In this case report, a novel N-acetylgalactosaminyltransferase 3 homozygous mutation (c.782 G>A; p.R261Q) associated with hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome is described. The patient had elbow, pelvis, and lower limb pain and a hard mass in the hip and olecranon regions. Increased levels of inorganic phosphorus (Pi) and C-reactive protein were observed. After treating the patient with conventional drugs, we tested denosumab, which reduced but did not normalize the Pi. Hyperphosphatemic tumoral calcinosis (HTC), also known as hyperphosphatemic familial tumoral calcinosis or familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, is a disorder of phosphate regulation. It is a rare disabling disorder manifesting as ectopic calcifications in periarticular regions and thereby causing limitation in joint motions and disability. Besides, inflammatory bony pains are also a peculiar feature of this disorder. Due to the extreme rarity of the disease and lack of clinical trials, the evidence regarding various management options is not robust. The management options include phosphate-lowering therapies, anti-inflammatory medications, and surgical excision of the calcific masses with significantly disabled cases.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, inherited autosomal recessive disorder caused by fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) gene variants. Here, we report the case of a Japanese boy who presented with a mass in his left elbow at the age of three. Laboratory test results of the patient revealed normocalcemia (10.3 mg/dL) and hyperphosphatemia (8.7 mg/dL); however, despite hyperphosphatemia, serum intact FGF23 level was low, renal tubular reabsorption of phosphate (TRP) level was inappropriately increased, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) level was inappropriately normal. Genetic analysis revealed maternal uniparental disomy (UPD) of chromosome 2, which included a novel GALNT3 variant (c.1780-1G>C). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of GALNT3 mRNA confirmed that this variant resulted in the destruction of exon 11. We resected the mass when the patient was five years old, owing to its gradual enlargement. No relapse or new pathological lesions were observed four years after tumor resection. This is the first case report of a Japanese patient with HFTC associated with a novel GALNT3 variant, as well as the first case of HFTC caused by maternal UPD of chromosome 2 that includes the GALNT3 variant.

A tumoral calcinosis is a rare benign pathology characterized by calcium deposits (calcium phosphate crystals) in the periarticular soft tissues, giving a truly pseudotumor appearance. The same patients with tumoral calcinosis may have manifestation of hyperostosis hyperphosphatemia syndrome. The association is called Hyperphosphatemic familial tumoral calcinosis which is the case with our patient. We present a unique case of a 10-year-old female child without any notable history. No notion of consanguinity, a non-painful swelling of the right elbow for the last 3 years. She was presented with tumoral calcinosis in the context of familial hyperphosphatemic calcinosis tumor in which the diagnosis of lymphangioma was evoked and then redressed.

Mutations in FGF23, KL, and GALNT3 have been identified as the cause for the development of hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC typically present in childhood or adolescence with periarticular soft tissue deposits that eventually progress to disrupt normal joint articulation. Mutations in the GALNT3 gene were shown to account for the hyperphosphatemic state in both HFTC and hyperostosis-hyperphosphatemia syndrome (HHS), the latter characterized by bone involvement. We present the case of a patient of a Druze ethnic origin with known HFTC that presented to our department with the first documented case of pathologic fracture occurring secondary to the disease. Our report introduces this new phenotypic presentation, suggests a potential role for prophylactic bone screening, and highlights the need for preconception genetic screening in selected populations.

Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.