Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations

Abstract

The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.

Figure 1

Plain radiographs of pelvis (1a) and knee (1b) with calcifications in Patient 1. Radiologic findings in Patient 2: Hyperostosis of the long bones with periosteal appositions and metaphyseal densification in diaphysis (2a); right elbow calcification (2b). Radiological findings in Patient 3: Pelvis showing coxa valga and epiphysiolysis (3a); first episode of hyperostosis with abnormal irregular hyperostosis of the right tibial diaphysis (3b); second episode of hyperostosis of the left tibial diaphysis (3c) with amelioration of the right diaphysis hyperostosis (3d). Arrow heads indicate calcifications and hyperostosis. Radiologic features in Patient 4: Dental radiograph demonstrating short bulbous roots in all teeth except teeth 14 and 24, which show complete root resorption. Pulp chambers and root canals are absent in all teeth with the following exceptions: teeth 38 and 48 (regular pulp chamber and root canal) and teeth 32 and 42 (residual root canal in the apical region only). Note that all exceptions are observed in two teeth lying symmetrically. The temporo-mandibular joint area lacked lesions, which are sometimes seen in patients with tumoral calcinosis. Teeth are numbered using the Two-Digit Fédération Dentaire Internationale (FDI) notation for adult teeth.

Figure 2

Mutational analysis of the GALNT3 gene. Electropherograms of PCR products show wild-type sequences (top) and mutated sequences (bottom) in four patients. Arrows indicate nucleotides involved in the mutations.