ORPHA: 306661;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q13.1 | ?Tumoral calcinosis, hyperphosphatemic, familial, 3 | 617994 | Autosomal recessive | 3 | KL | 604824 |
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.
Hyperphosphatemic familial tumoral calcinosis (HFTC) 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' (HHS) 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.
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.
The transmission pattern of HFTC3 in the patient reported by Ichikawa et al. (2007) was consistent with autosomal recessive inheritance.
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).
Chefetz, I., Heller, R., Galli-Tsinopoulou, A., Richard, G., Wollnik, B., Indelman, M., Koerber, F., Topaz, O., Bergman, R., Sprecher, E., Schoenau, E. A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum. Genet. 118: 261-266, 2005. [PubMed: 16151858] [Full Text: https://doi.org/10.1007/s00439-005-0026-8]
Frishberg, Y., Topaz, O., Bergman, R., Behar, D., Fisher, D., Gordon, D., Richard, G., Sprecher, E. Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. J. Molec. Med. 83: 33-38, 2005. Note: Erratum: J. Molec. Med. 83: 240 only, 2005. [PubMed: 15599692] [Full Text: https://doi.org/10.1007/s00109-004-0610-8]
Ichikawa, S., Baujat, G., Seyahi, A., Garoufali, A. G., Imel, E. A., Padgett, L. R., Austin, A. M., Sorenson, A. H., Pejin, Z., Topouchian, V., Quartier, P., Cormier-Daire, V., Dechaux, M., Malandrinou, F. C., Singhellakis, P. N., Le Merrer, M., Econs, M. J. Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am. J. Med. Genet. 152A: 896-903, 2010. [PubMed: 20358599] [Full Text: https://doi.org/10.1002/ajmg.a.33337]
Ichikawa, S., Imel, E. A., Kreiter, M. L., Yu, X., Mackenzie, D. S., Sorenson, A. H., Goetz, R., Mohammadi, M., White, K. E., Econs, M. J. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J. Clin. Invest. 117: 2684-2691, 2007. [PubMed: 17710231] [Full Text: https://doi.org/10.1172/JCI31330]
Ichikawa, S., Lyles, K. W., Econs, M. J. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J. Clin. Endocr. Metab. 90: 2420-2423, 2005. [PubMed: 15687324] [Full Text: https://doi.org/10.1210/jc.2004-2302]