Did you mean: hypophosphatemic rickets
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Nature Reviews. Nephrology Jul 2019X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb...
X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.
Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arnold-Chiari Malformation; Biomarkers; Bone Density Conservation Agents; Bone and Bones; Continuity of Patient Care; Craniosynostoses; Delphi Technique; Dental Care; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Growth Hormone; Hearing Loss; Humans; Immunologic Factors; Life Style; Mutation; Orthopedic Procedures; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphates; Physical Therapy Modalities; Radiography; Vitamin D
PubMed: 31068690
DOI: 10.1038/s41581-019-0152-5 -
The Journal of Clinical Endocrinology... Dec 2022Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic...
Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical examination, laboratory investigations, genetic analysis (especially in the absence of a guiding family history), and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.
Topics: Adult; Child; Child, Preschool; Humans; Familial Hypophosphatemic Rickets; Osteomalacia; Fibroblast Growth Factors; Rickets, Hypophosphatemic; Hypophosphatemia; Phosphates
PubMed: 35981346
DOI: 10.1210/clinem/dgac488 -
Journal of Bone and Mineral Research :... Jul 2011X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and support... (Review)
Review
X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines, which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the Advances in Rare Bone Diseases Scientific Conference held at the NIH in October 2008. We briefly review the clinical and pathophysiologic features of the disorder and offer this guide in response to the conference recommendation, based on our collective accumulated experience in the management of this complex disorder.
Topics: Familial Hypophosphatemic Rickets; Genetic Diseases, X-Linked; Humans; Practice Guidelines as Topic; Radiography
PubMed: 21538511
DOI: 10.1002/jbmr.340 -
Hormone Research in Paediatrics 2022Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by... (Review)
Review
Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.
Topics: Animals; Dogs; Humans; Cod Liver Oil; Familial Hypophosphatemic Rickets; Parathyroid Hormone; Rickets; Vitamin D; Vitamins
PubMed: 36446330
DOI: 10.1159/000527011 -
Frontiers in Endocrinology 2021X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the gene lead to elevated... (Review)
Review
X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the 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.
Topics: Alkaline Phosphatase; Antibodies, Monoclonal, Humanized; Belgium; Consensus; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Humans; Hypophosphatemia; Interdisciplinary Communication; Mutation; Osteomalacia; PHEX Phosphate Regulating Neutral Endopeptidase; Severity of Illness Index; Societies, Medical; Treatment Outcome; Vitamin D
PubMed: 33815294
DOI: 10.3389/fendo.2021.641543 -
Pediatric Nephrology (Berlin, Germany) Oct 2022Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of...
Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.
Topics: Calcium; Child; Familial Hypophosphatemic Rickets; Fanconi Syndrome; Fibroblast Growth Factors; Humans; Osteomalacia; Paraneoplastic Syndromes; Phosphates; Rickets; Rickets, Hypophosphatemic; Vitamin D
PubMed: 35352187
DOI: 10.1007/s00467-022-05505-5 -
Frontiers in Endocrinology 2021X-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... (Review)
Review
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.
Topics: Antibodies, Monoclonal, Humanized; Calcium; Child; Familial Hypophosphatemic Rickets; Humans; Parathyroid Hormone; Vitamin D
PubMed: 34421819
DOI: 10.3389/fendo.2021.688309 -
Lancet (London, England) Jun 2019X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.
METHODS
In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.
FINDINGS
Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.
INTERPRETATION
Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.
FUNDING
Ultragenyx Pharmaceutical and Kyowa Kirin International.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Body Height; Child; Child Development; Child, Preschool; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Humans; Immunologic Factors; Infant; Male; Severity of Illness Index; Treatment Outcome
PubMed: 31104833
DOI: 10.1016/S0140-6736(19)30654-3 -
Frontiers in Endocrinology 2022Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for... (Review)
Review
Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for maintaining phosphate homeostasis and is mainly produced by osteocytes. FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys. Osteocytes are cells of osteoblastic lineage that have undergone terminal differentiation and become embedded in mineralized bone matrix. Osteocytes express and other multiple genes responsible for hereditary hypophosphatemic rickets, which include (), (), and (). Since inactivating mutations in , , and boost the production of FGF23, these molecules might be considered as local negative regulators of FGF23. Mouse studies have suggested that enhanced FGF receptor (FGFR) signaling is involved in the overproduction of FGF23 in -deficient X-linked hypophosphatemic rickets (XLH) and -deficient autosomal recessive hypophosphatemic rickets type 1. Since FGFR is involved in the transduction of signals evoked by extracellular Pi, Pi sensing in osteocytes may be abnormal in these diseases. Serum levels of sclerostin, an inhibitor Wnt/β-catenin signaling secreted by osteocytes, are increased in XLH patients, and mouse studies have suggested the potential of inhibiting sclerostin as a new therapeutic option for the disease. The elucidation of complex abnormalities in the osteocytes of FGF23-related hypophosphatemic diseases will provide a more detailed understanding of their pathogenesis and more effective treatments.
Topics: Animals; Calcium-Binding Proteins; Endopeptidases; Extracellular Matrix Proteins; Familial Hypophosphatemic Rickets; Fibroblast Growth Factors; Hydroxyapatites; Mice; Osteocytes; Phosphates; Phosphorus; Receptors, Fibroblast Growth Factor; Rickets, Hypophosphatemic; beta Catenin
PubMed: 36246908
DOI: 10.3389/fendo.2022.1005189 -
The Journal of Clinical Endocrinology... Jul 2022Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown.
OBJECTIVE
This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH.
METHODS
This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64.
RESULTS
The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, -0.86; older, -1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, -31.15% of upper normal limit [ULN]; older, -52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children.
CONCLUSION
Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D.
Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Familial Hypophosphatemic Rickets; Fibroblast Growth Factors; Humans; Hypophosphatemia
PubMed: 35533340
DOI: 10.1210/clinem/dgac296