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, as well as inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)2D]. Three of the patients also had confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia due to 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.

Vitamin D deficiency in white, apparently healthy, free-living adults in a temperate region

“…[26][27][28] Our findings in a large number of adult subjects with a broad spectrum of age and the persistence of the correlation even when only the subjects with abnormally low serum 25(OH)Vitamin D concentrations were considered, and also in women without or with OP+OPenia, strongly suggest that the serum levels of 25(OH)Vitamin D possibly play a substantial role in serum 1-25(OH)2Vitamin D production. This is further substantiated by the recent study of Rejnmark et al 29 concluding that in postmenopausal women serum 25(OH)Vitamin D concentration is the major determinant of serum levels of 1-25(OH)2Vitamin D. 29,30 Of particular interest is also the finding of a considerable negative linear correlation between 25(OH) Vitamin D and Intact PTH concentrations not only in the whole group but also separately in the women without or with OP+OPenia.…”

Uremic tumoral calcinosis in the cervical spine: case report

“…Other possible predisposing factors are genetic mutations in the FGF23 and GALNT3 genes, leading to a decrease in the level of functional fibroblast growth factors, which is associated with hyperphosphatemic tumoral calcinosis. 1,8,15 In the spine, the differential diagnosis of a growing, calcified, paraspinal mass commonly includes sarcomas, primary osteochondral tumors, infection, and myositis ossificans. We stress the importance of including UTC in the differential diagnosis when managing a patient who may have an underlying metabolic disturbance.…”

Monogenic Phosphate Balance Disorders

“…The clinical phenotype is autosomal dominant hypophosphatemic rickets 2000). Homozygous inactivating missense mutations in FGF23 lead to hyperphosphatemic familial tumoral calcinosis, due to decreased renal excretion of phosphate and increased renal α-hydroxylation of vitamin D (Benet-Pages, Orlik et al 2005;Ichikawa, Baujat et al 2010). …”

“…There are several mutations in the GALNT3 gene, and the same mutation can lead to TC in some patients and HHS in other (Ichikawa, Baujat et al 2010). TC is characterized by ectopic calcifications in soft tissues and around large joints, recognized clinically as palpable masses and/or on radiography.…”

“…The levels of serum calcium and parathyroid hormone are normal. Some authors suggest that TC and HHS are clinical variants of the same disease (Ichikawa, Baujat et al 2010). …”