Background: Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) and Hyperphosphatemic Hyperostosis Syndrome (HHS) are two phenotypes of a disease associated with autosomal recessive mutations in FGF23, GALNT3 and KL, leading to reduced levels and clinical effects of fibroblast growth factor 23 (FGF23). We describe a consanguineous family with two affected individuals with HFTC and HHS caused by a novel homozygous mutation in GALNT3. We also review the literature on GALNT3-associated HFTC and HHS.
Results: Calcific tumours appeared at three weeks of age in the sister and at 14 years of age in the brother. The sister displayed episodic diaphysitis from age 9 years. Abnormal dental roots, tooth loss and musculoskeletal complaints were present in both from their mid-twenties. The sister had calcifications in the placenta, iliac vessels and thyroid cartilage, and developed band keratopathy. New calcific tumours appeared more than 20 years after the initial episodes, delaying diagnosis and treatment. Both subjects 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. Mutation analysis identified a novel homozygous G-to T substitution in exon 3 of GALNT3 (c.767G>T; p.G256V). A review of all 52 previously published cases of GALNT3, FGF23, and KL associated HFTC and HHS, showed that more subjects than previously recognized have a combined phenotype of HFTC and HHS.
Conclusion: We have described HFTC and HHS in a consanguineous Caucasian family with a novel GALNT3 mutation, demonstrating great phenotypic variability and long asymptomatic intervals, with HFTC from infancy and later symptoms of HHS in the sister, and classic HFTC in the brother. HHS and HFTC are probably two distinct phenotypes in a spectrum of GALNT3 and FGF23 mutation related calcification disorders, where additional factors determining the phenotypic expression, are yet to be clarified.