Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

• DOI: 10.1111/bjh.16543
• Publication Date: 2020-02-27T08:29:55Z
• Authors: Elise Fournier; Camille Debord; Valérie Soenen; Nathalie Trillot; Fanny Gonzales; Véronique Tintiller; Louis Terriou; Coralie Derrieux; Wadih Abou Chahla; Camille Paris; Céline Berthon; Thomas Boyer; Anne Lambilliotte; Pierre Boisseau; Soraya Wuillème; Marc Fouassier; Sophie Susen; Claude Preudhomme; Nicolas Duployez
• Keywords: ETV6; Platelet disorder; RUNX1

Germline mutations in runt-related transcription factor 1 (RUNX1), ETS variant 6 (ETV6) and ankyrin repeat domain 26 (ANKRD26) have been recognised as responsible of autosomal dominant inherited thrombocytopenia or platelet disorder, with an increased risk developing haematological malignancies (HM), mainly acute leukaemia (AL) myelodysplastic syndrome (MDS) (Duployez et al., 2016). Importantly, while all these disorders are associated abnormalities count functions, may be mild a bleeding tendency absent contributing to lack clinical recognition. Platelet-aggregation studies also difficult assess the setting thrombocytopenia. Another major concern is early detection progression-associated genetic morphological findings. Only few focussed on aspects bone marrow (BM) from patients germline disorder. Overall, regarding rarity disorders, more cases need described support their conclusions deliver strong messages pathologists. We report here BM findings six diagnosed congenital thrombocytopenia, predisposition HM absence active define baseline aspect still under-recognised disorders. RUNX1 (n = 3), ETV6 1) ANKRD26 2) was performed genomic DNA extracted both peripheral blood (PB) samples by targeted high-throughput sequencing (HTS). In for whom hereditary transmission could not demonstrated, status mutation determined using skin fibroblasts. None had additional lesions 36 genes-HTS panel single nucleotide polymorphism (SNP)-array karyotyping (Appendix S1). Four (B, C, E F) no personal history two (A D) were complete remission (CR; demonstrated sensitive molecular approaches). Morphological investigations at end induction 2 years after CR A D (Antony-Debré 2016; Duployez 2018). Clinical information about provided Appendix S1. The biological characteristics time aspirate presented Table 1. All harboured severe-to-moderate (range: 19–100 × 109/l). displayed megakaryocyte (MK) lineage. large proportion MKs small size hypolobulated/unilobulated nuclei (Fig 1). More rarely, showed multiple separate nuclear lobes, but this feature restricted three mutation. It should noticed that PB patient during treatment AL reflect unaffected RUNX1-mutated carrier. Additionally, although aspirate, prior chemotherapy confounding MK morphology. remaining normal values white cell haemoglobin concentration. There dysplasia other lineages blasts <5% all. cellularity number age A, B, F. assessed because haemodilution. While World Health Organization (WHO) classification recently incorporated myeloid neoplasms distinct entities, recommendations concerning diagnoses management lacking. Notably, morphology poorly documented before occurrence MDS and/or AL. Distinguishing important accurate diagnosis, predicting outcomes directing therapy. Despite recent advances cytogenetic screening, cytological features aspirates remain key elements diagnosing routine practice. Here, we dysplasia, including MKs, common asymptomatic isolated progression disease. These observations corroborate vitro (Hock 2004; Antony-Debré 2012; Bluteau 2014), showing block maturation affecting ploidisation proplatelet formation secondary defects haematopoietic factors. Awareness critical over diagnose HM, especially context. On hand, presence characteristic dysmegakaryopoiesis unexplained alert possibility underlying young patients. Our consistent previous reports investigating (Latger-Cannard 2011; Kanagal-Shamanna 2017; Chisholm 2019), (Zhang 2015; Poggi 2017) (Noris Perez Botero 2015) mutations. Together, highlight importance initial examination predisposition, demonstrate specific criteria diagnosis Interestingly, group MD Anderson Cancer Center has proposed individuals familial disorder/acute (Kanagal-Shamanna 2017). one minor required make MDS. Major include: (i) identification mutation; (ii) anaemia leucopenia addition thrombocytopenia; (iii) exclusion non-neoplastic causes cytopenias; (iv) <20%. Minor myelodysplasia least acquired clonal abnormality. latter exclude events haematopoiesis indeterminate potential (Steensma 2015), such methyltransferase 3 alpha (DNMT3A) Thus, propose extend those propensity develop 2016 revision WHO HM. summary, due RUNX1, ANKRD26, usually display nuclei, which considered myelodysplasia-related change. authors competing interests. Elise Fournier, Camille Debord, Valérie Soenen, Coralie Derrieux, Thomas Boyer, Soraya Wuillème Nicolas examinations. Pierre Boisseau, Claude Preudhomme analyses. Nathalie Trillot, Fanny Gonzales, Paris, Wadih Abou Chahla, Louis Terriou, Céline Berthon, Anne Lambilliotte, Véronique Tintiller, Marc Fouassier Sophie Susen data. Fournier wrote manuscript, approved authors. Supplemental methods. Please note: publisher content functionality any supporting supplied Any queries (other than missing content) directed corresponding author article.