#187950
ICD+
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| THROMBOCYTHEMIA, ESSENTIAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| THROMBOCYTOSIS, PRIMARY THROMBOCYTOSIS, AUTOSOMAL DOMINANT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that essential thrombocythemia can be caused by mutation in the thrombopoietin gene (THPO; 600044) on chromosome 3 or the THPO receptor gene (MPL; 159530) on chromosome 1p34. Susceptibility to thrombocytosis has been found to be associated with a polymorphism in the MPL gene. A somatic mutation in the JAK2 gene (147796) on chromosome 9p is found in a high proportion of cases with essential thrombocythemia. Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fickers and Speck (1974) reported familial occurrence of thrombocythemia, with transition into blastic crisis in some patients. Dodsworth (1980) described primary thrombocytosis in monozygotic twins. Slee et al. (1981) described a family in which a form of myeloproliferative disease involving the megakaryocytic cell line occurred in 3 generations, resulting in thrombocytosis in several members. An autosomal dominant transmission with incomplete penetrance was proposed. Case (1984) reported the clinical findings of 33 patients with essential thrombocythemia, all of whom met rigid criteria for diagnosis of this myeloproliferative disorder. Constitutional symptoms were present in 90%, with 25% having thrombohemorrhagic manifestations. All patients had hypercellular marrows with megakaryocytic hyperplasia and dysplasia. The median platelet count at diagnosis was 17 million with a range as high as 70 million per cu mm. Eyster et al. (1986) reported a family in which 5 members from 3 successive generations had autosomal dominant essential thrombocythemia. Age ranged from 2 to 62 years. The proposita was a 26-year-old woman with persistently elevated platelet count, mild splenomegaly, normal hemoglobin level, normal white blood cell count, and abnormal platelet aggregation. Megakaryocytes were increased in number and size. Platelet arachidonic acid metabolites and serum thrombopoietin levels were normal. Her 2 sons, aged 4 and 2 years, had platelet counts of 951,000 and 1,070,000 per cu mm. Her mother had platelet counts of about 900,000 per cu mm. Bone marrow karyotypes were normal. The proband's mother and her sister had thrombocythemia; both had had myocardial infarction at ages 52 and 57, respectively. The authors concluded that young women and children with essential thrombocythemia may have long survival without treatment. Familial thrombocytosis was also reported by Fernandez-Robles et al. (1990). Of the 11 persons with essential thrombocythemia identified by Schlemper et al. (1994) in 4 generations of a Dutch family, 5 were asymptomatic, 3 had both vasoocclusive and hemorrhagic manifestations, and 3 had only vasoocclusive features. The platelet count ranged from 500 to 1700 x 10(9)/l. Symptoms correlated with age but not with platelet count. ADP-induced platelet aggregation was the best distinguishing characteristic between patients and unaffected members of the family. No chromosome abnormalities were found. The propositus presented at the age of 32 years with recurrent transient symptoms of 'cold tip feeling,' erythromelalgia, and acrocyanosis of the toes, which eventually led to gangrene and amputation of a toe in 1968. There was 1 instance of male-to-male transmission. Van Dijken et al. (1996) observed chronic thrombocytosis in an infant from the family reported by Schlemper et al. (1994). The mother was known to have familial thrombocytosis for which she was treated with low-dose aspirin. At age 6 weeks, her son was malnourished, had enlarged liver and spleen, and marked leukocytosis with an abnormal differential white cell count. Although leukemia was suspected, the hematologic picture began to normalize about the age of 1 year and hepatosplenomegaly decreased. At the age of 5 years he was apparently well with only a just palpable spleen, like most of his family members with thrombocytosis. Kikuchi et al. (1995) observed 4 cases of thrombocytosis in 3 successive generations of a Japanese family. A high peripheral platelet count was found incidentally in the proband with cutaneous malignant lymphoma which was thought to be coincidental. Bone marrow examinations showed megakaryocytic hyperplasia. Neither Philadelphia chromosome nor chimeric BCR/ABL junction was detected in marrow cells. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kaywin et al. (1978) reported 4 male patients with essential thrombocythemia. Platelets from 2 of these patients showed dysfunction, including failure to aggregate or release serotonin in response to concentrations of epinephrine that aggregated platelets of normal controls. Platelets from these 2 men contained only about half as many binding alpha-adrenergic binding sites compared to control platelets. Platelets from the other 2 patients showed normal epinephrine responses and receptor site numbers. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sweet et al. (1979), Norrby et al. (1982), Carbonell et al. (1982), and Bernstein et al. (1982) described cases of leukemia or preleukemia associated with thrombocytosis and an insertion in chromosome 3, ins(3;3)(q26;q21q26). Bernstein et al. (1982), who referred to this as 'homologous translocation,' described 3 patients with acute nonlymphocytic leukemia (ANLL) and thrombocytosis associated with inv(3)(q21q26). Carroll et al. (1986) described sideroblastic anemia and thrombocytosis causing recurrent and ultimately fatal thromboembolism in a patient with 46,XY,ins(3;3)(q26;q21q26) in bone marrow cells. The observations suggested that a gene on 3q may regulate megakaryopoiesis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Somatic Mutations Baxter et al. (2005) and Kralovics et al. (2005) found that 57% (29 of 51) and 23% (21 of 93) of patients with essential thrombocytopenia, respectively, carried a somatic mutation in the JAK2 gene (V617F; 147796.0001). Pardanani et al. (2006) identified a somatic mutation in the MPL gene (W515L; 159530.0011) in 4 unrelated patients with essential thrombocythemia. Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow cells from 320 patients with myeloid cancers and identified TET2 defects in 10 patients with essential thrombocythemia, all but 1 of whom also displayed the JAK2 V617F mutation. In a 45-year-old man with no cardiovascular risk factors who presented in cardiogenic shock and was found to have coronary occlusion, myocardial infarction, and multiple myocardial microthrombi, Lata et al. (2010) identified at least 1 mutated V617F JAK2 allele on a peripheral blood smear. The patient, who had a platelet count of 529,000 per cubic millimeter, died in irreversible asystole after multiple percutaneous transluminal coronary angioplasties, stenting, and intracoronary fibrinolysis. Considering this to represent a fulminant initial presentation of occult essential thrombocythemia, Lata et al. (2010) stated that screening for the JAK2 mutation would likely be of value in selected patients with otherwise unexplained coronary ischemic events and mild thrombocytosis. Germline Mutations In a 4-generation Dutch kindred with essential thrombocythemia originally reported by Schlemper et al. (1994), Wiestner et al. (1998) identified a heterozygous mutation in the THPO gene (600044.0001). In affected members of the Japanese family reported by Kikuchi et al. (1995), Ghilardi et al. (1999) identified a heterozygous gain-of-function mutation in the THPO gene (600044.0003). Moliterno et al. (2004) found that approximately 7% of African Americans are heterozygous for a single nucleotide substitution in the MPL gene, 1238G-T, which results in a lys39-to-asn substitution (K39N; 159530.0009). African Americans with the K39N polymorphism, which the authors designated MPL Baltimore, had a significantly higher platelet count than controls without the polymorphism (p less than 0.001) and reduced platelet protein MPL expression. Moliterno et al. (2004) concluded that K39N represents a functional MPL polymorphism and is associated with altered protein expression of the thrombopoietin receptor and a clinical phenotype of thrombocytosis. Although DNA was isolated from platelets or peripheral blood from most individuals in the study, K39N was also present in DNA obtained from buccal smears from 2 of the patients available for study. In affected members of a Japanese family with autosomal dominant essential thrombocythemia, Ding et al. (2004) identified a heterozygous activating mutation in the MPL gene (159530.0010). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early studies suggested a site for primary thrombocytosis on 21q11-qter based on several studies reporting deletion of this region in patients with the disorder (Rajendra et al., 1981). Zaccaria and Tura (1978) found partial deletion of the long arm of chromosome 21 in 5 patients with primary thrombocytosis, Petit and Van den Berghe (1979) observed a patient with an acquired deletion of 22q. However, Case (1984) could not confirm the reported association of 21q- in a study of 33 patients with essential thrombocythemia. Emilia et al. (1985) concluded that no chromosomal abnormality is consistently associated with essential thrombocytosis, and specifically noted that evidence did not indicate a clear relationship to deletion of 21q. Verhest and Monsieur (1983) found the Philadelphia chromosome (see 151410) in a patient with essential thrombocythemia with leukemic transformation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fialkow et al. (1981); Gaetani et al. (1982); Singal et al. (1983) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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