Journal of Rawalpindi Medical College (JRMC); 2016;20(1):67-69

Case Report Gray Syndrome

Nadeem Ikram 1, Muhammad Ali Khalid 2, Omar Kaleem 2 Department of Pathology Benazir Bhutto Hospital and Rawalpindi Medical College,Rawalpindi; 2. Department of Medicine Benazir Bhutto Hospital and Rawalpindi Medical College Introduction going for bone marrow examination revealed giant Inherited thrombocytopenias constitute an important , with decreased granularity (Figure 1). A group . They are classified on the basis of inheritance probable diagnosis of Gray Platelet Syndrome was pattern and platelet morphology. At many times they made. Patient revealed a raised vitamin B12 ,i.e. remain undiagnosed or diagnosed as immune 1326ng/L (reference range: 208-964 pg/ml), with thrombocytopenic . All this leads to treatment normal folic acid .On detail inquiry the information failure. Out of all these inherited thrombocytopenias, gathered showed that one of her brother and sister gray platelet syndrome (GPS) is an entity least were also suffering from similar complaints. recognized. Reports on GPS are limited to case Peripheral blood examination of them also showed presentations. Long term follow up date demonstrated similar platelets morphology. She was put on tab the progressive nature of and Norethisterone ,tab Tranexamic acid,tab. Ibert myelofibrosis of GPS resulting in fatal haemorrhages folic,tab. Vitami( K 10 mg),inhaled Desmopressin in many patients. 1, 2 A case of GPS is presented (0.01mg) and tab.Desmopression( 0.2mg). She is on which shares many features typical for the disease, one month follow up and is asymptomatic so far . but remain undiagnosed for a long time which is also not an unusual happening

Case Report A 15 year old girl presented with complaint of excessive menstrual for last two weeks. She gave history of recurrent bruising over limbs and abdomen from the age of 3 years.She was referred to tertiary care hospital by the local medical practitioner. Blood complete picture performed at that time revealed platelet count of 26000/cmm. Bleeding time was prolonged (more than 15 minutes). Other Figure 1: Gray platelet syndrome (Peripheral blood film)- parameters were within normal limits . Bone marrow Giant and poorly stained platelets (arrow heads) aspiration performed at that time was suggestive of excessive peripheral destruction of platelets, immune? (thrombocytopenia with increased ). She was treated with steroids .After two years she again developed similar features. Bone marrow was repeated and was again consistent with excessive peripheral destruction of platelets (immune?). She remained symptomatic with multiple episodes of , bruising and ecchymoses. At the age of 13 she started having menorrhagia. She received platelet transfusion many times. was suggested but patient refused. Autoimmune profile was Figure 2: Gray platelet syndrome (Peripheral blood film)- negative. She was managed on the lines of ITP. Giant and poorly stained platelets (arrow heads) Echocardiography revealed mitral prolapse. In view of her longstanding illness and repeated hospital Discussion admissions with failure to improve despite steroid Gray platelet syndrome is a rare entity. According to therapy a repeat bone marrow examination was British journal of haematology there are less than 100 advised. Peripheral blood film examination before reported cases of gray platelet syndrome (GPS) uptil

67 Journal of Rawalpindi Medical College (JRMC); 2016;20(1):67-69 few years back. 3 American journal blood described a gene . Mutation of this gene leads to deficiency of case series of 25 patients of GPS, from 14 families of alpha granules causing GPS. 6 In GPS, the proteins different ethnicities. Idiopathic thrombocytopenic Table 2: Congenital Thrombocytopenia- purpura was initial diagnosis in majority of cases. 2 Classificaiton on the basis of platelet size 4,5 Same happened with this case. Unfortunately at many High Mean MYH9- related disorders times the patients with inherited thrombocytopenias Platelet May- Hegglin disorder go through splenectomy as they are labeled as ITP . Volume Sebastain anomaly Now there are many distinct entities included in the (MPV) Fachtner anomaly list of congenital thrombocytopenias. On the basis of Epstein anomaly) inheritance as autosomal dominant, recessive or X- Gray platelet syndrome linked. Then on the basis of platelet size as with Mediterranean macrothrombocytopenia decreased volume or with normal volume and then Bernard Soulier Syndrome megathromboytes. It is important to rule out the GATa-1 mutation possibility of all these (Table 1 &2). Paris-Trousseau syndrome

Low Mean Variant (type 2B Table 1: Congenital Thrombocytopenia- On the Platelet and Platelet type) basis of inheritance Volume 22 q 11 deletion syndrome (DiGeorge Autosomal Recessive Thrombocytopenia with absent (MPV) Syndrome) Thrombocytopenias Radii (TAR) Wiskott-Aldrich Syndrome Bernard Soulier Syndrome Normal ATRUS Syndrome Gray platelet Syndrome Mean Thrombocytopenia with absent Radii MYH9 Related Disorders: Platelet (TAR) (i)May- Hegglin disorder Volume Congenital amegakaryocytic (ii)Sebastain anomaly (MPV) thrombocytpenias (iii)Fachtner anomaly (iv)Epstein anomaly Familial platelet disordser with predisposition to AML Autosomal Mediterranean Dominant macrothrombocytopenia THC2 (Autosomal dominant thrombocytopenia with incomplete Thrombocytopenias Familial platelet disorder with differentiation and predisposition to AML linkage to chromosome 10 Amegakaryocytic X-linked thrombocytopenia with GARa-1 thrombocytopenia with radial- mutation ulner synostosis (ATRUS) Variant von Willebrand disease normally stored in alpha granule are released into the (type 2b and platelet type) bone marrow leading to myelofibrosis and ultimately X-linked X-linked splenomegaly. Absence of clotting proteins in platelets microthrombocytopenia (WAS lead to functional platelet defect causing bleeding gene mutation) tendency. Low platelet counts, Prolonged bleeding X-linked time,grey giant platelets on peripheral blood are macrothrombocytopenia with important findings. Eventually patient may develop dyserythropoiesis(GATA-1 bone marrow fibrosis, because of the release of mutationaaa) fibrogenic factors from platelets’ alpha granules . Mild Di George syndrome (22 q 11 to moderate bone marrow fibrosis is described in most, deletion syndrome) but not all cases of GPS. Megathrombocytopenias are the commonest cause of GPS is also labelled as “Platelet Alpha Granule inherited forms of thrombocytopenia. Among these a Deficiency”, as congenitally there is deficiency of α- series of diseases have been characterized at molecular granules of platelets because of which the platelets are level, whereas other clinical entities still await clear not properly stained on Rowmanosky stains . Gene identification of molecular defect. GPS in an autosomal that encodes for alpha granule is present on recessive pattern revealed mutations within NBEAL2 chromosome 3p. Now the mutated gene of gray gene, although a dominant transmission has shown a platelet syndrome is identified and is labeled as HZF missense mutation at position 759 in the GATA-1 gene

68 Journal of Rawalpindi Medical College (JRMC); 2016;20(1):67-69

, inducing an amino acid change (Arg 216 glu) . The myelofibrosis in the case series described by American varied inheritance pattern raises the possibility that Association of Haematology and mitral prolapse in GPS can be caused by defects in more than on gene present case. Eventually patient may develop bone defect. 7 An X-linked GPS has also been identified. In marrow fibrosis , because of the release of fibrogenic the study by Aygun MG (2010) majoritry of the cases factors form platelets’ alpha granules. 9,10 had an autosomal recessive inheritance . 2 Measurement of platelet α-granule proteins can be In present case there are many other cases in the same measured by ELISA in whole platelet lysate.Electron family having similar complaints, so most likely microscopy is gold standard and absence of alpha autosomal recessive inheritance can be there. Then in granules is diagnostic our set up where consanguineous marriages are References common, that also supports it. The present patient also 1. Margaglime M and Ames RJ. Congenital platelet disorders. had increased vitramin B12 levels. In the reported In Hoffbrand AV, Higgs DR, keeling DM,eds. Postgraduate series all had raised vitamin B12 levels. The present Haematology, 7th ed. Willey Blackwall 2016; 761-72 patient did not develop bone marrow fibrosis. In the 2. Aygun MG, Elboum YZ, Gumruk F, Geiger D, Cetin M. Gray platelet syndrome: Natural history of a large patient cohort natural course almost all develop myelofibrosis due to and locus assignment to chromosome 3p. Blood release of fibrogenic factors from platelets 2010;116:4990- 5001 The inherited thrombocytopenias patients do not 3. MAggs HB, Chalmers EA, Collins PW, Harrison P, Kitchen S. respond to steroid treatment or intravenous A review of inherited platelet disorders with guidelines for 9 their management on behalf of the UKHCDO. British Journal immunoglobulins and this therapy may be harmful. It of Haematology 2006; 135; 603-33 is not unusual in our set up that congenital 4. Drachman JG. Inherited thrombocytopenias . When a low thrombocytopenias are diagnosed after a lapse of platelet count does not mean ITP. Blood 2004; 103: 390-98 many years and after having numerous episodes of 5. Lambert Mp. What to do when you suspect an inherited platelet disorder. Am Soc Hematol Edu Program 2011; 377- bleeding. There are even cases diagnosed as ITP , 83) went through splenectomy and afterword were 6. Xuan, M., & Yang, R. C.. Advances in grey platelet syndrome diagnosed as suffering from some type of congenital Zhonghua Xue Ye Xue Za Zhi, 2012; 33(6): 502-04. thrombocytopenia. 7. Falik- Zaccai TC, Anikster Y, Riveran CE. A new genetic isolate of gray platelet syndrome :clinical, cellular and The α- granules are principal storage sites for hematologic characteristics. Moelcular, Genetics and hemostatic proteins such as fibrinogen, vWF, Metabolism 2001; 74:303-13 thrombocpondin, factor V and for growth factor such 8. Benit L, Crama EM, Masse JM. Molecular study of as platelet derived growth factor and transforming hematopoietic zinc finger gene in three inherited families with gray platelet syndrome. J Thromb Haemost 2005; 3(9): growth factor β. One result of absent of α- granules 2077-80 is a continued release of growth factors and cytokines 9. Agarwal AC and Rodgers GM. Miscelleneous causes of into marrow, causing myelofibrosis.10 Mild to thrombocytopenias . In Greer JP, Arber Da, glader B, List A, moderate myelofibrosis has been described in some eds. Wintrobe’s Clinical ,13th ed, 2014. 11 Lippincott , Philadelphia. 1100-05 but not all GPS patients. 10. Nurden A and Nurden P. Gray platelet syndrome- Clinical Elevated Vitamin B12 levels can be used as a spectrum of disease. Blood Rev 2001; 21;21-36 biochemical marker in patients with suspected GPS. 11. Jantunen E, Hanninen A, Naukkarineu A, Vornanen M. Gray Further progress may bring into light different platelet syndrome with splenomegaly and signs of extramedullary haematopoiesis. American Journal of associations with gray platelet syndrome, for example Hematology 1994; 46:218-24 increased vitamin B12, splenomegaly and

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