A number sign (#) is used with this entry because of evidence that platelet-type bleeding disorder-21 (BDPLT21) is caused by heterozygous mutation in the FLI1 gene (193067) on chromosome 11q24. One family with a homozygous mutation in the FLI1 gene has been reported.

Heterozygous deletion of the FLI1 gene is believed to be responsible for the thrombocytopenia found in Paris-Trousseau type of thrombocytopenia (TCPT; 188025) and Jacobsen Syndrome (JBS; 147791), both of which are contiguous gene deletion syndromes.

BDPLT21 is a hematologic disorder characterized by increased risk of bleeding resulting from a functional platelet defect. Platelets have decreased or even absent dense bodies and abnormally enlarged and fused alpha-granules, and they show defective secretion and aggregation responses to agonists. Platelets are usually enlarged, and some patients may have mild to moderate thrombocytopenia (summary by Saultier et al., 2017).

For a discussion of genetic heterogeneity of BDPLT, see 231200.

Stockley et al. (2013) reported 7 patients from 3 unrelated families with BDPLT21. All patients had excessive bleeding associated with a significant reduction in platelet ATP secretion in response to all agonists tested, consistent with a defect in dense granule secretion. Three of the patients had mild thrombocytopenia. In 2 families, the platelet defect was associated with alopecia, eczema and/or psoriasis, and recurrent viral infections.

Saultier et al. (2017) reported a father and son and an unrelated woman with BDPLT21 manifest as congenital macrothrombocytopenia. The father and son had not experienced significant bleeding episodes, whereas the 52-year-old woman had a history of excessive bleeding, predominantly gynecologic and obstetric, and involving the oral cavity. Patient platelets contained enlarged fused alpha-granules and almost complete absence of dense granules. Cultured patient-derived megakaryocytes were smaller and formed very few proplatelets compared to controls; patient megakaryocytes also had a lower percentage of mature markers compared to controls, suggesting impaired megakaryocyte differentiation. A small number (7-9%) of platelets from 2 patients showed glycogen-containing vacuoles, and a smaller number (3%) of platelets from 1 patient showed autophagosomes. The overall findings suggested a defect in vesicle biogenesis or trafficking.

Autosomal Recessive BDPLT21

Stevenson et al. (2015) reported 2 adult sibs, born of consanguineous Caucasian parents, with a lifelong bleeding disorder characterized by moderate to severe mucosal bleeding and menorrhagia associated with thrombocytopenia and enlarged platelets. Patient platelets showed reduced aggregation in response to ADP and collagen, but normal response to arachidonic acid and ristocetin. Platelet electron microscopy showed some platelets with large, fused, and electron-dense alpha-granules characteristic of the defects observed in Paris-Trousseau thrombocytopenia. There were no other clinical features associated with Paris-Trousseau syndrome or Jacobsen Syndrome. The parents were unaffected.

The transmission pattern of BDPLT21 in the families reported by Stockley et al. (2013) and Saultier et al. (2017) was consistent with autosomal dominant inheritance.

The transmission pattern of BDPLT21 in the family reported by Stevenson et al. (2015) was consistent with autosomal recessive inheritance.

In affected members of 3 unrelated families with BDPLT21, Stockley et al. (2013) identified heterozygous mutations in the FLI1 gene (193067.0001-193067.0003). The mutations, which were found by next-generation sequencing analysis of candidate genes in 13 families with an inherited platelet disorder, were confirmed by Sanger sequencing. There were 2 missense mutations and 1 frameshift mutation. In vitro functional expression assays showed that the missense FLI1 variants were unable to bind to a transcription site in the promoter for GP6 (605546), one of the genes that is regulated by FLI1. Coexpression of the variants with wildtype FLI1 resulted in a significant reduction in transcriptional activity to 60% of wildtype alone. Patient platelets showed abnormal persistent expression of MYH10 (160776), suggesting that this may be a biomarker for FLI1 mutations.

In 3 members of 2 unrelated families with BDPLT21, Saultier et al. (2017) identified heterozygous missense mutations in the FLI1 gene (193067.0004-193067.0005). In vitro functional expression studies using a luciferase reporter showed that both mutations resulted in reduced transcriptional activity compared to wildtype. The mutant proteins were unable to inhibit luciferase activity as well as the wildtype protein; however, cotransfection of mutant FLI1 and wildtype led to normal transcriptional activity. Western blot analysis and immunofluorescence staining showed that both mutant proteins were located primarily in the cytoplasm rather than the nucleus, suggesting altered subcellular localization. Flow cytometric studies of patient platelets showed abnormal persistent expression of MYH10.

In 2 sibs, born of consanguineous parents, with autosomal recessive BDPLT21, Stevenson et al. (2015) identified a homozygous missense mutation in the FLI1 gene (R324W; 193067.0006). The mutation was found by Sanger sequencing and segregated with the disorder in the family. Western blot analysis and in vitro luciferase assays in HEK293 cells showed that the mutation caused a significant decrease in transcriptional activity compared to wildtype as well as decreased levels of platelet GP6, GP9 (173515), and GPIIb (ITGA2B, 607759)/GPIIIa (ITGB3, 173470), indicating a transcriptional defect affecting the promoter of known target genes. MYH10 was detected in the platelets of the probands. Stevenson et al. (2015) noted the unusual recessive inheritance pattern in this family and stated that neither parent had observable platelet defects or abnormal expression of MYH10, suggesting that the R324W mutant retains residual activity and is not a null allele. Other FLI1 mutations that cause disease in the heterozygous state are likely more damaging to protein function.