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THROMBOCYTOPENIA 2; THC2

THROMBOCYTOPENIA 2; THC2

Alternative titles; symbolsTHROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 2▼ DescriptionThrombocytopenia-2 (THC2) is an autosomal dominant nonsyndromic disorder character...

Alternative titles; symbols

  • THROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 2

▼ Description
Thrombocytopenia-2 (THC2) 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).

For a discussion of genetic heterogeneity of thrombocytopenia, see 313900.

▼ Clinical Features
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.

▼ Heterogeneity
Families with apparent autosomal dominant inheritance of thrombocytopenia presumably due to other causes have been reported. Helmerhorst et al. (1984) described a family in which 3 members, a brother and sister and a female second cousin of theirs had thrombocytopenia, chromosomal changes like those of Fanconi anemia (but without the developmental features of that disorder) and antiplatelet antibodies. One patient, the cousin, had bone marrow hypoplasia and died from metastatic squamous carcinoma of the mouth at age 27.

Stavem et al. (1986) demonstrated a plasma factor in a patient with hereditary thrombocytopenia. Transfused normal platelets as well as the patients' own platelets had a shortened survival in the patients' circulation. However, the patients' platelets survived normally when transfused to a normal recipient. Platelet-associated immunoglobulins or circulating platelet antibodies were not detected. Daily infusion of platelet-poor plasma resulted in a rise in the platelet count and a decrease in bleeding time. The maximal rise in platelet count and decrease in bleeding time was observed 7 days after a course of infusion on each of the 5 successive days. Return of the platelet count and bleeding time to pretreatment levels occurred 16 days after platelet-poor plasma was discontinued. The response was similar on the second infusion experiment. It was concluded 'that the afflicted family members must have a deficiency of some plasma principal necessary to keep platelets fit and circulating.'

Majado et al. (1992) described benefit from splenectomy in a mother and 1 of her 3 affected children. The mother had splenectomy because of a mistaken diagnosis of idiopathic thrombocytopenic purpura. Because of the benefit, splenectomy was performed also in the oldest child.

▼ Mapping
By genomewide analysis of a large Italian family with autosomal dominant thrombocytopenia, Savoia et al. (1999) found linkage to a 6-cM locus on chromosome 10p12-p11.1 between D10S586 and D10S1639. The locus was designated THC2. A maximum lod score of 8.12 at recombination fraction 0.00 was obtained with the microsatellite D10S588.

By linkage analysis in a large family segregating thrombocytopenia, Drachman et al. (2000) reported a maximum 2-point lod score of 5.68 on proximal 10p.

▼ Cytogenetics
Using short- and long-read whole-genome sequencing in a multigenerational family with thrombocytopenia-2, Wahlster et al. (2021) identified a complex paired-duplication inversion affecting a 1.3-Mb region on chromosome 10, which resulted in a WAC (615049)-ANKRD26 fusion transcript. The fusion transcript consisted of the proximal promoter and exon 1 of the WAC gene and exons 10-34 of the ANKRD26 gene. Characterization of the breakpoint sites showed microhomology between Alu repeats consisting of 45 and 2 bp. mRNA levels of ANKRD26 were shown to be upregulated in the peripehral blood mononuclear cells (PBMCs) of one of the affected family members. The WAC/ANKRD26 fusion transcript enabled translation of a truncated form of ANKRD26 starting from a methionine located in exon 11 (exon 11+ ANKRD26) that would remove all ankyrin repeats but retain the coiled-coil domain. Expression of the exon 11+ ANKRD26 in primary human CD34+ hematopoietic stem cells resulted in increased MAPK activation. Murphy and Mead (2021) commented that whereas in conventional cases of THC2, patients are predisposed to myeloid malignancies, it is not known whether overexpression of a truncated ANKRD26 will lead to a similar susceptibility.

▼ Molecular Genetics
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. 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. One of the families with an ANKRD26 mutation had previously been reported by Savoia et al. (1999) and had been found by Punzo et al. (2010) to have a mutation in the ACBD5 gene (616618). Pippucci et al. (2011) found no mutations in either the ACBD5 or MASTL (608221) gene in 4 families with autosomal dominant thrombocytopenia mapping to chromosome 10.

Associations Pending Confirmation

Gandhi et al. (2003) identified a heterozygous missense variant in the MASTL gene (E167D; 608221.0001) in affected members of the family with thrombocytopenia mapped to 10p by Drachman et al. (2000).

▼ History
Naparstek et al. (1984) concluded that the mutation for autosomal dominant thrombocytopenia is not linked to HLA.

Tags: 10p12.1