Tumoral calcinosis is a rare autosomal recessive disease characterized by hyperphosphatemia due to increased renal phosphate reabsorption leading to soft tissue calcifications. The levels of fibroblast growth factor 23 (FGF23), a hormone required for normal renal phosphate reabsorption, are typically low in the classic form of the disease due to homozygous missense mutations in FGF23 or in the UDP-Nacetyl-alpha-D galactosamine:polypeptide N-acetylgalactosaminyl transferase (GALNT3). Recessive inactivating mutation in Klotho, a coreceptor for FGF23, also result in tumoral calcinosis, most likely due to an end-organ defect in renal responsiveness to FGF23, as reported in one case. A 35-year-old man, son of a first-cousin marriage, presented with a phenotype consistent with tumoral calcinosis, with a young-onset ectopic calcific lesion at the hip (size: 330 ml) recurred after multiple resections. Serum phosphate was persistently elevated (6.6 mg/dl), renal phosphate reabsorption (TmP/GFR=1.74, 0.71.45) and 1,25(OH)2 vitamin D (105 pg/ml, 2067) were increased, with normal serum calcium, PTH and urinary calcium excretion. The induction of renal acidosis with acetazolamide along with the use of aluminium-based phosphate binders led to a normalization of renal phosphate reabsorption leading to a marked decrease of serum phosphate (5.2 mg/dl) and a shrinkage of the calcified mass (down to 75 ml). Intact and C-terminal FGF23 levels were inappropriately high in this patient (101 pg/ml and 504 RU/ml, respectively), suggesting an end-organ resistance to FGF23. Mutational analysis of FGF23, GALNT3 and Klotho genes revealed a previously unreported 4 bp omozygous deletion in the third exon of GALNT3 gene (c.249, del. TCAG) leading to a 256 AA truncated protein. No mutations in FGF23 gene were found. Three polymorphisms in Klotho gene were detected. The high intact FGF23 levels could be explained, at least in part, by an alteration in signal transduction or a biologically inactive form of FGF23.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology