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Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

ABSTRACT: Objective:Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods:Here we present nationwide initial and follow-up data on HR. Results:From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7±2.4 years. During the first 3-years of treatment (n=91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p>0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year PTH was higher. However, higher treatment doses of phosphate and calcitriol were found in the NC group. Conclusion:HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

SUBMITTER: S?klar Z

PROVIDER: S-EPMC7291408 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

Şıklar Zeynep Z Turan Serap S Bereket Abdullah A Baş Firdevs F Güran Tülay T Akberzade Azad A Abacı Ayhan A Demir Korcan K Böber Ece E Özbek Mehmet Nuri MN Kara Cengiz C Poyrazoğlu Şükran Ş Aydın Murat M Kardelen Aslı A Tarım Ömer Ö Eren Erdal E Hatipoğlu Nihal N Büyükinan Muammer M Akyürek Nesibe N Çetinkaya Semra S Bayramoğlu Elvan E Selver Eklioğlu Beray B Uçaktürk Ahmet A Abalı Saygın S Gökşen Damla D Kor Yılmaz Y Ünal Edip E Esen İhsan İ Yıldırım Ruken R Akın Onur O Çayır Atilla A Dilek Emine E Kırel Birgül B Anık Ahmet A Çatlı Gönül G Berberoğlu Merih M

Journal of clinical research in pediatric endocrinology 20190913 2

<h4>Objective</h4>Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options.<h4>Methods</h4>Here we present nationwide initial and follow-up data on HR.<h4>Results</h4>From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed <i>PHEX</i> mutation in 80% of patients. The mean follow-up period was 6.7± ...[more]

PMID: 31514490

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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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Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

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Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

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