X-Linked Hypophosphatemia: A New Era in Management

Dahir, Kathryn; Roberts, Mary Scott; Krolczyk, Stan; Simmons, Jill H.

doi:10.1210/jendso/bvaa151

Cited by 42 publications

(76 citation statements)

References 70 publications

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“…Most of the patients have osteoarticular and muscle pain with weakness, and they frequently show fatigue that reduces exercise tolerance. Fractures are uncommon in pediatric patients with XLH, but osteomalacic fractures (pseudofractures) may affect older patients (8,14,15). Moreover, an unexpected increase in mortality in later life has been observed (16).…”

Section: Clinical Phenotypementioning

confidence: 99%

“…The short biologic half-life of oral inorganic phosphate salts requires frequent administrations up to six times/day. Compliance with this treatment represents a major issue, mainly in infancy and puberty (8,15,(21)(22)(23)(24). Conventional treatment, which has been in place for approximately four decades, transiently increases serum phosphate concentration without notable changes in the maximum tubular reabsorption of phosphate normalized to the glomerular filtration rate (TmP/GFR).…”

Section: Medical Treatmentmentioning

confidence: 99%

“…Conventional therapy requires balancing the benefits of treatment with complicated monitoring and potential risks of overtreatment. Gastrointestinal symptoms (diarrhea, bloody stools, and abdominal pain), endocrine abnormalities (hypercalcemia and hyperparathyroidism), and renal complications (hypercalciuria and nephrocalcinosis) may frequently occur in patients receiving long-term conventional treatment (8,15,(21)(22)(23)(24). The effect of conventional treatment in improving linear growth is variable and it has been related to the age at diagnosis and onset of treatment.…”

Section: Medical Treatmentmentioning

confidence: 99%

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X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

Baroncelli

Mora

2021

Front. Endocrinol.

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X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

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Section: Clinical Phenotypementioning

confidence: 99%

Section: Medical Treatmentmentioning

confidence: 99%

Section: Medical Treatmentmentioning

confidence: 99%

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X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

Baroncelli

Mora

2021

Front. Endocrinol.

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“…These findings are consistent with the diffuse osteomalacia observed in Hyp mice (9,10,31) as well as in humans with XLH. (32,33) In WT mice, Matsuo and colleagues (34) were able to identify voids as large capillary loops lined with endothelial cells in the orbicular apophysis of the malleus during the first weeks of life. In the close vicinity of these capillaries, specific type I and type II collagen-producing hypermineralizing "auditory osteoblasts" were recently identified, (35) and new matrix production led to a rapid decrease of the diameter of the capillaries.…”

Section: Discussionmentioning

confidence: 99%

Conductive Hearing Loss in the Hyp Mouse Model of X-Linked Hypophosphatemia Is Accompanied by Hypomineralization of the Auditory Ossicles

Delsmann

Seist

Stürznickel

et al. 2020

Journal of Bone and Mineral Research

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X-linked hypophosphatemia (XLH) is a hereditary musculoskeletal disorder caused by loss-of-function mutations in the PHEX gene. In XLH, increased circulating fibroblast growth factor 23 (FGF23) levels cause renal phosphate wasting and low concentrations of 1,25-dihydroxyvitamin D, leading to an early clinical manifestation of rickets. Importantly, hearing loss is commonly observed in XLH patients. We present here data from two XLH patients with marked conductive hearing loss. To decipher the underlying pathophysiology of hearing loss in XLH, we utilized the Hyp mouse model of XLH and measured auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) to functionally assess hearing. As evidenced by the increased ABR/DPOAE threshold shifts in the mid-frequency range, these measurements indicated a predominantly conductive hearing loss in Hyp mice compared to wild-type (WT) mice. Therefore, we carried out an in-depth histomorphometric and scanning electron microscopic analysis of the auditory ossicles. Quantitative backscattered electron imaging (qBEI) indicated a severe hypomineralization of the ossicles in Hyp mice, evidenced by lower calcium content (CaMean) and higher void volume (ie, porosity) compared to WT mice. Histologically, voids correlated with unmineralized bone (ie, osteoid), and the osteoid volume per bone volume (OV/BV) was markedly higher in Hyp mice than WT mice. The density of osteocyte lacunae was lower in Hyp mice than in WT mice, whereas osteocyte lacunae were enlarged. Taken together, our findings highlight the importance of ossicular mineralization for hearing conduction and point toward the potential benefit of improving mineralization to prevent hearing loss in XLH.

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“…Because of the efficacy of genetic testing, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of phosphate‐wasting disorders. ( 11 , 12 , 13 )…”

Section: Introductionmentioning

confidence: 99%

Rare Diseases That Impersonate One Another:X‐LinkedHypophosphatemia andTumor‐InducedOsteomalacia, a Retrospective Analysis of Discriminating Features

et al. 2022

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Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual‐energy X‐ray absorptiometry (DXA) scans reveal lower Z‐scores in the hip (−1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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X-Linked Hypophosphatemia: A New Era in Management

Cited by 42 publications

References 70 publications

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

Conductive Hearing Loss in the Hyp Mouse Model of X-Linked Hypophosphatemia Is Accompanied by Hypomineralization of the Auditory Ossicles

Rare Diseases That Impersonate One Another:X‐LinkedHypophosphatemia andTumor‐InducedOsteomalacia, a Retrospective Analysis of Discriminating Features

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