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Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).

ABSTRACT: Hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM #211900) is an autosomal recessive metabolic disorder characterized by hyperphosphatemia, tooth root defects, and the progressive deposition of calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone.(1) In this HFTC case report, we document the dental phenotype associated with a homozygous missense mutation (g.29077 C>T; c.484 C>T; p.Arg162*) in GALNT3 (OMIM 6017563), a gene encoding UDP-GalNAc transferase 3 that catalyzes the first step of O-linked oligosaccharide biosynthesis in the Golgi. The medical and dental pathology is believed to be caused primarily by high serum phosphate levels (hyperphosphatemia), which, in turn, is caused by failure of GALNT3 to glycosylate the phosphate regulator protein FGF23, impairing its ability inhibit reabsorption of filtered phosphate in the kidneys.

SUBMITTER: Vieira AR

PROVIDER: S-EPMC4640955 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).

Vieira Alexandre R AR Lee Moses M Vairo Filippo F Loguercio Leite Julio Cesar JC Munerato Maria Cristina MC Visioli Fernanda F D'Ávila Stéphanie Rodrigues SR Wang Shih-Kai SK Choi Murim M Simmer James P JP Hu Jan C-C JC

Oral surgery, oral medicine, oral pathology and oral radiology 20150528 6

Hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM #211900) is an autosomal recessive metabolic disorder characterized by hyperphosphatemia, tooth root defects, and the progressive deposition of calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone.(1) In this HFTC case report, we document the dental phenotype associated with a homozygous missense mutation (g.29077 C>T; c.484 C>T; p.Arg162*) in GALNT3 (OMIM 6017563), a gene encoding UDP-GalNAc transferase 3 ...[more]

PMID: 26337219

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Project description:Hyperphosphatemic familial tumoral calcinosis (HFTC) presents with varied neurological manifestations that have been reported in the literature like facial palsy, vision and hearing impairment, stroke, and headache. In this article, we reported a 12-year-old girl child patient with recurrent facial weakness with bilateral hearing impairment and multiple ulcerative lesions on lower limbs and elbows. On examination, she had lower motor neuron (LMN) facial palsy with conductive hearing loss. The investigations showed hyperphosphatemia (9.3 mg/dL) with normal serum calcium (10.4 mg/dL), alkaline phosphatase (147.9 U/L), parathyroid hormone (23.12 pg/mL), and renal function tests. Elevated serum calcium and phosphorus product (96.72 mg 2 /mL 2 ) and elevated renal tubular reabsorption of phosphate (TMPxGFR) value (9.16) were noted. Skeletal survey showed hyperostosis in the long bone diaphysis, vertebrae, ribs, pelvic bone, skull, and facial bones with narrowing of cranial ostium, characteristically without any peri-articular soft tissue calcifications. An angiogram showed multiple intravascular calcifications. She was managed with a low-phosphate diet, sevelamer, niacinamide, acetazolamide, sucroferric oxyhydroxide to lower serum phosphate level, and topical sodium thiosulfate ectopic cutaneous calcification. Exome sequencing showed novel homozygous inframe deletion of ACG in FGF23 gene exon 3 at c.374_376 delins position (p. Asp125del) in the proband and a mutation in the heterozygous state in the mother and elder sibling, thus confirming a molecular diagnosis of HFTC. Our case had a unique neurological presentation of recurrent bilateral lower motor nerve facial palsy, hearing loss, multiple ectopic cutaneous calcifications without peri-articular deposits, multiple intravascular, intracranial, and vertebral endplate calcification, which has not been reported earlier. The proband showed a novel pathogenic variant suggesting an expanding phenotype of HFTC.

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

Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).

Publications

Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).

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