David R. Weber

Fat and lean BMI reference curves in children and adolescents and their utility in identifying excess adiposity compared with BMI and percentage body fat

BACKGROUND Body mass index (BMI) and percentage body fat (%BF) are widely used to assess adiposity. These indexes fail to account for independent contributions of fat mass (FM) and lean body mass (LBM) to body weight, which vary according to age, sex, pubertal status, and population ancestry in the pediatric population. OBJECTIVE The objective was to develop pediatric reference curves for fat mass index (FMI) and lean body mass index (LBMI) and evaluate the effects of population ancestry and LBM on measures of excess adiposity (BMI, %BF, and FMI). DESIGN Sex-specific FMI and LBMI reference curves relative to age for children and adolescents aged 8-20 y were generated from cross-sectional body-composition data measured by dual-energy X-ray absorptiometry from NHANES. RESULTS The mean LBMI z score was higher in blacks (males: 0.26; females: 0.45) than in whites (males: -0.07; females: -0.09) and Mexican Americans (males: 0.05; females: -0.09). The positive predictive value of overweight by BMI to identify excess adiposity defined by FMI was lower in blacks (males: 35.9%; females: 30.3%) than in whites (males: 65.4%; females: 52.2%) and Mexican Americans (males: 73.3%; females: 68.3%). Participants classified as having excess adiposity by FMI but normal adiposity by %BF had significantly higher BMI, LBMI, and height z scores than did those classified as having excess adiposity by %BF but normal adiposity by FMI. CONCLUSIONS Relative to FMI, the prevalence of excess adiposity is overestimated by BMI in blacks and underestimated by %BF in individuals with high LBM. The use of FMI and LBMI improves on the use of %BF and BMI by allowing for the independent assessment of FM and LBM.

Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN)

OBJECTIVE This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span. RESEARCH DESIGN AND METHODS This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes. RESULTS A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years. CONCLUSIONS Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.

A Comparison of Fat and Lean Body Mass Index to BMI for the Identification of Metabolic Syndrome in Children and Adolescents

CONTEXT The use of body mass index (BMI) to assess risk for cardiometabolic disease in the pediatric population may be limited by a failure to differentiate between fat and lean body mass. OBJECTIVES The objectives of the study were to identify biologically based criteria for the definition of obesity using fat (FMI) and lean body mass index (LBMI) and to compare the ability of FMI and LBMI to BMI to identify the presence of metabolic syndrome (MetSyn). DESIGN This was a cross-sectional study using National Health and Nutrition Examination Survey 1999-2006 data. PARTICIPANTS A total of 3004 participants aged 12-20 years with dual-energy X-ray absorptiometry body composition and fasting laboratory data participated in the study. MAIN OUTCOME MEASURES Adjusted odds ratios for MetSyn according to FMI and LBMI status and area under the curve for the identification of MetSyn were measured. RESULTS Receiver-operating characteristic curve analyses identified the 80th percentile for FMI and the 74th percentile for LBMI as the optimal cut points for the identification of MetSyn. There was no difference in the area under the curve for FMI [0.867; 95% confidence interval (CI) 0.838-0.891] vs BMI (0.868; 95% CI 0.837-0.894) Z-scores for MetSyn discrimination. Separate multivariate regression models identified odds ratios for the identification of MetSyn of 6.2 (95% CI 3.3-11.5) for BMI-Z, 6.4 (95% CI 3.7-11.1) for FMI-Z, and 4.6 (95% CI 3.0-7.1) for LBMI-Z. Models containing both FMI-Z and LBMI-Z revealed that greater LBMI-Z was associated with greater odds of low high-density lipoprotein (1.5; 95% CI 1.2-1.9), high blood pressure (1.8; 95% CI 1.1-2.9), and insulin resistance (1.8; 95% CI 1.4-2.5), independent of FMI-Z. CONCLUSIONS The use of FMI and LBMI does not improve upon BMI for the identification of MetSyn in the pediatric population. Unexpectedly, higher LBMI was associated with greater odds of multiple cardiometabolic risk factors independent of FMI. The use of FMI and LBMI allow for the independent evaluation of relationships between body compartments and disease and warrants future research.

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.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience

CONTEXT Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. OBJECTIVE The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Childrens Hospital of Philadelphia. RESULTS Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. CONCLUSION Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan

Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy.

Development of Novel Methods to Define Deficits in Appendicular Lean Mass Relative to Fat Mass.

Background Recent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity. Methods Whole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population. Results Positive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not. Conclusions Adjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.

Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia.

Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood.

Anthropometric measures of abdominal adiposity for the identification of cardiometabolic risk factors in adolescents

Sagittal abdominal diameter (SAD) was obtained in 65 adolescents referred for assessment of cardiometabolic risk. We found that SAD was associated with cardiometabolic risk factors independent of BMI in males, but that SAD was not superior to BMI or other measures of abdominal adiposity for the detection of metabolic syndrome.

Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Abstract Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor (INSR) gene. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance due to INSR mutation(s). Traditional subcutaneous therapy may be limited by the shortened IGF-1 half-life in these patients. We report the case of a female with molecularly confirmed DS treated with continuous rhIGF-1 therapy via an insulin pump. With treatment, the patient’s hemoglobin A1c decreased from 9.8% to 8.8%, and her weight increased by 0.8 kg. Development of an ovarian tumor complicated her course, but it was unclear whether this was related to rhIGF-1 therapy. Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.