Bleeding Disorder, Platelet-Type, 17

A number sign (#) is used with this entry because of evidence that platelet-type bleeding disorder-17 (BDPLT17) is caused by heterozygous mutation in the GFI1B gene (604383) on chromosome 9q34.

Description

Platelet-type bleeding disorder-17 is an autosomal dominant disorder characterized by increased bleeding tendency due to abnormal platelet function. It is a type of 'gray platelet syndrome' because the platelets appear abnormal on light microscopy. Electron microscopy shows decreased or absent alpha-granules within platelets, and bone marrow biopsy shows increased numbers of abnormal megakaryocytes, suggesting a defect in megakaryopoiesis and platelet production. The bleeding severity is variable (summary by Monteferrario et al., 2014).

Clinical Features

Quick and Hussey (1962) reported hereditary thrombasthenia-thrombocytopenia, which they differentiated from von Willebrand disease (see, e.g., 193400) by a negative tourniquet test and poor prothrombin consumption. Onset was in infancy with a hemophilia-like picture and prolonged bleeding time. Platelets were normal in number, and the disorder was not influenced by splenectomy.

Seip (1964) observed autosomal dominant transmission of hypoplastic thrombocytopenia in 2 families. Marrow preparations showed normal or increased megakaryocytes with little or no sign of active thrombopoiesis. No response to adrenal steroids or splenectomy was noted. Seip and Kjaerheim (1965) studied a mother and her only son. Symptoms and signs were present from birth. Bleeding time exceeded 30 minutes, and platelet counts varied from 60,000 to 120,000. Electron microscopy showed vacuoles in the platelets and some had abnormal granules.

Kurstjens et al. (1968) reported a large family in which 8 individuals in 3 generations had a bleeding disorder associated with thrombocytopenia and platelet dysfunction. Features included spontaneous epistaxis, gastrointestinal bleeding, bleeding after tooth extraction, frequent bruises, and hematomas. Females had menorrhagia and postpartum hemorrhaging. Splenectomy performed in 2 patients did not improve the thrombocytopenia. Light microscopy showed that a number of the platelets were unusually large, and electron microscopy showed small or absent alpha-granules within platelets. Patient platelets had decreased release of platelet factor-3. Platelet survival was normal. Bone marrow biopsy showed slightly increased number of abnormal megakaryocytes with irregular nuclei; signs of platelet production were virtually absent. Erythropoiesis and granulopoiesis were normal. Kurstjens et al. (1968) noted the phenotypic similarities to the disorder described by Quick and Hussey (1962). Monteferrario et al. (2014) restudied the family reported by Kurstjens et al. (1968). Patient blood smears showed a ghostlike, gray appearance of enlarged platelets, and electron microscopy showed a marked reduction in the number of alpha-granules within platelets. Platelets showed reduced platelet factor-4 (PF4; 173460) and decreased beta-thromboglobulin (see 121010). Bone marrow biopsy from 1 patient showed myelofibrosis, increased numbers of megakaryocytes that were pleomorphic in size and shape, and emperipolesis. Megakaryocytes had dysplastic features, including hypolobulation of the nucleus and multiple separated nuclei. The megakaryocytes were clustered along bone marrow sinuses and had stretched features.

Ardlie et al. (1976) reported a large family in which 10 individuals spanning 3 generations had a bleeding disorder due to congenital thrombocytopenic thrombopathy. The disorder was characterized by thrombocytopenia, morphologically abnormal platelets, prolonged bleeding time, platelet coagulant activity deficiency, and abnormal platelet aggregation. The patients' platelets adhered to collagen, but aggregation was reversible, and there was decreased release of platelet constituents. The deficiency of platelet coagulant activity caused a delay and decrease in the conversion of prothrombin to thrombin, which may have caused an unstable hemostatic plug. Stevenson et al. (2013) reported follow-up of the then 4-generation Caucasian family reported by Ardlie et al. (1976). Affected individuals had a bleeding disorder manifest as excessive bruising from childhood, epistaxis, and prolonged bleeding from cuts and superficial injuries. Bleeding also occurred after dental extraction and minor surgeries and trauma. All affected individuals had moderate thrombocytopenia, and peripheral blood smear showed large platelets and anisopoikilocytosis of red cells. Flow cytometry showed normal levels of platelet surface glycoproteins; however, SELP (173610) was significantly reduced after ADP activation compared to controls.

Ferreira et al. (2017) reported 2 patients with combined alpha-delta storage pool deficiency. The first patient was a 13-year-old boy who presented at birth with scalp petechiae, severe thrombocytopenia, and transient anemia with anisocytosis. He had numerous episodes of epistaxis and required platelet transfusions. Platelet size was normal. There were decreased alpha-granules and dense bodies. Bone marrow showed dysplastic megakaryocytes. The patient also had subglandular hypospadias requiring surgical repair and unilateral periventricular heterotopia. The second patient was an 8-year-old boy born to reportedly nonconsanguineous Mexican parents who presented with spontaneous petechiae at 3 months of age and was found to have thrombocytopenia. Bone marrow biopsy at 10 months showed megakaryocytes suggestive of idiopathic thrombocytopenic purpura, but he did not respond to intravenous immunoglobulins. He had spontaneous bruising, petechiae, and epistaxis and required platelet transfusions for surgery or prolonged bleeding. He had significantly decreased alpha-granules and virtually absent dense granules. He also presented with persistent patent ductus arteriosus.

Mapping

By linkage analysis in the family with thrombopathic thrombocytopenia reported by Kurstjens et al. (1968), Monteferrario et al. (2014) found linkage to a region on chromosome 9q34 (maximum lod score of 3.9). By linkage analysis of the family with thrombopathic thrombocytopenia reported by Ardlie et al. (1976), Stevenson et al. (2013) found linkage to a region on chromosome 9q34 (maximum lod score of 4.51).

Molecular Genetics

In affected members of a family with platelet-type bleeding disorder-17, originally reported by Kurstjens et al. (1968), Monteferrario et al. (2014) identified a heterozygous truncating mutation in the GFI1B gene (Q287X; 604383.0001). The mutation was found by linkage analysis followed by candidate gene sequencing. The surface expression of several platelet markers, including alpha-2-beta integrin (ITGA2B; 607759), was normal, but 5 of 6 affected individuals had a marked decrease in the expression of platelet glycoprotein Ib-alpha (CD42B, GP1BA; 606672). Patient platelets also showed increased expression of CD34 (142230). In vitro functional expression studies showed that the mutant protein lacked transcriptional repression activity and acted in a dominant-negative manner when coexpressed with the wildtype protein. Expression of the mutation in mouse bone marrow cells resulted in dysplastic megakaryocytes with hypolobulated nuclei, irregular contours, and multiple separated nuclei, similar to the features observed in patient cells. The findings indicated that GFI1B has an important role in megakaryopoiesis and normal platelet production.

In affected members of a large family with BDPLT17 originally reported by Ardlie et al. (1976), Stevenson et al. (2013) identified a heterozygous truncating mutation in the GFI1B gene (604383.0002). In vitro cellular functional expression assays showed that the mutant protein was unable to repress the transcription of the target gene TGFBR3 (600742) and of itself, even when expressed with wildtype GFI1B. Patient platelets had decreased levels of the alpha-granule-related protein P-selectin (SELP), with smaller reductions in ITGB3 (173470) and GP1BA, compared to controls. These findings were associated with decreased alpha-granules observed by electron microscopy in patient platelets.

Ferreira et al. (2017) reported 2 unrelated patients with combined alpha-delta storage pool deficiency. The first, a 13-year-old boy, had a de novo heterozygous nonsense mutation in the GFI1B gene (604383.0003). The second, an 8-year-old boy, was homozygous for a missense mutation in the GFI1B gene (604383.0004).

Inheritance

The transmission pattern of thrombopathic thrombocytopenia in the families reported by Kurstjens et al. (1968) and Ardlie et al. (1976) was consistent with autosomal dominant inheritance.