Avascular Necrosis Of Femoral Head, Primary, 2

A number sign (#) is used with this entry because of evidence that primary avascular necrosis of the femoral head-2 (ANFH2) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24. One such family has been reported.

For a phenotypic description and discussion of genetic heterogeneity of primary avascular necrosis of the femoral head, see ANFH1 (608805).

Clinical Features

Mah et al. (2016) studied 3 affected sisters and 1 affected brother from a Greek family with bilateral avascular necrosis of the femoral head. The 3 older sibs developed hip pain at approximately 30 years of age and were diagnosed in their late 30s to mid-40s. The proband, however, developed hip pain at age 20 years and was diagnosed at age 21; he underwent hip core decompressions and bone grafting at age 28. The affected sibs were negative for osteonecrosis-associated thrombophilia markers, and they did not harbor other risk factors for osteonecrosis. Their parents and grandparents were deceased, but the sibs recalled symptoms of joint pain in their father that were never evaluated.

Molecular Genetics

In 4 affected sibs from a Greek family with avascular necrosis of the femoral head who were negative for mutation in the COL2A1 gene (120140), Mah et al. (2016) performed exome sequencing and identified heterozygosity for a truncating mutation in the TRPV4 gene (605427.0034). The mutation was not present in an unaffected brother or in public variant databases; DNA was not available from their deceased parents. Screening of 49 sporadic patients with ANFH showed that they did not carry the TRPV4 truncating mutation. Complete physical examination by a medical geneticist with experience in skeletal dysplasias, as well as neurologic examination by a neurologist with expertise in polyneuropathy, did not reveal any evidence for previously reported TRPV4-associated skeletal dysplasias or neuropathies in the affected sibs.