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Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood.

ABSTRACT: Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis characterized, when severely expressed, by osteomalacia, suppressed levels of calcitriol, and renal phosphate wasting due to elevated levels of fibroblast growth factor 23 (FGF23). The disease is caused by heterozygous FGF23 mutations at the RXXR site that prevent cleavage of the intact hormone.An FGF23 mutation was identified in the proband an 85-year-old woman with elevated FGF23 levels, and her clinical course was characterized. Medical records revealed she was treated for rickets as an infant. She was then asymptomatic until soon after her 4th pregnancy, when she suffered incapacitating bone pain and weakness, age 37. Symptoms remitted with brief treatment.The proband and one son, but not other family members, were found to be heterozygous for the R176Q mutation in FGF23. Expression of this germ line mutation was strikingly different in both individuals in terms of skeletal health, FGF23 levels and disease activity.The identified FGF23 mutation in two members of this family raises questions about molecular mechanisms that have led to intermittent increases in FGF23 synthesis and secretion, and disease expression.

SUBMITTER: Seton M

PROVIDER: S-EPMC5103613 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood.

Seton Margaret M Jüppner Harald H

Bone 20121119 2

<h4>Background</h4>Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis characterized, when severely expressed, by osteomalacia, suppressed levels of calcitriol, and renal phosphate wasting due to elevated levels of fibroblast growth factor 23 (FGF23). The disease is caused by heterozygous FGF23 mutations at the RXXR site that prevent cleavage of the intact hormone.<h4>Objectives</h4>An FGF23 mutation was identified in the proband an 85-year-old ...[more]

PMID: 23174215

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Project description:Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12?months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 ?g/dL; or serum iron 50 to 100 ?g/dL combined with hypophosphatemia and intact FGF23?>30?pg/mL at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65?mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ?20% from baseline. Six adults (three male, three female) having the FGF23-R176Q mutation were enrolled; five completed the 12-month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5?mg/dL) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/mL at baseline to 47 (17, 78) pg/mL at month 4 and 42 (19, 63) pg/mL at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/mL at baseline to 78.0 (49.6, 261.0) ng/mL at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron-deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. © 2019 American Society for Bone and Mineral Research.

Project description:We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)(2) vitamin D (1x10(-7) M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 h. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR.

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Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood.

Publications

Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood.

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