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Vitamin D has a role in regulating immune function, and its deficiency is a suggested risk factor for childhood pneumonia. Our aim was to assess whether oral supplementation of vitamin D3 (cholecalciferol) will reduce the incidence and severity of pneumonia in a high-risk infant population. We did a randomised placebo-controlled trial to compare oral 100 000 IU (2·5 mg) vitamin D3 with placebo given to children aged 1–11 months in Kabul, Afghanistan. Randomisation was by use of a computer-generated list. Vitamin D or placebo was given by fieldworkers once every 3 months for 18 months. Children presenting at the study hospital with signs of pneumonia had their diagnosis confirmed radiographically. Our primary outcome was the first or only episode of radiologically confirmed pneumonia. Our analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00548379. 1524 children were assigned to receive vitamin D3 and 1522 placebo. There was no significant difference between the incidence of first or only pneumonia between the vitamin D (0·145 per child per year, 95% CI 0·129–0·164) and the placebo group (0.137, 0·121–0·155); the incidence rate ratio was 1·06 (95% CI 0·89–1·27). From 652 children during five separate periods of testing serum calcifediol, only one child in each of two testing periods had results greater than 375 nmol/L in the intervention group—a toxic level. Quarterly bolus doses of oral vitamin D3 supplementation to infants are not an effective intervention to reduce the incidence of pneumonia in infants in this setting. Wellcome Trust and British Council.

Purpose Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Background X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient’s lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. Results The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately − 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. Conclusion The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

Background ABCC6 deficiency is caused by variants in the ABCC6 gene, leading to dysfunction of the ABCC6 protein. This can result in the development of the infantile phenotype, generalized arterial calcification of infancy type 2 (GACI2), or the adolescent-adult phenotype, pseudoxanthoma elasticum (PXE). To date, the impact of ABCC6 deficiency in a pediatric population has not been comprehensively studied. This analysis aimed to collectively characterize the genotypic and phenotypic presentation of ABCC6 deficiency in the pediatric population. Results A literature review and analysis identified 95 individuals with ABCC6 variant(s) and documented clinical manifestations occurring from ages 0 to < 18 years. Of the 133 ABCC6 variants found, 57.1% were pathogenic, 26.3% were likely pathogenic, and 10.5% were of uncertain significance. A high prevalence of ectopic calcification with cardiovascular, dermatologic, neurologic, and ocular complications was observed across this pediatric ABCC6 deficiency cohort. While 56% were diagnosed with GACI and 44% with PXE, many individuals exhibited overlapping features of both conditions. There was a relatively high frequency of clinical manifestations through 6 years of age with lower frequency from ages 7 to 18 years. There was significant phenotypic variability observed across patients harboring the same ABCC6 variant(s). Conclusions These findings demonstrate the wide spectrum and early emergence of cardiovascular, neurologic, and ocular complications in pediatric patients with ABCC6 deficiency. Given the variability of clinical presentations and absence of systematic phenotype characterization, pediatric ABCC6 deficiency is likely underdiagnosed. Establishing guidelines for assessment, genetic diagnosis, monitoring, and prognostic counseling would assist in the timely diagnosis and multidisciplinary management of pediatric patients with ABCC6 deficiency.

ObjectivesTo investigate whether dietary calcium intake will modify the relationship between serum 25-hydroxyvitamin D3 (25OHD) with intact serum parathyroid hormone (PTH) concentrations in apparently healthy Indian adolescents.Study designCross-sectional study.Setting and participantsApparently healthy adolescents aged 10–14 years (n=181), from Gujarat, western India. Study conducted from January 2012 to March 2014.MethodsSerum 25OHD concentrations and intact serum PTH concentrations (both using chemiluminescent microparticle immunoassay) were measured. Diet was recorded through 24 h diet recall and calcium intake was computed (C-diet V.2.1). To assess relationship between 25OHD and PTH, data were dichotomised according to median calcium intakes (520 mg/day) and relationship between serum 25OHD and PTH in the two subgroups was plotted.ResultsSubjects with calcium intakes above median (>520 mg/day) had lower intact serum PTH values for given serum 25OHD concentration while those with calcium intakes below median (<520 mg/day) had higher intact serum PTH values for given serum 25OHD concentration. Serum 25OHD concentration was negatively correlated with intact serum PTH concentration at lower as well as higher calcium intakes (r=− 0.606 and −0.483, respectively, p<0.01 for both). Using a regression analysis, predicted values for intact serum PTH concentration for the given serum 25OHD concentrations were plotted. The plot revealed a negative shift with increasing calcium intake.ConclusionsDietary calcium intake modifies the relationship between serum 25OHD concentrations and intact serum PTH concentrations. Thus, dietary calcium intake should be taken into account when assessing an individual's vitamin D status.

Background: X-linked hypophosphatemia (XLH) is a rare, progressive disorder characterized by excess fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D synthesis. Burosumab is a recombinant human monoclonal antibody that inhibits FGF23, restoring patient serum phosphate levels. Safety data on long-term burosumab treatment are currently limited. Objectives: This post-authorization safety study (PASS) aims to monitor long-term safety outcomes in children and adolescents (1–17 years) treated with burosumab for XLH. This first interim analysis reports the initial PASS safety outcomes. Design: A 10-year retrospective and prospective cohort study. Methods: This PASS utilizes International XLH Registry (NCT03193476) data, which includes standard diagnostic and monitoring practice data at participating European centers. Results: At data cut-off (13 May 2021), 647 participants were included in the International XLH Registry; 367 were receiving burosumab, of which 67 provided consent to be included in the PASS. Mean (SD) follow-up time was 2.2 (1.0) years. Mean (SD) age was 7.3 (4.3) years (range 1.0–17.5 years). Mean duration of burosumab exposure was 29.7 (25.0) months. Overall, 25/67 participants (37.3%) experienced ⩾1 adverse event (AE) during follow-up; 83 AEs were reported. There were no deaths, no AEs leading to treatment withdrawal, nor serious AEs related to treatment. The most frequently reported AEs were classified as ‘musculoskeletal and connective tissue disorders’, with ‘pain in extremity’ most frequently reported, followed by ‘infections and infestations’, with ‘tooth abscess’ the most frequently reported. Conclusion: In this first interim analysis of the PASS, covering the initial 2 years of data collection, the safety profile of burosumab is consistent with previously reported safety data. The PASS will provide long-term safety data over its 10-year duration for healthcare providers and participants with XLH that contribute to improvements in the knowledge of burosumab safety. Trial registration: European Union electronic Register of Post-Authorisation Studies: EUPAS32190.

Background Hypophosphatasia (HPP) is a rare, heterogeneous disease caused by low tissue-nonspecific alkaline phosphatase activity and associated with a range of signs and symptoms, including bone mineralization defects, respiratory problems, seizures, premature tooth loss, and fractures. Data from patients with HPP and their healthcare resource utilization are lacking. We evaluated healthcare utilization for 3 patients with differing severities of HPP. Results Patient 1 had perinatal HPP (received enzyme replacement therapy asfotase alfa under a compassionate use program), Patient 2 had infantile HPP, and Patient 3 had childhood HPP. Healthcare resources used in the National Health Service, England, were identified from coded activities in the hospital database and detailed medical records. These data showed that healthcare utilization was directly related to disease severity. Patient 1 had respiratory complications necessitating prolonged admission for ventilation from birth. Over 2.5 years, this patient was hospitalized 725 days, with visits from 16 specialists. Patient 2 had HPP-associated signs and symptoms starting in infancy, was treated for craniosynostosis, experienced multiple fractures, and required outpatient management for > 18 years. Patient 3 developed signs and symptoms of HPP in childhood and received outpatient and day case treatment for dental, orthopedic, and cardiovascular problems over 24 years. Healthcare utilization varied with severity and complexity of disease manifestations between these patients. Conclusions With the recent approval of asfotase alfa for HPP, data from this analysis may help mobilize multidisciplinary healthcare resources for management of HPP by elucidating healthcare resource needs of patients who show a spectrum of clinical manifestations of HPP.

Background Perinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Effective management of such complications is of key clinical importance. In some infants with HPP, severe tracheobronchomalacia (TBM) contributes to respiratory difficulties. The objective of this study is to characterize the clinical features, investigations and management in these patients. Methods We report a case series of five infants with perinatal HPP, with confirmed TBM, who were treated with asfotase alfa and observed for 3–7 years. Additionally, we reviewed respiratory function data in a subgroup of patients with perinatal and infantile HPP included in the clinical trials of asfotase alfa, who required high-pressure respiratory support (positive end-expiratory pressure [PEEP] ≥6 cm H 2 O and/or peak inspiratory pressure ≥18 cm H 2 O) during the studies. Results The case series showed that TBM contributed significantly to respiratory morbidity, and prolonged respiratory support with high PEEP was required. However, TBM improved over time, allowing weaning of all patients from ventilator use. The review of clinical trial data included 20 patients and found a high degree of heterogeneity in PEEP requirements across the cohort; median PEEP was 8 cm H 2 O at any time and some patients presented with high PEEP (≥8 cm H 2 O) over periods of more than 6 months. Conclusion In infants with HPP presenting with persistent respiratory complications, it is important to screen for TBM and initiate appropriate respiratory support and treatment with asfotase alfa at an early stage. Trial registration ClinicalTrials.gov numbers: NCT00744042 , registered 27 August 2008; NCT01205152 , registered 17 September 2010; NCT01176266 , registered 29 July 2010.

Abstract Context X-linked hypophosphatemia (XLH) is a rare genetic disorder causing renal phosphate wasting, which predicates musculoskeletal manifestations such as rickets. Diagnosis is often delayed. Objective To explore the recording of clinical features, and the diagnostic odyssey of children and adolescents with XLH in primary care electronic healthcare records (EHRs) in the United Kingdom. Methods Using the Optimum Patient Care Research Database, individuals aged 20 years or younger after January 1, 2000, at date of recorded XLH diagnosis were identified using Systematized Nomenclature of Medicine Clinical Terms (SNOMED)/Read codes and age-matched to 100 controls. Recording of XLH-related clinical features was summarized then compared between cases and controls using chi-squared or Fisher's exact test. Results In total, 261 XLH cases were identified; 99 met the inclusion criteria. Of these, 84/99 had at least 1 XLH-related clinical feature recorded in their primary care EHR. Clinical codes for rickets, genu varum, and low phosphate were recorded prior to XLH diagnosis in under 20% of cases (median of 1, 1, and 3 years prior, respectively). Rickets, genu varum, low phosphate, nephrocalcinosis, and growth delay were significantly more likely to be recorded in cases. Conclusion This characterization of the EHR phenotypes of children and adolescents with XLH may inform future case-finding approaches to expedite diagnosis in primary care.

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year. Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab. Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports. Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab. Registry identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).