Leanne Ward

Vitamin D–deficiency rickets among children in Canada

Background: Based on regional and anecdotal reports, there is concern that vitamin D–deficiency rickets is persistent in Canada despite guidelines for its prevention. We sought to determine the incidence and clinical characteristics of vitamin D–deficiency rickets among children living in Canada. Methods: A total of 2325 Canadian pediatricians were surveyed monthly from July 1, 2002, to June 30, 2004, through the Canadian Paediatric Surveillance Program to determine the incidence, geographic distribution and clinical profiles of confirmed cases of vitamin D-deficiency rickets. We calculated incidence rates based on the number of confirmed cases over the product of the length of the study period (2 years) and the estimates of the population by age group. Results: There were 104 confirmed cases of vitamin D– deficiency rickets during the study period. The overall annual incidence rate was 2.9 cases per 100 000. The incidence rates were highest among children residing in the the north (Yukon Territory, Northwest Territories and Nunavut). The mean age at diagnosis was 1.4 years (standard deviation [SD] 0.9, min–max 2 weeks–6.3 years). Sixty-eight children (65%) had lived in urban areas most of their lives, and 57 (55%) of the cases were identified in Ontario. Ninety-two (89%) of the children had intermediate or darker skin. Ninety-eight (94%) had been breast-fed, and 3 children (2.9%) had been fed standard infant formula. None of the breast-fed infants had received vitamin D supplementation according to current guidelines (400 IU/d). Maternal risk factors included limited sun exposure and a lack of vitamin D from diet or supplements during pregnancy and lactation. The majority of children showed clinically important morbidity at diagnosis, including hypocalcemic seizures (20 cases, 19%). Interpretation: Vitamin D–deficiency rickets is persistent in Canada, particularly among children who reside in the north and among infants with darker skin who are breast-fed without appropriate vitamin D supplementation. Since there were no reported cases of breast-fed children having received regular vitamin D (400 IU/d) from birth who developed rickets, the current guidelines for rickets prevention can be effective but are not being consistently implemented. The exception appears to be infants, including those fed standard infant formula, born to mothers with a profound vitamin D deficiency, in which case the current guidelines may not be adequate to rescue infants from the vitamin D-deficient state.

Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib.

Epigenetic defects in the imprinted GNAS cluster are associated with pseudohypoparathyroidism type Ib. In two kindreds with this disorder, we now report deletions that remove the differentially methylated region encompassing exon NESP55 and exons 3 and 4 of the antisense transcript. When inherited from a female, either deletion abolishes all maternal GNAS imprints and derepresses maternally silenced transcripts, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.

Clinical Review: Bisphosphonate Use in Childhood Osteoporosis

CONTEXT As awareness of osteoporosis in childhood has increased, so have pressures to consider use of the pharmacological agents used to treat osteoporosis in adults. This review examines available research on the efficacy and safety of bisphosphonate therapy for pediatric osteoporosis. EVIDENCE ACQUISITION We reviewed the medical literature for key articles and consensus statements on the use of bisphosphonates in children through June 2008. EVIDENCE SYNTHESIS We compared reports using varying bisphosphonate agents, doses, and duration of therapy to treat osteogenesis imperfecta and a variety of secondary causes of osteoporosis in children. Conclusions drawn from a recently published Cochrane analysis and the consensus statements from experts in the field were considered as well. CONCLUSIONS Use of bisphosphonate therapy in pediatric patients remains controversial because of inadequate long-term efficacy and safety data. For this reason, many experts recommend limiting use of these agents to those children with recurrent extremity fractures, symptomatic vertebral collapse, and reduced bone mass. Current data are inadequate to support the use of bisphosphonates in children to treat reductions in bone mass/density alone. More research is needed to define appropriate indications for bisphosphonate therapy and the optimal agent, dose, and duration of use in pediatric patients.

A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy

Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing’s syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors.

Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review

BACKGROUND Many residents of the United States and Canada depend on dietary sources of vitamin D to help maintain vitamin D status. Because few natural food sources contain vitamin D, fortified foods may be required. OBJECTIVE We aimed to determine the effects of vitamin D-fortified foods on serum 25-hydroxyvitamin D [25(OH)D] concentrations. DESIGN We searched MEDLINE (1966 to June Week 3 2006), Embase, CINAHL, AMED, Biological Abstracts, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) comparing vitamin D-fortified foods with a control and reporting serum 25(OH)D concentrations. Two reviewers independently determined study eligibility, assessed trial quality, and extracted relevant data. Disagreements were resolved by consensus. Meta-analyses of absolute mean change in 25(OH)D were conducted by using a random-effects model, with evaluation of heterogeneity. RESULTS Nine RCTs (n = 889 subjects) were included, of which 8 consistently showed a significant beneficial effect of food fortification on 25(OH)D concentrations. Although 7 RCTs (n = 585 subjects) potentially were meta-analyzable, we were unable to combine the overall results because of significant heterogeneity. The individual treatment effects ranged from 14.5 (95% CIs: 10.6, 18.4) nmol/L to 34.5 (17.64, 51.36) nmol/L (3.4-25 microg vitamin D/d). Subgroup analyses showed a reduction in heterogeneity and significant treatment effect when 4 trials that used milk as the fortified food source were combined. CONCLUSION Most trials were small in size and inadequately reported allocation concealment, but results showed that vitamin D-fortified foods improved vitamin D status in adults.

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.

Vitamin D deficiency in the 21st century: a persistent problem among Canadian infants and mothers

Vitamin D deficiency is an age-old public health problem. It was first described, as rickets, in the mid-17th century by Francis Glisson and other fellows of the Royal College of Physicians in London. Although there has long been a folk understanding of the therapeutic benefit of cod-liver oil (such

Osteoporosis due to Glucocorticoid Use in Children with Chronic Illness

Osteoporosis is increasingly recognized as a complication of chronic childhood illnesses, particularly when glucocorticoids (GCs) are necessary for treatment. Elucidation of the mechanisms leading to bone fragility in these settings requires disentanglement of the relative contributions of myriad risk factors, including disease activity, muscle weakness, immobilization, delayed growth and puberty, compromised nutrition, and osteotoxic medications. Over the years, bone mass and density evaluations by dual energy X-ray absorptiometry (DXA) have become popular for assessing bone health in children; however, such measurements are difficult to interpret because of the confounding effect of bone size and the lack of DXA-based densitometric criteria for defining osteoporosis in childhood. Recently, a new diagnostic approach for evaluation of densitometric data in children has been suggested, driven by Frost’s mechanostat theory. A diagnostic algorithm based on the mechanostat theory of bone-muscle development is proposed for the characterization of bone disease in children with chronic illness. In addition to DXA-based assessments, techniques such as peripheral quantitative computerized tomography and ilial histomorphometry, for which there are pediatric reference data, are gaining ground in the characterization of skeletal changes due to chronic illness. Although these diagnostic techniques expand our understanding of osteoporosis in children, they do not replace clinical assessment. Concrete clinical evidence for GC-induced bone fragility can be seen in spinal changes due to vertebral compression, with spinal morphometry emerging as an essential, but frequently overlooked, tool in the evaluation of children’s bone health. Presently, osteoporosis treatment in the chronic illness setting remains experimental and should be restricted to clinical studies. Following an understanding of the natural history of GC-induced osteoporosis in children, randomized, placebo-controlled prevention and intervention trials will be the next step toward the development of clinical practice guidelines.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

DMP1 C-terminal mutant mice recapture the human ARHR tooth phenotype

DMP1 mutations in autosomal recessive hypophosphatemic rickets (ARHR) patients and mice lacking Dmp1 display an overlapping pathophysiology, such as hypophosphatemia. However, subtle differences exist between the mouse model and human ARHR patients. These differences could be due to a species specificity of human versus mouse, or it may be that the mutant DMP1 in humans maintains partial function of DMP1. In this study we report a deformed tooth phenotype in a human DMP1 deletion mutation case. Unexpectedly, the deletion of nucleotides 1484 to 1490 (c.1484_1490delCTATCAC, delMut, resulting in replacement of the last 18 residues with 33 random amino acids) showed a severe dentin and enamel defect similar to a dentinogenesis imperfecta (DI) III–like phenotype. To address the molecular mechanism behind this phenotype, we generated delMut transgenic mice with the endogenous Dmp1 gene removed. These mutant mice did not recapture the abnormal phenotype observed in the human patient but displayed a mild rachitic tooth phenotype in comparison with that in the Dmp1‐null mice, suggesting that the DI III–like phenotype may be due to an as‐yet‐undetermined acquired gene modifier. The mechanism studies showed that the mutant fragment maintains partial function of DMP1 such as stimulating MAP kinase signaling in vitro. Last, the in vitro and in vivo data support a role of odontoblasts in the control of fibroblast growth factor 23 (FGF‐23) regulation during early postnatal development, although this regulation on Pi homeostasis is likely limited.