Intact FGF23 concentration in healthy infants, children, and adolescents, and diagnostic usefulness in patients with X-linked hypophosphatemic rickets.

OBJECTIVE: FGF23 measurement may have a diagnostic role to investigate patients with phosphate disorders. However, normal values for infants, children, and adolescents have not been defined. METHODS: In a total of 282 (males 145, females 137) healthy infants (n = 30), prepubertal (n = 147), pubertal (n = 59), and postpubertal (n = 46), and in twenty patients with X-linked hypophosphatemic rickets (XLH, age 10.2 ± 5.6 years) serum phosphate (automated analyzer), and plasma intact FGF23 (immunochemiluminescent sandwich assay, DiaSorin) concentrations were measured. RESULTS: Intact FGF23 concentrations were higher in healthy infants than in prepubertal (P < 0.01) and postpubertal subjects (P < 0.05); pubertal subjects showed higher values (P < 0.05) than postpubertal subjects. Serum phosphate concentrations were higher (P < 0.001) in healthy infants than in prepubertal, pubertal, and postpubertal subjects. Pubertal subjects had higher (P < 0.001) serum phosphate concentrations than postpubertal subjects. Intact FGF23 and serum phosphate concentrations did not differ (P = NS) by sex, age of menarche, and time after menarche. In healthy subjects, there was no correlation between intact FGF23 and serum phosphate concentrations. Intact FGF23 concentrations were higher (P < 0.0001) in patients with XLH than in healthy subjects according to chronological age and pubertal development. In all patients, intact FGF23 concentrations were above 40 pg/mL; intact FGF23 concentrations were inversely correlated with serum phosphate concentrations (r = -0.65; P < 0.01). CONCLUSION: In healthy subjects, chronological age and puberty were main determinants of intact FGF23 concentrations. Intact FGF23 concentrations may be a useful marker for the early diagnosis of XLH in pediatric patients.

The effect of burosumab on intact and C-terminal FGF23 measurements.

OBJECTIVE: To investigate the effect of CRYSVITA® (burosumab-twza) on FGF23 measurements in an intact and a C-terminal immunoassay. METHODS: An intact serum FGF23 (MedFrontier) and a C-terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4-11.3 µg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post-burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurements RESULTS: Spiking burosumab (1.4-11.3 µg/ml) into sample pools resulted in a dose-dependent negative analytical interference on intact FGF23 measurements and no significant interference for C-terminal FGF23 measurements. However, more than a 500-fold median increase (post- vs. pre-burosumab administration) in in vivo FGF23 concentrations were observed by both assays. CONCLUSIONS: Therapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C-terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C-terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results. SUMMARY: This article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C-terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

Evaluation of the trabecular bone score in 35 children and adults with X-linked hypophosphatemic rickets.

INTRODUCTION:  The aim of this study is to evaluate and compare the trabecular bone scores (TBSs) of 11 children and 24 adults with X-linked hypophosphatemic rickets (XLH) and non-XLH subjects from a tertiary center. MATERIALS AND METHODS:  The areal bone mineral density at the lumbar spine (LS-aBMD) and LS-aBMD Z score were analyzed by dual-energy X-ray absorptiometry. The bone mineral apparent density (BMAD) and LS-aBMD Z score adjusted for height Z score (LS-aBMD-HAZ) were calculated. The TBS was determined using TBS iNsight software based on DXA images from the Hologic QDR 4500 device. RESULTS: The XLH patients exhibited a higher mean LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). LS-aBMD-HAZ and BMAD were greater in the XLH children than those in their corresponding non-XLH subjects (p < 0.01 and p = 0.02), and the XLH children trended toward a greater TBS (p = 0.06). The XLH adults had a higher LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). When stratified by metabolic status according to the serum values of bone formation markers, compensated adult patients had a higher LS-aBMD Z score, BMAD, and TBS than non-XLH subjects (p < 0.01). Noncompensated patients had higher LS-aBMD Z scores and BMAD results than non-XLH subjects. However, TBS values did not differ statistically significantly between those groups (p = 0.45). CONCLUSION: The higher LS-aBMD Z score, BMAD, and TBS result in the XLH patients compared to non-XLH subjects indicates an increased amount of trabecular bone within the lumbar spine, regardless of extraskeletal calcifications.

Sex differences of burosumab in children with X-linked hypophosphataemic rickets.

BACKGROUND: The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8 mg/kg every 2 weeks). PATIENTS AND METHODS: In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. RESULTS: We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5 years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18 mmol/L in males and 0.86 ± 0.22 mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11 mmol/L in males and 0.76 ± 0.23 mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19 mg/kg subcutaneously every 14 days (males: 0.79 ± 0.19 mg/kg; females: 0.87 ± 0.21 mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21 mmol/L) and females (1.27 ± 0.25 mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41 mg/kg to achieve a phosphate of 0.87 ± 0.11 mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79 days, the mean burosumab dose/kg in males was 1.68 ± 0.61 mg/kg, mean serum phosphate was 1.08 ± 0.23 mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6 nmol/L. CONCLUSIONS: Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses.

Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders.

OBJECTIVE: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.

Two De Novo Mosaic Variants Within the Same Site of PHEX Gene in a Girl with X-Linked Hypophosphatemic Rickets.

X-linked hypophosphatemic rickets (XLH) is the most common form of hypophosphatemic rickets, which is caused by the deficiencies of PHEX gene with an X-linked dominant inheritance pattern. As at least several thousands of XLH patients have been diagnosed, only several males and fewer females with mosaicism of PHEX gene were found. Here we describe an XLH girl with two de novo mosaic variants within the same site of PHEX gene. To rapidly screen all of the causative genes of hypophosphatemic rickets and rule out other diseases, DNA samples were initially analyzed using whole exome sequencing (WES). Interestingly, two different pathogenic mosaic variants, a known c.1809G > A(p.W603*) variant and a novel c.1809G > T(p.W603C) variant within the same site of PHEX gene, were identified in the proband by WES. Subsequent Sanger sequencing confirmed the presence and de novo pattern of these two mosaic variants in the proband, which were absent in her healthy parents. This is the first case to report two different mosaic variants of PHEX gene in an XLH individual. This XLH girl has a de novo mosaic genotype of c.1809 = /G > T/G > A in PHEX gene. Our report adds an unusual mocaicism case for XLH and expands the mutational event and spectrum of PHEX gene. Our report also alerts clinicians and geneticists to be cautious about mocaicism and detection methods.

Performance evaluation of the new chemiluminescent intact FGF23 assay relative to the existing assay system.

INTRODUCTION: This study assessed the performance of a new fully automated immunoassay for fibroblast growth factor (FGF) 23 (Determinar CL FGF23 CL) among healthy individuals and those with chronic hypophosphatemia compared with the previous assay (Kainos FGF23 KI). MATERIALS AND METHODS: A total of 380 serum samples from healthy participants were collected to determine the reference range of FGF23 levels with CL. A total of 200 serum samples from 22 hypophosphatemic patients were collected simultaneously to compare the difference in FGF23 levels between CL and KI. The Mann-Whitney U test and linear regression analysis were adopted to assess the differences and linearity between the two assays. RESULTS: The median FGF23 levels among healthy individuals was 31.7 (interquartile: 26.4-37.5) pg/mL. When the reference range was calculated as the mean ± 2 standard deviation (2SD), it was 16.1-49.3 pg/mL. A total of 363 individuals (96%) among normal cases fell in this range. Among 200 samples from patients with chronic hypophosphatemic disorder, the median FGF23 levels analyzed by CL and KI were 123.0 (90.2-237.7) and 172.5 (115.8-290.7) pg/mL. KI yielded significantly higher FGF23 values than CL (p < 0.001). A linear regression model revealed the correlation between KI (x) and CL (y), which had a slope of 0.76 with a y-intercept of -0.32 and high linearity (R2 = 0.99). CONCLUSION: The new measurement kit yielded lower FGF23 values when compared with the previous assay. Clinicians should consider this discrepancy when they assay intact FGF23 values with CL.

Pulp chamber features, prevalence of abscesses, disease severity, and PHEX mutation in X-linked hypophosphatemic rickets.

INTRODUCTION: Rickets, growth failure, and recurrent periapical abscesses with fistulae are main signs in patients with X-linked hypophosphatemic rickets (XLH). Prevalence of abscesses, pulp chamber features, biochemical findings, disease severity, and PHEX gene mutation were examined. MATERIALS AND METHODS: Pulp chambers size, shape, and morphology were assessed by orthopantomography in XLH patients (n = 24, age 5.8 ± 1.6 years) and in sex and age-matched healthy controls (n = 23, age 6.2 ± 1.4 years). XLH patients received conventional treatment (3.5 ± 1.9 years). Pulp chamber features were assessed in teeth of primary dentition and in the permanent left mandibular first molar and compared with those of controls. Rickets severity score was assessed at wrist, knee, and ankle. RESULTS: The mean pulp chamber area/tooth area ratio, mean pulp chamber height/pulp chamber width ratio, and prominence of pulp horns into the tooth crown in primary and secondary molars were significantly higher in patients than in controls and in patients suffered abscesses than in patients without abscesses. Sixteen patients (67%) had a history of abscesses; incisors were affected more than canines and molars. Severity of rickets and mean serum parathyroid hormone (PTH) levels were significantly higher, and mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels significantly lower in patients suffered abscesses than in patients without abscesses. PHEX gene mutations were not correlated with dental phenotype and disease severity. CONCLUSION: Enlarged pulp chambers with altered shape and morphology affected the majority of XLH patients predisposing to recurrent periapical abscesses with fistulae. Dental phenotype was associated with severity of rickets, high serum PTH, and low serum 1,25(OH)2D levels.

Plasma intact fibroblast growth factor 23 level is a useful tool for diagnostic approach of renal hypophosphatemia.

BACKGROUND: Primary hypophosphatemic syndromes are a heterogeneous group of rare diseases. In recent years, fibroblast growth factor 23 (FGF23) has been postulated as a useful tool for differential diagnosis of hypophosphatemic rickets characterized by impaired renal phosphate reabsorption. This study aimed to investigate the utility of FGF23 to discriminate between X-linked hypophosphatemic rickets (XLH), an FGF23-driven disease, from other causes of renal phosphate wasting such as Fanconi syndrome (FS), a generalized dysfunction of the proximal tubule unrelated to FGF23. METHODS: Circulating levels of intact FGF23 (iFGF23) were measured in nine children with XLH receiving conventional therapy (six girls, mean ± SD age 10.8 ± 6.7 years) and nine children with secondary FS (four girls, mean ± SD age 9.9 ± 5.2 years), using an automated chemiluminescent immunoassay. Phosphate, calcium, creatinine, estimated glomerular filtration rate (eGFR), intact parathormone (iPTH), and urinary parameters were evaluated simultaneously. Maximum renal tubular threshold for phosphate reabsorption (TmP/GFR) was also estimated. RESULTS: Plasma iFGF23 concentrations in patients with XLH were significantly higher than those in the SF group: 146.2 ± 69.2 ng/L vs. 29.5 ± 15.0 ng/L (p < 0.001). Remarkably, we did not observe an overlap between XLH and FS patients. Significant hypophosphatemia (2.55 ± 0.50 mg/dL) and secondary hyperparathyroidism (iPTH 109.4 ± 58.1 ng/mL) were present in XLH patients, while FS patients showed modest hypophosphatemia (3.97 ± 0.68 mg/dL), higher TmP/GFR compared with XLH, lower eGFR and hypercalciuria. CONCLUSIONS: This study supports the value of measuring FGF23 levels as a useful tool to exclude XLH in patients with increased phosphate wasting of kidney origin. Graphical Abstract.

A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) in X-linked hypophosphatemic rickets with mild bone phenotypes.

X-linked hypophosphatemic rickets (XLH) is primarily characterized by renal phosphate wasting with hypophosphatemia, short stature, and bone deformity of the leg. Here we present a male case of XLH with relatively mild bone deformity caused by a mosaic mutation of the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Polymerase chain reaction (PCR) direct sequencing revealed a novel in-frame deletion, NM-000444.6:c.671-685del p.Gln224-Ser228del, at exon 6 in PHEX as a mosaic pattern. This mutation was not found in any database and may result in a significant change in higher-order protein structure and function. TA cloning of the PCR product and clone sequencing estimated the mutation allele frequency at 21%. Literature review of the previously reported three cases with novel mosaic mutations in PHEX, together with the present case, suggests that the rates of the mutation allele correlate with phenotype severity to some extent. We initially treated him with nutritional vitamin D supplements and phosphate salts. However, to avoid the development of secondary/tertiary hyperparathyroidism, we had switched nutritional to active vitamin D supplementation with reduced phosphorus salts. The present report contributes to understanding the relationship between the mosaic rate, in addition to the mutation locus, of the PHEX gene, and clinical features of XLH.

Imaging of pediatric bone and growth disorders: Of diagnostic workhorses and new horizons.

Children and adolescents with bone and growth disorders require interdisciplinary care from various specialists including pediatric radiologists with a focus on musculoskeletal disorders. This article covers routine topics, differential diagnoses, and selected research imaging in children with osteogenesis imperfecta (OI), X­linked hypophosphatemic rickets (XLH), achondroplasia, and other bone and growth disorders from the standpoint of a tertiary referral center.

The first Korean case report with scaphocephaly as the initial sign of X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemic rickets (XLH) can occasionally cause premature fusion of cranial sutures through an increased level of fibroblast growth factor 23 (FGF-23), which leads to the dysregulation of phosphate and vitamin D metabolism. Secondary craniosynostosis has long been considered to present late after XLH has already been diagnosed either clinically or genetically. CASE PRESENTATION: We present observations of a male infant showing sagittal synostosis as the first sign of XLH. Our patient did not show any other skeletal deformities except macrocephaly with a long head shape. There is a family history of genetically unconfirmed hypophosphatemic rickets in his mother. Direct sequencing by genomic polymerase chain reaction revealed that the patient has a large deletion comprising exons 1-3 of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. CONCLUSION: Our observations suggest that craniosynostosis secondary to rickets can develop in early infancy. Careful monitoring of head shape and growth is therefore critical for early detection of craniosynostosis in XLH.

Effects of growth hormone treatment on adult height in severely short children with X-linked hypophosphatemic rickets.

BACKGROUND: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. METHODS: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepubertal children with XLH on phosphate and active vitamin D treatment. The changes in SD scores (SDS) of height, sitting height, leg and arm length, and sitting height index (i.e., the ratio between sitting height and height) were analyzed in 11 out of 16 patients followed-up until adult height. RESULTS: At baseline, XLH patients showed disproportionately short stature with reduced standardized height (-3.2 ± 0.6), sitting height (-1.7 ± 0.6), leg (-3.7 ± 0.7) and arm (-2.5 ± 0.8) length, and markedly elevated sitting height index (3.3 ± 0.6; each p < 0.01 versus healthy children). In GH-treated patients, adult height, sitting height, leg length, and arm length exceeded baseline values by 0.7 SDS, 1.7 SDS, 0.7 SDS, and 1.2 SDS respectively, although this was only significant for sitting height. In controls, no significant changes in linear body dimensions were noted. Adult height did not statistically differ between groups (-2.4 ± 0.7 vs -3.3 ± 1.2, p = 0.082). GH did not exaggerate body disproportion. CONCLUSIONS: Growth hormone treatment did not significantly increase adult height in this group of short children with XLH, which may be at least partly due to the small number of patients included in our study.

Evaluation of bone mineral density and microarchitectural parameters by DXA and HR-pQCT in 37 children and adults with X-linked hypophosphatemic rickets.

In X-linked hypophosphatemic (XLH) rickets, dual-energy X-ray absorptiometry (DXA) measurements must be analyzed with caution. High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex. INTRODUCTION: The purpose of this study is to evaluate bone mineral density (BMD) and microarchitecture in 37 patients (13 children and 24 adults) with XLH confirmed by PHEX mutations from a tertiary center compared to healthy controls. METHODS: Areal BMD (aBMD) was evaluated by DXA, whereas volumetric BMD (vBMD) and microarchitectural parameters were analyzed by HR-pQCT. RESULTS: Adult XLH patients had higher lumbar aBMD (p < 0.01) than the controls. At the radius, the vBMD was similar between XLH patients and controls. At the tibia, XLH patients had lower total vBMD (p = 0.04), likely resulting from decreased trabecular vBMD (p < 0.01), and this difference was observed in the children and adult groups. Analysis based on metabolic status showed that the adult XLH patients with non-compensated disease had lower cortical vBMD at the tibia than the compensated XLH patients (p = 0.03). The microarchitectural differences at the radius and tibia included lower trabecular number (p < 0.01), greater trabecular separation (p < 0.01), and higher trabecular network inhomogeneity (p < 0.01) in XLH patients compared to their controls. At the radius, adults exhibited greater trabecular deficits than were seen in children. CONCLUSIONS: In XLH patients, DXA measurements must be analyzed with caution due to the interference of anatomic and anthropometric factors. HR-pQCT analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex.

Muscle-Bone Interactions in Pediatric Bone Diseases.

PURPOSE: Here, we review the skeletal effects of pediatric muscle disorders as well as muscle impairment in pediatric bone disorders. RECENT FINDINGS: When starting in utero, muscle disorders can lead to congenital multiple contractures. Pediatric-onset muscle weakness such as cerebral palsy, Duchenne muscular dystrophy, spinal muscular atrophy, or spina bifida typically are associated with small diameter of long-bone shafts, low density of metaphyseal bone, and increased fracture incidence in the lower extremities, in particular, the distal femur. Primary bone diseases can affect muscles through generic mechanisms, such as decreased physical activity or in disease-specific ways. For example, the collagen defect underlying the bone fragility of osteogenesis imperfecta may also affect muscle force generation or transmission. Transforming growth factor beta released from bone in Camurati Engelman disease may decrease muscle function. FUTURE DIRECTIONS: Considering muscle-bone interactions does not only contribute to the understanding of musculoskeletal disorders but also can identify new targets for therapeutic interventions.

Spontaneous Growth and Effect of Early Therapy with Calcitriol and Phosphate in X-linked Hypophosphatemic Rickets.

Whereas nutritional vitamin D deficient rickets affects many people world-wide, X-linked hypophosphatemic rickets (XLH, MIM 307800) has a prevalence of only 1:25.000. Like other rare diseases burden of disease in XLH and the effect of the current standard of care are inadequately described. Only few height data of untreated patients with XLH have been published. Here we report on height before start of therapy of 127 patients with XLH from 49 centres. One investigator collected all data from patient files documented at regular visits by treating physicians. Height standard deviation score (HSDS) was calculated and the geometrical mean was analysed. At birth all patients had a documented height within the healthy reference population. In this cross-sectional analysis of documented height at time of diagnosis decelerates until a mean age of 4.3 years to a nadir, i.e. lowest HSDS of -3.2 HSDS. Afterwards a spontaneous catch-up growth of +1.3 HSDS occurs until start of puberty. To assess the impact of calcitriol and phosphate supplementation on growth we analysed from a cohort of 18 patients treated at the Dept. of Paediatrics at O.-v.-Guericke-University Magdeburg. In this subgroup, size at birth and all time lowest HSDS (r=0.56 p=0.002) are correlated as well as all time low HSDS and last height during puberty (r=0.62 p=0.001). 10 of 18 patients were treated before age 18 months. Within this group the mean HSDS decelerates to -2.2 SDS at age 4.4 y. and increased to -1.4 SDS at age 9.9 years. Adult height, i.e. mean age 17.6 years was -2.4 HSDS. In conclusion, untreated children with XLR are characterized by normal length at birth, diminished growth rate compared to reference children until 4.3 years and spontaneous catch-up growth of 1.3 HSDS until start of puberty. Improved growth rate in XLR children occured by combined phosphate and calcitriol treatment before 18 months.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets.

BACKGROUND AND OBJECTIVE: X-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia. Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions. Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few. In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. METHODS: Five Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8-1.2 mg/kg, s. c. QW2). Burosumab was continued for 12-48 months and, once discontinued, patients were followed-up for 6-12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3-6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. RESULTS: At entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DISCUSSION: Our data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Non-Surgical Strategies for Managing Skeletal Deformities in a Child with X-Linked Hereditary Hypophosphatemic Ricket: Insights and Perspectives.

This case report sheds light on the management of skeletal deformity in a young child with X-linked hypophosphatemia (XLH), emphasizing the significance of a timely orthotic intervention alongside pharmacological treatment, which is a strategy not frequently highlighted in the XLH literature. The patient, a 2-year-and-7-month-old female, presented with classic XLH symptoms, including short stature, pronounced genu varum, and hypophosphatemia, with deformities observed in both the coronal and sagittal planes of the femur and tibia. Despite initial reliance on pharmacotherapy, which proved insufficient for skeletal realignment, the integration of orthotic treatment at age 3 marked a pivotal turn in the management strategy. By the age of 5 years and 9 months, this combined approach yielded significant improvements: the deformities in the femur and tibia were notably corrected, tibial torsion was addressed, and enhanced limb alignment was achieved, as corroborated by radiographic evidence. This case underscores the effectiveness of orthotic intervention as a critical and underemphasized adjunct to pharmacological therapy in managing XLH in early childhood. It advocates for the early inclusion of orthotic measures to optimize treatment outcomes and expand the range of management strategies for limb deformities.

Increased Col10a1 expression is not causative for the phenotype of Phex-deficient Hyp mice.

X-linked hypophosphatemic rickets (XLHR) is a severe disorder of phosphate homeostasis and skeletal mineralization caused by mutations of PHEX, encoding a bone-specific endopeptidase. Phex-deficient Hyp mice have been extensively studied to understand the molecular bases of XLHR, and here it was found that Fgf23, encoding a major phosphaturic hormone, was transcriptionally activated in bone-forming osteoblasts. We and others could additionally show that Col10a1 expression is increased in Hyp osteoblasts and bones, thereby raising the possibility that ectopic production of type X collagen could contribute to the impaired mineralization of the Hyp bone matrix. Here we show that an additional deficiency of the Col10a1 gene does not overtly affect the skeletal phenotype of Hyp mice. More specifically, Col10a1-deficient Hyp mice displayed severe disturbances of skeletal growth, bone mass acquisition and bone matrix mineralization, and they were essentially indistinguishable from Hyp littermates. This was confirmed by non-decalcified histology and bone-specific histomorphometry quantifying all relevant parameters of growth plate maturation, trabecular bone architecture and osteoid accumulation. Taken together, our results show that increased Col10a1 expression in Phex-deficient osteoblasts is not a major cause of the XLHR phenotype, which was an important issue to address based on the previous findings.

A De Novo Mosaic PHEX Variant Causing Sporadic X-Linked Hypophosphatemic Rickets in a 2-Year-Old Girl.

Pathogenic variants in the PHEX gene are causative of X-linked hypophosphatemic rickets (XLH). We present a case of a 2-year-old girl with hypophosphatemic rickets with genu varum and short stature without any family history of XLH. Next generation sequencing of the PHEX gene identified a splice donor variant, NM_000444.6:c.1173 + 5G > A in intron 10. This variant had a mosaic pattern with only 22% of the sequence reads showing the variant allele and was not present in the girl's parents, both of whom had a normal phenotype. This is a sporadic case of a de novo mosaic splice-site variant in the PHEX gene.