Thrombocytopenia-2 is an autosomal dominant nonsyndromic disorder characterized by decreased numbers of normal platelets, resulting in a mild bleeding tendency. Laboratory studies show no defects in platelet function or morphology, and bone marrow examination shows normal numbers of ... Thrombocytopenia-2 is an autosomal dominant nonsyndromic disorder characterized by decreased numbers of normal platelets, resulting in a mild bleeding tendency. Laboratory studies show no defects in platelet function or morphology, and bone marrow examination shows normal numbers of megakaryocytes and normal maturation stages, suggesting defective platelet production or release (summary by Pippucci et al., 2011).
- Early Descriptions of Autosomal Dominant Thrombocytopenia
Seip (1963) described a mother and her 2 sons with thrombocytopenia. Platelet antibodies were not demonstrated. One son had bilateral aplasia of the twelfth rib and mild right hydronephrosis. ... - Early Descriptions of Autosomal Dominant Thrombocytopenia Seip (1963) described a mother and her 2 sons with thrombocytopenia. Platelet antibodies were not demonstrated. One son had bilateral aplasia of the twelfth rib and mild right hydronephrosis. The other son had frequent episodes of hematuria and recurrent hydronephrosis. Ata et al. (1965) found undue bleeding in 10 members of 6 sibships in 5 generations of a family. Inheritance was thought to be autosomal dominant with incomplete penetrance in females. Splenectomy performed in 3 affected persons corrected thrombocytopenia. The only affected woman recovered spontaneously. Harms and Sachs (1965) described 3 sisters, their mother and their maternal grandmother with chronic idiopathic thrombocytopenia and platelet autoantibodies associated with a diminution of clotting factor IX (F9; 300746). A particularly convincing pedigree studied by Bithell et al. (1965) had 8 proven cases of thrombocytopenia in 3 generations. In addition, a history of hemorrhagic diathesis was given by 7 other persons so that at least 4 generations and 11 sibships were involved. Murphy et al. (1969) described a family with 5 cases of thrombocytopenia in 3 generations, with no example of male-to-male transmission. Shortened platelet life span was demonstrated and was shown to be an intrinsic property of the platelet. Morphologic and biochemical studies failed to elucidate the nature of the defect. Other apparently dominant pedigrees were reported by Bethard and Boyer (1964) and Wooley (1956). Stavem et al. (1969) described a family with autosomal dominant hereditary thrombocytopenia. Affected family members showed severe nosebleeds in childhood, prolonged bleeding after tooth extractions, and, in females, a tendency to menorrhagia but not to increased postpartum bleeding. Platelet counts usually fluctuated between 30,000 and 80,000. The number and appearance of the megakaryocytes were normal and the platelets, although somewhat larger than normal, were otherwise morphologically not remarkable. The bleeding time was excessively prolonged in spite of only moderately reduced platelet count. On the other hand, the patients had normal tourniquet tests. Najean and Lecompte (1990) studied 54 cases with chronic thrombocytopenia, a normal autologous and homologous platelet life span, increased mean platelet volume without Dohle bodies, absence of any functional platelet abnormalities, and a normal megakaryocyte count. Previous treatment with corticosteroids, immunoglobulins, androgens, immunosuppressor agents, and splenectomy were ineffective. Many relatives were found to be affected also in an autosomal dominant pedigree pattern with many instances of male-to-male transmission. Najean and Lecompte (1990) suggested that the condition is a frequent one that has escaped attention previously due to the mild clinical manifestations. - Families With Proven Mutations in the ANKRD26 Gene Savoia et al. (1999) reported a large Italian family with autosomal dominant thrombocytopenia. Patients showed a moderate thrombocytopenia with minimal symptoms. Laboratory studies showed normocellular bone marrow, normal medium platelet volume, and positive aggregation tests, indicating normal function. Iolascon et al. (1999) reviewed the clinical features of the 17 living affected members of this family; none had major bleeding episodes. Drachman et al. (2000) reported a large family with autosomal dominant, moderate, lifelong thrombocytopenia with a propensity toward easy bruising and minor bleeding. There was no evident association with hematopoietic malignancy or progression to aplastic anemia. Immunosuppression and splenectomy were of no therapeutic help. Affected individuals had normal platelet size and modestly increased thrombopoietin (THPO; 600044) levels. Hematopoietic colony assays from bone marrow and peripheral blood demonstrated that megakaryocyte precursors were dramatically increased in both number and size in affected individuals. This finding and electron microscopic studies indicated that megakaryocytes had markedly delayed nuclear and cytoplasmic differentiation.
Although Gandhi et al. (2003) identified a heterozygous missense variant in the MASTL gene (E167D; 608221.0001) in affected members of the family reported by Drachman et al. (2000), and Punzo et al. (2010) identified a heterozygous variant in ... Although Gandhi et al. (2003) identified a heterozygous missense variant in the MASTL gene (E167D; 608221.0001) in affected members of the family reported by Drachman et al. (2000), and Punzo et al. (2010) identified a heterozygous variant in the ACBD5 gene in the family reported by Savoia et al. (1999), Pippucci et al. (2011) found no mutations in either the MASTL or ACBD5 gene in 4 families with autosomal dominant thrombocytopenia mapping to chromosome 10. However, Pippucci et al. (2011) identified 6 different heterozygous mutations in the 5-prime promoter region of the ANKRD26 gene on chromosome 10p12-p11.1 (see, e.g., 610855.0001-610855.0003), which maps to the THC2 locus, in 9 of 20 unrelated families with autosomal dominant nonsyndromic thrombocytopenia-2. One of the families with an ANKRD26 mutation was the family reported by Savoia et al. (1999) and Punzo et al. (2010), suggesting that the ACBD5 variant did not cause the disorder. Pippucci et al. (2011) used in vitro functional expression assays in Dami human megakaryoblastic cells to show that the ANKRD26 mutations resulted in increased expression, particularly when the cells were stimulated toward maturation. The findings suggested a gain-of-function effect. Pippucci et al. (2011) speculated that the ANKRD26 mutations interfere with mechanisms controlling the expression of ANKRD26, which would then affect megakaryopoiesis and platelet production, perhaps by inducing apoptosis.