M. Zulf Mughal

Consensus Statement: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

BACKGROUND Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial

Summary Background 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. Methods 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. Findings 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. Interpretations 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. Funding Wellcome Trust and British Council.

Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.

Objectives  To determine whether (i) supplementation of oral 100 000 iu of vitamin D3 (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes.

UK reference data for the Hologic QDR Discovery dual-energy x ray absorptiometry scanner in healthy children and young adults aged 6–17 years

Background: The use and correct interpretation of bone densitometry measurements in paediatric patients relies on the availability of appropriate reference data. Ideally, such data should be matched for sex, chronological age, height, weight, pubertal development and ethnicity. Aim: To provide UK-specific reference data for the Hologic QDR Discovery dual-energy x ray absorptiometry (DXA) scanners. Methods: Healthy, Caucasian children aged 5–18 years were recruited from local schools, colleges, general practitioner surgeries and staff from the University of Manchester, Manchester, UK. Suitable participants had DXA measurements taken of the lumbar spine, hip and total body. Sex-specific reference centile curves for bone mineral apparent density (BMAD; spine and femoral neck) are provided, using the approach suggested by Mølgaard et al. to interpret the scans. LMS (λ, μ, ς) tables for calculation of individual standard deviation scores (SDSs) were produced; a weblink is provided to these tables to allow calculation of an individual child’s SDSs. Results: The total study population consisted of 442 participants (239 male). The total numbers of scans available for analysis were 431 of the lumbar spine, 426 of the total body and 393 of the proximal femur. Data are provided for clinical interpretation of the spine and femoral neck scans based on BMAD (g/cm3), which reduces the size dependence of DXA areal bone mineral density (g/cm2). The spine and total-body data are also presented for interpretation of results using the approach suggested by Mølgaard et al. Conclusions: This article provides the first sex-specific and ethnicity-specific reference databases for UK, which should allow the clinician to assess bone mineral density in paediatric patients, measured by the Hologic QDR Discovery DXA scanner.

Bone health in children and adolescents with chronic diseases that may affect the skeleton: The 2013 ISCD pediatric official positions

The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management.

Chronic Recurrent Multifocal Osteomyelitis Mimicked in Childhood Hypophosphatasia

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by low serum alkaline phosphatase (ALP) activity caused by inactivating mutations within TNSALP, the gene that encodes the “tissue‐nonspecific” isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate, inhibits hydroxyapatite crystal growth leading to rickets or osteomalacia. Chronic recurrent multifocal osteomyelitis (CRMO) is the pediatric syndrome of periarticular pain and radiographic changes resembling infectious osteomyelitis but without lesional pathogens. Some consider CRMO to be an autoinflammatory disease. An unrelated boy and girl with the childhood form of HPP suffered chronic, multifocal, periarticular pain, and soft tissue swelling. To investigate this unusual complication, we evaluated their cumulative clinical, biochemical, radiological, and histopathological findings and performed mutation analysis of their TNSALP alleles. The earliest radiographic disturbances were typical of childhood HPP. Subsequently, changes consistent with CRMO developed at sites where there was pain, including lucencies, osteosclerosis, and marked expansion of the underlying metaphyses. Bone marrow edema was shown by MRI. Biopsies of affected bone showed nonspecific histopathological findings and no pathogens. The boy was heterozygous (c.1133A>T, p.D378V) and the girl compound heterozygous (c.350A>G, p.Y117C, c.400_401AC>CA, p.T134H) for different TNSALP missense mutations. Nonsteroidal anti‐inflammatory drugs diminished their pain, which improved or resolved at maturity. HPP should be considered when CRMO is a diagnostic possibility. Metaphyseal radiographic changes and marrow edema associated with periarticular bone pain and soft tissue swelling suggestive of osteomyelitis can complicate childhood HPP.

Normative data and percentile curves for Dual Energy X-ray Absorptiometry in healthy Indian girls and boys aged 5–17 years

For the correct interpretation of Dual Energy X-ray Absorptiometry (DXA) measurements in children, the use of age, gender, height, weight and ethnicity specific reference data is crucially important. In the absence of such a database for Indian children, the present study aimed to provide gender and age specific data on bone parameters and reference percentile curves for the assessment of bone status in 5-17 year old Indian boys and girls. A cross sectional study was conducted from May 2006 to July 2010 on 920 (480 boys) apparently healthy children from schools and colleges in Pune City, India. The GE-Lunar DPX Pro Pencil Beam DXA scanner was used to measure bone mineral content (BMC [g]), bone area (BA [cm(2)]) and bone mineral density (BMD [g/cm(2)]) at total body, lumbar spine and left femur. Reference percentile curves by age were derived separately for boys and girls for the total body BMC (TBBMC), total body BA (TBBA), lumbar spine bone mineral apparent density (BMAD [g/cm(3)]), and left femoral neck BMAD. We have also presented percentile curves for TBBA for height, TBBMC for TBBA, LBM for height and TBBMC for LBM for normalizing bone data for Indian children. Mean TBBMC, TBBA and TBBMD were expressed by age groups and Tanner stages for boys and girls separately. The average increase in TBBMC and TBBA with age was of the order of 8 to 12% at each age group. After 16 years of age, TBBMC and TBBA were significantly higher in boys than in girls (p<0.01). Maximal increase in TBBMD occurred around the age of 13 years in girls and three years later in boys. Reference data provided may be used for the clinical assessment of bone status of Indian children and adolescents.

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 (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+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.

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 Kabuls 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 < 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.