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.

Figure 1. Clinical findings in FTC

(a) Computed tomographic scan showing a calcified mass in the soft tissue adjacent to the right major Trochanter (red arrow). (b) Calcified tumor on the right wrist of a 5-year-old boy with NFTC. (c) A skin biopsy obtained from an 8-year-old female patient with NFTC have calcified materials in the upper and middle dermis (hematoxylin and eosin, × 400). (d) Calcified nodules in a 70-year-old patient with dermatomyositis and acquired calcinosis cutis.

Figure 2. FTC-associated molecules and the regulation of phosphate homeostasis

Two genes have been found to be associated with classical FTC, GALNT3 encoding ppGalNacT3 (1) and FGF23 encoding the phosphatonin FGF23 (2). Increased phosphate levels upregulate the activity of ppGAlNacT3 (3) as well as FGF23 (4). ppGalNacT3 then O-glycosylates FGF23 (5), thereby protecting it from the proteolytic activity of subtilisin-like proprotein convertases (SPC) (6). FGF23 then signals through its receptor in the presence of Klotho (7), resulting in decreased transport of phosphate through the Na–Pi transporters (8) and inhibiting vitamin-D1 hydroxylation (9). Since 1,25-dihydroxyvitamin-D acts by promoting phosphate absorption through the small intestine (10), the effect of FGF23 on vitamin-D metabolism results in decreased entry of phosphate into the circulation (11). In contrast, 1,25-dihydroxyvitamin-D augments FGF23 signaling (12), but inhibits ppGalNacT3 expression (13), thereby establishing a double-regulatory feedback loop mechanism. Of note, FGF23 influences bone mineralization (14). The entire system is also under the regulation of parathyroid hormone, which promotes phosphate excretion through kidney (15) and mobilizes phosphate from the bone (16), thus integrating calcium- and phosphate-regulatory systems. As a consequence of hyperphosphatemia, FGF7 is induced (17), which results in expression and activation of several MMPs (18), which are known to mediate ectopic calcification (19). Since FGF7 mainly originates from the dermis, this may explain the propensity of ectopic calcification to develop in the skin in HFTC. Additional elements involved in the regulation of FGF23 activity include PHEX and DMP1, which inhibit FGF23 activity through still poorly understood mechanisms (possibly including a direct interaction between them) (20). Loss-of-function mutations in the genes encoding these two molecules are associated with increased FGF23 activity and hypophosphatemia.