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X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia.In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events.The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity.In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).

ContextPercutaneous epiphysiodesis (PE) around the knee to reduce predicted excessive final height. Studies until now included small numbers of patients and short follow-up periods.Objective and designThis Dutch multicentre, long-term, retrospective, follow-up study aimed to assess adult height (AH), complications, knee function and patient satisfaction after PE. The primary hypothesis was that PE around the knee in constitutionally tall boys and girls is an effective treatment for reducing final height with low complication rates and a high level of patient satisfaction.Participants77 treated adolescents and 60 comparisons.InterventionPercutaneous epiphysiodesis.OutcomeAH, complications, knee function, satisfaction.ResultsIn the PE-treated group, final height was 7.0 cm (±6.3 cm) lower than predicted in boys and 5.9 cm (±3.7 cm) lower than predicted in girls. Short-term complications in file search were seen in 5.1% (three infections, one temporary nerve injury), one requiring reoperation. Long-term complications in file search were seen in 2.6% (axis deformity 1.3%, prominent head of fibula 1.3%). No significant difference in knee function was found between treated cases and comparisons. Satisfaction was high in both the comparison and PE groups; most patients in the PE group recommended PE as the treatment for close relatives with tall stature.ConclusionPE is safe and effective in children with predicted excessive AH. There was no difference in patient satisfaction between the PE and comparison group. Careful and detailed counselling is needed before embarking on treatment.

Background Children with severe neurological impairment and intellectual disability are prone to low bone quality and fractures. Objective We studied the feasibility of automated radiogrammetry in assessing bone quality in this specific group of children. We measured outcome of bone quality and, because these children tend to have altered skeletal maturation, we also studied bone age. Materials and methods We used hand radiographs obtained in 95 children (mean age 11.4 years) presenting at outpatient paediatric clinics. We used BoneXpert software to determine bone quality, expressed as paediatric bone index and bone age. Results Regarding feasibility, we successfully obtained a paediatric bone index in 60 children (63.2%). The results on bone quality showed a mean paediatric bone index standard deviation score of −1.85, significantly lower than that of healthy peers (P

Purpose: In patients with XLH, high circulating FGF23 induces renal phosphate (Pi) wasting, hypophosphatemia, rickets, and short stature. Current treatment with oral phosphate/active vitamin D is suboptimal in many patients. Methods: In a Phase 2 study, we randomized 52 children with XLH (ages 5-12 years, ≤Tanner 2) to receive KRN23 subcutaneously, either biweekly …

We report on a female patient with XY sex reversal with clitoromegaly, neonatal male testosterone and AMH levels, and a normal urine steroid profile. Array CGH revealed a de novo microdeletion of chromosome 9q33.3, including the NR5A1 gene. NR5A1 encodes for the steroidogenic factor-1 (SF-1) and heterozygous mutations in this gene were recently identified as an important cause of XY sex reversal. However, a deletion of NR5A1 has only been reported once. Patients with a mutation in NR5A1, have severe underandrogenisation with mild testicular dysgenesis. Müllerian structures may be present, while postnatal testosterone levels may be normal. This points towards a predominantly early embryonic effect of low, local, androgen levels, with or without reduced AMH levels. We recommend not only NR5A1 mutation screening, but also copy number analysis in patients with 46,XY sex reversal of unknown cause, even in the absence of dysmorphisms or congenital abnormalities.

Vitamin D is a key hormone in the regulation of calcium and phosphorus metabolism and plays a pivotal role in bone health, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Great interest has been placed in recent years on vitamin D's extraskeletal actions. However, while recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious and autoimmune diseases, the actual impact of vitamin D status on the global health of children and adolescents, other than bone, remains a subject of debate. In the meantime, pediatricians still need to evaluate the determinants of vitamin D status and consider vitamin D supplementation in children and adolescents at risk of deficiency. This review is the result of an expert meeting that was held during the congress "Update on vitamin D and bone disease in childhood" convened in Pisa, Italy, in May 2013. CONCLUSION: The collaboration of the international group of experts produced this "state of the art" review on vitamin D in childhood and adolescence. After dealing with vitamin D status and its determinants, the review outlines the current debate on vitamin D's health benefits, concluding with a practical approach to vitamin D supplementation during childhood and adolescence. WHAT IS KNOWN: • Vitamin D deficiency is a worldwide health problem. • Vitamin D deficiency affects not only musculoskeletal health but also a potentially wide range of acute and chronic diseases. What is New: • We reviewed the literature focusing on randomized controlled trials of vitamin D supplementation during childhood and adolescence. • This review will help pediatricians to appreciate the clinical relevance of an adequate vitamin D status and it will provide a practical approach to vitamin D supplementation.

The clinical relevance of low IGF-I levels, caused by cranial radiotherapy, in adult childhood cancer survivors has not been studied extensively. We evaluated whether IGF-I is a useful marker for altered body composition and growth hormone deficiency (GHD) in this group.We analyzed retrospective data from 610 adult childhood cancer survivors, retrieved from the late effects clinic. Median age at diagnosis was 6 years (interquartile range 3-11) and follow-up time was 18 years (13-24). We assessed IGF-I standard deviation scores (SDS), anthropometrical measures, growth hormone stimulation tests in patients with clinical signs of GHD, and measures of body composition (assessed by dual X-ray absorptiometry, Lunar Prodigy).In 58 cranially irradiated acute leukemia survivors (25 Gy (24-25)) and 56 locally irradiated brain tumor survivors (42 Gy (35-54)) we found significantly lower IGF-I SDS (P0.001), lower height SDS (P0.001), higher body mass index (P = 0.01), higher waist-hip ratio (WHR; P = 0.001), higher total fat percentage SDS (P0.001), and lower lean body mass SDS (P0.001), as compared to 452 not cranially irradiated survivors. IGF-I showed a weak inverse correlation with BMI (r = -0.12, P = 0.04), WHR (r = -0.15, P = 0.01), total fat percentage (r = - 0.14, P = 0.02), and a positive correlation with lean body mass (r = 0.15, P = 0.01). In patients with low IGF-I levels, IGF-I did not significantly differ between subjects with and without GHD as determined by GH-stimulation testing (P = 0.39).This study shows that IGF-I has limited value as a marker for alterations in body composition in adult childhood cancer survivors.

Background In XLH, high circulating FGF23 causes hypophosphatemia, rickets, and short stature. Objective and hypotheses To evaluate KRN23 effects on serum phosphate (Pi) level and rickets severity in XLH children in a phase 2 study. Method Fifty-two XLH children (ages 5-12 years, ≤ Tanner 2) received KRN23 subcutaneously biweekly (Q2 W) or monthly (Q4 W). Serum Pi was measured at 2-week intervals. KRN23 dose was titrated (maximum 2 mg/kg) targeting age-appropriate serum Pi concentrations. Rickets severity was assessed by the Thacher Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C: −3 = worsening; +3 = complete healing). Results The first 36 subjects had a mean 6.6 years of standard-of-care treatment before washout. KRN23 increased serum Pi from baseline in all subjects to near normal levels (mean increase 0.30 mmol/L at 38 weeks; P Conclusion KRN23 improved phosphorus homeostasis and rickets in children with XLH.