Short stature and language development in the United Kingdom: a longitudinal analysis of children from the Millennium Cohort Study.

BACKGROUND: In low- and middle-income countries, poverty and impaired growth prevent children from meeting their cognitive developmental potential. There are few studies investigating these relationships in high-income settings. METHODS: Participants were 12,536 children born between 2000 and 2002 in the UK and participating in the Millennium Cohort Study (MCS). Short stature was defined as having a height-for-age 2 or more standard deviations below the median (≤ - 2 SDS) at age 3 years. Standardized British Abilities Scales II (BAS II) language measures, used to assess language development at ages 3, 5, 7 and 11 years, were the main outcome assessed. RESULTS: Children with short stature at age 3 years (4.1%) had language development scores that were consistently lower from ages 3 to 11 years (- 0.26 standard deviations (SD) (95% CI - 0.37, - 0.15)). This effect was attenuated but remained significant after adjustment for covariates. Trajectory analysis produced four distinct patterns of language development scores (low-declining, low-improving, average and high). Multinomial logistic regression models showed that children with short stature had a higher risk of being in the low-declining group, relative to the average group (relative risk ratio (RRR) = 2.11 (95% CI 1.51, 2.95)). They were also less likely to be in the high-scoring group (RRR = 0.65 (0.52, 0.82)). Children with short stature at age 3 years who had 'caught up' by age 5 years (height-for-age ≥ 2 SDS) did not have significantly different scores from children with persistent short stature, but had a higher probability of being in the high-performing group than children without catch-up growth (RRR = 1.84 (1.11, 3.07)). CONCLUSIONS: Short stature at age 3 years was associated with lower language development scores at ages 3 to 11 years in UK children. These associations remained significant after adjustment for socioeconomic, child and parental factors.

The Association Between Puberty Timing and Body Mass Index in a Longitudinal Setting: The Contribution of Genetic Factors.

We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition.

Regional differences in short stature in England between 2006 and 2019: A cross-sectional analysis from the National Child Measurement Programme.

BACKGROUND: Short stature, defined as height for age more than 2 standard deviations (SDs) below the population median, is an important indicator of child health. Short stature (often termed stunting) has been widely researched in low- and middle-income countries (LMICs), but less is known about the extent and burden in high-income settings. We aimed to map the prevalence of short stature in children aged 4-5 years in England between 2006 and 2019. METHODS AND FINDINGS: We used data from the National Child Measurement Programme (NCMP) for the school years 2006-2007 to 2018-2019. All children attending state-maintained primary schools in England are invited to participate in the NCMP, and heights from a total of 7,062,071 children aged 4-5 years were analysed. We assessed short stature, defined as a height-for-age standard deviation score (SDS) below -2 using the United Kingdom WHO references, by sex, index of multiple deprivation (IMD), ethnicity, and region. Geographic clustering of short stature was analysed using spatial analysis in SaTScan. The prevalence of short stature in England was 1.93% (95% confidence interval (CI) 1.92-1.94). Ethnicity adjusted spatial analyses showed geographic heterogeneity of short stature, with high prevalence clusters more likely in the North and Midlands, leading to 4-fold variation between local authorities (LAs) with highest and lowest prevalence of short stature. Short stature was linearly associated with IMD, with almost 2-fold higher prevalence in the most compared with least deprived decile (2.56% (2.53-2.59) vs. 1.38% (1.35-1.41)). There was ethnic heterogeneity: Short stature prevalence was lowest in Black children (0.64% (0.61-0.67)) and highest in Indian children (2.52% (2.45-2.60)) and children in other ethnic categories (2.57% (2.51-2.64)). Girls were more likely to have short stature than boys (2.09% (2.07-2.10) vs. 1.77% (1.76-1.78), respectively). Short stature prevalence declined over time, from 2.03% (2.01-2.05) in 2006-2010 to 1.82% (1.80-1.84) in 2016-2019. Short stature declined at all levels of area deprivation, with faster declines in more deprived areas, but disparities by IMD quintile were persistent. This study was conducted cross-sectionally at an area level, and, therefore, we cannot make any inferences about the individual causes of short stature. CONCLUSIONS: In this study, we observed a clear social gradient and striking regional variation in short stature across England, including a North-South divide. These findings provide impetus for further investigation into potential socioeconomic influences on height and the factors underlying regional variation.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.

Screening of hydrocephalus in infants using either WHO or population-based head circumference reference charts.

AIM: The aim was to compare the performances of the World Health Organization (WHO) and population-based (PB) references in the screening for hydrocephalus in infants aged <2 years. METHODS: We collected 341 longitudinal head circumference (HC) measurements of hydrocephalic infants and 120 181 measurements of 15 145 healthy infants from primary care. The measurements were converted into z-scores, and a new screening parameter, change in HC standard deviation score (SDS) over time (ΔHC SDS), was calculated. Comparisons were made using receiver operating characteristics analysis and linear mixed models. RESULTS: The mean HC SDSWHO was 3.5 and the mean HC SDSPB was 2.9 in the hydrocephalic infants, and in healthy children, those numbers were 1.0 SDSWHO and 0 SDSPB , respectively. The best screening accuracy was obtained with the PB reference in combination with the ΔHC SDS parameter (AUC 0.89). The accuracy of the WHO standard could be improved to a similar level by customising the screening cut-offs of HC SDS according to the population and combining screening parameters. CONCLUSIONS: Auxology alone was not sufficient for the screening of hydrocephalus. The WHO standard should be validated in the population, and population-specific cut-offs for normality defined before its introduction.

Sexual dimorphism in postnatal gonadotrophin levels in infancy reflects diverse maturation of the ovarian and testicular hormone synthesis.

BACKGROUND: The postnatal gonadotrophin surge is sexually dimorphic: FSH levels predominate in girls and LH levels in boys. However, in preterm (PT) girls, both gonadotrophin levels are higher than in PT boys. OBJECTIVE: To evaluate how gonadal maturation contributes to the sex differences in FSH and LH. DESIGN: Monthly follow-up of 58 full-term (FT, 29 boys) and 67 PT (33 boys) infants from 1 week (D7) to 6 months of age (M1-M6). Analyses were also carried out according to postmenstrual (PM) age in PT infants. METHODS: Urinary LH, FSH, oestradiol (E2), testosterone (T) and serum inhibin B (InhB) levels. RESULTS: High gonadotrophin levels in PT girls abruptly decreased (P < .001) by M2, corresponding to a PM age of 38-42 weeks, and LH levels fell below the levels found in boys. This decrease was parallel to a steep increase in E2 levels (P < .001), and, from M4 to M6, LH and E2 correlated positively in PT girls (P < .01). T levels in PT boys increased earlier than E2 levels in PT girls. In addition, InhB levels were high in PT boys already at D7, in contrast to low InhB in PT girls. InhB and FSH correlated negatively in the whole group (P < .001). CONCLUSIONS: Ovarian hormone synthesis is immature and incapable of responding to gonadotrophin stimulus before 38-42 PM weeks in PT girls, which may explain their highly elevated FSH and LH levels. The higher InhB levels in boys compared to girls may explain sexual dimorphism in FSH levels.

The Genetic Basis of Delayed Puberty.

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty "brake." These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

IGSF1 variants in boys with familial delayed puberty.

UNLABELLED: The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein mainly expressed in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). As this syndrome was discovered in patients with CeH, it is unknown whether IGSF1 mutations might also cause delayed puberty without CeH. We therefore determined the prevalence of IGSF1 sequence variants in 30 patients with an apparent X-linked form of constitutional delay of growth and puberty (CDGP). In four families, we discovered three novel variants of unknown clinical significance (VUCSs), with possible pathogenicity predicted by in silico analysis. However, the genotype did not fully cosegregate with CDGP, all three VUCSs showed normal plasma membrane expression in transfected HEK293 cells, and no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. The observation of hyperprolactinemia in two carriers remains unexplained. CONCLUSION: There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP.

Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications.

Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.

The crosstalk between FGF21 and GH leads to weakened GH receptor signaling and IGF1 expression and is associated with growth failure in very preterm infants.

Background: Fibroblast growth factor 21 (FGF21) is an essential metabolic regulator that adapts to changes in nutritional status. Severe childhood undernutrition induces elevated FGF21 levels, contributing to growth hormone (GH) resistance and subsequent linear growth attenuation potentially through a direct action on chondrocytes. Methods: In this study, we assessed expression of the components of both GH and FGF21 pathways in rare and unique human growth plates obtained from children. Moreover, we investigated the mechanistic interplay of FGF21 on GH receptor (GHR) signaling in a heterologous system. Results: Chronic FGF21 exposure increased GH-induced GHR turnover and SOCS2 expression, leading to the inhibition of STAT5 phosphorylation and IGF-1 expression. The clinical significance of FGF21 signaling through GH receptors was tested in nutritionally driven growth failure seen in very preterm (VPT) infants right after birth. VPT infants display an immediate linear growth failure after birth followed by growth catch-up. Consistent with the in vitro model data, we show that circulating FGF21 levels were elevated during deflection in linear growth compared to catch-up growth and were inversely correlated with the length velocity and circulating IGF1 levels. Conclusions: This study further supports a central role of FGF21 in GH resistance and linear growth failure and suggests a direct action on the growth plate.

A Digital Health Solution for Child Growth Monitoring at Home: Testing the Accuracy of a Novel "GrowthMonitor" Smartphone Application to Detect Abnormal Height and Body Mass Indices.

Objective: To develop and evaluate a smartphone application that accurately measures height and provides notifications when abnormalities are detected. Patients and Methods: A total of 145 (75 boys) participants with a mean age ± SD of 8.7±4.5 years (range, 1.0-17.0 years), from the Children's Hospital at Barts Health Trust, London, United Kingdom, were enrolled in the study. "GrowthMonitor" (UCL Creatives) iPhone application (GMA) measures height using augmented reality. Using population-based (UK-WHO) references, algorithms calculated height SD score (HSDS), distance from target height (THSDSDEV), and HSDS change over time (ΔHSDS). Pre-established thresholds discriminated normal/abnormal growth. The GMA and a stadiometer (Harpenden; gold standard) measured standing heights of children at routine clinic visits. A subset of parents used GMA to measure their child's height at home. Outcome targets were 95% of GMA measurements within ±0.5 SDS of the stadiometer and the correct identification of abnormal HSDS, THSDSDEV, and ΔHSDS. Results: Bland-Altman plots revealed no appreciable bias in differences between paired study team GMA and stadiometer height measurements, with a mean of the differences of 0.11 cm with 95% limits of agreement of -2.21 to 2.42 cm. There was no evidence of greater bias occurring for either shorter/younger children or taller/older children. The 2 methods of measurements were highly correlated (R=0.999). GrowthMonitor iPhone application measurements performed by parents in clinic and at home were slightly less accurate. The κ coefficient indicated reliable and consistent agreement of flag alerts for HSDS (κ=0.74) and THSDSDEV (κ=0.88) between 83 paired GMA and stadiometer measurements. GrowthMonitor iPhone application yielded a detection rate of 96% and 97% for HSDS-based and THSDSDEV-based red flags, respectively. Forty-two (18 boys) participants had GMA calculated ΔHSDS using an additional height measurement 6-16 months later, and no abnormal flag alerts were triggered for ΔHSDS values. Conclusion: GrowthMonitor iPhone application provides the potential for parents/carers and health care professionals to capture serial height measurements at home and without specialized equipment. Reliable interpretation and flagging of abnormal measurements indicate the potential of this technology to transform childhood growth monitoring.

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .

SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.

Innervation of the hypothalamic median eminence by Gonadotropin-Releasing Hormone (GnRH) neurons is vital to ensure puberty onset and successful reproduction. However, the molecular and cellular mechanisms underlying median eminence development and pubertal timing are incompletely understood. Here we show that Semaphorin-6A is strongly expressed by median eminence-resident oligodendrocytes positioned adjacent to GnRH neuron projections and fenestrated capillaries, and that Semaphorin-6A is required for GnRH neuron innervation and puberty onset. In vitro and in vivo experiments reveal an unexpected function for Semaphorin-6A, via its receptor Plexin-A2, in the control of median eminence vascular permeability to maintain neuroendocrine homeostasis. To support the significance of these findings in humans, we identify patients with delayed puberty carrying a novel pathogenic variant of SEMA6A. In all, our data reveal a role for Semaphorin-6A in regulating GnRH neuron patterning by tuning the median eminence vascular barrier and thereby controlling puberty onset.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Testosterone measured in infancy predicts subsequent sex-typed behavior in boys and in girls.

The testes are active during gestation, as well as during early infancy. Testosterone elevation during fetal development has been shown to play a role in human neurobehavioral sexual differentiation. The role of early postnatal gonadal activation in human psychosexual development is largely unknown, however. We measured testosterone in 48 full term infants (22 boys, 26 girls) by monthly urinary sampling from day 7 postnatal to age 6 months, and related the area under the curve (AUC) for testosterone during the first 6 months postnatal to subsequent sex-typed behavior, at the age of 14 months, using the Pre-School Activities Inventory (PSAI), and playroom observation of toy choices. In boys, testosterone AUC correlated significantly with PSAI scores (Spearman's rho = 0.54, p = 0.04). In addition, play with a train and with a baby doll showed the anticipated sex differences, and play with the train correlated significantly and positively with testosterone AUC in girls (Spearman's rho = 0.43, p = 0.05), while play with the doll correlated significantly and negatively with testosterone AUC in boys (Spearman's rho = -0.48, p < 0.03). These results may support a role for testosterone during early infancy in human neurobehavioral sexual differentiation.

Genetic and environmental influences on chest circumference during infancy: a longitudinal study of japanese twins.

BACKGROUND: Chest circumference (CC) is suggested to be a good indicator of early life nutrition, but little is known on the heritability of CC. Thus we analysed the effects of genetic and environmental factors on the development of CC in Japanese infants. METHODS: CC was measured longitudinally from birth until 1 year of age in a cohort of 211 monozygotic and 160 dizygotic complete Japanese twin pairs born in 1989-2002. The data were analysed using applications of structural linear equation modelling for twin data. RESULTS: No sex-specific differences in the variance components were found. Environmental factors unique to each twin explained the major part of the variation of CC at birth whereas environmental factors shared by co-twins were more important at 1-3 months of age. From 3 months of age, the effect of genetic factors become steadily stronger and they explained the majority of the variation at 1 year of age. Strong genetic continuity in the development of CC was found, but also new sets of genes were activated during the first year of life. The origin of the environmental part of the variation could be tracked before 3 months of age. A substantial part of common and specific environmental factors affecting CC affected also birthweight. CONCLUSIONS: CC is sensitive to intrauterine environmental factors, but these effects diminish during the first year of life, at least if postnatal environment is good. CC can be a useful indicator when identifying newborns who have suffered suboptimal pre-natal conditions.

Genetics of head circumference in infancy: a longitudinal study of Japanese twins.

OBJECTIVES: Previous studies have shown strong genetic influence to head circumference (HC), but still little is known on the development of genetic etiology of HC in infancy, especially in non-Caucasian populations. Thus, we decided to analyze the genetics of HC growth in Japanese infants. METHODS: Longitudinal measures of HC were available from birth to 13 months of age in 206 monozygotic and 156 dizygotic complete twin pairs. Genetic modeling for twin data was used. RESULTS: We found only little evidence for sex-specific differences in the genetics of HC and thus analyzed boys and girls together. After 5 months of age the heritability of HC was high, but before that age also a substantial common environmental component was present. Not only strong genetic persistence for HC was found but also a new genetic variation emerged. New environmental variation shared by co-twins affecting HC was found until 3 months of age, and this effect was further transmitted until 1 year of age. CONCLUSIONS: HC and its growth are strongly genetically regulated. Largely, the same genetic factors affect the variation of HC at different ages, and new genetic variation emerged during the first year of life. Knowledge on the genetic component in the variation of HC may help to design tools for defining abnormal growth of HC in population-based screenings for related disorders.