Thrombocythemia 1

A number sign (#) is used with this entry because thrombocythemia-1 (THCYT1) is caused by heterozygous mutation in the thrombopoietin gene (THPO; 600044) on chromosome 3q27.

Thrombocythemia, or thrombocytosis, is a myeloproliferative disorder characterized by excessive platelet production resulting in increased numbers of circulating platelets. Thrombocythemia can be associated with thrombotic or hemorrhagic episodes and occasional leukemic transformation (summary by Wiestner et al., 1998).

Genetic Heterogeneity of Thrombocythemia

THCYT2 (601977) is caused by germline or somatic mutation in the THPO receptor gene (MPL; 159530) on chromosome 1p34; THCYT3 (614521) is caused by germline or somatic mutation in the JAK2 gene (147796) on chromosome 9p; and a possible X-linked form (THCYTX; 300331) has been reported.

Somatic mutations in the TET2 (612839), ASXL1 (612990), SH2B3 (605093), and SF3B1 (605590) genes have also been found in cases of essential thrombocythemia. Somatic mutation in the CALR gene (109091) occurs in approximately 70% of essential thrombocythemia patients who lack JAK2 and MPL mutations (Klampfl et al., 2013; Nangalia et al., 2013).

Early Descriptions

Fickers and Speck (1974) reported familial occurrence of thrombocythemia, with transition into blastic crisis in some patients.

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. 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.

In 5 healthy members of 3 generations of a family, Cohen et al. (1997) described a benign form of familial thrombocytosis. All 5 had moderate thrombocytosis (422,000 to 662,000/mm(3); normal range 130,000-350,000/mm(3)) and low mean platelet volume (5.9-6.9 fl; normal range of 7.8-12 fl). Medical history and a 5-year follow-up of the subjects did not suggest any untoward effects. Cohen et al. (1997) suggested that abnormally elevated platelet counts can be classified into 3 groups: reactive thrombocytosis, essential thrombocytosis (a neoplastic disorder), and familial thrombocytosis. Families of the last-mentioned type were reported by Fickers and Speck (1974), Eyster et al. (1986), Fernandez-Robles et al. (1990), and Kikuchi et al. (1995). None of these families appeared to have had small platelets, suggesting that the family of Cohen et al. (1997) may have a different variant.

Genetically Confirmed Thrombocythemia 1

Schlemper et al. (1994) reported a large 4-generation Dutch family with hereditary thrombocythemia. Of 11 affected individuals, 5 were asymptomatic, 3 had both vasoocclusive and hemorrhagic manifestations, and 3 had only vasoocclusive features. The platelet count ranged from 500 to 1,700 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.

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.

Dodsworth (1980) described primary thrombocytosis in monozygotic twins. Familial thrombocytosis was reported by Fernandez-Robles et al. (1990).

Wiestner et al. (1998) confirmed autosomal dominant inheritance of thrombocythemia-1.

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.

In a 4-generation Dutch kindred with essential thrombocythemia originally reported by Schlemper et al. (1994), Wiestner et al. (1998) identified a heterozygous germline 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 germline mutation in the THPO gene (600044.0003).

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.