Joint models reveal genetic architecture of pubertal stage transitions and their association with BMI in admixed Chilean population.

Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractures, and psychopathologies. Thus, knowing the age at which puberty is attained is crucial as it can serve as a risk factor for future diseases. Pubertal development is divided into five stages of sexual maturation in boys and girls according to the standardized Tanner scale. We performed genome-wide association studies (GWAS) on the "Growth and Obesity Chilean Cohort Study" cohort composed of admixed children with mainly European and Native American ancestry. Using joint models that integrate time-to-event data with longitudinal trajectories of body mass index (BMI), we identified genetic variants associated with phenotypic transitions between pairs of Tanner stages. We identified $42$ novel significant associations, most of them in boys. The GWAS on Tanner $3\rightarrow 4$ transition in boys captured an association peak around the growth-related genes LARS2 and LIMD1 genes, the former of which causes ovarian dysfunction when mutated. The associated variants are expression and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier puberty onset in boys but not in girls. Finally, the joint models identified a longitudinal BMI parameter significantly associated with several Tanner stages' transitions, confirming the association of BMI with pubertal timing.

Post menarcheal growth patterns in a contemporary cohort of Latino girls.

INTRODUCTION: Menarche is the last stage of pubertal development, which coincides with the completion of longitudinal growth. As a consequence of the lack of national and up-to-date data related to post-menarcheal (PM) growth, the aim of our work was to evaluate post menarcheal growth in a group of contemporary healthy Chilean girls followed, prospectively, until 4 years post-menarche. METHODS: This study was nested within the GOCS cohort, in a prospective fashion. The girls were followed yearly after menarche for at least four years. We modeled each girl growth using a Super Imposition by Translation and Rotation (SITAR) model. RESULTS: A total of 534 girls were evaluated prospectively, 399 girls had height measured two years after menarche, 421 after three years, and 364 of 534 had height measured at four year post menarche. Expected height gained PM, in the complete study group was 6.6 ± 2.5 cm. We observed that the largest gain in height occurred after the first year PM (3.8 1.5 cm). According to the age of menarche, the group with earlier menarche (< 11 years old ) had a greater height gain in cm after four years PM ( 8.2± 3.2 cm ) and the smallest gain was among girls with menarche at an age older than 13 yr (4.4±1.6) ( p<0.001). Age at menarche was significantly associated with all post menarche growth patterns (size, timing and intensity), indicating that girls with older age at menarche grew taller, later and slower than girls with younger age at menarche. Adjusting PM growth pattern by BMI maintained all these association. Applying the SITAR model specifically , girls experiencing menarche after the age of 13 years exhibited slower growth , occurring slightly earlier and with less intensity when adjusted by BMI at menarche . CONCLUSION: In a national and updated dataset we observed that girls grew until 4 years post menarche an average of 6.6 ± 2.5 cm., with greatest gain occurring in the first year PM , (3.8 ± 1.5 cm). Age at menarche was associated with menarche growth patterns.

Association between plasma leptin/adiponectin ratio and insulin resistance indexes in prepubertal children.

Objective: To assess the association between leptin/adiponectin ratio (LAR) and insulin resistance surrogates in prepubertal children. Materials and methods: Study based on data from the Growth and Obesity Chilean Cohort Study (GOCS) involving 968 Chilean prepubertal children. Plasma insulin, leptin, and adiponectin were determined by immunoassays. Several common insulin resistance surrogates were calculated, including the homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride/HDL cholesterol index, triglyceride-glucose (TyG) index, and the TyG index corrected for body mass index (BMI; TyG-BMI) and waist circumference (WC; TyG-WC). Associations among variables were assessed using multiple linear and logistic regression analysis. Results: There was a significant direct association between plasma leptin and LAR with BMI z-score but no association between plasma adiponectin and adiposity. After adjustments for sex and age, LAR was significantly associated with all insulin resistance surrogates (which were categorized using the 75th percentile as the cutoff point), with the TyG-WC index emerging as the surrogate with the highest magnitude of association (odds ratio [OR] 2.44, 95% confidence interval [CI] 2.05-2.9). After additional adjustment for BMI z-score, only the association between LAR and TyG-WC remained significant (OR 1.64, 95% CI 1.27-2.12). Conclusion: Plasma leptin and LAR were strongly associated with several common insulin resistance surrogates in prepubertal children, most notably with the TyG-WC index. Associations between LAR and insulin resistance indexes were mainly driven by the effect of plasma leptin, which is also directly associated with increased adiposity.

Association between plasma leptin/adiponectin ratio and insulin resistance indexes in prepubertal children

ABSTRACT Objective: To assess the association between leptin/adiponectin ratio (LAR) and insulin resistance surrogates in prepubertal children. Subjects and methods: Study based on data from the Growth and Obesity Chilean Cohort Study (GOCS) involving 968 Chilean prepubertal children. Plasma insulin, leptin, and adiponectin were determined by immunoassays. Several common insulin resistance surrogates were calculated, including the homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride/HDL cholesterol index, triglyceride-glucose (TyG) index, and the TyG index corrected for body mass index (BMI; TyG-BMI) and waist circumference (WC; TyG-WC). Associations among variables were assessed using multiple linear and logistic regression analysis. Results: There was a significant direct association between plasma leptin and LAR with BMI z-score but no association between plasma adiponectin and adiposity. After adjustments for sex and age, LAR was significantly associated with all insulin resistance surrogates (which were categorized using the 75th percentile as the cutoff point), with the TyG-WC index emerging as the surrogate with the highest magnitude of association (odds ratio [OR] 2.44, 95% confidence interval [CI] 2.05-2.9). After additional adjustment for BMI z-score, only the association between LAR and TyG-WC remained significant (OR 1.64, 95% CI 1.27-2.12). Conclusion: Plasma leptin and LAR were strongly associated with several common insulin resistance surrogates in prepubertal children, most notably with the TyG-WC index. Associations between LAR and insulin resistance indexes were mainly driven by the effect of plasma leptin, which is also directly associated with increased adiposity.

Identifying patient-related predictors of permanent growth hormone deficiency.

Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

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.

Association Between Markers of Adiposity During Childhood and Puberty Onset in Latino Girls.

CONTEXT: Prepubertal adiposity is associated with earlier puberty. It is unclear when this association starts, if all adiposity markers are similarly associated, and whether all pubertal milestones are similarly affected. OBJECTIVE: To evaluate the association between different adiposity markers during childhood and the timing of different pubertal milestones in Latino girls. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal follow-up of 539 female participants of the Chilean Growth and Obesity Cohort recruited from childcare centers (mean age 3.5 years) from the southeast area of Santiago, Chile. Participants were singletons born between 2002 and 2003 within the normal birthweight range. Since 2006, a trained dietitian measured weight, height, waist circumference (WC) and skinfolds to estimate body mass index (BMI) Centers for Disease Control and Prevention percentiles, central obesity, percentage of fat mass (%FM), and fat mass index (FMI, fat mass/height2). MAIN OUTCOME: Since 2009, sexual maturation was assessed every 6 months to assess age at (1) thelarche, (2) pubarche, (3) menarche, and (4) peak height velocity (PHV). RESULTS: At thelarche, 12.5% were obese and 2% had central obesity. The median age of pubarche, menarche, and PHV were all associated with markers of adiposity at different time points during childhood whereas thelarche only with %FM and FMI. Adiposity clusters models showed that children with trajectories of high WC, %FM, and FMI during childhood were related with earlier thelarche, pubarche, menarche, and PHV but BMI trajectories only with menarche and PHV. CONCLUSIONS: Higher WC, %FM, and FMI were associated with earlier age at thelarche, pubarche, menarche, and PHV. The effect of BMI was less consistent.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.

Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 µg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 µg/dL] and High DHEAS (HD) [≥42 µg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.

The Association of Accelerated Early Growth, Timing of Puberty, and Metabolic Consequences in Children.

Accelerated early growth and early timing of puberty or pubertal variant have been noticed as risk factors for metabolic syndrome, more frequently observed in children born small for gestational age (SGA) or children with premature adrenarche (PA). Children with SGA, especially if they make an accelerated catch-up growth in early life, carry a higher risk for long-term metabolic consequences, such as type 2 diabetes, insulin resistance, and cardiovascular diseases. Furthermore, multiple studies support that these children, either born SGA or with a history of PA, may have earlier pubertal timing, which is also associated with various metabolic risks. This review aims to summarize the recent studies investigating the association between early infantile growth, the timing of puberty, and metabolic risks to expand our knowledge and gain more insight into the underlying pathophysiology.

New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry.

Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at 1.5 - 2.5 years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P = 9.8 × 10 - 9 ). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Age-AR was significantly lower (P = 0.004 ) by 1.94 years and BMI at AR was significantly higher (P = 0.04 ) by 1.2 kg/ m 2 , in Mapuche children compared with Europeans.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Higher Prepubertal IGF-1 Concentrations Associate to Earlier Pubertal Tempo in Both Sexes.

INTRODUCTION: Pubertal onset is triggered by multiple neuroendocrine interactions. The role of prepubertal IGF-1 in this process has not been explored in both sexes. Our objective was to analyze the association of prepubertal IGF-1 concentration with age at thelarche (B2) and menarche (M) in girls and age at gonadarche (G2) in boys. METHODS: This is a longitudinal study (n = 1,196 boys and girls) within the Growth and Obesity Chilean Cohort Study (GOCS). At age ≈ 6.7 years, blood sample was taken for IGF-1. Subjects were divided into 4 groups according to the onset age of the pubertal event. RESULTS: Higher prepubertal IGF-1 levels were observed at earlier ages of B2 (p = 0.003) and M onset (p = 0.041). A taller prepubertal height was observed at younger ages of B2 and M (p=<0.001 and 0.002, respectively). The hazard proportional regression models (HR) showed that with an increase of 1 SD in IGF-1, the HR of presenting B2 at younger ages was 1.25, and this association was maintained when adjusted for confounding variables. Similarly, the HR of presenting M at earlier ages was 1.21. This association was maintained only when adjusting for body mass index but not using further confounders. In boys, prepubertal IGF-1 showed a tendency to be significantly higher in children with earlier G2 and taller height (both p < 0.001). The HR of presenting G2 at younger ages was 1.22, and this association was maintained after adjusting for confounders. CONCLUSIONS: Higher IGF-1 levels in mid-childhood are associated with earlier puberty onset. The role of IGF-1 in the onset of puberty requires further investigation.

Management of Growth Disorders in Puberty: GH, GnRHa, and Aromatase Inhibitors: A Clinical Review.

Pubertal children with significant growth retardation represent a considerable therapeutic challenge. In growth hormone (GH) deficiency, and in those without identifiable pathologies (idiopathic short stature), the impact of using GH is significantly hindered by the relentless tempo of bone age acceleration caused by sex steroids, limiting time available for growth. Estrogen principally modulates epiphyseal fusion in females and males. GH production rates and growth velocity more than double during puberty, and high-dose GH use has shown dose-dependent increases in linear growth, but also can raise insulin-like growth factor I concentrations supraphysiologically, and increase treatment costs. Gonadotropin-releasing hormone analogs (GnRHas) suppress physiologic puberty, and when used in combination with GH can meaningfully increase height potential in males and females while rendering adolescents temporarily hypogonadal at a critical time in development. Aromatase inhibitors (AIs) block androgen to estrogen conversion, slowing down growth plate fusion, while allowing normal virilization in males and stimulating longitudinal bone growth via androgen receptor effects on the growth plate. Here, we review the physiology of pubertal growth, estrogen and androgen action on the epiphyses, and the therapeutic impact of GH, alone and in combination with GnRHa and with AIs. The pharmacology of potent oral AIs, and pivotal work on their efficacy and safety in children is also reviewed. Time-limited use of AIs is a viable alternative to promote growth in pubertal males, particularly combined with GH. Use of targeted growth-promoting therapies in adolescence must consider the impact of sex steroids on growth plate fusion, and treatment should be individualized.

Assessment of a consensus definition of obesity and metabolic health phenotypes in children at different pubertal stages.

Not all individuals with obesity develop metabolic complications, which has brought about the concepts of metabolically healthy and unhealthy obesity (MHO/MUO). However, inconsistent definitions of these conditions have limited their understanding. We assessed whether a recently-proposed consensus definition for MHO/MUO correlates with adiposity and reflects metabolic risk parameters during puberty. Low-middle income children from the Growth and Obesity Cohort Study (Santiago, Chile) were included (n = 949; 1692 visits at Tanner (T)2, T4 and/or one-year post menarche (1YPM)). Anthropometry, body composition and metabolic parameters were compared between MUO and MHO, and also in children without obesity. The risk for presenting MUO phenotype was significantly elevated with higher waist-height ratio (T2), zBMI (T2, T4), trunk fat, and C-reactive protein (T4). Elevated cardiometabolic indices were important predictors of the "unhealthy" phenotype allocation in children with or without obesity. Our observations suggest that the consensus definition in children at T2, T4 and 1YPM reflects metabolic risk and central obesity. Metabolic health phenotype allocation by this equation enables easy detection of risk factors that call for action to prevent long-term metabolic derangements in children with obesity and, importantly, also those without obesity.

The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.

PURPOSE: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS: A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay. RESULTS: Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities. CONCLUSION: This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

Habitual Phytoestrogen Intake Is Associated with Breast Composition in Girls at 2 Years after Menarche Onset.

BACKGROUND: High phytoestrogen intake during adolescence is associated with a reduced risk of breast cancer. Breast density (BD) is a strong predictor of breast cancer and can be considered an early marker. We aim to assess the association between the mean habitual intake of isoflavones, lignans, and total phytoestrogens intake during puberty until 2 years after menarche onset and absolute fibroglandular volume (AFGV) and percentage of fibroglandular volume (%FGV) in Hispanic girls at the end of puberty. METHODS: Longitudinal study set up in the Growth and Obesity Chilean Cohort Study (GOCS). We included 329 girls with dietary data (multiple 24-hours recalls) from puberty until 2 years after menarche onset (81% had 2-4 recalls). Two international datasets were used to estimate isoflavones, lignans, and total phytoestrogens in the diet. Breast composition was measured by dual energy X-ray absorptiometry at 2 years after menarche. Multiple linear regression models were used to assess the association between isoflavones, lignans, and total phytoestrogens intake and AFGV and %FGV. RESULTS: The average total phytoestrogen intake was 1 mg/day and %FGV was 50.7% (SD = 15.2) and AFGV 218.8 cm3 (SD = 79.3). An inverse association was found between consumption of isoflavones and AFGV, as well as, with total phytoestrogens [Q4 vs. Q1 adjusted model ß = -49.2 cm3; 95% CI (-85.5 to -13.0)]. CONCLUSIONS: Girls with a higher intake of total phytoestrogens and isoflavones during puberty until 2 years after menarche onset had significantly lower AFGV. IMPACT: Although the intake of phytoestrogens is low in Western populations, higher consumption of them during a critical period of life like puberty could be beneficial to reduce breast cancer during adulthood.

Novel OTX2 loss of function variant associated with congenital hypopituitarism without eye abnormalities.

OBJECTIVES: The normal development of the pituitary gland requires multiple induction signals and transcription factors encoded by more than 30 genes, including OTX2. OTX2 mutations have been described with eye abnormalities and variable congenital hypopituitarism, but rarely with hypopituitarism without ocular manifestations. CASE PRESENTATION: We report a girl with hypopituitarism associated with pituitary hypoplasia and pituitary stalk atrophy, without ocular manifestations. NGS revealed a novel heterozygous mutation in OTX2 c.426dupC:p.(Ser143Leufs*2). CONCLUSIONS: Mutations in the transcription factor OTX2 have been associated with ocular, craniofacial, and pituitary development anomalies. Here we describe a novel mutation in OTX2 associated with hypopituitarism without an ocular phenotype.

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps.

Objective: To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants. Design: Observational study. Methods: Probands' phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports. Results: Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): -2.8 (0.9) and -3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: -4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference -3.0 (range: -4.7 to -1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process. Conclusions: Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Genome-Wide Association Study and Polygenic Risk Scores of Serum DHEAS Levels in a Chilean Children Cohort.

CONTEXT: Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. OBJECTIVE: We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. METHODS: Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. RESULTS: We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10-8). In addition, variants suggestive of association (P < 1 × 10-5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. CONCLUSION: Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.