Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, DMP1 or ENPP1, and activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single-base change near the polyadenylation (pA) signal in the 3'-UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3'-UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3'-UTR region showed the c.*231A > G mutation in four unrelated boys. Then, among an additional 22 of our 72 "sporadic" XLH patients, one boy and one girl were found to have the 3'-UTR defect, totaling six patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; ie, a ∼2:1 gender ratio consistent with XLH. However, finding five boys and only one girl with this 3'-UTR mutation presented an unexplained gender bias (p = 0.02). Haplotyping for the five boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their six mothers had been studied clinically and biochemically (three radiologically). Remarkably, the seemingly unaffected mothers of four of these boys carried the 3'-UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR.
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http://dx.doi.org/10.1002/jbmr.2307 | DOI Listing |
Diagnostics (Basel)
July 2023
CEINGE-Advanced Biotechnologies Franco Salvatore, 80145 Naples, Italy.
Pathogenic variants in the gene cause rare and severe X-linked dominant hypophosphataemia (XLH), a form of heritable hypophosphatemic rickets (HR) characterized by renal phosphate wasting and elevated fibroblast growth factor 23 (FGF23) levels. Burosumab, the approved human monoclonal anti-FGF23 antibody, is the treatment of choice for XLH. The genetic and phenotypic heterogeneity of HR often delays XLH diagnoses, with critical effects on disease course and therapy.
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August 2023
Child Health Research Centre, Faculty of Medicine, The University of Queensland, Australia; Department of Endocrinology and Diabetes, Queensland Children's Hospital, Brisbane, Queensland, Australia.
Int J Rheum Dis
May 2023
Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
Front Endocrinol (Lausanne)
September 2022
Shanghai Clinical Research Center of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Objective: The aim of this study was to fully describe the clinical and genetic characteristics, including clinical manifestations, intact fibroblast growth factor 23 (iFGF23) levels, and presence of gene mutations, of 22 and 7 patients with familial and sporadic X-linked dominant hypophosphatemia (XLH), respectively.
Methods: Demographic data, clinical features, biochemical indicators, and imaging data of 29 patients were collected. All 22 exons and exon-intron boundaries of the gene were amplified by polymerase chain reaction (PCR) and directly sequenced.
Front Cell Dev Biol
June 2021
Shanghai Clinical Research Center of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
X-linked hypophosphatemia (XLH) is caused by inactivating mutations in the () gene, resulting in an excess of circulating intact fibroblast growth factor-23 (iFGF-23) and a waste of renal phosphate. In the present study, we retrospectively reviewed the clinical and molecular features of 153 Chinese patients, representing 87 familial and 66 sporadic cases with XLH. A total of 153 patients with XLH presented with signs or symptoms at a median age of 18.
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