Capturing additional genetic risk from family history for improved polygenic risk prediction

Family history of complex traits may reflect transmitted rare pathogenic variants, intrafamilial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. We applied our model to predict adult height for 941 children in the Avon Longitudinal Study of Parents and Children cohort as well as 11 complex diseases for ~400,000 European ancestry participants in the UK Biobank. Parental history brought consistent significant improvements in the predictive power of polygenic risk prediction. For instance, a joint predictor was able to explain ~55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Our work showcases an innovative paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.

LSALO-BP: A Hybrid Model for Children Adulthood Height Prediction

The prediction of children's adult height is a common procedure in childhood endocrinology. Through the prediction of children's adult height, it is possible to find abnormalities in children's growth and development. Many jobs in today's society have certain requirements for height, so the accuracy of children adulthood height prediction is important for children. Current methods for predicting adult height of children have some shortcomings such as inaccurate accuracy. To deal with these problems, this paper analyzes the data collected by the Chinese children and adolescents' physical and growth health projects in primary and secondary schools in Zhejiang Province, and proposes a method for predicting adult height based on back propagation neural network (BPNN) with the body composition of children and adolescents as input. Since the BP algorithm has the risk of falling into local optimization, and we propose LSALO-BP model that incorporates the ant lion optimizer (LSALO) into the BP algorithm as location strategy to avoid local optimization. The improvements achieved by the ant lion algorithm are mainly reflected in: improving the ant's walk mode, and enhancing the global search ability of the LSALO algorithm. The comparison experiment of 10 benchmark functions proves the feasibility and effectiveness of the location strategy. The LSALO-BP model is applied to the prediction of adult height of children and adolescents. The experimental results show that compared with other models, the LSALO-BP prediction model has increased the prediction accuracy by 6.67%~16.08% for boys and 4.67%~6.6% for girls, which can more accurately predict the adult height of children and adolescents.

A Matter of Time: Delayed Presentation and Rapid Progression from Gonadotropin-Independent to Gonadotropin-Dependent Precocious Puberty following Successful Treatment for a Leydig Cell Tumor

Leydig cell tumors, most often benign, are a rare cause of isosexual gonadotropin-independent precocious puberty in boys due to secretion of testosterone. Very rarely do these tumors produce estrogen, causing gynecomastia. Testicular sparing surgery is the mainstay of treatment currently although radical orchidectomy was the choice in the past. Following surgery, clinical signs improve along with a revision of biochemical changes. Occasionally, it has been reported few children are progressed to gonadotropin-dependent precocious puberty (GDPP) after initial clinical and biochemical recovery. Gonadotropin receptor analogs have been successful on them to halt the progression of puberty, and growth hormone administration has been used to optimize the adult height. Here, we report a case of a 10-year-old boy who presented very late due to failure in recognition of features of puberty due to a Leydig cell tumor. Even though he underwent successful radical orchidectomy, just within 1 month following surgery, he entered GDPP in contrast to the published cases where it was earliest detected at 3 months.

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height

ObjectivesGrowth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children.MethodsRetrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement.ResultsANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (p<0.001), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from −3.10 ± 0.84 to −2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH.ConclusionsrhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes.

Maturity Has a Greater Association than Relative Age with Physical Performance in English Male Academy Soccer Players

This study aimed to: (1) examine differences in physical performance across birth-quartiles and maturity-status, and (2) determine the relationships among relative age, maturation and physical performance in young male soccer players. The sample included 199 males aged between 8.1 and 18.9 years, from two professional soccer academies in the English Football League. Data were collected for height, weight, self-reported biological parent heights, 30 m sprint time and countermovement jump (CMJ) height. Relative age was conveyed as a decimal, while maturity status was determined as the percentage of predicted adult height (PAH). There were no significant differences in any measure between birth quartiles, however early maturers outperformed on-time and later maturers in most performance measures. Pearson-product-moment correlations revealed that maturation was inversely associated with 30 m sprint time in U12 to U16 (r = −0.370–0.738; p < 0.05), but only positively associated with CMJ performance in U12 (r = 0.497; p < 0.05). In contrast, relative age was unrelated to sprint performance and only significantly associated with superior CMJ performance in U16. This study indicates that maturity has a greater association with sprint performance than relative age in English male academy soccer players. Practitioners should monitor and assess biological maturation in young soccer players to attempt to control for the influence on physical performance, and avoid biasing selection on absolute performance rather than identifying the most talented player.

Should Skeletal Maturation Be Manipulated for Extra Height Gain?

Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone or in combination with recombinant human growth hormone (rhGH). GnRHa is effective in attaining a normal adult height (AH) in the treatment of children with central precocious puberty, but its effect in short children with normal timing of puberty is equivocal. If rhGH-treated children with growth hormone deficiency or those who were born small-for-gestational age are still short at pubertal onset, co-treatment with a GnRHa for 2-3 years increases AH. A similar effect was seen by adding rhGH to GnRHa treatment of children with central precocious puberty with a poor AH prediction and by adding rhGH plus GnRHa to children with congenital adrenal hyperplasia with a poor predicted adult height on conventional treatment with gluco- and mineralocorticoids. In girls with idiopathic short stature and relatively early puberty, rhGH plus GnRHa increases AH. Administration of letrozole to boys with constitutional delay of growth puberty may increase AH, and rhGH plus anastrozole may increase AH in boys with growth hormone deficiency or idiopathic short stature, but the lack of data on attained AH and potential selective loss-of-follow-up in several studies precludes firm conclusions. GnRHas appear to have a good overall safety profile, while for aromatase inhibitors conflicting data have been reported.

Most Short Children with Cystic Fibrosis Do Not Catch Up by Adulthood

Poor linear growth is common in children with cystic fibrosis (CF) and predicts pulmonary status and mortality. Growth impairment develops in infancy, prior to pulmonary decline and despite aggressive nutritional measures. We hypothesized that growth restriction during early childhood in CF is associated with reduced adult height. We used the Cystic Fibrosis Foundation (CFF) patient registry to identify CF adults between 2011 and 2015 (ages 18–19 y, n = 3655) and had height for age (HFA) records between ages 2 and 4 y. We found that only 26% CF adults were ≥median HFA and 25% were <10th percentile. Between 2 and 4 years, those with height < 10th percentile had increased odds of being <10th percentile in adulthood compared to children ≥ 10th percentile (OR = 7.7). Of HFA measured between the 10th and 25th percentiles at ages 2–4, 58% were <25th percentile as adults. Only 13% between the 10th and 25th percentile HFA at age 2–4 years were >50th percentile as adults. Maximum height between ages 2 and 4 highly correlated with adult height. These results demonstrate that low early childhood CF height correlates with height in adulthood. Since linear growth correlates with lung growth, identifying both risk factors and interventions for growth failure (nutritional support, confounders of clinical care, and potential endocrine involvement) could lead to improved overall health.

An Approach to the Evaluation and Management of the Obese Child with Early Puberty

With the decline in age at onset of puberty and increasing prevalence of childhood obesity, early breast development in young, obese girls has become a more frequent occurrence. Here, we examine available literature to answer a series of questions regarding how obesity impacts the evaluation and management of precocious puberty. We focus on girls as the literature is more robust, but include boys where literature permits.Suggestions include: (1) Age cut-offs for evaluation of precocious puberty should not differ substantially from those used for non-obese children. Obese girls with confirmed thelarche should be evaluated for gonadotropin-dependent, central precocious puberty (CPP) to determine if further investigation or treatment is warranted. (2) Basal luteinizing hormone (LH) levels remain a recommended first-line test. However, if stimulation testing is utilized, there is a theoretical possibility that the lower peak LH responses seen in obesity could lead to a false negative result. (3) Advanced bone age (BA) is common among obese girls even without early puberty; hence its diagnostic utility is limited. (4) Obesity does not eliminate the need for MRI in girls with true CPP. Age and clinical features should determine who warrants neuroimaging. (5) BA can be used to predict adult height in obese girls with CPP to inform counselling around treatment. (6) Use of gonadotropin-releasing hormone analogues (GnRHa) leads to increased adult height in obese girls. (7) Obesity should not limit GnRHa use as these agents do not worsen weight status in obese girls with CPP.