Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3mutation; case report and review of the literature

Abstract

BackgroundHyperphosphatemic Familial Tumoral Calcinosis (HFTC) and Hyperphosphatemic Hyperostosis Syndrome (HHS) are associated with autosomal recessive mutations in three different genes, FGF23, GALNT3 and KL, leading to reduced levels of fibroblast growth factor 23 (FGF23) and subsequent clinical effects.ResultsWe describe a consanguineous family with two affected siblings with HFTC and HHS caused by a novel homozygous G-to T substitution in exon 3 of GALNT3 (c.767 G > T; p.Gly256Val), demonstrating great phenotypic variation and long asymptomatic intervals. Calcific tumors appeared at 14 years of age in the male, and the female displayed episodic diaphysitis from age 9 years. Symptoms of eye involvement were present in both from childhood, and progressed into band keratopathy in the female. Abnormal dental roots and tooth loss, as well as myalgia were present in both from their mid-twenties, while the female also had calcifications in the placenta, the iliac vessels and thyroid cartilage. New calcific tumors appeared more than 20 years after the initial episodes, delaying diagnosis and treatment until the ages of 37 and 50 years, respectively. Both siblings had elevated serum phosphate levels, inappropriately elevated tubular maximum phosphate reabsorption per unit glomerular filtration rate (TmP/GFR), reduced levels of intact FGF23 and increased levels of c-terminal FGF23. Review of all 54 previously published cases of GALNT3, FGF23, and KL associated HFTC and HHS demonstrated that more subjects than previously recognized have a combined phenotype.ConclusionWe have described HFTC and HHS in a consanguineous Caucasian family with a novel GALNT3 mutation, demonstrating new phenotypic features and significant variability in the natural course of the disease. A review of the literature, show that more subjects than previously recognized have a combined phenotype of HFTC and HHS. HHS and HFTC are two distinct phenotypes in a spectrum of GALNT3 mutation related calcification disorders, where the additional factors determining the phenotypic expression, are yet to be clarified.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-014-0098-3) contains supplementary material, which is available to authorized users.

Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC)

“…27 Even if the GALNT3 mRNA was not degraded, there would definitely be a loss of function because only 162 out of 633 amino acids would be translated, deleting both the glycosyl transferase (aa 188–374) and ricin-B-lectin domains (aa 497–630). 16 In any case, there did not appear to be any significant dominant negative effects caused by the truncated protein, as the condition is recessive (no disease phenotype is observed in heterozygotes (the parents). Therefore it is apparent that pathogenesis resulted from a loss of GALNT3 function.…”

“…Ectopic calcifications are often observed in the thyroid cartilage and the large muscles of the lower extremities but can occur at many sites, such as the placenta, iliac vessels, and bone (resembling osteoarthritis). 16 HFTC is a group of autosomal recessive soft tissue calcification conditions caused by a breakdown of the FGF23 system for lowering elevated serum phosphate, which is accomplished primarily by reducing the reabsorption of filtered phosphate in the kidneys. Loss of function mutations in both alleles of GALNT3 , 17 FGF23 , 1,18-20 and KL (KLOTHO) 21 cause tumoral calcinosis.…”

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.…”

Primary tumor (tumoral) calcification is a rare disease in the practice of a rheumatologist and orthopedist: experience with the use of an interleukin-1 inhibitor in combination with surgical correction

“…Механизмы, объясняющие, как гиперфосфатемия реализуется в непосредственно туморальный кальциноз, практически не изучены. Описаны случаи туморального кальциноза с нормальными показателями фосфорного обмена, а также случаи, при которых не выявлено мутаций в указанных генах, что, наиболее вероятно, связано с наличием других механизмов развития данного заболевания [8].…”