Abstract
Purpose
X-linked hypophosphatemia (XLH) is the most common inherited renal phosphate wasting disorder and is often misdiagnosed as vitamin D deficiency. This study aims to provide clinical and mutational characteristics of 65 XLH pediatric patients in southern China.
Methods
In this work, a combination of DNA sequencing and qPCR analysis was used to study the PHEX gene in 80 pediatric patients diagnosed with hypophosphatemia. The clinical and laboratory data of confirmed 65 XLH patients were assessed and analyzed retrospectively.
Results
In 65 XLH patients from 61 families, 51 different variants in the PHEX gene were identified, including 23 previously reported variants and 28 novel variants. In this cohort of XLH patients, the c.1601C>T(p.Pro534Leu) variant appears more frequently. Fourteen uncommon XLH cases were described, including four boys with de novo mosaic variants, eight patients with large deletions and a pair of monozygotic twins. The clinical manifestations in this cohort are very similar to those previously reported.
Conclusion
This study extends the mutational spectrum of the PHEX gene, which will contribute to accurate diagnosis. This study also suggests a supplementary qPCR or MLPA assay may be performed along with classical sequencing to confirm the gross insertion/deletion.
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References
Alizadeh Naderi AS, Reilly RF (2010) Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 6:657–665
Carpenter TO (2012) The expanding family of hypophosphatemic syndromes. J Bone Miner Metab 30:1–9
Jan de Beur SM, Levine MA (2002) Molecular pathogenesis of hypophosphatemic rickets. J Clin Endocrinol Metab 87:2467–2473
Pavone V, Testa G, Gioitta Iachino S et al (2015) Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol 25:221–226
Gaucher C, Walrant-Debray O, Nguyen TM et al (2009) PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet 125:401–411
Holm IA, Nelson AE, Robinson BG et al (2001) Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 86:3889–3899
Tyynismaa H, Kaitila I, Näntö-Salonen K et al (2000) Identification of fifteen novel PHEX gene mutations in Finnish patients with hypophosphatemic rickets. Hum Mutat 15:383–384
Ruppe MD, Brosnan PG, Au KS et al (2011) Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. Clin Endocrinol (Oxf) 74:312–318
Beck-Nielsen SS, Brock-Jacobsen B, Gram J et al (2009) Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 160:491–497
Endo I, Fukumoto S, Ozono K et al (2015) Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr J 62:811–816
Rafaelsen S, Johansson S, Ræder H et al (2016) Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 174:125–136
Francis F, Hennig S, Korn B et al (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. HYP Consort Nat Genet 11:130–136
Liu S, Tang W, Fang J et al (2009) Novel regulators of Fgf23 expression and mineralization in Hyp bone. Mol Endocrinol 23:1505–1518
Martin A, Liu S, David V et al (2011) Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551–2562
Igaki JM, Yamada M, Yamazaki Y et al (2011) High iFGF23 level despite hypophosphatemia is one of the clinical indicators to make diagnosis of XLH. Endocr J 58:647–655
Andrukhova O, Slavic S, Smorodchenko A et al (2014) FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 6:744–759
Shimada T, Hasegawa H, Yamazaki Y et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435
Murali SK, Andrukhova O, Clinkenbeard EL et al (2016) Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in hyp mice. PLoS Biol 14:e1002427
Quinlan C, Guegan K, Offiah A et al (2012) Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol 27:581–588
Cho HY, Lee BH, Kang JH et al (2005) A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res 58:329–333
Li H, Ji CY, Zong XN et al (2009) Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Zhonghua Er Ke Za Zhi 47:487–492 (Article in Chinese)
Lin Y, Cai Y, Xu J et al (2020) 'Isolated' germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets. Eur J Endocrinol 182:K1–K6
Drezner MK, Lyles KW, Haussler MR et al (1980) Evaluation of a role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia. J Clin Invest 66:1020–1032
Santos F, Smith MJ, Chan JC (1986) Hypercalciuria associated with long-term administration of calcitriol (1,25-dihydroxyvitamin D3). Action of hydrochlorothiazide. Am J Dis Child 140:139–142
Clausmeyer S, Hesse V, Clemens PC et al (2009) Mutational analysis of the PHEX gene: novel point mutations and detection of large deletions by MLPA in patients with X-linked hypophosphatemic rickets. Calcif Tissue Int 85:211–220
Beck-Nielsen SS, Brixen K, Gram J et al (2012) Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet 57:453–458
Capelli S, Donghi V, Maruca K et al (2015) Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. Bone 79:143–149
Morey M, Castro-Feijóo L, Barreiro J et al (2011) Genetic diagnosis of X-linked dominant Hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type. BMC Med Genet 12:116
Song HR, Park JW, Cho DY et al (2007) PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. J Korean Med Sci 22:981–986
Francis F, Strom TM, Hennig S et al (1997) Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. Genome Res 7:573–585
Zhang C, Zhao Z, Sun Y et al (2019) Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia. Bone 121:212–220
Li SS, Gu JM, Yu WJ et al (2016) Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets. Int J Mol Med 38:1703–1714
Rowe PS, Oudet CL, Francis F et al (1997) Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). Hum Mol Genet 6:539–549
Weng C, Chen J, Sun L et al (2016) A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets. J Hum Gene 61:223–227
Goji K, Ozaki K, Sadewa AH et al (2006) Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait. J Clin Endocrinol Metab 91:365–370
Pasmant E, Pacot L (2020) Should we genotype the sperm of fathers from patients with 'de novo' mutations? Eur J Endocrinol 182:C1–C3
Mumm S, Huskey M, Cajic A et al (2015) PHEX 3′-UTR c.*231A%3eG near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets. J Bone Miner Res 30:137–143
Acknowledgements
We would like to thank the enrolled family for participation in this study. We thank Dr. Gendie Lash at Guangzhou Women and Children's Medical Center and Dr. Ting Wu for correcting the English of our manuscript. We also thank the Department of Radiology and Clinical Laboratory at Guangzhou Women and Children’s Medical Center for assistance with radiological and laboratory examinations.
Funding
This work was supported in part by the National Natural Science Foundation of China (Grant number 81701128), and the fund from Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center (Grant number Pre-NSFC-2019-008).
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All the listed authors were involved in drafting or editing this article, and approved its submission and publication. LL and CZ conceived and designed the study. LL, CZ, XL, JC, YH, XM, ZZ, WZ, CL, ZL, JX and YL recruited the family, collected their medical history and data, and inquired the family pedigree. YL, JX, HS, LS, MW, YC, DW, ZL and XY performed the experiments and acquired the data. YL and JX analyzed the data. LL, CZ and YL wrote the paper.
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This study was approved by the Institutional Review Board of Guangzhou Women and Children’s Medical Center (Guangzhou, China) (No. 2015-82).
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Informed consent was obtained from all the subjects or their tutors (for under-aged participants).
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Lin, Y., Xu, J., Li, X. et al. Novel variants and uncommon cases among southern Chinese children with X-linked hypophosphatemia. J Endocrinol Invest 43, 1577–1590 (2020). https://doi.org/10.1007/s40618-020-01240-6
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DOI: https://doi.org/10.1007/s40618-020-01240-6