Familial Tumoral Calcinosis: From Characterization of a Rare Phenotype to the Pathogenesis of Ectopic Calcification

Abstract

Familial tumoral calcinosis (FTC) refers to a heterogeneous group of inherited disorders characterized by the occurrence of cutaneous and subcutaneous calcified masses. Two major forms of the disease are now recognized. Hyperphosphatemic FTC has been shown to result from mutations in three genes: fibroblast growth factor-23 (FGF23), coding for a potent phosphaturic protein, KL encoding Klotho, which serves as a co-receptor for FGF23, and GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation; defective function of any one of these three proteins results in hyperphosphatemia and ectopic calcification. The second form of the disease is characterized by absence of metabolic abnormalities, and is, therefore, termed normophosphatemic FTC. This variant was found to be associated with absence of functional SAMD9, a putative tumor suppressor and anti-inflammatory protein. The data gathered through the study of these rare disorders have recently led to the discovery of novel aspects of the pathogenesis of common disorders in humans, underscoring the potential concealed within the study of rare diseases.

Clinical Consequences of Mutations in Sodium Phosphate Cotransporters

“…Although human renal Npt2a expression has not been examined directly, serum from patients afflicted with these disorders decreases phosphate transport and Npt2a expression in cultured proximal tubule cell lines, suggesting a similar in vivo phenomenon. Conversely, decreased FGF23/Klotho activity as seen with loss-offunction mutations in FGF23 or GALNT3, the enzyme responsible for O-glycosylation of FGF23, results in hyperphosphatemic tumoral calcinosis, characterized by hyperphosphatemia, decreased renal phosphate excretion, and extraskeletal calcifications (47)(48)(49). As for the phosphaturic syndromes, no studies have actually examined the renal expression of Npt2a in human participants with tumoral calcinosis.…”

Calcium orthophosphates (CaPO 4 ): Occurrence and properties

“…One author has mentioned on ''apatite diseases'' which are characterized by the appearance of needle-like crystals comparable to those of bone apatite in the fibrous connective tissue (Mohr 2003). All these cases are examples of a calcinosis (Sprecher 2010;Slavin et al 2012;Kim et al 2013;Burns et al 2013), which might be described as a formation of undesired CaPO 4 deposits in any soft tissue. In dentistry, a calculus or a tartar refers to a hardened plaque on the teeth, formed by the presence of saliva, debris and minerals (White 1997).…”

Striking Pathology Gold: A Singular Experience with Daily Reverberations: Sinonasal Hemangiopericytoma (Glomangiopericytoma) and Oncogenic Osteomalacia

“…Fibrous dysplasia [57] and schwannomas, in the setting of neurofibromatosis-1 [58,59] have also been rarely associated with OO. Lastly, and of interest to surgical pathologists, familial tumoral calcinosis, a rare autosomal recessive condition characterized by progressively enlarging soft tissue calcium deposits, is associated with genetic mutations involving either FGF23, Klotho, or GALNT3, which encodes a glycosyltransferase responsible for FGF23 O-glycosylation [60].…”