Normophosphatemic familial tumoral calcinosis (NFTC)

(OMIM phenotype number #610455)

Normophosphatemic familial tumoral calcinosis (NFTC) is an autosomal recessive disorder characterized by calcium deposition in skin and mucosae, unremitting pain and life-threatening skin infections. It can be caused by mutation in the gene encoding the sterile alpha motif domain-containing-9 protein (SAMD9). Calcifications usually develop over areas subjected to repeated trauma and are associated with marked inflammatory manifestations. It has been hypothesized that SAMD9 may be under the regulation of TNF-α (a major pro-inflammatory cytokine and inducer of apoptosis), probably, involved in the pathogenesis of extra-osseous calcification. Recently, it has been suggested that SAMD9 is an interferon- γ (IFN-γ)-responsive protein, and interacts with RGL2, diminishing the expression of EGR1, a important protein for the pathogenesis of ectopic calcification and inflammation. At last, several studies have suggested that SAMD9 might have also a role as a tumor suppressor gene, but no increased incidence of cancerous conditions has been described in this disease. However, further studies are needed to elucidate the physiological function of SAMD9.

Gene

SAMD9 gene, 7q21.2 (OMIM gene/locus number #610456)

Phenotype

Reddish to hyperpigmented skin lesions, soft tissue masses at the extremities, calcified ulcerating nodules (massive calcium deposition in mid- and lower dermis), severe conjunctivitis, severe gingivitis, and no altered skeletal mineralization.

Main biochemical alterations

Normal Pi, and normal Ur P.

Images

Normophosphatemic familial tumoral calcinosis (NFTC)

Fig. Clinical features of NFTC, including heralding erythematous papular eruption (a), small calcified tumors ulcerating and discharging chalk-like materials on the surface of the skin (b), and severe gingivitis (c) and calcified material in the upper dermis, as revealed by histopathological examination (d).

Reproduced from Am J Hum Genet, Vol 79, Topaz O, Indelman M, Chefetz I, et al. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis, Pages 759-64, Copyright 2006, with permission from Elsevier.


References
  1. Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis. J Invest Dermatol. 2011 Mar;131(3):662-9.
  2. Topaz O, Indelman M, Chefetz I, et al. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet. 2006 Oct;79(4):759-64.
  3. Chefetz I, Ben Amitai D, Browning S, et al.  Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008 Jun;128(6):1423-9.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org