Earlier Onset in Autosomal Dominant Hypophosphatemic Rickets of R179 than R176 Mutations in Fibroblast Growth Factor 23: Report of 20 Chinese Cases and Review of the Literature

  • Chang Liu
  • Zhen Zhao
  • Ou Wang
  • Mei Li
  • Xiaoping Xing
  • Evelyn Hsieh
  • Seiji Fukumoto
  • Yan JiangEmail author
  • Weibo XiaEmail author
Original Research


Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disorder characterized by variant onset ages and diverse phenotypes. Our aim is to explore the genotype–phenotype correlations between ADHR patients with R176 and R179 mutations in FGF23 gene. Clinical manifestations, laboratory examinations, and genetic analyses were collected from 20 patients in six Chinese ADHR kindreds in our hospital. Previously published ADHR literatures were reviewed. Among 20 Chinese ADHR mutation carriers, 11 patients revealed overt symptoms. 10/11 (90.9%) of which were females. Patients with R179 mutations presented with earlier onset than those with R176 mutation [1.3 (1.0, 37.0) years vs. 28.5 (19.0, 44.0) years]. More patients with R179 mutations had a history of rickets with lower extremity deformity [3/4 (75%) vs. 1/7 (14.3%), p < 0.05]. The serum phosphate, i-FGF23 and c-FGF23 levels of patients with R179 and R176 mutations were 0.47 ± 0.14 mmol/L versus 0.57 ± 0.17 mmol/L, 79.6 ± 87.0 pg/mL versus 79.9 ± 107.4 pg/mL, and 33.4 ± 3.0 RU/mL versus 121.3 ± 177.6 RU/mL, respectively. 7/11 of patients had iron deficiency at onset of disease. When combined with previously reported seven ADHR families, difference was observed in the age of onset among symptomatic patients with R179 and R176 mutations [1.0 (0.9, 37.0) years vs. 24.5 (1.2, 57.0) years, p < 0.05]. Patients with R179 mutation were more likely to have rickets than R176 mutation (11/13, 84.6% vs. 5/20, 25.0%, p < 0.01) and lower extremity deformity (10/13, 76.9% vs. 6/19, 31.6%, p < 0.01). ADHR patients with R179 mutations had earlier onset age and more rickets compared to those with mutations in R176, which partially explained the clinical heterogeneity of ADHR.


Autosomal dominant hypophosphatemic rickets Fibroblast growth factor 23 Mutations 



We appreciate our patients and their families for their participation in this study. This study was supported by a grant from The Ministry of Science and Technology of the Peoples Republic of China (National Science and Technology Major Projects for Major New Drugs Innovation and Development 2008ZX09312-016), the National Natural Science Foundation of China (No.81070687, 81170805, and 81670714), the Beijing Natural Science Foundation (No. 7121012), the Scientific Research Foundation of Beijing Medical Development (No. 2007–3029), National Key Program of Clinical Science (WBYZ2011-873), and the CAMS Innovation Fund for Medical Sciences (No.2016-I2 M-3-003). Dr. Hsieh is supported by an International Research Scientist Development Award (K01TW009995) from the NIH/Fogarty International Center.

Author Contributions

CL, ZZ, YJ, and WX designed the study and prepared the first draft of the paper. ZZ contributed to the experimental work. CL was responsible for statistical analysis of the data. All listed authors revised the paper critically for intellectual content and approved the final version of the submitted manuscript. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Compliance with Ethical Standards

Conflict of interest

Chang Liu, Zhen Zhao, Ou Wang, Mei Lia, Xiaoping Xing, Evelyn Hsieh, Seiji Fukumoto,Yan Jiang, and Weibo Xia declare that they don’t have any conflicts of interest in this work.

Human and Animal Rights and Informed Consent

This study was approved by the Department of Scientific Research of PUMCH. All participants provided written informed consents.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of HealthPeking Union Medical College Hospital, Chinese Academy of Medical SciencesBeijingChina
  2. 2.Section of Rheumatology, Department of Internal MedicineYale School of MedicineNew HavenUSA
  3. 3.Fujii Memorial Institute of Medical SciencesTokushimaJapan

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