Thrombocytopenia 3

A number sign (#) is used with this entry because of evidence that thrombocytopenia-3 (THC3) is caused by homozygous mutation in the FYB gene (602731) on chromosome 5p13.

Description

Thrombocytopenia-3 is an autosomal recessive hematologic disorder characterized by onset of small-platelet thrombocytopenia in infancy. Patients may show variable bleeding tendency, manifest as petechiae, epistaxis, or heavy menstrual bleeding (summary by Levin et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see 313900.

Clinical Features

Levin et al. (2013) reported 5 patients from a consanguineous Arab family with small-platelet thrombocytopenia apparent from infancy. The males had low-degree bleeding episodes, whereas 2 females developed severe bleeding during menstruation. Levin et al. (2015) reported follow-up of this family, noting that the patients had normal growth and development and absence of infections. Bone marrow aspirate from 1 patient showed reduced numbers of mature multilobulated megakaryocytes compared to controls, as well as increased megakaryocytes with nuclear hypersegmentation, suggesting abnormal maturation of megakaryocytes.

Hamamy et al. (2014) reported a highly consanguineous kindred from northern Iraq in which 3 children had small-platelet thrombocytopenia. The patients presented in the first 5 years of life with evidence of bleeding, including generalized petechial rash and/or epistaxis. Laboratory studies showed normal hemoglobin concentration and leukocyte counts. There were no giant platelets. Bone marrow examination showed normocellular marrow with normal numbers of megakaryocytes and no abnormal cells. None of the patients had hepatosplenomegaly, skeletal or growth abnormalities, or immune defects.

Inheritance

The transmission pattern of THC3 in the family reported by Hamamy et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 members of a highly consanguineous kindred from northern Iraq with THC3, Hamamy et al. (2014) identified a homozygous frameshift mutation in the FYB gene (602731.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In 5 patients from a large consanguineous Arab family with THC3, Levin et al. (2015) identified a homozygous truncating mutation in the FYB gene (602731.0002). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient platelets showed reduced pseudopodium formation and the presence of trapped platelets between fibrin fibers after thrombin addition compared to controls. Flow cytometric studies showed that patient fibroblasts had increased basal expression of P-selectin (173610) and PAC1, and reduced increments of activation markers after stimulation with ADP. Levin et al. (2015) noted that FYB is important for platelet activation, and that FYB-knockout mice have moderate thrombocytopenia.

History

Schaar (1963) described 4 brothers with idiopathic thrombocytopenic purpura that appeared in early infancy and was symptomatic. Three of the boys were well 14 years, 6 years, and 3 years following splenectomy. The other brother died of pneumococcal septicemia 3.5 years after splenectomy. The disorder was not associated with any other blood dyscrasia, platelet antibodies, or maternal antibodies. A platelet-stimulating factor was present.

Bloom et al. (1966) described a form of constitutional aplastic anemia with 'amegakaryocytic thrombocytopenia present at birth or early infancy, followed later in childhood by pancytopenia.' They called it type II constitutional aplastic anemia.

Maternal-fetal incompatibility of platelet antigens was a cause of neonatal thrombocytopenia in multiple sibs (Paganelli, 1969), simulating recessive inheritance. These patients were chronically thrombocytopenic but responded to the transfusion of normal plasma. Autosomal recessive inheritance has been reported by Roberts and Smith (1950) and by Wilson et al. (1963).