Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing

Shah, Anuja; Miller, Clinton; Nast, Cynthia C.; Adams, Mark D.; Truitt, Barbara; Tayek, John A.; Tong, Lili; Mehtani, Parag; Monteón, Francisco; Sedor, John R.; Clinkenbeard, Erica L.; White, Kenneth E.; Mehrotra, Rajnish; LaPage, Janine; Dickson, Patricia I.; Adler, Sharon G.; Iyengar, Sudha K.

doi:10.1093/ndt/gfu324

Cited by 21 publications

(16 citation statements)

References 42 publications

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“…The greatest potential risk associated with FTC/HHS may be vascular calcification (26, 27). Two of the five subjects evaluated had coronary calcifications, with Agatston scores above the 95th percentile.…”

Section: Discussionmentioning

confidence: 99%

“…The greatest potential risk associated with FTC/HHS may be vascular calcification. (26,27) Two of the five subjects evaluated had coronary calcifications, with Agatston scores above the 95th percentile. As the two affected had other risk factors for cardiac calcification, the lack of cardiac calcification in other subjects may be a function of young age and other factors.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Ramnitz

Gourh

Goldbach‐Mansky

et al. 2016

Journal of Bone and Mineral Research

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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 while 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 7 subjects; no causative mutation was found in the eighth. Biopsies from 4 subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in 1 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 2 subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and peri-lesional 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Ramnitz

Gourh

Goldbach‐Mansky

et al. 2016

Journal of Bone and Mineral Research

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“…This expression profile is reflective of patients with hfTC GALNT3 and FGF23 missense mutations, (21,22,50) where the ability to produce FGF23 at minimal levels and carry out lowlevel renal phosphate metabolism likely prevents early death, as reported in complete Fgf23-null mice (28,29) or a severe hfTC phenotype as reported in a family with an FGF23 deletion and missense mutation. (51) Serum FGF23 was detectable after targeting recombination to osteoblasts and osteocytes; therefore, it is possible that FGF23 is also produced in other cell types within bone such as chondrocytes, (52) or extraskeletal tissues such as skin and brain, (53) as well as heart. (54) Additionally, it cannot be ruled out at this time that some inefficiency of the respective Cre transgenic lines accounts in part for the detectable serum FGF23.…”

Section: Discussionmentioning

confidence: 99%

Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia

Clinkenbeard

Cass

et al. 2016

Journal of Bone and Mineral Research

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The transgenic and knock out (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened life span, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed (‘f’)-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele (‘Δ’) had undetectable serum intact FGF23, elevated serum phosphate (p<0.05), and increased kidney Cyp27b1 mRNA (p<0.05) similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge Fgf23Δ/f mice were mated with early osteoblast type Iα1 collagen 2.3kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23Δ/f/Col2.3-cre+ and Fgf23Δ/f/Dmp1-cre+ exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high phosphate diet Cre− mice had 2.1–2.5 fold increased serum FGF23 (p<0.01), but Col2.3-cre+ mice had no significant increase, and Dmp1-cre+ mice had only a 37% increase (p<0.01) despite prevailing hyperphosphatemia in both models. The Fgf23Δ/f/Col2.3-cre was bred onto the Hyp (murine XLH model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23Δ/f/Col2.3-cre+ mice had serum FGF23 <4% of Hyp (p<0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome.

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“…In our study, FGF23 levels were measured using an ELISA which recognizes both the intact molecule and the carboxy-terminal fragment of FGF23. In individuals with severe ectopic vascular calcifications due to a mutation in the FGF23 gene, high circulating carboxy-terminal FGF23 levels were detected, whereas intact FGF23 levels were undetectable [44]. Since carboxy-terminal fragments of FGF23 lack biological function as opposed to intact FGF23, measurement of both intact and carboxy-terminal FGF23 levels may give better insight into the mechanism underlying vascular calcification, especially if subjects with vascular calcification have no or low levels of intact FGF23 and high levels of carboxy-terminal fragment.…”

Section: Discussionmentioning

confidence: 99%

Serum fetuin-A levels and abdominal aortic calcification in healthy men — The STRAMBO study

Schoppet

Rauner

Benner³

et al. 2015

Bone

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Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing

Cited by 21 publications

References 42 publications

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia

Serum fetuin-A levels and abdominal aortic calcification in healthy men — The STRAMBO study

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