Hyperphosphatemic familial tumoral calcinosis (HFTC) / hyperostosis hyperphosphatemia syndrome (HHS)

(OMIM phenotype number #211900)

Familial tumoral calcinosis (FTC) is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications, in cutaneous and subcutaneous tissues, especially around large joints (hip, elbow or shoulder). Calcifications lead to painful skin ulcerations, secondary skin and bone infections, and contractures. FTC is inherited in an autosomal recessive mode, but autosomal dominant inheritance has also been described. The disease usually appears before the second decade of life. Two forms of FTC have been described: Hyperphosphatemic familial tumoral calcinosis (HFTC), and Normophosphatemic FTC (NFTC). HFTC, also called hyperostosis hyperphosphatemia syndrome (HHS), is caused by mutations in the GALNT3, FGF23, and KLOTHO gene. It is a rare congenital disorder in which the differential diagnosis from other syndromes associated with extraskeletal calcifications may be difficult. The disease was initially found to result from mutations in GALNT3 encoding a glycosyltransferase, and mutations in FGF23, encoding a potent phosphaturic protein. Recent studies have shown that FGF23 requires an additional co-factor, Klotho (KL), to bind and signal through its cognate fibroblast growth factor receptors (FGFRs), and loss-of-function mutations in human KL impair FGF23 bioactivity, leading to severe tumoral calcinosis. HFTC represents the metabolic mirror image of autosomal dominant hypophosphatemic rickets (ADHR) caused by gain of function mutations in the fibroblast growth factor 23 (FGF23) gene.

Treatment of tumoral calcinosis varies depending on the type of the lesion, stage of the pathology, and symptoms of the patient. Primary treatment is early surgical excision, although there is a high rate of recurrence. Medical therapies with phosphate depletion, dietary deprivation of phosphorus and phosphate binding chelating agents, such as oral aluminium hydroxide, has shown variable positive outcomes in both NFTC and HFTC.

Gene

  • FGF23 gene, 12p13.32 (OMIM gene/locus number #605380)
  • GALNT3 gene, 2q24.3 (OMIM gene/locus number #601756)
  • KLOTHO gene, 13q13.1 (OMIM gene/locus number #604824)

Phenotype

Periarticular cystic and solid tumoral calcifications with hyperphosphatemia and hypophosphaturia and elevated serum of calcitriol, soft tissue masses around major joints, dental abnormalities, ocular involvement with range from angioid streaks to corneal calcification deposits and neuronal calcifications, altered skeletal mineralization, and low/normal bone mass.

Main biochemical alterations

Low Ur P, high Pi, high TmP/GFR, normal Ca, normal Ur Ca, normal PTH, normal 25 OH D, high 1,25(OH)2D, and low intact FGF23.
 

References

  1. Benet-Pagès A, Orlik P, Strom TM, et al. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005 Feb 1;14(3):385-90.
  2. Chefetz I, Heller R, Galli-Tsinopoulou A, et al. A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. Hum Genet. 2005 Nov;118(2):261-6.
  3. Ichikawa S, Baujat G, Seyahi A, et al. Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am J Med Genet A. 2010 Apr;152A(4):896-903.
  4. Ichikawa S, Guigonis V, Imel EA, et al. Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab. 2007 May;92(5):1943-7.
  5. Ichikawa S, Imel EA, Kreiter ML, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest. 2007 Sep;117(9):2684-91.
  6. Fathi I, Sakr M. World J Clin Cases. 2014 Sep 16;2(9):409-14. Review of tumoral calcinosis: A rare clinico-pathological entity.
  7. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  8. http://www.omim.org