Functional Characterization of PHEX Gene Variants in Children With X-Linked Hypophosphatemic Rickets Shows No Evidence of Genotype–Phenotype Correlation

Zheng, Bixia; Wang, Chunli; Chen, Qiuxia; Che, Ruochen; Sha, Yugen; Zhao, Fei; Ding, Guofu; Zhou, Wei; Jia, Zhanjun; Huang, Songming; Chen, Ying; Zhang, Aihua

doi:10.1002/jbmr.4035

Cited by 27 publications

(28 citation statements)

References 31 publications

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“…[ 3 , 9 ] The hypocalcemic vitamin D pathway defects include nutritional rickets, which are caused by inadequate vitamin D supply, [ 10 ] VDDR-I, which is caused by mutations in the CYP27B1 gene leading to 1-α-hydroxylase deficiency, [ 11 ] and vitamin D-dependent rickets type II (VDDR-II), which is caused by mutations in the vitamin D receptor ( VDR ) gene. [ 12 ] Regarding hypophosphatemic rickets, X-linked hypophosphatemia (XLH), which is caused by inactivating mutations in the PHEX gene, [ 13 ] and autosomal dominant hypophosphatemic rickets (ADHR), which is caused by mutations in FGF23 , dentin matrix protein 1 ( DMP1 ) and ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) [ 9 ] are the most common forms. Although there are various forms of rickets, the clinical understanding of each form is quite variable.…”

Section: Discussionmentioning

confidence: 99%

Long-term dental intervention and laboratory examination in a patient with Vitamin D-dependent rickets type I

et al. 2020

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Rationale: Vitamin D-dependent rickets type I (VDDR-I) is a rare form of rickets, which is an autosomal recessive disease caused by 1α-hydroxylase enzyme deficiency. However, long-term dental management and microscopic morphology of teeth remain largely unclear. Patient concerns: We report the case of a 10-year-old Chinese boy complaining of yellowish-brown teeth with extensive caries. Diagnoses: Clinical and laboratory examinations were performed, and VDDR-I was confirmed. Scanning electron microscopy confirmed amelogenesis imperfecta. Interventions: The patient had been taking drugs intervention for VDDR-I from the age of 3 years. The decayed teeth were treated, and metal-preformed crowns were placed to prevent further impairment. Sequence tooth extraction and remineralization therapy were also performed. Outcomes: After 3 years of follow-up, the patient exhibited normal tooth replacement and an acceptable oral hygiene status. However, the new erupted teeth had amelogenesis imperfecta. Lessons: This case is the first to confirm amelogenesis imperfecta in a patient with VDDR-I that was not prevented by drug intervention. Importantly, it provides evidence that long-term dental intervention in patients with VDDR-I can result in an acceptable oral hygiene status. Therefore, early and long-term dental intervention is necessary in VDDR-I patients.

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Section: Discussionmentioning

confidence: 99%

Long-term dental intervention and laboratory examination in a patient with Vitamin D-dependent rickets type I

et al. 2020

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“…X-linked hypophosphatemia (XLH) is a rare inherited disease caused by an inactivating mutation in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. 1 , 2 PHEX is expressed primarily in osteoblasts where it encodes an enzyme that degrades local small integrin-binding ligand N-linked glycoproteins (SIBLING proteins), particularly osteopontin. 3 An intact PHEX also suppresses the production of the serum phosphatonin fibroblast growth factor 23 (FGF23).…”

Section: Introductionmentioning

confidence: 99%

Body composition and cardiometabolic health of pediatric patients with X-linked hypophosphatemia (XLH) under burosumab therapy

Brener

Lebenthal

Cleper

et al. 2021

Therapeutic Advances in Endocrinology

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Background: Burosumab, a recombinant anti-FGF23 monoclonal antibody, was recently introduced as a treatment for X-linked hypophosphatemia (XLH). Burosumab normalizes blood phosphate levels, thereby healing rickets, decreasing leg bowing, and reducing pain. We aimed to explore the body composition and cardiometabolic health of pediatric patients with XLH treated with burosumab. Methods: This observational real-life study was conducted on growing children and adolescents. The outcome measures included changes in sex- and age-adjusted anthropometric and body composition parameters [fat mass (FM), fat-free mass (FFM), appendicular skeletal muscle mass (ASMM), muscle-to-fat ratio (MFR)], blood pressure, laboratory evaluation, and radiographic rickets severity [Thacher Rickets Severity Score (TRSS)]. Body composition was assessed by bioelectrical impedance analysis (BIA). Percentiles for FFM% and ASMM% were calculated according to BIA pediatric reference curves. The delta variable was calculated as the variable at 12 months minus the variable at baseline. Results: A total of 15 pediatric patients with XLH are treated in our clinic; included in the analyses were 7 children and adolescents (3 males, mean age 8.7 ± 3.2 years) with XLH without comorbidities. Baseline BIA revealed an unfavorable physique, with increased body fat percentage in five patients and decreased muscle mass in six. Indices of lean body mass significantly increased after 6 and 12 months of treatment: FFM(kg) ( p = 0.001, p = 0.046, respectively) and ASMM(kg) ( p = 0.012, p = 0.034, respectively), without any significant change in FM(kg). The percentile of ASMM% increased significantly after 6 months of treatment ( p = 0.006) and stabilized thereafter. TRSS improved significantly after 12 months of therapy ( p = 0.005). Age was positively correlated with delta TRSS ( r = 0.814, p = 0.026), and delta TRSS was negatively correlated with delta MFR ( r = −0.826, p = 0.022). Conclusions: There was a heretofore unrecognized improvement in body composition of growing children and adolescents with XLH who were treated with burosumab. These findings highlight the need to initiate burosumab treatment at a younger age when rickets is less severe.

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“…Genetic testing also examines the 3' untranslated region in which mutations associated with milder XLH phenotypes have been reported (111)(112)(113). In general however, mutations can affect any exon, without a clear genotype-phenotype correlation (114).…”

Section: Genetic Testingmentioning

confidence: 99%

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

et al. 2021

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X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.

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Functional Characterization of PHEX Gene Variants in Children With X-Linked Hypophosphatemic Rickets Shows No Evidence of Genotype–Phenotype Correlation

Cited by 27 publications

References 31 publications

Long-term dental intervention and laboratory examination in a patient with Vitamin D-dependent rickets type I

Long-term dental intervention and laboratory examination in a patient with Vitamin D-dependent rickets type I

Body composition and cardiometabolic health of pediatric patients with X-linked hypophosphatemia (XLH) under burosumab therapy

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

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