A Large Deletion With a Large Impact: Homozygous 5,600 bp Deletion of the GALNT3 Gene Causing Hyperphosphatemic Tumoral Calcinosis

Hyperphosphatemic familial tumoral calcinosis (HTC) is a rare disease caused by autosomal recessive loss of function variants in the genes encoding fibroblast growth factor 23 (FGF-23), Klotho, or GalNAc-T3. This results in reduced phosphate excretion in the renal proximal tubule, leading to hyperphosphatemia. The clinical manifestations of HTC are mainly periarticular calcifications accompanied by pain and disability, inflammation, and dental problems. Inactive forms or reduced levels of FGF-23 or resistance to the FGF-23/Klotho complex are the main pathophysiologic characteristics underlying this disease. Treatment options to reduce blood phosphate levels have only been studied in case reports and small cohorts, with positive effects from phosphate binders, acetazolamide, anti-inflammatory drugs, probenecid, nicotinamide, and sodium thiosulfate. In this report, we present the case of a 50-year-old woman with a large (at least 5,600 base pair) deletion in the gene encoding for GalNAc-T3 ( GALNT3 ) who experienced bone pain during childhood and calcifications of her lower limbs at least since her mid-thirties. Intragenic GALNT3 copy number variants have, to our knowledge, not yet been described as a cause of HTC.