Gray Platelet Syndrome

Alternative Names

  • GPS
  • Bleeding Disorder, Platelet-Type, 4
  • BDPLT4
  • Platelet Alpha-Granule Deficiency
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Coagulation defects, purpura and other haemorrhagic conditions

OMIM Number

139090

Mode of Inheritance

Autosomal dominant, autosomal recessive

Gene Map Locus

3p21.31

Description

The gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by thrombocytopenia, splenomegaly, myelofibrosis, and a marked decrease or absence of alpha-granules and platelet-specific alpha-granule proteins. In GPS patients, the platelets appear large and contain few granules, giving them a gray appearance on Wright-stained smears. GPS has been described in both males and females. The disorder has been reported as autosomal dominant, but in several cases a recessive inheritance was suggested.

Gray platelet syndrome (GPS) is linked to mutations in the NBEAL2 gene on chromosome 3p21. NBEAL2 belongs to the BEACH (beige and CHS1) domain-containing protein family, which includes NBEAL1, neurobeachin (NBEA), CHS1 (LYST), and LRBA. NBEAL2 is predicted to have a role in alpha-granule biogenesis in megakaryocytes.

Molecular Genetics

Gray platelet syndrome (GPS) is linked to mutations in the NBEAL2 gene on chromosome 3p21. NBEAL2 belongs to the BEACH (beige and CHS1) domain-containing protein family, which includes NBEAL1, neurobeachin (NBEA), CHS1 (LYST), and LRBA. NBEAL2 is predicted to have a role in alpha-granule biogenesis in megakaryocytes.

Epidemiology in the Arab World

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Other Reports

Palestine

Alkhairy (1995) reported the gray platelet syndrome in a Palestinian female teenager from Saudi Arabia with menorrhagia and thrombocytopenia from menarche at 11 years. This was the first report of gray platelet syndrome in an Arab patient. The proband was an 18 year old who presented for the first time with a history of dizziness and general fatiguability of two weeks duration. She had a history of easy bruising and epistaxis since childhood. Three of her 5 sibs, all male, had a bleeding tendency. All 3 bled for 24 hours after hospital-based circumcision and required multiple ligations to achieve hemostasis. All 4 affected sibs displayed typical morphology of gray platelet syndrome. The parents were first cousins of Palestinian origin with normal hematologic parameters. The fact that four siblings of both sexes are simultaneously involved indicates that their disorder is inherited in autosomal recessive manner; though gonadal mosaicism for a dominant gene defect cannot be excluded.[Alkhairy KS. The gray platelet syndrome in four members of a Palestinian Arab family. Emirates Med J. 1995; 13: 137-41.]

Falick-Zaccai et al. (2001) described two siblings with the gray platelet syndrome who are members of a Muslim Bedouin genetic isolate in the north of Palestine. The children, an 8-year-old girl and a 5-year-old boy, had characteristic pale blue platelets lacking alpha granules on electron microscopy. Platelet aggregation studies were normal. The girl underwent a bone marrow aspiration and biopsy which showed mild myelofibrosis and extensive emperipolesis, i.e., the passage of other hematopoietic cells through megakaryocytes. Both children lacked high-molecular-weight multimers of von Willebrand factor (vWF) and had reduced activity and antigens of vWf. Platelet activation was approximately normal when ADP was employed as agonist, but significantly impaired using the thrombin receptor-activating peptide (TRAP). These findings are explained in light of the mechanism of action of each agonist. Falick-Zaccai et al. (2001) proposed a recessive inheritance of the gray platelet syndrome in the family since the parents of the affected individuals were normal. However, they noted that one cousin required splenectomy due to severe thrombocytopenia and splenomegaly, and a total of five additional family members were previously diagnosed with gray platelet syndrome. Four of the five had myelofibrosis documented on bone marrow examination. In 2010, Gunay-Aygun et al. reported 14 families with GPS, including 11 with clear autosomal recessive inheritance, as evidenced by consanguinity or multiple affected sibs with unaffected parents. The families included the one reported by Falick-Zaccai et al. (2001) and another Bedouin consanguineous family that had a male diagnosed with the disease at 46 years of age. This patient had splenomegaly, but without hemorrhages.

Saudi Arabia

See also: Palestine > Alkhairy (1995).

Somalia

White et al. (2006) evaluated what was considered as the first family from East Africa with two affected members, a brother and sister with gray platelet syndrome. Neither child has had significant bleeding problems. Electron microscopic studies revealed almost complete absence of alpha granules from their platelets. Instead their platelets were filled with vacuoles similar in size to the missing granules. Dense bodies were normal in number in the girl's platelets, but markedly increased in her brother's cells. Tannic acid staining revealed that very few of the vacuoles were connected to channels of the open canalicular system. As a result, contents of the residual alpha granule vacuoles must leak out of the organelles and diffuse through megakaryocyte and platelet cytoplasm to the outside. The route of escape may differ from other hypogranular platelet syndromes, such as alpha-delta platelet storage pool deficiency. In 2010, Gunay-Aygun et al. reported 14 families with GPS, including 11 with clear autosomal recessive inheritance, as evidenced by consanguinity or multiple affected sibs with unaffected parents. The families had various backgrounds, including the Somali family originally reported by White et al. (2006). Gunay-Aygun et al. (2010) mapped the GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1 using genome-wide linkage analysis.

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