Most RUNX1-RT patients had low glycoprotein Ia (GPIa) levels, which may be a useful disease biomarker. Sixteen distinct genetic variants in RUNX1, four in ETV6 and four in ANKRD26 were identified in patients. The clinical profile showed immune, skin, gastrointestinal and other comorbidities in many patients. One third of the cases developed a malignancy: This included eight RUNX1-RT patients with myelodysplastic syndrome (MDS), five with acute myeloid leukaemia (AML), and one with chronic myeloid leukaemia (CML) Ph+. One patient with ETV6-RT subsequently developed B-cell acute lymphoblastic leukaemia (B-ALL) during childhood. Three cases with ANKRD26-RT demonstrated a multifaceted clinical presentation, including B-ALL Ph+, MDS and breast cancer. The high incidence of HM development highlights the importance of early diagnosis in life.

Keywords: ANKRD26; ETV6; RUNX1; IT; inherited thrombocytopenia; malignancy predisposition.

FIGURE 1

Familial, haematological and platelet features in patients with RUNX1‐RT, ETV6‐RT or ANKRD26‐RT. (A) Dot plot showing the number of affected members per family with a background of thrombocytopenia or neoplasia. (B) Age at first detection of thrombocytopenia. (C) Age at molecular diagnosis. (D–H) Laboratory findings and blood smears in patients: (D) Platelet counts, (E) Mean platelet volume (MPV), (F) haemoglobin levels, (G) leucocyte counts, (H) neutrophil counts. (I) Representative blood films in these patients showing (i) thrombocytopenia without morphological abnormalities, (ii) macrothrombocytopenia and (iii) granulocyte hyposegmentation. Bar: 5 μm. (J) Bleeding tendency assessed by the ISTH‐BAT in women, men and children (<18 years) at diagnosis. (K–O) Bar charts showing the distribution of patients with normal versus abnormal values in different platelet function tests: (K) PFA‐100 test using both collagen‐ADP (col‐ADP) and collagen‐epinephrine (col‐epi) cartridges. (L) Agonist‐induced platelet aggregation (LTA). (M) Flow cytometry assessment of PAC‐1 (αIIbβ3 activation), CD62 (α‐granule secretion) or CD63 (δ‐granule secretion) following agonist stimulation. (N) δ‐granule content assessed by whole‐mount electron microscopy (EM‐WM). (O) Glycoprotein Ia (GPIa, collagen receptor), assessed by flow cytometry. Dotted lines indicate abnormal cut‐off (platelets: <150 × 10⁹/L; MPV: 7.2–11.7 fL; female haemoglobin: 12.1–15.1 g/dL; male haemoglobin: 13.8–17.2 g/dL; leucocytes: 4.5–11 × 10⁹/L; neutrophils: 2.5–7 × 10⁹/L; BS females ≥6, BS males ≥4, BS children ≥3). Graphs were generated with GraphPad 9.

FIGURE 2

Genetic analysis in patients with suspected inherited thrombocytopenia identified germline variants in (A) RUNX1, (B) ETV6 and (C) ANKRD26. The type of variant is indicated by shape and colour. Each shape represents one family. Dark red text denotes a pathogenic variant (PV) classification according to ClinVar (and ClinGen for RUNX1). Light red text indicates likely pathogenic (LP) variants, grey represents variants of uncertain significance (VUS) and orange denotes conflicting pathogenicity classifications. Underlined variants are de novo. The diagram displays the various domains, start and end amino acids and exons. ETS, a family of transcriptional activators or repressors; PNT, pointed domain; RHD, Runt homology domain; TAD, transactivation domain.