Deep phenotyping of pubertal development in Norwegian children: the Bergen Growth Study 2.

BACKGROUND: The Bergen Growth Study 2 (BGS2) aims to characterise somatic and endocrine changes in healthy Norwegian children using a novel methodology. SUBJECTS AND METHODS: A cross-sectional sample of 1285 children aged 6-16 years was examined in 2016 using novel objective ultrasound assessments of breast developmental stages and testicular volume in addition to the traditional Tanner pubertal stages. Blood samples allowed for measurements of pubertal hormones, endocrine disruptive chemicals, and genetic analyses. RESULTS: Ultrasound staging of breast development in girls showed a high degree of agreement within and between observers, and ultrasound measurement of testicular volume in boys also showed small intra- and interobserver differences. The median age was 10.4 years for Tanner B2 (pubertal onset) and 12.7 years for menarche. Norwegian boys reached a pubertal testicular volume at a mean age of 11.7 years. Continuous reference curves for testicular volume and sex hormones were constructed using the LMS method. CONCLUSIONS: Ultrasound-based assessments of puberty provided novel references for breast developmental stages and enabled the measurement of testicular volume on a continuous scale. Endocrine z-scores allowed for an intuitive interpretation of changing hormonal levels during puberty on a quantitative scale, which, in turn, provides opportunities for further analysis of pubertal development using machine-learning approaches.

Norwegian children and adolescents in blended families are at risk of larger one-year BMI increments.

AIM: To study how sociodemographic factors and family structure associate with baseline BMI z-scores (BMIz) and BMIz change in 767 Norwegian children aged 6-15 years. METHODS: Baseline BMIz and 1-year BMIz increments in children from the Bergen Growth Study were analysed with linear and logistic regression, according to sociodemographic factors and family structure. A blended family was defined as including a step-parent and/or half-sibling. RESULTS: In a fully adjusted regression model, baseline BMIz were only significantly associated with maternal BMI (b = 0.087, 95%CI 0.067, 0.107). Body Mass Index z-scores increments were larger in children living in a blended family (b = 0.060, 95%CI 0.006, 0.115), with a lower parental education (b = 0.127, 95%CI 0.029, 0.226) and with a higher maternal BMI (b = 0.008, 95%CI 0.001, 0.014). The odds for a large BMIz increment (>1 SD) were higher in children living in blended families (OR 1.82, 95%CI 1.16, 2.88) and with higher maternal BMI (OR 1.07, 95%CI 1.01, 1.13) and lower in 9-11-year-old children (OR 0.44, 95%CI 0.26, 0.77) compared with 12-15-year-olds. CONCLUSION: Body Mass Index z-scores increments were more strongly associated with sociodemographic factors and living in a blended family than baseline BMIz values. BMI z-scores increments could be useful for identifying children at risk of becoming overweight or obese.

Reference data for testicular volume measured with ultrasound and pubic hair in Norwegian boys are comparable with Northern European populations.

AIM: To estimate references for testicular volume measured with ultrasound and Tanner stages of pubic hair in Norwegian boys, and to compare the timing of puberty with data from similar populations. METHODS: Testicular volume was derived from ultrasound measurements of testicular volume in a cross-sectional study of 514 healthy boys. A continuous testicular volume for age reference curve was estimated with the LMS method. Tanner stages for pubic hair were clinically assessed in 452 boys. Age references for pubertal milestones were estimated with probit regression. RESULTS: Puberty onset, defined by an ultrasound testicular volume of 2.7 mL, equivalent to an orchidometer volume of 4 mL, occurred at a mean (SD) age of 11.7 (1.1) years. The reference range was 9.7 (3rd) to 13.7 years (97th percentile). Pubic hair (Tanner stage 2) appeared on average at 11.8 (1.2) years with a corresponding reference range of 9.5-14.1 years. CONCLUSION: The references for testicular volume measured with ultrasound are continuous in age and allow for the quantification of pubertal development. The age distribution of reaching pubertal milestones was comparable with data from other Northern European countries.

A family-oriented intervention programme to curtail obesity from five years of age had no effect over no intervention.

AIM: To examine the effect of a family-oriented multidisciplinary intervention programme to curtail weight increase in young children with obesity. METHODS: Children who weighed more than one kilogram above the 97th percentile for height at the preschool assessment in Oppland County, Norway, were identified. Parents residing in one part of the county were invited to participate in a group-based three-year intervention programme while the rest had no interventions. Body mass index (BMI) and family characteristics at entry and measurements at birth were explanatory variables, and change in BMI standard deviation score (SDS) the outcome measure. For the intervention group, outcome was also related to skinfold thicknesses, waist-to-height ratio and physical ability. RESULTS: The programme was completed by 31 families in the intervention and 33 in the control group. At entry, the respective median (interquartile) age was 5.83 (0.36) and 5.74 (0.66) years, and the BMI SDS 2.35 (1.06) and 1.95 (0.49), P = .012. The median decrease in BMI SDS was 0.19 in both groups. The decline increased with increasing BMI SDS at entry, but irrespective of group. Social or behavioural factor or other anthropometric measures were not associated with outcome. CONCLUSION: The intervention programme had no effect on BMI SDS.

Associations between different weight-related anthropometric traits and lifestyle factors in Norwegian children and adolescents: A case for measuring skinfolds.

OBJECTIVES: The purpose of this study was to investigate the association between weight-related anthropometric measures and children's eating habits, physical activity and sedentary lifestyle at a population level. METHODS: Data from the Bergen Growth Study were used to study the association of z-scores of waist circumference (WC), weight-to-height ratio (WHtR), subscapularis (SSF) and triceps (TSF) skinfolds and BMI, with lifestyle factors in 3063 Norwegian children (1543 boys) aged 4-15 years, using linear regression analysis. Each sex was analyzed separately. RESULTS: In a fully adjusted model with additional correction for BMI z-scores, the consumption of vegetables was associated with higher WC (b = 0.03) and TSF (b = 0.05) z-scores in girls. Sedentary behavior was not associated with any of the anthropometric measures. Physical activity was negatively associated with SSF (b = -0.07) and TSF (b = -0.07) z-scores in boys, while a significant negative association was observed with WC (b = -0.02), WHtR (b = -0.03), SSF (b = -0.04) and TSF (b = -0.06) in girls. CONCLUSION: Physical activity was negatively associated with skinfolds in both sexes. The BMI was not related to the level of physical activity, and should be complemented with direct measures of fat tissue, like skinfolds, when studying the effect of physical activity on body composition in children.

Ultrasound-based measurements of testicular volume in 6- to 16-year-old boys - intra- and interobserver agreement and comparison with Prader orchidometry.

BACKGROUND: Prader orchidometry has been the standard method for evaluating testicular size. As this technique is subjective and tends to overestimate the testicular volume, ultrasound (US) has been proposed as more reliable. OBJECTIVE: To evaluate the intra- and interobserver agreement of US measurements of testicular volume and to compare US with the Prader orchidometer. MATERIALS AND METHODS: Dimensions of the right testicle were measured using US in 57 boys ages 6.5 to 16.4 years (mean: 12.0 years). The measurements were performed twice by one main observer and once by a second observer. A third observer estimated testicular volume using a Prader orchidometer. Agreement was investigated with Bland-Altman plots, summarized as the mean and standard deviation (SD) of differences, 95% limits of agreement and technical error of measurement. RESULTS: Mean intra-observer difference of testicular volume was 2.2%, SD=9.2% (limits of agreement: -20.3 to 15.9%) and technical error of measurement 6.5%. The mean interobserver difference was 4.8%, SD=20.7% (limits of agreement: -35.7 to 45.3%) and technical error of measurement 14.6%. Comparing US and orchidometer volumes required conversion that was nonlinear and volume dependent, estimated as VolOM = 1.96×VolUS0.71. The mean difference after transformation was 0.7% with an SD of 18.0% (limits of agreement: -34.5 to 35.9%). CONCLUSION: Our results showed a small mean intra- and interobserver difference that indicates the potential of US for measurement of testicular volume at group level. The intra-observer error was limited, which justifies its use in longitudinal follow-up of testicular development in an individual child, but the larger interobserver variability indicates the need for good standardization of methods. Agreement between the two methods requires a power transformation.

Ultrasound assessment of pubertal breast development in girls: intra- and interobserver agreement.

BACKGROUND: Clinical assessment of pubertal breast development using Tanner staging is subjective. This has led to the introduction of ultrasound (US), aiming for a more objective analysis. However, information regarding its reliability is lacking. OBJECTIVE: To examine intra- and interobserver agreement of breast maturity staging using US and to examine the precision of direct measurements of the gland. MATERIALS AND METHODS: Fifty-seven healthy girls (mean age: 10.9 years, range: 6.1 to 15.9 years) were examined independently by two observers using US of the left breast to score the glandular maturity stage on a 0-5 scale, and to measure the depth and diameter. One observer repeated the examination after 20 to 35 min to assess intra-observer agreement. Cohen's kappa with linear weights was used to examine intra- and interobserver agreement of the US staging, while the measurement precision was analyzed using Bland-Altman plots and 95% limits of agreement. RESULTS: The agreement of US staging on a 0-5 scale was very good (kappa 0.84; 95% confidence interval [CI] 0.78-0.91) for intra-observer observation and good (kappa 0.71; 95% CI 0.62-0.80) for interobserver observation. Measurements of glandular depth and diameter were unbiased for a single observer, but the variances were large both within and between observers. CONCLUSION: US using a scale from 0 to 5 is a reliable method to stage the development of glandular breast tissue during puberty in healthy girls. Measurements of glandular depth and diameter were found to be imprecise.

Timing of menarche in Norwegian girls: associations with body mass index, waist circumference and skinfold thickness.

BACKGROUND: Research studies show conflicting results regarding the association between menarche and body weight. The purpose of the present study was to investigate if anthropometric indicators of body composition, body mass index (BMI), waist circumference (WC), triceps (TSF) and subscapular skinfold (SSF) thicknesses, were differentially associated with age at menarche in Norwegian girls. METHODS: The association between menarche and BMI, WC, TSF and SSF was investigated in 1481 girls aged 8-15.5 years, and in a subgroup of 181 girls with menarche during the 12 months prior to examination. Anthropometric measures were categorized as low (< -1SDS), average (-1 ≤ SDS ≤ +1) or high (> 1SDS), and menarche according to this classification was analysed with Kaplan-Meier curves and unadjusted and adjusted Cox regression. RESULTS: The median age at menarche in the total sample was 13.1 years. In the unadjusted models, low categories of all traits were associated with later menarche, and high categories with earlier menarche. When adjusted for other covariates, earlier menarche was only related with a high BMI (Hazard Ratio 1.41, 95% confidence interval (CI) 1.07, 1.85), and later menarche with a low BMI (HR 0.53, 95%CI 0.38, 0.75) and low SSF (HR 0.54, 95%CI 0.39, 0.75). In girls with recent menarche, early menarche was significantly associated with a high BMI in the final model (HR 1.79, 95%CI 1.23, 2.62). CONCLUSIONS: The timing of menarche was associated with the BMI, WC, TSF and SSF, but more strongly so with the BMI. These associations may be related to a common tempo of growth, as the mean age at menarche has remained stable during the last decades during a time period while the prevalence of overweight and obesity has increased significantly.

BMI and BMI SDS in childhood: annual increments and conditional change.

Background Early detection of abnormal weight gain in childhood may be important for preventive purposes. It is still debated which annual changes in BMI should warrant attention. Aim To analyse 1-year increments of Body Mass Index (BMI) and standardised BMI (BMI SDS) in childhood and explore conditional change in BMI SDS as an alternative method to evaluate 1-year changes in BMI. Subjects and methods The distributions of 1-year increments of BMI (kg/m2) and BMI SDS are summarised by percentiles. Differences according to sex, age, height, weight, initial BMI and weight status on the BMI and BMI SDS increments were assessed with multiple linear regression. Conditional change in BMI SDS was based on the correlation between annual BMI measurements converted to SDS. Results BMI increments depended significantly on sex, height, weight and initial BMI. Changes in BMI SDS depended significantly only on the initial BMI SDS. The distribution of conditional change in BMI SDS using a two-correlation model was close to normal (mean = 0.11, SD = 1.02, n = 1167), with 3.2% (2.3-4.4%) of the observations below -2 SD and 2.8% (2.0-4.0%) above +2 SD. Conclusion Conditional change in BMI SDS can be used to detect unexpected large changes in BMI SDS. Although this method requires the use of a computer, it may be clinically useful to detect aberrant weight development.

Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.

BACKGROUND: Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) and Hyperphosphatemic Hyperostosis Syndrome (HHS) are associated with autosomal recessive mutations in three different genes, FGF23, GALNT3 and KL, leading to reduced levels of fibroblast growth factor 23 (FGF23) and subsequent clinical effects. RESULTS: We describe a consanguineous family with two affected siblings with HFTC and HHS caused by a novel homozygous G-to T substitution in exon 3 of GALNT3 (c.767 G > T; p.Gly256Val), demonstrating great phenotypic variation and long asymptomatic intervals. Calcific tumors appeared at 14 years of age in the male, and the female displayed episodic diaphysitis from age 9 years. Symptoms of eye involvement were present in both from childhood, and progressed into band keratopathy in the female. Abnormal dental roots and tooth loss, as well as myalgia were present in both from their mid-twenties, while the female also had calcifications in the placenta, the iliac vessels and thyroid cartilage. New calcific tumors appeared more than 20 years after the initial episodes, delaying diagnosis and treatment until the ages of 37 and 50 years, respectively. Both siblings had elevated serum phosphate levels, inappropriately elevated tubular maximum phosphate reabsorption per unit glomerular filtration rate (TmP/GFR), reduced levels of intact FGF23 and increased levels of c-terminal FGF23. Review of all 54 previously published cases of GALNT3, FGF23, and KL associated HFTC and HHS demonstrated that more subjects than previously recognized have a combined phenotype. CONCLUSION: We have described HFTC and HHS in a consanguineous Caucasian family with a novel GALNT3 mutation, demonstrating new phenotypic features and significant variability in the natural course of the disease. A review of the literature, show that more subjects than previously recognized have a combined phenotype of HFTC and HHS. HHS and HFTC are two distinct phenotypes in a spectrum of GALNT3 mutation related calcification disorders, where the additional factors determining the phenotypic expression, are yet to be clarified.

Interrelationships between anthropometric variables and overweight in childhood and adolescence.

OBJECTIVES: To answer the questions: how does body mass index (BMI) correlate to five overweight related anthropometric variables during different ages in childhood, and which anthropometric variables contribute most to variation in BMI during childhood? METHODS: Data on BMI, height (H), sitting height (SH), waist circumference (WC), waist to height ratio (WHtR), waist to sitting height ratio (WSHtR), subscapular skinfold (SSF), and triceps skinfold (TSF), from 4,576 Norwegian children 4.00-15.99 years of age, were transformed to standard deviation scores (SDS) and studied using correlation and multiple regression analyses. RESULTS: The correlations between BMI SDS and the standardized anthropometric variables were in general strong and positive. For all variables, the correlations were weakest in the youngest age group and highest between 7 and 12 years. WC SDS and WHtR SDS were most strongly correlated with BMI SDS through all ages and in both sexes. A model with seven anthropometric variables adjusted for age and sex explained 81.4% of the variation in BMI SDS. When adjusted for all other variables, WC SDS contributed most to the variation in BMI SDS (b = 0.467, CI [0.372, 0.562]). Age group, but not sex, contributed significantly to variation in BMI SDS. CONCLUSION: The interrelationships between BMI SDS and five standardized overweight related anthropometric variables were dependent on age, being weakest in the youngest age group. Independent of sex and age, WC SDS was in this study superior to other anthropometric variables in contributing to variation in BMI SDS during childhood.

TV viewing and obesity among Norwegian children: the importance of parental education.

AIM: To analyse the effect of lifestyle factors on the prevalence of overweight and obesity in 6-15-year-old Norwegian children. METHODS: Questionnaire data on lifestyle factors (sedentary behaviour, activity and eating habits) and prevalence numbers of overweight and obesity based on measured height and weight were analysed using multinomial logistic regression in a sample of 2281 children included in the Bergen Growth Study. RESULTS: More screen time increased the risk of overweight (odds ratio (OR): 1.25; p = 0.02) and obesity (OR: 1.12; p = 0.02) as did the presence of a TV in the child's bedroom (OR: 1.26 (overweight), OR: 1.81 (obese); p = 0.04). The obese children reported less sugar intake than the not overweight children (OR: 0.58; p = 0.01). Higher parental education was associated with less screen time (p = 0.02), lower frequency of TV in the child's bedroom (p = 0.001), more sports (p = 0.005), as well as eating more fruit and vegetables, less sweets, soft drinks and fast food, and more regular meals (for all, p < 0.03). CONCLUSION: Indicators of sedentary lifestyle, such as screen time and the presence of a TV in the child's bedroom, were associated with overweight and obesity in Norwegian schoolchildren. Higher parental education was generally associated with less obesogenic lifestyle.

Growth references for 0-19 year-old Norwegian children for length/height, weight, body mass index and head circumference.

BACKGROUND: Previous growth references for Norwegian children were based on measurements from the 1970s and 1980s. New reference data, collected through the Bergen Growth Study and the Medical Birth Registry of Norway, are presented as LMS values. MATERIALS AND METHODS: A cross-sectional sample of children aged 0-19 years in stratified randomized design measured in 2003-2006 as a part of the Bergen Growth Study (n = 7291) and birth data of children born in 1999-2003 from the Medical Birth Registry of Norway (n = 12 576) was used to estimate the new references by the means of the LMS method. Measurement reliability was assessed by test-rest studies. RESULTS: New references were constructed for length/height, weight, body mass index (BMI) and head circumference. Length/height and weight for children aged 0-4 years were similar to previous Norwegian references, but mean height increased up to a maximum of 3.4 cm in boys and 2.5 cm in girls during the pubertal years. Mean height was similar to (or slightly higher) in comparison with other recent European references. Reliability of the measurements compared well with published estimates. CONCLUSION: Because of the observed secular trends in growth, it is advised to use the new references, which have been endorsed by the Norwegian Department of Health.

Levels of per- and polyfluoroalkyl substances (PFAS) in Norwegian children stratified by age and sex - Data from the Bergen Growth Study 2.

BACKGROUND AND AIM: Due to the persistence, bioaccumulation and potential adverse health effects, there have been restrictions and phase out in the production of certain per- and polyfluoroalkyl substances (PFAS) since the early 2000s. Published serum levels of PFAS during childhood are variable and may reflect the impact of age, sex, sampling year and exposure history. Surveying the concentrations of PFAS in children is vital to provide information regarding exposure during this critical time of development. The aim of the current study was therefore to evaluate serum concentrations of PFAS in Norwegian schoolchildren according to age and sex. MATERIAL AND METHODS: Serum samples from 1094 children (645 girls and 449 boys) aged 6-16 years, attending schools in Bergen, Norway, were analyzed for 19 PFAS. The samples were collected in 2016 as part of the Bergen Growth Study 2. Statistical analyses included Student t-test, one-way ANOVA and Spearman's correlation analysis of log-transformed data. RESULTS: Of the 19 PFAS examined, 11 were detected in the serum samples. Perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS) and perfluorononaoic acid (PFNA) were present in all samples with geometric means of 2.67, 1.35, 0.47 and 0.68 ng/mL, respectively. In total, 203 children (19%) had PFAS levels above the safety limits set by the German Human Biomonitoring Commission. Significantly higher serum concentrations were found in boys compared to girls for PFOS, PFNA, PFHxS and perfluoroheptanesulfonic acid (PFHpS). Furthermore, serum concentrations of PFOS, PFOA, PFHxS and PFHpS were significantly higher in children under the age of 12 years than in older children. CONCLUSIONS: PFAS exposure was widespread in the sample population of Norwegian children analyzed in this study. Approximately one out of five children had PFAS levels above safety limits, indicating a potential risk of negative health effects. The majority of the analyzed PFAS showed higher levels in boys than in girls and decreased serum concentrations with age, which may be explained by changes related to growth and maturation.

Reference Curves for Pediatric Endocrinology: Leveraging Biomarker Z-Scores for Clinical Classifications.

CONTEXT: Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age. OBJECTIVE: We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI). METHODS: Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established "LMS" growth chart algorithm in R. RESULTS: Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (ß = 0.5, P < 0.001) and leptin (ß = 0.6, P < 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (ß = -0.4, P < 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class. CONCLUSION: Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.

Parental perception of overweight and underweight in children and adolescents.

AIMS: To compare the parental perception of overweight and underweight in their children to objective criteria, based on body mass index (BMI), waist circumference and triceps skinfold thickness, and to explore the effects of potential determinants. METHODS: Logistic regression of anthropometric measurements, socio-demographic characteristics and self-reported parental height and weight on the parental perception of their child's weight status in 3770 children aged 2-19. RESULTS: Seventy per cent of overweight/obese children and 40.8% of underweight children were perceived having normal weight by parents. In 2- to 5-year-old overweight children, 91.2% were considered to have normal weight. For a given BMI, primary school age children, adolescents and girls had a higher probability to be assigned as overweight, whereas adolescents and girls had a lower probability to be assigned as underweight. Overweight parents more readily assigned their children as underweight, but there was no effect of parental educational level or parental underweight. CONCLUSION: Parental ability to recognize overweight or underweight in their offspring was generally poor. The findings emphasize the need for objective criteria based on physical measurements in the routine follow up of children, as parental ability to recognize weight problems in their children is nonreliable.

[Trichorhinophalangeal syndrome--clinical presentation and genetics]. / Trikorhinofalangealt syndrom--klinisk presentasjon og genetikk.

BACKGROUND: The trichorhinophalangeal syndrome (TRPS) is a hereditary, skeletal dysplasia which has a characteristic clinical presentation and is classified in types 1, 2 and 3, based on phenotype and genotype. Typical findings may be mild and many patients probably remain undiagnosed. MATERIAL AND METHODS: The paper is based on four case reports and provides a short review of the condition. RESULTS: Our four patients all have typical facial features, such as a large nose and thin upper lip, thin hair and short curved fingers with characteristic radiological findings. The condition is autosomal dominant and caused by a mutation in the TRPS1 gene, which codes a gene-regulating protein involved in development of hair and modulation of chondrocytes. The diagnosis can be based on clinical findings, but DNA-analysis can be of help in unclear situations. Two of our patients were diagnosed from clinical and radiological findings, but for the two others genetic examinations were done as well. There is no causal treatment, but the diagnosis can give patients an explanation of their problems, and genetic counseling for the patient and family can be offered. Orthopedic surgery and cosmetic aids are valuable for many. INTERPRETATION: In an increasingly technified medical daily life, the clinical view is still the most important tool in diagnosing patients with this condition.