X-Linked Hypophosphatemia: A New Era in Management.
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ABSTRACT:
SUBMITTER: Dahir K
PROVIDER: S-EPMC7649833 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
X-Linked Hypophosphatemia: A New Era in Management.
Dahir Kathryn K Roberts Mary Scott MS Krolczyk Stan S Simmons Jill H JH
Journal of the Endocrine Society 20201014 12
X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive musculoskeletal disease that often causes pain and short stature, as well as decreased physical function, mobility, and quality of life. Hypophosphatemia in XLH is caused by loss of function mutations in the phosphate-regulating endopeptidase homolog X-linked (<i>PHEX</i>) gene, resulting in excess levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), which leads to renal phosphate wasting and decreased ...[more]
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Project description:X-linked hypophosphatemia (XLH) is associated with a pervasive, severe degenerative osteoarthritis. We conducted a retrospective chart review/patient survey using the Knee or Hip Osteoarthritis Outcome Score Physical Function Short Form. Fourteen total knee arthroplasties and 7 total hip arthroplasties among 11 patients were included. The mean KOOS-PS score was 31.4?±?9.7 with a mean follow up of 6.9 years. Mean HOOS-PS score was 14.8?±?12.9?at a mean follow up of 7.6 years. One knee failed due to aseptic loosening and one hip was revised due to polyethylene wear. In conclusion, total joint arthroplasty is beneficial in XLH.
| S-EPMC6324762 | biostudies-literature
Project description:IntroductionX-linked hypophosphatemia (XLH) is a rare inherited cause of hypophosphatemic rickets and osteomalacia. It is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX). This results in increased plasma fibroblast growth factor-23 (FGF23), which leads to loss of renal sodium-phosphate co-transporter expression leading to chronic renal phosphate excretion. It also leads to low serum 1,25-dihydroxyvitamin D (1,25(OH)2D), resulting in impaired intestinal phosphate absorption. Chronic hypophosphatemia in XLH leads to impaired endochondral mineralization of the growth plates of long bones with bony deformities. XLH in children and adolescents also causes impaired growth, myopathy, bone pain, and dental abscesses. XLH is the most frequent inherited cause of phosphopenic rickets/osteomalacia. Hypophosphatemia is also found in calcipenic rickets/osteomalacia as a result of secondary hyperparathyroidism. Thus, chronic hypophosphatemia is a common etiologic factor in all types of rickets.ResultsThere is considerable overlap between symptoms and signs of phosphopenic and calcipenic rickets/osteomalacia. Wrong diagnosis leads to inappropriate treatment of rickets/osteomalacia. Nutritional rickets and osteomalacia are common in the Gulf Cooperation Council countries which include Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman. Due to high levels of consanguinity in the region, genetic causes of phosphopenic and calcipenic rickets/osteomalacia are also common.ConclusionThis guideline was developed to provide an approach to the diagnosis of XLH, especially where there is no family history of the disease, and that other related conditions are not mistaken for XLH. We also guide the medical management of XLH with conventional treatment and with burosumab, a recombinant human IgG1 monoclonal antibody to FGF23.
| S-EPMC7929956 | biostudies-literature
Project description:Background: X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations. Methods: PHEX mutations were detected in 55 out of 81 patients who clinically presented with hypophosphatemic rickets. The patients were grouped into nontruncating (n = 9) and truncating (n = 46) mutation groups; their initial presentation as well as long-term clinical findings were evaluated according to these groups. Results: Initial findings, including presenting symptoms, onset age, height standard deviation scores (SDS), and laboratory tests, including serum phosphate level and tubular resorption of phosphate, were not significantly different between the two groups (onset age: nontruncating mutation group, 2.0 years, truncating mutation group, 2.2 years; height SDS: nontruncating mutation group, -1.9, truncating mutation group, -1.7; serum phosphate: nontruncating mutation group, 2.5 mg/dL, truncating mutation group, 2.6 mg/dL). However, at their last follow-up, the serum phosphate level was significantly lower in patients with truncating mutations (nontruncating mutation group: 3.2 mg/dl, truncating mutation group: 2.3 mg/dl; P = 0.006). Additionally, 62.5% of patients with truncating mutations developed nephrocalcinosis at their last follow-up, while none of the patients with nontruncating mutations developed nephrocalcinosis (P = 0.015). Orthopedic surgery due to bony deformations was performed significantly more often in patients with truncating mutations (52.3 vs. 10.0%, P = 0.019). Conclusion: Although considerable inconsistency exists regarding the correlation of truncating mutations and their disease phenotype in several other studies, we cautiously suggest that there would be genotype-phenotype correlation in some aspects of disease manifestation after long-term follow-up. This information can be used when consulting patients with confirmed XLH regarding their disease prognosis.
| S-EPMC8382157 | biostudies-literature
Project description:ContextWe characterized linear growth in infants and children with X-linked hypophosphatemia (XLH).ObjectiveProvide linear growth curves for children with XLH from birth to early adolescence.DesignData from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301).SettingMedical centers with expertise in treating XLH.PatientsChildren with XLH, 1-14 years of age.InterventionNone.Main outcome measureHeight-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms.ResultsA total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old.ConclusionChildren with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH.
| S-EPMC7448934 | biostudies-literature
Project description:X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.
| S-EPMC9778127 | biostudies-literature
Project description:BackgroundX-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.MethodsThe role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.ResultsThe pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.ConclusionsBy describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.
| S-EPMC6390548 | biostudies-literature
Project description:BackgroundX-linked hypophosphatemia (XLH) is the most common inherited form of rickets. The presence of sequence variations in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene is associated with increased production of fibroblast growth factor 23 (FGF23). This results in renal phosphate wasting and impaired skeletal mineralization. Spontaneous dental abscesses, caused by endodontic infections resulting from hypomineralization of dentin, are a known dental complication of XLH. There is no objective method to evaluate the severity of dentin dysplasia. The purpose of this study was to develop a quantitative method to evaluate dentin dysplasia using orthopantomography that would allow the values in patients with XLH to be compared with the values in healthy participants of the same age.MethodsThe severity of dentin dysplasia was analyzed by measuring the pulp cavity area of the tooth using orthopantomographic images. The teeth analyzed were mandibular second primary molars and mandibular first permanent molars with complete root formation. Teeth with dental caries, restorations, or root resorption were excluded.ResultsThis retrospective observational study included a total of 200 images of healthy participants (aged 2-15 years) divided into five age groups and 42 images of 17 patients with XLH. There was a significant tendency for the pulp cavity area to decrease with increasing age in primary and permanent teeth. The pulp chambers of patients with XLH were larger than those of healthy participants in primary and permanent teeth.ConclusionWe have established a method of using orthopantomography for quantitative assessment of dentin dysplasia in XLH from the primary dentition to the permanent dentition. Evaluating the severity of dentin hypomineralization by this method is useful in the diagnosis of the dental manifestations of XLH. Early diagnosis of XLH enables oral management and leads to prevention of dental abscesses.
| S-EPMC11280221 | biostudies-literature
Project description:X-linked hypophosphatemia (XLH) is a skeletal disease caused by inactivating mutations in the PHEX gene. Mutated or absent PHEX protein/enzyme leads to a decreased serum phosphate level, which cause mineralization defects in the skeleton and teeth (osteomalacia/odontomalacia). It is not yet altogether clear whether these manifestations are caused solely by insufficient circulating phosphate availability for mineralization or also by a direct, local intrinsic effect caused by impaired PHEX activity. Here, we evaluated the local role of PHEX in a 3-dimensional model of extracellular matrix (ECM) mineralization. Dense collagen hydrogels were seeded either with human dental pulp cells from patients with characterized PHEX mutations or with sex- and age-matched healthy controls and cultured up to 24 d using osteogenic medium with standard phosphate concentration. Calcium quantification, micro-computed tomography, and histology with von Kossa staining for mineral showed significantly lower mineralization in XLH cell-seeded scaffolds, using nonparametric statistical tests. While apatitic mineralization was observed along collagen fibrils by electron microscopy in both groups, Raman microspectrometry indicated that XLH cells harboring the PHEX mutation produced less mineralized scaffolds having impaired mineral quality with less carbonate substitution and lower crystallinity. In the XLH cultures, immunoblotting revealed more abundant osteopontin (OPN), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) than controls, as well as the presence of fragments of these proteins not found in controls, suggesting a role for PHEX in SIBLING protein degradation. Immunohistochemistry revealed altered OPN and DMP1 associated with an increased alkaline phosphatase staining in the XLH cultures. These results are consistent with impaired PHEX activity having local ECM effects in XLH. Future treatments for XLH should target both systemic and local manifestations.
| S-EPMC6429567 | biostudies-literature
Project description:BackgroundX-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH.ResultsThe RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was - 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below-2. All cases had hypophosphatemia, serum phosphate being - 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype-phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis.ConclusionsThis study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.
| S-EPMC7912818 | biostudies-literature
Project description:The pathophysiology of the osteomalacia in X-linked hypophosphatemia is uncertain. In this project, genomic DNA microarrays were used to identify novel genes with abnormal mRNA expression levels in mice with the dominant Hyp mutation of the Phex gene. Femoral shafts from five-week-old C57BL/6J mice, male and female, normal and Hyp (hemizygous male and heterozygous female), were flushed with saline to remove the marrow. RNA was extracted from each bone, pooled between two mice for each array, processed to cRNA, and hybridized to Affymetrix Mouse 430 2.0 GeneChip microarrays with probe sets for 45,101 genes. Twenty microarrays (40 mice) were done with 5 arrays for each treatment group (normal male, Hyp male, normal female and Hyp female). For each gene, factorial analysis of variance was performed for the main effects of genotype (normal vs. Hyp), sex (male vs. female), and genotype-by-sex interaction. The mRNA levels for 54 % of the genes on each array were scored as present. At P < 0.01, 2,635 genes were significant for genotype, 1,488 for sex, and 509 for genotype-by-sex interaction. There were two probes sets for the Phex gene. Probe 1450445, at the 3â end of the coding sequence, was low in normal samples (246 ± 37 (10), mean ± SEM (n)) and absent in Hyp samples. Probe 1421979, at the far 3â end of the untranslated region of the cDNA, 3,000 base pairs from the coding sequence, was high in normal mice (3,915 ± 315 (10); 8x brighter than the average gene), undetectable in Hyp males, and 725 ± 93 (5) in Hyp females. Both probe sets were scored as absent in kidney tissue. In Hyp bone, male and female, there was significant down-regulation of markers of osteoblasts and bone matrix synthesis with significant up-regulation of markers of blood vessel formation and cytoskeleton. No prominent skeletal gene was up-regulated in Hyp to attempt to compensate for the low skeletal mineralization. The genes with significant genotype-by-sex interaction did not show a marked fold difference between male and female Hyp mice. In conclusion, male and female Hyp mice showed similar depression of mRNA levels of genes related to bone synthesis in the femoral shaft. There was a high signal level from probes for a sequence in the 3â untranslated region of the Phex gene of normal, but not Hyp, mice, suggesting the need for further study of the molecular organization of this gene. Experiment Overall Design: Equal amounts of RNA from two mice, matched for genotype and sex were pooled to create each sample for microarray analysis. Four treatment groups were done: (1) Normal male mice, (2) Hyp male mice, (3) normal female mice, and (4) Hyp female mice. Five replicates were done with each replicate containing one sample from each of the four treatment groups for a total of 20 independent samples (40 mice total). Each replicate was matched for littermates and parallel processing.
2008-06-14 | E-GEOD-5657 | biostudies-arrayexpress