Erythrocytosis, Familial, 4

A number sign (#) is used with this entry because of evidence that this form of familial erythrocytosis is caused by a gain-of-function mutation in the HIF2A gene (EPAS1; 603349).

For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100).

Description

Familial erythrocytosis-4 is an autosomal dominant disorder characterized by increased serum red blood cell mass and hemoglobin concentration and elevated serum erythropoietin (EPO; 133170).

Clinical Features

Percy et al. (2008) described a United Kingdom family with erythrocytosis in 3 generations. The index patient was a 43-year-old man who, at 23 years of age, had been found to have an elevated hemoglobin level (21 g/dl) and elevated hematocrit (64%) with normal white cell and platelet counts. Hematocrit was maintained below 45% by venesection 2 to 3 times yearly. A deep venous thrombosis had developed at 42 years of age. The patient's mother had a hemoglobin level of 16.3 g/dl at 35 years of age, and hematocrit was 50% with normal white cell and platelet counts. Red cell mass was elevated at 33 ml/kg. She was treated by regular venesection. The patient's 89-year-old maternal grandmother presented at 54 years of age with elevated values for hemoglobin, hematocrit, and red cell mass, with normal white cell and platelet counts. Venesection had been performed 2 or 3 times yearly to maintain the hematocrit below 50% until age 81 years, after which time it was not required. The patient's father and brother were unaffected.

Molecular Genetics

In affected members of a family with erythrocytosis, Percy et al. (2008) detected heterozygosity for a gly537-to-trp mutation in the HIF2A gene (G537W; 603349.0001). Functional studies indicated that this mutation led to stabilization of the HIF2A protein and suggested that wildtype HIF2A protein regulates production of erythropoietin in adults.

Perrotta and Della Ragione (2008) stated that they analyzed the HIF1A (603348) and HIF2A genes in 125 patients with familial erythrocytosis; none of the patients had a mutation in HIF1A, but 1 patient had a mutation (G537R; 603349.0002) involving the same residue of the HIF2A gene previously identified by Percy et al. (2008).

Percy et al. (2008) identified heterozygous mutations in exon 12 of the EPAS1 gene (603349.0002-603349.0003) in 4 unrelated patients with erythrocytosis. Three patients had the same mutation.