Thrombocytopenia

The inherited thrombocytopenias (IT) are clinically and genetically heterogeneous hereditary disorders. They are defined by a persistently reduced platelet count and, in many forms, additional qualitative platelet defects; clinical expression ranges from incidental laboratory findings to overt mucocutaneous bleeding. Onset is predominantly congenital or in early childhood across the majority of forms, although milder disorders may not be recognised until adolescence or adulthood. Both non-syndromic presentations, restricted to a reduced platelet count with or without abnormal platelet morphology, and syndromic presentations with extra-haematological features (such as immunodeficiency, skeletal anomalies, renal or auditory involvement, or characteristic neutrophil inclusions) are recognised; in a subset of inherited forms, thrombocytopenia coexists with a predisposition to myeloid or lymphoid malignancy. Inherited thrombocytopenia is poorly recognised in general clinical practice and frequently misdiagnosed as immune thrombocytopenia (ITP), the most common acquired form; this misclassification can delay accurate counselling and appropriate treatment.

Literature generally estimates the overall prevalence of inherited thrombocytopenias to range between 1 in 100,000 to 1 in 10,000. However, population genomic data suggest that the prevalence of underlying pathogenic genetic variants is substantially higher than the number of clinically diagnosed cases, indicating a significant degree of underdiagnosis or misdiagnosis. Across published cohorts, no causative gene variant is identified in approximately 50% of individuals with suspected inherited thrombocytopenia despite high-throughput sequencing.

More than 40 genes are currently associated with inherited thrombocytopenia. The genetic forms span macrothrombocytopenia, syndromic forms with extra-haematological involvement, and forms predisposing to haematological malignancy; representative entities caused by germline pathogenic variants include MYH9-related disease (macrothrombocytopenia with neutrophil myosin aggregates), WAS-related disorders (thrombocytopenia with eczema and immunodeficiency), and RUNX1-FPDMM (autosomal dominant thrombocytopenia with increased leukaemia risk).

The genetic conditions associated with inherited thrombocytopenia follow heterogeneous inheritance patterns. Autosomal dominant inheritance predominates by number of disorders across the catalogued spectrum, with autosomal recessive and X-linked forms also represented; submicroscopic chromosomal microdeletions (notably involving the 11q23 region) account for a further subset of cases.

• Where inherited thrombocytopenia is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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