Tumoral Calcinosis, Normophosphatemic, Familial

A number sign (#) is used with this entry because of evidence that normophosphatemic familial tumoral calcinosis can be caused by mutation in the gene encoding the sterile alpha motif domain-containing-9 protein (SAMD9; 610456).

Clinical Features

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 FTC 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 normophosphatemic FTC (NFTC) are nonallelic.

Mapping

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.

Molecular Genetics

In 5 Jewish Yemenite families with NFTC, Topaz et al. (2006) screened the SAMD9 gene, found within the 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 sequence (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.