Pubertal growth in height, sitting height and leg length in achondroplasia.

Background: Children with achondroplasia (ACH) appear to lack a pubertal growth spurt in height.Aim To explore the growth spurt in height and its segments sitting height and leg length, in a large sample of ACH cases using growth curve modelling.Subjects and methods: Height and sitting height were measured longitudinally in ACH children, and the data were analysed using the SITAR (SuperImposition by Translation and Rotation) growth model, which estimates a mean growth curve and random effects for individuals defining differences in size, pubertal timing and intensity.Results: Out of 402 ACH children, 85 boys and 75 girls aged 7-20 years had respectively 529 and 454 measurements of height and sitting height, with leg length calculated by difference. SITAR analysis identified peaks in mean height velocity at 13.3 and 11.3 years in boys and girls, with peak velocities of 4.3 and 4.4 cm/year. Mean peak velocity for sitting height was 3.0 cm/year, but leg length showed no peak. The SITAR models explained 92% to 99% of the cross-sectional variance.Conclusion: ACH children do experience a growth spurt in puberty, but only half that of control children. The spurt is due entirely to sitting height, with no leg length spurt.

Sample size and sample composition for constructing growth reference centiles.

Growth reference centile charts are widely used in child health to assess weight, height and other age-varying measurements. The centiles are easy to construct from reference data, using the LMS method or GAMLSS (Generalised Additive Models for Location Scale and Shape). However, there is as yet no clear guidance on how to design such studies, and in particular how many reference data to collect, and this has led to study sizes varying widely. The paper aims to provide a theoretical framework for optimally designing growth reference studies based on cross-sectional data. Centiles for weight, height, body mass index and head circumference, in 6878 boys aged 0-21 years from the Fourth Dutch Growth Study, were fitted using GAMLSS. The effect on precision of varying the sample size and the distribution of measurement ages (sample composition) was explored by fitting a series of GAMLSS models to simulated data. Sample composition was defined as uniform on the ageλ scale, where λ was chosen to give constant precision across the age range. Precision was measured on the z-score scale, and was the same for all four measurements, with a standard error of 0.041 z-score units for the median and 0.066 for the 2nd and 98th centiles. Compared to a naïve calculation, the process of smoothing the centiles increased the notional sample size two- to threefold by 'borrowing strength'. The sample composition for estimating the median curve was optimal for λ=0.4, reflecting considerable over-sampling of infants compared to children. However, for the 2nd and 98th centiles, λ=0.75 was optimal, with less infant over-sampling. The conclusion is that both sample size and sample composition need to be optimised. The paper provides practical advice on design, and concludes that optimally designed studies need 7000-25,000 subjects per sex.

Tanner's tempo of growth in adolescence: recent SITAR insights with the Harpenden Growth Study and ALSPAC.

Background: James Tanner emphasised the "tempo" of growth, i.e. the adolescent spurt as summarised by its timing (age at peak velocity or APV) and intensity (peak velocity, PV).Aim: The paper applies the SITAR growth curve model to pubertal growth data with the aim of clarifying the growth pattern across multiple measurements and the spectrum of APV and PV.Subjects and methods: Data for 7-20 years on ten anthropometric measurements in 619 children from the Harpenden Growth Study, and on height in 10410 children from the ALSPAC study, were analysed using SITAR (SuperImposition by Translation And Rotation). SITAR models pubertal growth as a mean curve with APV and PV fitted as subject-specific random effects, and a random measurement intercept.Results: Mean APV for Harpenden girls and boys averaged 12.0 and 13.9 years across the ten measurements. PV expressed as percent per year lay in the narrow range 4-8%. Splitting the ALSPAC subjects into 9 by 5 APV and PV groups and fitting separate SITAR models to each group confirmed SITAR's good fit while highlighting the spectrum of growth patterns.Conclusion: SITAR works well to summarise pubertal growth. The disappointment is that Tanner did not live to see it in action.

Commentary: Methods for calculating growth trajectories and constructing growth centiles.

This commentary rounds off a collection of papers focusing on statistical methods for analysing growth data. In two papers, Anderson and colleagues discuss growth trajectory models in early life, using data on height and weight from the HBGDki initiative, while two papers from Ohuma and Altman review methods for centile construction, with data from the INTERGROWTH-21st project used to provide worked examples of centiles for birthweight and fetal head circumference. Anderson et al focus on four growth trajectory models: quadratic Laird-Ware, SITAR, brokenstick, and FACE, where the latter two fit better than the former two applied to length data in individuals. On this basis, they recommend brokenstick and FACE for future work. However, they do not discuss the timescale on which the growth models assess growth faltering nor the relevance of this timescale to later health outcome. Models that best detect short-term fluctuations in growth (brokenstick and FACE) may not necessarily be best at predicting later outcome. It is premature to exclude the quadratic Laird-Ware or SITAR models, which give a parsimonious summary of growth in individuals over a longer timescale. Ohuma and Altman highlight the poor quality of reporting in fetal centile studies, and they provide recommendations for good practice. Their birthweight centiles example illustrates both the power of the GAMLSS software and its capacity for misuse. The longitudinal fetal head circumference centiles are biased such that 5% of infants are below the 3rd centile and 5% above the 97th .

Pathways into and out of overweight and obesity from infancy to mid-childhood.

OBJECTIVES: To investigate whether high weight in infancy predicts obesity in childhood. METHOD: Data from two UK cohorts (Newcastle Growth and Development N = 795, Gateshead Millennium N = 393) and one Finnish (Tampere N = 1262) were combined. Z scores of weight at 3 and 12 months and body mass index (BMI) at 5 and 8 years were categorized as raised/overweight (1 to <2 SD) or high/obese (≥2 SD). RESULTS: The majority of infants with raised or high weight at birth tended to revert to normal by 3 months and to track in the same category from 3 to 12 months. Although infants with high weight were five times more likely to have BMI ≥ 2 SD at 8 years (p < 0.001), only 22% went on to have BMI ≥ 2 SD, while 64% of infants with raised weight had normal BMI at 8 years. Of children with BMI ≥ 2 SD aged 8 years, only 22% had raised weight in infancy and half had BMI ≥ 2 SD for the first time at that age. CONCLUSIONS: Infants with raised weight in infancy tend to remain so, but most children who go on to have BMI ≥ 2 SD were not unusually heavy infants and the majority of infants with high weight reverted to overweight or normal weight in childhood.

Fifty years of child height and weight in Japan and South Korea: Contrasting secular trend patterns analyzed by SITAR.

Objectives Japanese and South Koreans have traditionally been shorter than Europeans, but have recently become appreciably taller. The aim was to quantify the secular trend patterns in height and weight growth in the two countries over 50 years using the SITAR growth curve model. Methods Data on mean height and weight by sex in 1-year age groups from 1 to 20 years were obtained by decade in South Korea (1965-2005) and Japan (1950-2010). The data were analyzed using SITAR (SuperImposition by Translation And Rotation), which estimates a mean curve and three adjustments-size, timing and intensity-reflecting how the individual surveys differ from the mean. A sensitivity analysis compared results for the Japanese data based on cohort as well as period. Results Growth patterns in the two countries changed dramatically over the study period, affecting not only height and weight but also developmental age, in that the growth period advanced in timing and shrank in duration. SITAR fitted the data well. The trends were larger in South Korea than Japan, and puberty timing in Japan stabilized by 1970. Most of the height increment seen in adults had already accrued by age 1.5 years, whereas the adult weight increment accrued throughout childhood. Conclusions The secular height trend in these countries represents increased growth in the long bones during infancy, so it can be viewed as the inverse of stunting. There are striking country differences in growth pattern, but they are not easily explained by differences in national income, diet or lifestyle.

The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.

Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth.

The physiological mechanisms that confer different outcomes in morbidity and mortality of the fetus exposed to stressful environments may be driven by significant differences in the expression and function of the placental glucocorticoid receptor (GR). The recent discovery that the placenta contains at least 8 different isoforms of the GR raises questions about the regulation and physiological relevance of the many GR variants expressed in the placenta. The current data also highlights that individual differences in glucocorticoid sensitivity, variations in the effect of different complications of pregnancy on birth outcomes and sex differences in the response to stress, may all be dependent on a specific GR isoform expression profile. This review will investigate the current state of knowledge of GR isoforms in the placenta and discuss the potential role of these multiple isoforms in regulating glucocorticoid sensitivity.

Using Super-Imposition by Translation And Rotation (SITAR) to relate pubertal growth to bone health in later life: the Medical Research Council (MRC) National Survey of Health and Development.

BACKGROUND: To explore associations between pubertal growth and later bone health in a cohort with infrequent measurements, using another cohort with more frequent measurements to support the modelling, data from the Medical Research Council (MRC) National Survey of Health and Development (2-26 years, 4901/30 004 subjects/measurements) and the Avon Longitudinal Study of Parents And Children (ALSPAC) (5-20 years) (10 896/74 120) were related to National Survey of Health and Development (NSHD) bone health outcomes at 60-64 years. METHODS: NSHD data were analysed using Super-Imposition by Translation And Rotation (SITAR) growth curve analysis, either alone or jointly with ALSPAC data. Improved estimation of pubertal growth parameters of size, tempo and velocity was assessed by changes in model fit and correlations with contemporary measures of pubertal timing. Bone outcomes of radius [trabecular volumetric bone mineral density (vBMD) and diaphysis cross-sectional area (CSA)] were regressed on the SITAR parameters, adjusted for current body size. RESULTS: The NSHD SITAR parameters were better estimated in conjunction with ALSPAC, i.e. more strongly correlated with pubertal timing. Trabecular vBMD was associated with early height tempo, whereas diaphysis CSA was related to weight size, early tempo and slow velocity, the bone outcomes being around 15% higher for the better vs worse growth pattern. CONCLUSIONS: By pooling NSHD and ALSPAC data, SITAR more accurately summarized pubertal growth and weight gain in NSHD, and in turn demonstrated notable associations between pubertal timing and later bone outcomes. These associations give insight into the importance of the pubertal period for future skeletal health and osteoporosis risk.

Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms.

During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1(-/-) mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1(-/-) mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1(-/-) mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development.

Associations of gender inequality with child malnutrition and mortality across 96 countries.

National efforts to reduce low birth weight (LBW) and child malnutrition and mortality prioritise economic growth. However, this may be ineffective, while rising gross domestic product (GDP) also imposes health costs, such as obesity and non-communicable disease. There is a need to identify other potential routes for improving child health. We investigated associations of the Gender Inequality Index (GII), a national marker of women's disadvantages in reproductive health, empowerment and labour market participation, with the prevalence of LBW, child malnutrition (stunting and wasting) and mortality under 5 years in 96 countries, adjusting for national GDP. The GII displaced GDP as a predictor of LBW, explaining 36% of the variance. Independent of GDP, the GII explained 10% of the variance in wasting and stunting and 41% of the variance in child mortality. Simulations indicated that reducing GII could lead to major reductions in LBW, child malnutrition and mortality in low- and middle-income countries. Independent of national wealth, reducing women's disempowerment relative to men may reduce LBW and promote child nutritional status and survival. Longitudinal studies are now needed to evaluate the impact of efforts to reduce societal gender inequality.

The evidential value of developmental age imaging for assessing age of majority.

AIM: To consider the evidential value of developmental age images for identifying age of majority. METHODS: The published literature on hand-wrist X-rays, MRI scans of the distal radius and orthopantomograms of the lower left third molar is considered in terms of the mean age of attainment of the adult appearance and the diagnostic test performance of the adult appearance to predict adult status, either administratively (under-17 football) or forensically. RESULTS: The mean age of attainment of a mature hand-wrist X-ray is under 18 years and most individuals are mature before age 18. For the MRI wrist scan and the third molar the age of attainment is over 19 years and the adult appearance is an indicator of adulthood, while the immature appearance is uninformative about likely age. So MRI and third molars have high specificity, but low sensitivity. CONCLUSIONS: Bone age assessed by hand-wrist X-ray is uninformative and should not be used. The adult appearance of MRI wrist scans and third molars provide evidence of being over-age, although there remains a small risk of minors being misclassified as adult. The immature appearance is uninformative about likely age and, overall, more than one third of assessments are wrong.

The relationship between Insulin-like Growth Factor 1, sex steroids and timing of the pubertal growth spurt.

OBJECTIVE: Progress through puberty involves a complex hormonal cascade, but the individual contributions of hormones, particularly IGF-1, are unknown. We reanalysed Chard growth study data to explore the tempo of puberty based on changes in both height and hormone levels, using a novel method of growth curve analysis. DESIGN AND SUBJECTS: Schoolboys (n = 54) and girls (n = 70) from Chard, Somerset, England, recruited in 1981 at age 8/9 and followed to age 16. MEASUREMENTS: Every 6 months, height and Tanner stages (genitalia, breast, pubic hair) were recorded, and in a subsample (24 boys, 27 girls), blood samples were taken. Serum IGF-1, testosterone (boys) and oestradiol (girls) were measured by radioimmunoassay. Individual growth curves for each outcome were analysed using variants of the super-imposition by translation and rotation (SITAR) method, which estimates a mean curve and subject-specific random effects corresponding to size, and age and magnitude of peak velocity. RESULTS: The SITAR models fitted the data well, explaining 99%, 65%, 86% and 47% of variance for height, IGF-1, testosterone and oestradiol, respectively, and 69-88% for the Tanner stages. During puberty, the variables all increased steeply in value in individuals, the ages at peak velocity for the different variables being highly correlated, particularly for IGF-1 vs height (r = 0·74 for girls, 0·92 for boys). CONCLUSIONS: IGF-1, like height, the sex steroids and Tanner stages, rises steeply in individuals during puberty, with the timings of the rises tightly synchronized within individuals. This suggests that IGF-1 may play an important role in determining the timing of puberty.