Thrombocytopenia 1

A number sign (#) is used with this entry because of evidence that X-linked thrombocytopenia (THC1) is caused by mutation in the WAS gene (300392), which is also involved in the Wiskott-Aldrich syndrome (301000).

Description

Hereditary nonsyndromic thrombocytopenia is characterized by decreased numbers of platelets and bleeding tendency (summary by Villa et al., 1995).

Genetic Heterogeneity of Hereditary Thrombocytopenia

Autosomal dominant forms of thrombocytopenia include THC2 (188000), caused by mutation in the ANKRD26 (610855) gene on chromosome 10; THC4 (612004), caused by mutation in the CYCS gene (123970) on chromosome 7; THC5 (616216), caused by mutation in the ETV6 gene (600618) on chromosome 12p13; and THC6 (616937), caused by mutation in the SRC gene (190090) on chromosome 20q12.

An autosomal recessive form (THC3; 273900) is caused by mutation in the FYB gene (602731) on chromosome 5p13.

Also see 188000 for discussion of a possible form of THC caused by mutation in the MASTL gene (608221) on chromosome 10.

Balduini and Savoia (2012) reviewed the familial forms of thrombocytopenia and their molecular bases.

Clinical Features

Vestermark and Vestermark (1964) found X-linked 'essential' thrombocytopenia in 2 generations of a family. One affected male became symptom-free spontaneously after puberty and one became symptom-free after splenectomy at the age of 18 years but died later of adrenal hemorrhage. Three other patients had, in addition to hemorrhagic diathesis, a mild tendency to infection and eczema. A probable X-linked thrombocytopenia was described by Ata et al. (1965) in 9 males in 6 sibships in 4 generations of a kindred, connected by females. In addition, 1 female was affected. She was karyologically normal and the father had no history of bleeding. Therefore, she probably represents unfortunate lyonization. She differed from the affected males in recovering spontaneously. Canales and Mauer (1967) studied a family containing 7 thrombocytopenic males in an X-linked recessive pedigree pattern. Although no eczema or undue susceptibility to infection was noted and bleeding symptoms were mild, 5 of the 7 showed reduced or absent isohemagglutinins and increased gamma-A globulin. In the 13 affected members of the kindred reported by Chiaro et al. (1972), bleeding had its onset at about age 6 years, and spontaneous remission of 'bleeding' but not of thrombocytopenia occurred in early adult life.

Inoue et al. (2002) reported what they believed to be the first confirmed report of XLT in a female. The 6-year-old girl, who had petechiae and thrombocytopenia from the age of 3 months, had a WASP mutation (300392.0016) and her WASP expression levels were one-third those of a healthy control. The patient's lymphocytes showed a random pattern of X-chromosome inactivation. Her 2-year-old brother also had XLT.

Intermittent X-Linked Thrombocytopenia

Notarangelo et al. (2002) reported 2 families in which affected males had a history of intermittent thrombocytopenia with consistently reduced platelet volume, in the absence of other clinical features, and carried missense mutations in the WASP gene that allowed substantial protein expression (300392.0013, 300392.0014). The authors stated that the phenotype represented the mildest consequence of WASP mutations; because none of the affected males had serious problems, no treatment was indicated. The authors suggested that males with persistently low mean platelet volume must be considered for mutation analysis at the WASP locus, regardless of the platelet count.

Similarities to Wiskott-Aldrich syndrome

Cohn et al. (1975) provided follow-up on the kindred of Vestermark and Vestermark (1964). They found evidence of an immunologic defect, thus raising questions of the distinctness of the disorder from Wiskott Aldrich syndrome and from the condition described in entry 314000. Donner et al. (1988) also suggested that X-linked thrombocytopenia and WAS may be related disorders. They studied a family in which 8 males had thrombocytopenia associated with reduced platelet volume, a feature found also in WAS, but no immunodeficiency. Linkage analysis in this family demonstrated linkage of the disorder to the region of Xp where the WAS locus maps.

Knox-Macaulay et al. (1993) described a Saudi Arabian family in which 3 brothers presented in early childhood with thrombocytopenia but without immunologic abnormalities. Results of DNA analysis with the probe M27-beta were consistent with X-linkage and indicated also that the locus of the relevant gene lies close to or is identical to the WAS locus. However, there were distinguishing features which included the presence of large and normal-sized platelets (rather than small platelets) and, as stated, freedom from immune deficiency. Mean platelet volume was increased and the bone marrow showed increased numbers of megakaryocytes.

Mapping

In a family in which 8 males had X-linked thrombocytopenia, Donner et al. (1988) found linkage of the disorder to DXS146, a marker on the proximal part of Xp (maximum lod = 3.42 at theta = 0.00); the WAS locus maps to the same region.

Molecular Genetics

Villa et al. (1995) presented clear evidence that X-linked thrombocytopenia is a disorder allelic to Wiskott-Aldrich syndrome. They found 3 different mutations in the WAS gene in 3 unrelated males with isolated thrombocytopenia and small-sized platelets (300392.0004-300392.0006). None of the 3 patients had other features of the Wiskott-Aldrich syndrome, and none of the 3 mutations had been found in patients with the Wiskott-Aldrich syndrome. Why some mutations impair only the megakaryocytic lineage whereas others affect the lymphoid lineage as well is not clear. Zhu et al. (1995) came to the same conclusion that X-linked thrombocytopenia and WAS are caused by mutations in the same gene. Patients with classic WAS had what they referred to as 'more complex' mutations, resulting in termination codons, frameshift, and early termination. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice site mutation affecting exon 9. Wengler et al. (1995) identified 15 novel mutations in patients with full-blown Wiskott-Aldrich syndrome. These mutations involved single basepair changes, or small insertions or deletions, all of which resulted in premature stop codon, frameshift with secondary premature stop codon, or splice site defect.