Vitamin D₃supplementation and childhood diarrhea: a randomized controlled trial.

OBJECTIVE: To investigate the effect of vitamin D3 supplementation on the incidence and risk for first and recurrent diarrheal illnesses among children in Kabul, Afghanistan. METHODS: This double-blind placebo-controlled trial randomized 3046 high-risk 1- to 11-month-old infants to receive 6 quarterly doses of oral vitamin D3 (cholecalciferol 100000 IU) or placebo in inner city Kabul. Data on diarrheal episodes (≥ 3 loose/liquid stools in 24 hours) was gathered through active and passive surveillance over 18 months of follow-up. Time to first diarrheal illness was analyzed by using Kaplan-Meier plots. Incidence rates and hazard ratios (HRs) were calculated by using recurrent event Poisson regression models. RESULTS: No significant difference existed in survival time to first diarrheal illness (log rank P = .55). The incidences of diarrheal episodes were 3.43 (95% confidence interval [CI], 3.28-3.59) and 3.59 per child-year (95% CI, 3.44-3.76) in the placebo and intervention arms, respectively. Vitamin D3 supplementation was found to have no effect on the risk for recurrent diarrheal disease in either intention-to-treat (HR, 1.05; 95% CI, 0.98-1.17; P = .15) or per protocol (HR, 1.05; 95% CI, 0.98-1.12; P = .14) analyses. The lack of preventive benefit remained when the randomized population was stratified by age groups, nutritional status, and seasons. CONCLUSIONS: Quarterly supplementation with vitamin D3 conferred no reduction on time to first illness or on the risk for recurrent diarrheal disease in this study. Similar supplementation to comparable populations is not recommended. Additional research in alternative settings may be helpful in elucidating the role of vitamin D3 supplementation for prevention of diarrheal diseases

Burosumab for X-linked hypophosphatemia in children and adolescents: opinion based on early experience in seven European countries

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthoo

P4HB recurrent missense mutation causing Cole-Carpenter syndrome

BACKGROUND: Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB. OBJECTIVES: Here, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production. METHODS: We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here. RESULTS: The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant). DISCUSSION: P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se. CONCLUSIONS: We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-Linked hypophosphataemia : rationale and description

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)(2)D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)(2)D 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.Peer reviewe

Determinants of the maternal 25-hydroxyvitamin D response to vitamin D supplementation during pregnancy

Context: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.Objective: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.Design: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.Setting: Hospital antenatal clinics.Participants: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.Interventions: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.Main Outcome Measure: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).Results: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P &lt; .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (? = ?0.81 [95% confidence interval ?1.39, ?0.22]), lower compliance with study medication (%) (? = ?0.28 [?0.072, ?0.48]), lower early pregnancy 25(OH)D (nmol/L) (? = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (? = ?10.5 [?6.4, ?14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.Conclusions: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.<br/

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue

Reduced bone mineral density in adults treated with high-dose corticosteroids for childhood nephrotic syndrome

Reduced bone mineral density in adults treated with high-dose corticosteroids for childhood nephrotic syndrome.BackgroundChildren with minimal change nephrotic syndrome (MCNS) receive repeated courses of high dose oral prednisolone. No previous study has investigated the impact of this on final bone mineral density (BMD). Young adults previously reported in a large follow-up study of children with MCNS were invited to participate in a cross-sectional study. Areal BMD (aBMD) of the spine (L1-4), left femoral neck, and total left hip was measured using dual x-ray absorptiometry (DXA), and volumetric BMD (vBMD) of the distal radius was measured by pQCT. BMD results were compared with reference data provided by the manufacturers of the densitometers.MethodsThirty-four (24 male) of the original cohort of 62 participated in the study. The mean (SD) final height Z score of the cohort was -0.45 (0.92) (P = 0.007) and mean BMI Z score 1.62 (1.53) (P < 0.0001).ResultsThere was a highly significant reduction in distal radial trabecular vBMD; the mean Z score was -0.95 (0.99) and T score -1.04 (1.01) (both P < 0.0001); however, there was no reduction in distal radial total vBMD, the mean Z score being 0.00 (0.95) and T score -0.08 (0.99), (P = 0.99 and 0.66, respectively). The aBMD of the lumbar spine and femoral neck also showed a reduction in T scores [-0.45 (1.27), P = 0.045 and -0.49 (0.86), P = 0.002, respectively], but not Z scores [-0.37 (1.28) and -0.15 (0.87), respectively, both P = NS]. Total hip aBMD was not different from the control population.ConclusionAdult survivors of childhood MCNS have a significant reduction in forearm trabecular vBMD, placing them at increased fracture risk at this site

Vitamin D status of socio-economically deprived children in Kabul, Afghanistan

Background: Cultural, environmental, and diet-related factors were postulated to lead to a high prevalence of vitamin D deficiency in Kabul\u27s socioeconomically deprived children under 5 years of age. We investigated the prevalence of plasma 25-hydroxyvitamin D (25-OHD) deficiency in such a group. Methods: Children between 6 months and up to 5 years of age were randomly sampled in the Chindawal area of Kabul in January 2005. Plasma samples were frozen to below -20 degrees C and 25(OH)D3 concentrations estimated by high-pressure liquid chromatography. Results: For all 107 children tested, the median plasma 25(OH)D concentration was 5 ng/mL with a range of 2-24 ng/mL, 73% had concentrations of \u3c 8 ng/mL, 13 other samples were not analyzed due to insufficiency of plasma, staff, or technical problems. About 35 others approached either did not give consent or blood could not be obtained. Conclusions: This study was conducted in a high-risk population at a peak season for vitamin D deficiency. We conclude that this population of children living in Kabul to be at great risk of developing vitamin D deficiency, rickets, and other possible immunological effects of deficiency