Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.
Highlights
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder resulting from disturbances in fibroblast growth factor 23 (FGF23)-mediated phosphate regulation
Investigation in HFTC has greatly expanded our knowledge of phosphate homeostasis, leading to novel insights into FGF23 signaling
HFTC may result from dysregulation in multiple pathways, resulting in states of FGF23 deficiency and/or resistance
Summary
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder resulting from disturbances in FGF23-mediated phosphate regulation. These mice did not develop calcifications on a normal diet, but treatment with a high phosphate diet induced calcifications in approximately half of the knockout mice [16] Another HFTC mouse created by ENU mutagenesis harbors a Trp589Arg mutation in Galnt, and has hyperphosphatemia with decreased intact FGF23 levels, elevated 1,25D, and subtle periarticular calcifications [17]. Pathogenic variants in GALNT3 or FGF23 result in functional FGF23 deficiency, hormone replacement therapy with FGF23 would be the ideal treatment for most causes of HFTC Until this becomes available, current interventions focus on managing blood phosphate, reducing pain and inflammation, and addressing calcifications and their complications. Investigation is needed to define optimal imaging strategies to detect, monitor, and predict lesion development
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