Familial
tumoral calcinosis (
FTC)/
hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding
fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing
hyperphosphatemia, increased renal tubular reabsorption of
phosphorus (TRP), elevated or inappropriately normal
1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or
diaphyseal hyperostosis. Eight subjects with
FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had
hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from
diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic
inflammation and elevated
C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic
inflammation, with areas of
heterotopic ossification observed in one subject. Treatment with low
phosphate diet,
phosphate binders, and
phosphaturia-inducing
therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic
inflammation,
interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of
calcinosis cutis and perilesional
inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of
FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic
inflammation has not been described previously in
FTC/HHS; the response to
IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of
heterotopic ossification reported in
FTC/HHS, possibly mediated by the adjacent
inflammation. © 2016 American Society for Bone and
Mineral Research.