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A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

ABSTRACT: A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology.FTC and HHS are caused by mutations in FGF23, GALNT3, or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D(3) (1,25-D(3)); FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis.A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment.Serum phosphorus was 7.3 mg/dL (2.5-4.8), TmP/GFR 6.99 mg/100 mL (2.97-4.45), 1,25-D(3) 35 pg/mL (22-67). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (20-108), but intact FGF23 was 7.4 pg/mL (10-50). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23.This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23.

SUBMITTER: Dumitrescu CE

PROVIDER: S-EPMC2692468 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

Dumitrescu C E CE Kelly M H MH Khosravi A A Hart T C TC Brahim J J White K E KE Farrow E G EG Nathan M H MH Murphey M D MD Collins M T MT

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20081104 7

<h4>Summary</h4>A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology.<h4>Introduction</h4>FTC and H ...[more]

PMID: 18982401

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Project description: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.

Project description:Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by mutations in FGF23, GALNT3, KLOTHO, or FGF23 autoantibodies. Prominent features include high blood phosphate and calcific masses, usually adjacent to large joints. Dental defects have been reported, but not systematically described. Seventeen patients with HFTC followed at the National Institutes of Health underwent detailed clinical, biochemical, molecular, and dental analyses. Studies of teeth included intraoral photos and radiographs, high-resolution μCT, histology, and scanning electron microscopy (SEM). A scoring system was developed to assess the severity of tooth phenotype. Pulp calcification was found in 13 of 14 evaluable patients. Short roots and midroot bulges with apical thinning were present in 12 of 13 patients. Premolars were most severely affected. μCT analyses of five HFTC teeth revealed that pulp density increased sevenfold, whereas the pulp volume decreased sevenfold in permanent HFTC teeth compared with age- and tooth-matched control teeth. Histology revealed loss of the polarized odontoblast cell layer and an obliterated pulp cavity that was filled with calcified material. The SEM showed altered pulp and cementum structures, without differences in enamel or dentin structures, when compared with control teeth. This study defines the spectrum and confirms the high penetrance of dental features in HFTC. The phenotypes appear to be independent of genetic/molecular etiology, suggesting hyperphosphatemia or FGF23 deficiency may be the pathomechanistic driver, with prominent effects on root and pulp structures, consistent with a role of phosphate and/or FGF23 in tooth development. Given the early appearance and high penetrance, cognizance of HFTC-related features may allow for earlier diagnosis and treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Dataset Information

A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

Publications

A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

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