Tumoral Calcinosis, Hyperphosphatemic, Familial, 3

A number sign (#) is used with this entry because of evidence that hyperphosphatemic familial tumoral calcinosis-3 (HFTC3) is caused by homozygous mutation in the KL gene (604824) on chromosome 13q13. One such patient has been reported.

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 (605380) 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

Ichikawa et al. (2007) reported a 13-year-old girl with tumoral calcinosis due to a homozygous mutation in the KL gene. She developed mild swelling of the malleolus and thenar eminence without erythema or warmth. Laboratory studies showed increased serum phosphorus, active vitamin D, and FGF23. Radiographs showed osteopenia, patchy sclerosis in the hands, feet, long bones, and calvaria, intracranial calcifications, and calcifications of the dura and carotid arteries. On presentation, she also had increased serum calcium and parathyroid hormone, which was successfully treated by subtotal parathyroidectomy of hyperplastic glands. Biochemical studies showed inappropriate tubular reabsorption of phosphorus and defective FGF23 signaling due to the mutant KL protein.

Molecular Genetics

Ichikawa et al. (2007) reported a 13-year-old girl with tumoral calcinosis due to a homozygous missense mutation (H193R; 604824.0002) in the KL gene (604824.0002).