ORPHA: 247511; DO: 0080338; MONDO: 0012353;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q42.2 | Erythrocytosis, familial, 3 | 609820 | Autosomal dominant | 3 | EGLN1 | 606425 |
A number sign (#) is used with this entry because of evidence that familial erythrocytosis-3 (ECYT3) is caused by heterozygous mutation in the EGLN1 gene (606425) on chromosome 1q42.
For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100).
Percy et al. (2006) reported a family in which a father, son, and daughter had erythrocytosis characterized by increased serum hemoglobin and hematocrit. Serum levels of erythropoietin (EPO; 133170) were inappropriately normal, suggesting dysregulation of the EPO axis.
Ladroue et al. (2008) reported a man with erythrocytosis and recurrent paraaortic paraganglioma. He had hypertension associated with the tumor. There was no family history of either disorder.
In all 3 affected members of a family with erythrocytosis, Percy et al. (2006) identified a heterozygous mutation in the EGLN1 gene (P317R; 606425.0001).
Percy et al. (2007) identified a second heterozygous mutation in the EGLN1 gene (R371H; 606425.0002) in a patient with modest erythrocytosis and inappropriately normal EPO levels.
In a man with erythrocytosis and recurrent paraaortic paraganglioma, Ladroue et al. (2008) identified a heterozygous mutation in the EGLN1 gene (H374R; 605425.0003). The authors noted that hereditary paraganglioma syndromes (see, e.g., PGL1; 168000) can be caused by mutations in genes encoding succinate dehydrogenase (see, e.g., SDHD; 602690), which result in accumulation of succinate and inhibition of PHD function with overexpression of hypoxia inducible factor (see, e.g., HIF1A; 603348). Examination of tumor tissue showed the H374R mutation and loss-of-heterozygosity for the wildtype EGLN1 allele. The findings suggested that EGLN1 may also act as a tumor-suppressor gene. Ladroue et al. (2008) suggested that alteration of the EGLN1/HIF pathway could contribute to the growth of a paraganglioma. No germline mutations were identified in the VHL gene (608537), which is involved in the same pathway.
Ladroue, C., Carcenac, R., Leporrier, M., Gad, S., Le Hello, C., Galateau-Salle, F., Feunteun, J., Pouyssegur, J., Richard, S., Gardie, B. PHD2 mutation and congenital erythrocytosis with paraganglioma. New. Eng. J. Med. 359: 2685-2692, 2008. [PubMed: 19092153] [Full Text: https://doi.org/10.1056/NEJMoa0806277]
Percy, M. J., Furlow, P. W., Beer, P. A., Lappin, T. R. J., McMullin, M. F., Lee, F. S. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood 110: 2193-2196, 2007. [PubMed: 17579185] [Full Text: https://doi.org/10.1182/blood-2007-04-084434]
Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R., Maxwell, P. H., McMullin, M. F., Lee, F. S. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc. Nat. Acad. Sci. 103: 654-659, 2006. [PubMed: 16407130] [Full Text: https://doi.org/10.1073/pnas.0508423103]