Feeding tube use and complications in Prader-Willi syndrome: Data from the Global Prader-Willi Syndrome Registry.

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team.

Hypercalcemia in Children Using the Ketogenic Diet: A Multicenter Study.

CONTEXT: The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria, and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment. OBJECTIVE: To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients. DESIGN: A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment, and course of this complication was collated centrally. RESULTS: There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range, 0.2-12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the 2 oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only 2 of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while 4 more stopped the diet during follow-up after resolution of hypercalcemia. CONCLUSIONS: Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia.

Body Mass Index Is a Better Indicator of Body Composition than Weight-for-Length at Age 1 Month.

OBJECTIVE: To assess whether body mass index (BMI) provides a better assessment of measured adiposity at age 1 month compared with weight-for-length (WFL). STUDY DESIGN: Participants were healthy term-born infants in the Infant Growth and Microbiome (n = 146) and the Baby Peas (n = 147) studies. Length, weight, and body composition by air displacement plethysmography were measured at 1 month. World Health Organization-based WFL and BMI z-scores were calculated. Within-cohort z-scores of percent fat-Z, fat mass-Z, fat mass/length2-Z, fat mass/length3-Z, fat-free mass-Z, and fat-free mass/length2-Z were calculated. Correlation and multiple linear regression (adjusted for birth weight) analyses tested the associations between body composition outcomes and BMI-Z vs WFL-Z. Quantile regression was used to test the stability of these associations across the distribution of body compositions. RESULTS: The sample was 52% female and 56% African American. Accounting for birth weight, both BMI-Z and WFL-Z were strongly associated with fat mass-Z (coefficients 0.56 and 0.35, respectively), FM/L2-Z (0.73 and 0.51), and FM/L3-Z (0.79 and 0.58), with stronger associations for BMI-Z compared with WFL-Z (P < .05). Even after accounting statistically for birth weight, BMI-Z was persistently more strongly associated than WFL-Z with body composition outcomes across the distribution of body composition outcomes. CONCLUSIONS: We demonstrate in 2 distinct cohorts that BMI is a better indicator of adiposity in early infancy compared with WFL. Our findings support the preferred use of BMI for growth and nutritional status assessment in infancy.

Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood.

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research.

Association Between Linear Growth and Bone Accrual in a Diverse Cohort of Children and Adolescents.

Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood. Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race. Design, Setting, and Participants: This investigation was a mixed longitudinal study with annual assessments for up to 7 years at 5 US clinical centers. Participants were healthy children, adolescents, and young adults. The study dates were July 2002 through March 2010. The dates of the analysis were June through December 2016. Main Outcomes and Measures: Anthropometrics, BMC, and body composition via dual-energy x-ray absorptiometry. The superimposition by translation and rotation (SITAR) analysis method was used to define the mean trajectories for height, WB lean soft tissue, appendicular lean soft tissue, and WB and skeletal site-specific BMC acquisition and to measure the age and magnitude of peak velocity for each parameter. The SITAR modeling was performed separately by sex and self-reported race. Results: Among 2014 healthy children, adolescents, and young adults (1022 [50.7%] female and 479 [23.8%] African American) aged 5 to 19 years at study entry, the mean age of peak height velocity was 13.1 years (95% CI, 13.0-13.2 years) in African American boys vs 13.4 years (95% CI, 13.3-13.4 years) in non-African American boys (difference, -0.3 years; 95% CI, -0.4 to -0.1 years) and 11.0 years (95% CI, 10.8-11.1 years) in African American girls vs 11.6 years (95% CI, 11.5-11.6 years) in non-African American girls (difference, -0.6 years; 95% CI, -0.7 to -0.5 years). Age of peak acquisition of WB BMC was 14.0 years (95% CI, 13.8-14.1 years) in African American boys vs 14.0 years (95% CI, 13.9-14.1 years) in non-African American boys (difference, -0.0 years; 95% CI, -0.2 to 0.2 years) and 12.1 years (95% CI, 12.0-12.3 years) in African American girls vs 12.4 years (95% CI, 12.3-12.5 years) in non-African American girls (difference, -0.3 years; 95% CI, -0.4 to -0.1 years). At age 7 years, children had acquired 69.5% to 74.5% of maximal observed height but only 29.6% to 38.1% of maximal observed WB BMC. Adolescents gained 32.7% to 35.8% of maximal observed WB BMC during the 2 years before and 2 years after peak height velocity. Another 6.9% to 10.7% of maximal observed WB BMC occurred after linear growth had ceased. In the group at highest risk for fracture, non-African American boys, peak fracture incidence occurred approximately 1 year before peak height velocity. Conclusions and Relevance: In this longitudinal study, height gains substantially outpaced gains in BMC during childhood, which could contribute to fracture risk. A significant proportion of bone is accrued after adult height is achieved. Therefore, late adolescence represents a potentially underrecognized window of opportunity to optimize bone mass.

A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites.

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10-5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children. © 2017 American Society for Bone and Mineral Research.

Relative Skeletal Maturation and Population Ancestry in Nonobese Children and Adolescents.

More rapid skeletal maturation in African-American (AA) children is recognized and generally attributed to an increased prevalence of obesity. The objective of the present study was to evaluate the effects of population ancestry on relative skeletal maturation in healthy, non-obese children and adolescents, accounting for body composition and sexual maturation. To do this, we leveraged a multiethnic, mixed-longitudinal study with annual assessments for up to 7 years (The Bone Mineral Density in Childhood Study and its ancillary cohort) conducted at five US clinical centers. Participants included 1592 children, skeletally immature (45% females, 19% AA) who were aged 5 to 17 years at study entry. The primary outcome measure was relative skeletal maturation as assessed by hand-wrist radiograph. Additional covariates measured included anthropometrics, body composition by dual-energy X-ray absorptiometry (DXA), and Tanner stage of sexual maturation. Using mixed effects longitudinal models, without covariates, advancement in relative skeletal maturation was noted in self-reported AA girls (∼0.33 years, p < 0.001) and boys (∼0.43 years, p < 0.001). Boys and girls of all ancestry groups showed independent positive associations of height, lean mass, fat mass, and puberty with relative skeletal maturation. The effect of ancestry was attenuated but persistent after accounting for covariates: for girls, 0.19 years (ancestry by self-report, p = 0.02) or 0.29 years (ancestry by admixture, p = 0.004); and for boys, 0.20 years (ancestry by self-report, p = 0.004), or 0.29 years (ancestry by admixture, p = 0.004). In summary, we conclude that advancement in relative skeletal maturation was associated with AA ancestry in healthy, non-obese children, independent of growth, body composition, and puberty. Further research into the mechanisms underlying this observation may provide insights into the regulation of skeletal maturation. © 2016 American Society for Bone and Mineral Research.

Infant BMI or Weight-for-Length and Obesity Risk in Early Childhood.

BACKGROUND: Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity. METHODS: Anthropometrics were extracted from electronic medical records for well-child visits for 73 949 full-term infants from a large pediatric network. World Health Organization WFL and BMI z scores (WFL-z and BMI-z, respectively) were calculated up to age 24 months. Correlation analyses assessed the agreement between WFL-z and BMI-z and within-subject tracking over time. Logistic regression determined odds of obesity at 2 years on the basis of adiposity classification at 2 months. RESULTS: Agreement between WFL-z and BMI-z increased from birth to 6 months and remained high thereafter. BMI-z at 2 months was more consistent with measurements at older ages than WFL-z at 2 months. Infants with high BMI (≥85th percentile) and reference WFL (5th-85th percentiles) at 2 months had greater odds of obesity at 2 years than those with high WFL (≥85th percentile) and reference BMI (5th-85th percentiles; odds ratio, 5.49 vs 1.40; P < .001). At 2 months, BMI had a higher positive predictive value than WFL for obesity at 2 years using cut-points of either the 85th percentile (31% vs 23%) or 97.7th percentile (47% vs 29%). CONCLUSIONS: High BMI in early infancy is more strongly associated with early childhood obesity than high WFL. Forty-seven percent of infants with BMI ≥97.7th percentile at 2 months (versus 29% of infants with WFL ≥97.7th percentile at 2 months) were obese at 2 years. Epidemiologic studies focused on assessing childhood obesity risk should consider using BMI in early infancy.

Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood.

Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high-, and low-impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome-wide association study (GWAS)-implicated BMD variants. We used dual-energy X-ray absorptiometry to estimate femoral neck, total hip, and spine areal-BMD and total body less head (TBLH) bone mineral content (BMC) Z-scores. The BMD genetic score was negatively associated with each bone Z-score (eg, TBLH-BMC: estimate = -0.03, p = 1.3 × 10(-6) ). Total PA was positively associated with bone Z-scores; these associations were driven by time spent in high-impact PA (eg, TBLH-BMC: estimate = 0.05, p = 4.0 × 10(-10) ) and were observed even for children with lower than average bone Z-scores. We found no evidence of PA-adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA-genetic score-Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH-BMC in males (p interaction = 7.1 × 10(-5) ), where PA was associated with higher TBLH-BMC Z-score among the BMD-lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10(-9) ). In conclusion, the beneficial effect of PA on bone, especially high-impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS-implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.

Rare EN1 Variants and Pediatric Bone Mass.

A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry-derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10(-4) ) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10(-4) ; beta females = 0.86, p = 6.6 × 10(-6) ) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated. © 2016 American Society for Bone and Mineral Research.

Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density.

Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X-ray scans, from which areal BMD (aBMD) Z-scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH-BMC) Z-scores. Sixty-three single-nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD-lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK-RANKL-OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z-scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z-scores (eg, spine aBMD Z-score: ßadult = -0.04, p = 3.4 × 10(-7) ; ßfracture = -0.02, p = 8.9 × 10(-6) ; ßWNT = -0.01, p = 3.9 × 10(-4) ). The overall adult GRS was more strongly associated with lower Z-scores in females (p-interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z-scores with increasing age (p-interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p-interaction > 0.05 for all sites). The RANK-RANKL-OPG GRS was more strongly associated in females with increasing age (p-interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z-scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z-scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling.

Iatrogenic Necrolytic Migratory Erythema in an Infant with Congenital Hyperinsulinism.

Necrolytic migratory erythema (NME) is a rare cutaneous finding characterized by painful, pruritic, scaly red patches and plaques, bullae, and superficial erosions. Typically NME is a paraneoplastic phenomenon associated with glucagonoma. We report the exceptional case of an infant who developed iatrogenic NME arising secondary to glucagon therapy for congenital hyperinsulinism.

Body mass index (BMI) trajectories in infancy differ by population ancestry and may presage disparities in early childhood obesity.

CONTEXT: No consensus definition exists for excess adiposity during infancy. After age 2 years, high body mass index (BMI) is related to adverse cardiometabolic outcomes. Before age 2 years, the utility of BMI as a metric of excess adiposity is unknown. OBJECTIVES: The objective of the study was to characterize infant BMI trajectories in a diverse, longitudinal cohort and investigate the relationship between the infancy BMI trajectory and childhood obesity. SUBJECTS: Healthy, nonpreterm infants (n = 2114) in the Genetic Causes for Complex Pediatric Disorders study (The Children's Hospital of Philadelphia) with six or more BMI measurements in the first 13.5 months participated in the study. DESIGN: For each infant, the BMI trajectory was modeled using polynomial regression. Independent effects of clinical factors on magnitude and timing of peak BMI were assessed. The relationship between infancy BMI and early childhood BMI (age 4 y) was examined (n = 1075). RESULTS: The cohort was 53% male and 61% African-American. Peak BMI was 18.6 ± 1.7 kg/m(2) and occurred at 8.6 ± 1.4 months. In multivariate analysis, boys had a higher (0.50 kg/m(2), P < .001) peak BMI than girls. The peak was higher (0.53 kg/m(2), P ≤ .001) and occurred earlier (by 12 d, P < .001) in African-American vs white children. The odds of obesity at age 4 years increased among children with higher (odds ratio 2.02; P < .001) and later (odds ratio 1.26; P = .02) infancy peak BMI. CONCLUSIONS: We demonstrate sex- and ancestry-specific differences in infancy BMI and an association of infancy peak BMI with childhood BMI. These findings support the potential utility of infancy BMI to identify children younger than age 2 years with increased risk for later obesity.

Splenectomy in children with "mild" hereditary spherocytosis.

Splenectomy is considered the treatment of choice for patients with "symptomatic" hereditary spherocytosis (HS). Published guidelines offering recommendations for splenectomy in HS categorize patients primarily based on hemoglobin concentration. We performed a retrospective review of 64 children having splenectomy for HS at Children's Medical Center Dallas. On the basis of hemoglobin concentration alone, 16 children (25%) had mild, 38 (59%) moderate, and 10 (16%) severe HS. However, when reticulocyte count was used to categorize disease severity, only 3 patients (5%) having splenectomy would be considered mild, 17 (27%) moderate, and 42 (66%) severe. Despite otherwise having "mild" disease defined by near-normal hemoglobin levels, many children with nontraditional or subjective signs and symptoms related to hemolytic rate received a splenectomy, and, therefore, reticulocyte count might be a more reliable laboratory marker suggesting consideration of splenectomy. A validated assessment tool incorporating quality of life indicators in addition to the traditional medical indications for splenectomy in HS would be valuable in assessing indications for the procedure.