Tumoral Calcinosis, Hyperphosphatemic, Familial, 2

A number sign (#) is used with this entry because of evidence that hyperphosphatemic familial tumoral calcinosis-2 (HFTC2) is caused by homozygous mutation in the FGF23 gene (605380) on chromosome 12p13.

Description

Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (Chefetz et al., 2005). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 or GALNT3 (601756) gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (Frishberg et al., 2005), Ichikawa et al. (2010) concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis.

HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; 193100), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (Chefetz et al., 2005; Ichikawa et al., 2005).

For a general phenotypic description and a discussion of genetic heterogeneity of HFTC, see 211900.

Clinical Features

Chefetz et al. (2005) reported a patient with a severe form of tumoral calcinosis. His parents were not known to be related but originated from the same Greek village located near the Turkish border. The patient was first seen at 5 years of age for surgical removal of calcified foci from the oral mucosa. Subsequently, he developed large subcutaneous tumors around his wrists, knees, and ankles. Small calcified deposits were visible at the external border of the lower eyelids. He showed persistent hyperphosphatemia at the age of 13 years. There was sonographic evidence of calcinosis of the renal medullae, and disseminated foci of vascular calcifications including aortic valve and arch. Eruption of permanent teeth was delayed, with 8 primary teeth still in place at the age of 12 years and 4 months. The patient suffered a left-sided facial nerve palsy at 13 years of age that was thought possibly to be caused by bony compression. Hearing was not impaired.

Molecular Genetics

In an individual with familial tumoral calcinosis in whom mutation in the GALNT3 gene had been excluded, Benet-Pages et al. (2005) identified a homozygous missense mutation (S71G; 605380.0003) in the FGF23 gene.

In a patient with tumoral calcinosis, Chefetz et al. (2005) identified a homozygous missense mutation (M6T; 605380.0004) in the FGF23 gene.

In 2 affected members of a consanguineous Arabian family with tumoral calcinosis, Araya et al. (2005) identified a homozygous missense mutation (S129F; 605380.0005) in the FGF23 gene. Two other members of the family were affected, but were unavailable for testing.