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Familial platelet disorder with associated myeloid malignancy
A rare, genetic, constitutional thrombocytopenia disease characterized by mild to moderate thrombocytopenia, abnormal platelet function and a propensity to develop hematological malignancies, mainly of myeloid origin.
ORPHA:71290Classification level: Disorder
- Familial platelet disorder with predisposition to acute myelogenous leukemia
- Familial platelet disorder with predisposition to myeloid malignancy
- Familial platelet disorder with propensity to acute myeloid leukemia
- Familial thrombocytopenia with propensity to acute myelogenous leukemia
- Prevalence: -
- Inheritance: Autosomal dominant
- Age of onset: -
- ICD-10: D69.4
- OMIM: 601399 616216
- UMLS: C1832388
- MeSH: -
- GARD: 10352
- MedDRA: -
The estimated prevalence at birth is less than 1/ 1 000 000. There are no available data on the incidence of the disease.
Patients present mild to moderate thrombocytopenia (with normal platelet size) and/or abnormalities of platelet function, in particular defective release of delta granules and/or aggregation defects. However, a clear bleeding history (i.e., severe epistaxis, easy bruising, petechial or prolonged bleeding) is absent in many affected individuals. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal or infancy period.
Heterozygous germline nonsense or missense variants as well as deletions in or of RUNX1 gene (21q22.12) have been identified as the causative alteration of the disease.
Diagnosis is suspected in patients who present with mild to moderate thrombocytopenia, thrombocyte aggregation defect and/or a hematological malignancy (mainly MDS/AML, but also T-ALL) and may have a history of the same in various other family members. Genetic testing including sequencing and copy number analyses that identifies a pathogenic variant in RUNX1 confirms diagnosis.
Differential diagnoses for hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome include several inherited disorders such as Congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), and Wiskott-Aldrich syndrome (WAS).
Prenatal diagnosis is possible in families in which a causative gene mutation has been previously identified in an affected family member.
The disease is inherited as an autosomal dominant trait exhibiting incomplete penetrance and variable expressivity. Genetic counseling informing patients with a causative mutation of the 50% risk of transmission to future offspring and their risk to leukemia should be offered in expert centers.
Management and treatment
Currently, hematopoietic stem cell transplantation (HSCT) in preleukaemic patients with the disease remains debatable due to transplantation-associated risks and incomplete penetrance of the disease. In patients with a hematologic malignancy, HSCT may be indicated. However, HSCT using cells of HLA-matched relatives carrying the familial gene variant have to be avoided.
Prognosis depends on the development of a hematological malignancy and its disease course.