Acquired Bernard-Soulier syndrome as the presenting feature of GATA2-related myeloid neoplasm in an adolescent: an insight into the mechanisms underlying the platelet defect

Abstract

Pseudo-Bernard-Soulier syndrome is an acquired rare bleeding condition characterized bythrombocytopenia, large platelets lacking functional GPIb-IX and impaired response toristocetin, mimicking classic Bernard-Soulier syndrome, which is caused by biallelic GPIb-IXmutations.1 It may develop secondary to autoimmune and lymphoproliferative disorders,myelodysplastic syndrome and Gaucher disease.1-4 GATA2 deficiency is a heterogeneousdisorder associated with protean clinical manifestations, including monocyte, dendritic, BandNK-cell deficiency, immunodeficiency, warts, lymphedema and predisposition to myeloidmalignancies.5 We report a girl with GATA2 deficiency who developed pseudo-Bernard-Soulier syndrome heralding the onset of a myeloid neoplasm consistent with atypical chronicmyeloid leukaemia (aCML) and deepen into the mechanisms linking the acquired plateletdefect to malignant transformation in this setting.A 12-year-old girl was referred for severe bleeding. She experienced epistaxis, bruising andhypermenorrhea since age 11, requiring blood transfusions, nasal packing and hormonaltherapy. She had macrothrombocytopenia (platelet count 60x109/L) and anemia (hemoglobin6.2 gr/dL, MCV 105 fL, reticulocytes 0.9%). Leukocyte count (6.5x109/L), coagulation testsand von Willebrand factor were normal. Impedance aggregometry showed absent responseto ristocetin with preserved response to other agonists. Large platelets were evident bymicroscopy and flow cytometry (Figure 1A), which revealed two platelet populations withdifferent GPIb-IX levels, one with complete absence of this complex (34-37% of platelets)and another which expressed GPIb-IX, albeit at reduced levels, as revealed by decreasedmean fluorescence intensity (Figure 1B), whereas GPIIb-IIIa was preserved or increased(not shown). Whole exome seguencing (WES) followed by a virtual platelet disorders panel,including GP1BA, GP1BB and GP9, was negative. Recent onset macrothrombocytopeniatogether with defective ristocetin-induced aggregation and GPIb-IX expression in theabsence of GP1BA/GP1BB/GP9 mutations was consistent with pseudo-Bernard-Souliersyndrome. The Institutional Ethics Committee approved the study and informed consent wasprovided.