Gray platelet syndrome

Gray platelet syndrome (GPS), or platelet alpha-granule deficiency,[1] is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis.[2] The name derives from the initial observation of gray appearance of platelets with a paucity of granules on blood films from a patient with a lifelong bleeding disorder.[3]

Gray platelet syndrome
Other namesPlatelet alpha-granule deficiency
Gray platelet syndrome is inherited in an autosomal recessive manner.
SpecialtyHematology 

Signs and symptoms

Signs of GPS typically arise at birth or in childhood, these signs and symptoms include thrombocytopenia, bruising susceptibility, and epistaxis. Typically, the observed low platelet count in individuals is progressive, this can result in fatal hemorrhages later in life. Additionally, females who are affected may experience irregular menstrual cycles and heavy menstrual bleeding.[4] Another common effect of GPS is myelofibrosis, where scar tissue builds up in the bone marrow causing it to be unable to produce a sufficient amount of blood cells. To compensate, other organs such as the spleen start to produce more blood cells which can lead to splenomegaly.[5]

Genetics

GPS is primarily inherited in an autosomal recessive manner. The gene that is mutated in GPS has been mapped to chromosome 3p[6] and identified as NBEAL2.[7] The location is 3p21.31.[8] This is caused by a homozygous or compound heterozygous mutations in the NBEAL2 gene.[9] NBEAL2 encodes a protein containing a BEACH domain that is predicted to be involved in vesicular trafficking. It is expressed in platelets and megakaryocytes and is required for the development of platelet alpha-granules.[10] NBEAL2 expression is also required for the development of thrombocytes in zebrafish.[11]

In Japan, GPS was found in 24 affected patients in a single family. There was at least 1 instance of male-to-male transmission, consistent with autosomal dominant inheritance.[12]

A study reported of 14 families with GPS, 11 families had clear autosomal recessive inheritance. This was evidenced by consanguinity or multiple affected siblings with unaffected parents. The families had various backgrounds, including Bedouin, Turkish, Mennonite, French, German, Somali, African American, and mixed Northern and Southern European.[6]

GPS is characterized by "thrombocytopenia, and abnormally large agranular platelets in peripheral blood smears."[13] The defect in GPS is the failure of megakaryocytes to package secretory proteins into alpha-granules. Patients with the GPS are affected by mild to moderate bleeding tendencies. Usually these are not major bleeds but there has been some life-threatening cases. Affected women will tend to have heavy, irregular periods. Myelofibrosis is a condition that usually comes with GPS.[14]

Diagnosis

GPS is diagnosed based on clinical findings and requires demonstration of absence or marked reduction of alpha-granules by electron microscopy (EM).[15] High serum vitamin B12 levels are common in patients diagnosed with GPS. Bone marrow sampling, though not required for diagnosis of GPS, might be necessary to evaluate myelofibrosis occurring in GPS and to exclude other disorders.[15]

Management

There is no specific treatment  for GPS, but it can be managed by anticipating and preventing the risks of bleeding. The treatment options include desmopressin.[16] Splenectomy can be used to increase the platelet counts in those whose platelet counts decrease to approximately 30,000/microliter.[16] Prognosis is generally good early in life when thrombocytopenia is mild.[16]

Epidemiology

Currently, only 60 cases have been recorded worldwide. While the prevalence of this syndrome is not known, it was found that it affects males and females equally.[17]

See also

References
  1. Online Mendelian Inheritance in Man (OMIM): 139090
  2. Nurden AT, Nurden P (January 2007). "The gray platelet syndrome: clinical spectrum of the disease". Blood Reviews. 21 (1): 21–36. doi:10.1016/j.blre.2005.12.003. PMID 16442192.
  3. Rao, A. Koneti; Rao, Deepak A. (2020-10-22). "Gray platelet syndrome: immunity goes awry". Blood. 136 (17): 1898–1900. doi:10.1182/blood.2020008196. ISSN 0006-4971. PMC 7582557. PMID 33091137.
  4. "Gray platelet syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-26.
  5. "Gray platelet syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 2021-04-26.
  6. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F, Geiger D, Cetin M, Khayat M, et al. (December 2010). "Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p". Blood. 116 (23): 4990–5001. doi:10.1182/blood-2010-05-286534. PMC 3012593. PMID 20709904.
  7. Kahr WH, Hinckley J, Li L, Schwertz H, Christensen H, Rowley JW, et al. (July 2011). "Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome". Nature Genetics. 43 (8): 738–40. doi:10.1038/ng.884. PMC 6050511. PMID 21765413.
  8. "OMIM Gene Map - Chromosome: 3". www.omim.org. Retrieved 2021-04-26.
  9. "OMIM Entry - # 139090 - GRAY PLATELET SYNDROME; GPS". www.omim.org. Retrieved 2021-04-26.
  10. Gunay-Aygun M, Falik-Zaccai TC, Vilboux T, Zivony-Elboum Y, Gumruk F, Cetin M, et al. (July 2011). "NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules". Nature Genetics. 43 (8): 732–4. doi:10.1038/ng.883. PMC 3154019. PMID 21765412.
  11. Albers CA, Cvejic A, Favier R, Bouwmans EE, Alessi MC, Bertone P, et al. (July 2011). "Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome". Nature Genetics. 43 (8): 735–7. doi:10.1038/ng.885. PMC 3428934. PMID 21765411.
  12. Mori K, Suzuki S, Sugai K (July 1984). "Electron microscopic and functional studies on platelets in gray platelet syndrome". The Tohoku Journal of Experimental Medicine. 143 (3): 261–87. doi:10.1620/tjem.143.261. PMID 6484975.
  13. Jantunen E, Hänninen A, Naukkarinen A, Vornanen M, Lahtinen R (July 1994). "Gray platelet syndrome with splenomegaly and signs of extramedullary hematopoiesis: a case report with review of the literature". American Journal of Hematology. 46 (3): 218–24. doi:10.1002/ajh.2830460311. PMID 8192152. S2CID 127060.
  14. "OMIM Entry - # 139090 - GRAY PLATELET SYNDROME; GPS". www.omim.org. Retrieved 2021-04-26.
  15. RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Gray platelet syndrome". www.orpha.net. Retrieved 2021-04-26.
  16. "Gray platelet syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-27.
  17. RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Gray platelet syndrome". www.orpha.net. Retrieved 2021-04-27.
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