Alternative titles; symbols
SNOMEDCT: 1162852008; ORPHA: 306658, 53715; DO: 0080170;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.2 | Tumoral calcinosis, familial, normophosphatemic | 610455 | Autosomal recessive | 3 | SAMD9 | 610456 |
A number sign (#) is used with this entry because of evidence that normophosphatemic familial tumoral calcinosis (NFTC) is caused by homozygous or compound heterozygous mutation in the SAMD9 gene (610456) on chromosome 7q21.
Familial tumoral calcinosis (FTC) is an uncommon life-threatening disorder characterized by massive periarticular, and seldom visceral, deposition of calcified tumors (Metzker et al., 1988). When associated with hyperphosphatemia, the disorder is known as hyperphosphatemic FTC (HFTC; 211900). Topaz et al. (2004) identified a subset of patients with familial tumor calcinosis who displayed normal circulating levels of phosphate. A total of 8 individuals were assessed in 5 families of Jewish Yemenite origin. All patients reported reddish-to-hyperpigmented skin lesions during the first year of life, which preceded the appearance of calcified nodules, distributed mainly over the extremities. In addition, severe conjunctivitis and gingivitis were observed in most of the affected individuals. Results of routine laboratory tests, including calcium, phosphate, vitamin D3 metabolites, and parathyroid-hormone levels, were normal. Histopathologic examination of lesional skin biopsies disclosed massive calcium deposition in the mid- and lower dermis. These individuals did not carry mutations in GALNT3 (601756) or FGF23 (605380), which suggested that HFTC and NFTC are not allelic.
Chefetz et al. (2008) described dizygotic twins with normophosphatemic familial tumoral calcinosis. All grandparents were of Jewish Yemenite origin with the exception of the paternal grandfather who was of Jewish Moroccan origin. The sibs, who were born at 26 weeks' gestation, presented at age 6 years with periarticular calcified masses. Physical examination revealed subcutaneous mobile calcified masses above the knees and elbows as well as minute calcified nodules on the sides of their feet. No preceding rash had been observed. Both patients also exhibited marked edema and redness of the gingiva. Routine blood chemistry, including phosphate, was normal.
Using the approach of homozygosity mapping, Topaz et al. (2006) identified a 7.6-Mb homozygous interval on 7q21-q21.3 that was shared by all patients in 5 Jewish Yemenite families.
In 5 Jewish Yemenite families with NFTC, Topaz et al. (2006) screened the SAMD9 gene, found within a shared homozygous interval, and detected a substitution of a negatively charged glutamic acid residue for a positively charged lysine residue at amino acid position 1495 of the protein (K1495E; 610456.0001). In a screening of 92 healthy, unrelated Jewish individuals born to couples who immigrated to Israel from Yemen, Topaz et al. (2006) found 1 individual who carried both K1495E and the disease haplotype in the heterozygous state, which corresponded to a carrier rate of approximately 0.01, fitting the expected prevalence of the disease in the Israeli Jewish Yemenite population.
Whereas HFTC models metastatic calcinosis, which refers to deposition of calcified materials due to abnormal calcium phosphate metabolism, as seen in chronic renal failure, NFTC shows a striking resemblance to acquired dystrophic calcinosis, in which tissue calcification occurs as a consequence of tissue injury/inflammation, as observed in many unrelated conditions such as vascular disease, cancer, and autoimmune disorders (Topaz et al., 2006). The conspicuous inflammatory malformations reported in NFTC, which are absent in HFTC, suggest that the SAMD9 protein may be involved in physiologic responses to tissue injury.
In dizygotic twins with NFTC from a Jewish Yemenite family, Chefetz et al. (2008) identified compound heterozygous mutations in the SMAD9 gene: the previously identified K1495E mutation and a novel nonsense mutation (R344X; 610446.0005). The mutations, which were identified by direct sequencing of the SMAD9 gene, segregated with the disorder in the family.
Chefetz et al. (2008) screened a large cohort of healthy unrelated individuals of Jewish Yemenite, Jewish non-Yemenite, and Yemenite non-Jewish origin for the K1495E and R344X variants in the SMAD9 gene and found that they were present only in the controls of Jewish Yemenite origin. Haplotype analysis demonstrated that the mutations arose in this population from 2 independent events. Chefetz et al. (2008) speculated that the occurrence of 2 rare mutations in a very small population is suggestive of positive selection; alternatively, it may reflect genetic drift or the effect of a population-specific modifier trait.
Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J. Invest. Derm. 128: 1423-1429, 2008. [PubMed: 18094730] [Full Text: https://doi.org/10.1038/sj.jid.5701203]
Metzker, A., Eisenstein, B., Oren, J., Samuel, R. Tumoral calcinosis revisited--common and uncommon features: report of ten cases and review. Europ. J. Pediat. 147: 128-132, 1988. [PubMed: 3366131] [Full Text: https://doi.org/10.1007/BF00442209]
Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am. J. Hum. Genet. 79: 759-764, 2006. [PubMed: 16960814] [Full Text: https://doi.org/10.1086/508069]
Topaz, O., Shurman, D. L., Bergman, R., Indelman, M., Ratajczak, P., Mizrachi, M., Khamaysi, Z., Behar, D., Petronius, D., Friedman, V., Zelikovic, I., Raimer, S., Metzker, A., Richard, G., Sprecher, E. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nature Genet. 36: 579-581, 2004. [PubMed: 15133511] [Full Text: https://doi.org/10.1038/ng1358]