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Aim: To test whether an audit and feedback-based intervention improved HbA1c 12 months after transfer to type 1 diabetes adult care., Methods: Multi-centre, quasi-experimental pre-post study of an AF-based intervention targeting paediatric diabetes teams, which encouraged the implementation of an evidence-informed structured transition process at five paediatric diabetes centres in Ontario, Canada. Participants entered the study at their final paediatric visit. A parallel control cohort was ascertained using population-based administrative datasets. The primary outcome was HbA1c 12 months after transfer. The main exposure was the study period: pre-implementation (June 2018-May 2019); early-implementation (June 2019-September 2020); and late-implementation (October 2020-September 2021). Multivariable linear regression models were fit separately in each cohort., Results: There were 449 and 2844 individuals in the intervention and control cohorts, respectively. Twelve months after transfer, participants in the late-implementation intervention cohort had an HbA1c that was, on average, 0.41% lower than participants in the pre-implementation period (p = 0.016). Among the control cohort, there was no significant difference in the HbA1c 12 months after transfer between study periods., Conclusions: We found an effect of the intervention on glycaemic management one year following transfer to adult care. Future work will focus on refining and testing the effectiveness of the intervention in an expanded number of study sites and in collaboration with adult diabetes care providers., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: The hypothalamus plays a central role in regulating puberty. However, our knowledge of the postnatal gene regulatory networks that control the pubertal transition in males and females is incomplete. Here, we investigate the age-, sex- and cell-type-specific gene regulation in the hypothalamus across the pubertal transition., Methods: We used RNA-seq to profile hypothalamic gene expression in male and female mice at five time points spanning the onset of puberty (postnatal days (PD) 12, 22, 27, 32, and 37). By combining this data with hypothalamic single nuclei RNA-seq data from pre- and postpubertal mice, we assigned gene expression changes to their most likely cell types of origin. In our colony, pubertal onset occurs earlier in male mice, allowing us to focus on genes whose expression is dynamic across ages and offset between sexes, and to explore the bases of sex effects., Results: Our age-by-sex pattern of expression enriched for biological pathways involved hormone production, neuronal activation, and glial maturation. Additionally, we inferred a robust expansion of oligodendrocytes precursor cells into mature oligodendrocytes spanning the prepubertal (PD12) to peri-pubertal (PD27) timepoints. Using spatial transcriptomic data from postpubertal mice, we observed the lateral hypothalamic area and zona incerta were the most oligodendrocyte-rich regions and that these cells expressed genes known to be involved in pubertal regulation., Conclusion: Together, by incorporating multiple biological timepoints and using sex as a variable, we identified gene and cell-type changes that may participate in orchestrating the pubertal transition and provided a resource for future studies of postnatal hypothalamic gene regulation., (© 2024. The Author(s).)

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four-core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune-modified Ccl2 -knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2 -knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT-induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children., Methods: Data from 291 children (Autism N = 104, ADHD N = 104, Autism + ADHD N = 17, neurotypical N = 66) aged 4-12 years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates., Results: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth., Conclusions: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations., (© 2024 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Gender dysphoria (GD) and obesity share commonalities, including associations with mental health comorbidities, disordered eating, body dissatisfaction and may intensify with physical and developmental changes during adolescence. While associations of obesity and gender diversity have been identified, rates of gender diversity among adolescents with obesity remain unclear. The aim was to examine gender diversity among adolescents with obesity in a weight management programme. A single-centre cross-sectional questionnaire study was conducted. Eligible adolescents received the Gender Identity/GD Questionnaire for Adolescents and Adults (GIDYQ-AA), a validated instrument measuring gender diversity and GD. Gender identities, sexual orientations, questionnaire scores, and frequency of GD (GIDYQ-AA score <3) were determined. The relationship of GIDYQ-AA scores and BMI Z-score (BMIz) was assessed. Of 72 consenting youth, 29 assigned females (AF) and 17 assigned males (AM) completed GIDYQ-AA and demographic questions. Seventeen (59%) AF reported non-heterosexual orientations, and 6 (21%) reported non-cisgender identities. One (6%) AM reported non-cisgender identity. Two (4%) AF individuals had GD based on GIDYQ-AA scores. GIDYQ-AA scores did not correlate with BMIz. In conclusion, adolescents with obesity, particularly AF with non-heterosexual orientation, reported high rates of non-cisgender identity and GD. Routine screening for gender-related concerns in weight management settings may be warranted., (© 2024 The Authors. Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Purpose: Transgender and gender diverse (TGD) youth in North American clinical reports are predominantly White with relatively high socioeconomic status suggesting that access to gender-affirming care is inequitable. This study examined whether socioeconomic and social determinant of health discrepancies exist between a clinical population of TGD youth and surrounding communities. Methods: Patient postal codes were used to link the Ontario Marginalization Index (ON-MARG) to a clinic-based TGD youth cohort ( n = 298). Using ON-MARG, each patient was assigned a quintile score from 1 (least marginalized) to 5 (most marginalized) on four marginalization measures. Mean quintile scores were compared to background populations. Census-based Toronto neighborhood-level data on ethnic diversity and educational status were also examined. Neighborhoods were categorized as highly represented, less represented, or unrepresented based on representation in the clinic cohort. One-way analysis of covariance was used to determine associations between neighborhood-level variables and the degree of neighborhood representation. Results: ON-MARG data demonstrated that clinic patients hailed from areas with more individuals having paid employment. Patients from Toronto and surrounding areas came, in general, from communities with fewer recent immigrants and visible minorities. Highly represented Toronto neighborhoods had smaller proportions of visible minorities and immigrants compared with less and unrepresented neighborhoods. Educational status, represented by adults with bachelor's degrees, was lower among unrepresented neighborhoods. Conclusion : TGD youth seen in clinic, particularly those from Toronto, are disproportionally White and socioeconomically advantaged. Further research is needed to better understand the underrepresentation of racialized and low-socioeconomic status youth and to inform strategies to improve access to care.

Context: Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found., Objective: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH., Design: Case-control study., Participants: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies., Main Outcome Measures: Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM)., Results: The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86)., Conclusions: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women., Objectives: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood., Population: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits., Preliminary Results: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO)., Conclusions: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development., (© 2023 His Majesty the King in Right of Canada and The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Health.)

Background: The pituitary gland regulates essential physiological processes such as growth, pubertal onset, stress response, metabolism, reproduction, and lactation. While sex biases in these functions and hormone production have been described, the underlying identity, temporal deployment, and cell-type specificity of sex-biased pituitary gene regulatory networks are not fully understood., Methods: To capture sex differences in pituitary gene regulation dynamics during postnatal development, we performed 3' untranslated region sequencing and small RNA sequencing to ascertain gene and microRNA expression, respectively, across five postnatal ages (postnatal days 12, 22, 27, 32, 37) that span the pubertal transition in female and male C57BL/6J mouse pituitaries (n = 5-6 biological replicates for each sex at each age)., Results: We observed over 900 instances of sex-biased gene expression and 17 sex-biased microRNAs, with the majority of sex differences occurring with puberty. Using miRNA-gene target interaction databases, we identified 18 sex-biased genes that were putative targets of 5 sex-biased microRNAs. In addition, by combining our bulk RNA-seq with publicly available male and female mouse pituitary single-nuclei RNA-seq data, we obtained evidence that cell-type proportion sex differences exist prior to puberty and persist post-puberty for three major hormone-producing cell types: somatotropes, lactotropes, and gonadotropes. Finally, we identified sex-biased genes in these three pituitary cell types after accounting for cell-type proportion differences between sexes., Conclusion: Our study reveals the identity and postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary. This work also highlights the importance of considering sex biases in cell-type composition when understanding sex differences in the processes regulated by the pituitary gland., (© 2022. The Author(s).)

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging, we studied the neuroanatomical differences among 11 distinct genetically modified mouse lines (n = 371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using Bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures-such as the corpus callosum, midbrain, and thalamus-were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks., (© 2022. The Author(s).)

Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With the declining 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 cutoffs for evaluation of precocious puberty should not differ substantially from those used for nonobese 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 magnetic resonance imaging 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 counseling 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: To promote resource stewardship in thyroid hormone testing at a pediatric tertiary care hospital., Study Design: Quality improvement approaches generated 3 change ideas that were implemented simultaneously in the hospital electronic medical record: (1) a reflex free thyroxine (fT4), whereby fT4 is automatically reported if the thyroid-stimulating hormone is outside the normal range; (2) a forced-function for thyroid hormone ordering, whereby a provider must select an appropriate indication for ordering fT4 or triiodothyronine (T3); and (3) a clinical decision support message displayed at the time of ordering thyroid function tests. Laboratory data were audited to determine the mean number of fT4 and T3 tests performed per week as well as indications for testing., Results: The mean number of fT4 and T3 tests processed per week decreased from 154 ± 21 and 11 ± 7, respectively, in the preintervention period, to 107 ± 12 (30% reduction) and 4 ± 3 (66% reduction) postintervention. These reductions were sustained for the full 20-week assessment period. Process and balancing measures revealed no unintended adverse consequences. Approximate cost savings were $43 000 per year., Conclusions: We describe the successful implementation of electronic medical record-based interventions (reflex fT4, forced-function selection of indication, decision support text) leading to sustained improvements in healthcare use, with significant associated cost-savings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Hypoglycemia is the most common acute complication of type 1 diabetes (T1D), and the potential short- and long-term sequelae can cause children and parents to develop significant fear of hypoglycemia (FOH). FOH and associated anxiety can be disruptive to activities of daily living and lead to reduced quality of life. We sought to determine the extent of FOH among parents of children with T1D within our clinic and to identify factors associated with greater FOH., Methods: Two hundred sixty-four parents of youth (2 to 18 years of age; mean ± standard deviation, 12.4±3.5 years) with T1D completed a survey that included demographic and disease-specific questions, the Spielberger State-Trait Anxiety Inventory and the Hypoglycemia Fear Survey---Parent version (HFS-P)., Results: Of the 264 participants, 207 completed the full HFS-P, with a mean score of 67±19 (range, 31 to 119). The most frequent worries related to the child being hypoglycemic while alone or asleep. Higher HFS-P scores were also associated with more frequent and severe hypoglycemic episodes, higher state-trait anxiety scores, use of a continuous glucose monitor and more frequent blood glucose checks. Higher HFS-P scores were also associated with worse parental sleep quality and less parental engagement with treatment plans., Conclusions: Parents of children with T1D experience FOH, especially during times of high vulnerability. Moreover, FOH could potentially impact clinical care (with parents being reluctant to administer suggested insulin doses) and quality of life (due to parental/child sleep disruption). Further studies are needed to develop and evaluate interventions aimed at reducing FOH in parents of youth with T1D., (Copyright © 2020 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: Gender-incongruent youth may present to gender-affirming medical care (GAMC) later in adolescence and puberty when hormone blockers provide less benefit. Factors influencing age of presentation to GAMC have not been described., Methods: A sequential mixed methods study. Participants were categorized on the basis of age at presentation to GAMC. Youth presenting at ≥15 years comprised the older-presenting youth, whereas those presenting at <15 years comprised the younger-presenting youth. Caregivers were categorized on the basis of the youth's age of presentation. Twenty-four individuals were interviewed, 6 youth and 6 caregivers from each age category. Thematic analysis identified themes related to timing of presentation to GAMC. Themes differentially endorsed between older and younger youth or between caregivers of older and younger youth were used to design a questionnaire distributed to 193 youths and 187 caregivers. Responses were compared between age groups for youths and caregivers., Results: Five themes differed between age groups: validity of gender identity, gender journey barriers, influential networks, perceptions of medical therapy, and health care system interactions. Questionnaires were completed by 121 youths and 121 caregivers. Compared with younger-presenting youth, older-presenting youth recognized gender incongruence at older ages, were less likely to have caregivers who helped them access care or LGBTQ+ (lesbian, gay, bisexual, transgender, queer) family members, more often endorsed familial religious affiliations, and experienced greater youth-caregiver disagreement around importance of GAMC., Conclusions: Family environment appears to be a key determinant of when youth present to GAMC. Whether this association occurs through affecting transgender identity formation and recognition requires further study., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Maternal environmental exposures, such as high-fat diets, diabetes and obesity, can induce long-term effects in offspring. These effects include increased risk of neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), depression and anxiety. The mechanisms underlying these late-life neurologic effects are unknown. In this article, we measured changes in the offspring brain and determined which brain regions are sensitive to maternal metabolic milieu and therefore may mediate NDD risk. We showed that mice exposed to a maternal high-fat diet display extensive brain changes in adulthood despite being switched to a low-fat diet at weaning. Brain regions impacted by early-life diet include the extended amygdalar system, which plays an important role in reward-seeking behaviour. Genes preferentially expressed in these regions have functions related to feeding behaviour, while also being implicated in human NDDs, such as autism. Our data demonstrated that exposure to maternal high-fat diet in early-life leads to brain alterations that persist into adulthood, even after dietary modifications.

Background: Carbohydrate counting is an important component of diabetes management, but it is challenging, often performed inaccurately, and can be a barrier to optimal diabetes management. iSpy is a novel mobile app that leverages machine learning to allow food identification through images and that was designed to assist youth with type 1 diabetes in counting carbohydrates., Objective: Our objective was to test the app's usability and potential impact on carbohydrate counting accuracy., Methods: Iterative usability testing (3 cycles) was conducted involving a total of 16 individuals aged 8.5-17.0 years with type 1 diabetes. Participants were provided a mobile device and asked to complete tasks using iSpy app features while thinking aloud. Errors were noted, acceptability was assessed, and refinement and retesting were performed across cycles. Subsequently, iSpy was evaluated in a pilot randomized controlled trial with 22 iSpy users and 22 usual care controls aged 10-17 years. Primary outcome was change in carbohydrate counting ability over 3 months. Secondary outcomes included levels of engagement and acceptability. Change in HbA 1c level was also assessed., Results: Use of iSpy was associated with improved carbohydrate counting accuracy (total grams per meal, P=.008), reduced frequency of individual counting errors greater than 10 g (P=.047), and lower HbA 1c levels (P=.03). Qualitative interviews and acceptability scale scores were positive. No major technical challenges were identified. Moreover, 43% (9/21) of iSpy participants were still engaged, with usage at least once every 2 weeks, at the end of the study., Conclusions: Our results provide evidence of efficacy and high acceptability of a novel carbohydrate counting app, supporting the advancement of digital health apps for diabetes care among youth with type 1 diabetes. Further testing is needed, but iSpy may be a useful adjunct to traditional diabetes management., Trial Registration: ClinicalTrials.gov NCT04354142; https://clinicaltrials.gov/ct2/show/NCT04354142., (©Jeffrey E Alfonsi, Elizabeth E Y Choi, Taha Arshad, Stacie-Ann S Sammott, Vanita Pais, Cynthia Nguyen, Bryan R Maguire, Jennifer N Stinson, Mark R Palmert. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 28.10.2020.)

Background: Gender-incongruent (GI) youth have high rates of mental health problems. Although gender-affirming medical care (GAMC) provides psychological benefit, some GI youth present to care at older ages. Whether a relationship exists between age of presentation to GAMC and mental health difficulties warrants study., Methods: A cross-sectional chart review of patients presenting to GAMC. Subjects were classified a priori as younger presenting youth (YPY) (<15 years of age at presentation) or older presenting youth (OPY) (≥15 years of age). Self-reported rates of mental health problems and medication use were compared between groups. Binary logistic regression analysis was used to identify determinants of mental health problems. Covariates included pubertal stage at presentation, social transition status, and assigned sex., Results: Of 300 youth, there were 116 YPY and 184 OPY. After presentation, more OPY than YPY reported a diagnosis of depression (46% vs 30%), had self-harmed (40% vs 28%), had considered suicide (52% vs 40%), had attempted suicide (17% vs 9%), and required psychoactive medications (36% vs 23%), with all P < .05. After controlling for covariates, late puberty (Tanner stage 4 or 5) was associated with depressive disorders (odds ratio 5.49; 95% confidence interval [CI]: 1.14-26.32) and anxiety disorders (odds ratio 4.18 [95% CI: 1.22-14.49]), whereas older age remained associated only with psychoactive medication use (odd ratio 1.31 [95% CI: 1.05-1.63])., Conclusions: Late pubertal stage and older age are associated with worse mental health among GI youth presenting to GAMC, suggesting that this group may be particularly vulnerable and in need of appropriate care., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated that they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Context: Clinicians, researchers, and global health advocates often include pubertal development in outcomes. However, assessments of pubertal stage can be challenging because of the sensitive nature and feasibility of clinical examinations, especially in larger settings., Objective: To determine the accuracy of self-assessed Tanner staging when compared with physically assessed Tanner stages by a clinician., Data Sources: MEDLINE, PubMed, Embase, Web of Science, Scopus, the Cochrane Library, CINAHL., Study Selection: Studies were included if they reported 5 × 5 tables of self-assessment compared to clinician-assessment for the 5-stage Tanner scale., Data Extraction: We extracted data to generate complete 5 × 5 tables for each study, including any subgroup eligible for the analysis, such as overweight/obese youth., Data Synthesis: After screening, 22 studies representing 21,801 participants met our inclusion criteria for the meta-analysis. Overall agreement was moderate or substantial between the 2 assessments, with breast stage 1, female pubic hair 1, male pubic hair 1, and male pubic hair 5 having the highest agreement. When stages were collapsed into pre- (Tanner stage 1), in (stages 2,3), and completing (stages 4,5) puberty, levels of agreement improved, especially for pre- and completing pubertal development. Most included studies comprised Caucasian youth. More studies are needed which include a broader range of geographic and socioeconomic settings, as well as a greater diversity of racial/ethnic groups., Conclusions: Self-assessment of puberty is most accurate when identifying Tanner stage 1, Tanner stage 5 and when development is categorized into prepuberty, in, and completing puberty phases. Use of self-assessment data should be structured accordingly., Protocol Registration: PROSPERO # CRD42018100205., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Screening for and diagnosing non classic congenital adrenal hyperplasia (NCCAH) uses serum 17-hydroxyprogesterone (17OHP) thresholds established from immunoassay data; however, a new liquid-chromatography tandem mass spectrometry (LC-MS/MS) method results in lower 17OHP values. The evolution of immunoassays is also challenging our diagnostic cut-off for glucocorticoid insufficiency and few data re-evaluate the utility of testing for glucocorticoid insufficiency in NCCAH., Objective: (1) Evaluate the 17OHP threshold that predicts NCCAH in children using LC-MS/MS, and (2) determine the prevalence of glucocorticoid insufficiency in NCCAH., Methods: A retrospective chart review of pediatric patients who underwent ACTH stimulation tests with cortisol and 17OHP measurements from 2011 to 2018 for assessment of NCCAH. Other adrenal pathologies were excluded. A cortisol < 415 nmol/L defined glucocorticoid insufficiency. Published correlation data determined a 17OHP of 3.3 nmol/L by LC-MS/MS was equivalent to 6 nmol/L by immunoassay. Data analysis was by measures of diagnostic accuracy., Results: Of 188 patients included, 23 (12%) had NCCAH (21/23 had genetic confirmation); the remaining 2 had peak 17OHP >  30 nmol/L. Baseline 17OHP ≥  6 nmol/L most accurately screened for NCCAH-sensitivity and specificity 96%. Almost all genetically confirmed NCCAH (20/21) had peak 17OHP > 30 nmol/L; all subjects with other diagnoses peaked < 30 nmol/L. Glucocorticoid insufficiency was present in 55% with NCCAH., Conclusions: Despite the increased specificity of LC-MS/MS, a baseline 17OHP ≥  6 nmol/L most accurately screened for NCCAH; this supports current practice guidelines. This threshold identified all with glucocorticoid insufficiency, notably prevalent in our cohort and for whom glucocorticoid stress dosing should be considered., (© Endocrine Society 2019.)

Background: When young adults transfer from pediatric to adult diabetes care they are at risk for deterioration of glycemic control, putting them at an increased risk of developing both acute and chronic complications. Despite increased awareness of these risks, there are gaps in care delivery during this vulnerable time and variability in the implementation of recommended transition practice. Audit and feedback (AF) interventions have a positive but variable effect on implementation of best practices. An expert group identified specific suggestions for optimizing the effectiveness of AF interventions. We aim to test an AF-based intervention incorporating these specific suggestions to improve transition practices and glycemic control in the first year after transfer from pediatric to adult diabetes care., Methods: This is a pragmatic quasi-experimental study; a series of three cohort studies (pre-implementation, early-implementation, and post-implementation) to compare the baseline adjusted hemoglobin A1c (HbA1c) in the 12 months after the final pediatric visit in five pediatric diabetes centres within the Ontario Pediatric Diabetes Network in Ontario, Canada. The intervention includes three components: 1) centre-level feedback reports compiling data from chart abstraction, linked provincial administrative datasets, and patient-reported experience measures; 2) webinars for facilitated conversations/coaching about the feedback; and 3) online repository of curated transition resources for providers. The primary outcome will be analyzed using a multivariable linear regression model. We will conduct a qualitative process evaluation to understand intervention fidelity and to provide insight into the mechanisms of action of our results., Discussion: There is a need to develop an innovative system-level approach to improve outcomes and the quality of care for young adults with type 1 diabetes during the vulnerable time when they transfer to adult care. Our research team, a collaboration of health services, implementation science, and quality improvement researchers, are designing, implementing, and evaluating an AF-based intervention using recommendations about how to optimize effectiveness. This knowledge will be generalizable to other care networks that aim to deliver uniformly high-quality care in diverse care settings., Trial Registration: ClinicalTrials.gov NCT03781973. Registered 13 December 2018. Date of enrolment of the first participant to the trial: June 1, 2019.

IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc. (ACP), and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes . The following article describes an initiative to improve retinopathy screening rates at the pediatric diabetes clinic of a large academic teaching hospital in Canada.

The hypothalamic-pituitary-gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic-pituitary-gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development.

Context: In children with isolated growth hormone (GH) deficiency (GHD), routine biochemical screening for multiple pituitary hormone deficiencies (MPHD) and adverse effects related to growth hormone (GH) treatment are frequently performed. More evidence is needed to support this practice., Objectives: To evaluate the rate of development of MPHD among children initially diagnosed with isolated GHD and to assess the utility of screening tests to identify complications of GH therapy., Design: Retrospective analysis of subjects treated with GH since 2005. For the first objective, only subjects diagnosed with GHD were included. Subjects were excluded if GHD was associated with an acquired disorder or condition known to be associated with pituitary abnormalities. For the second objective, other GH-treated diagnoses were included., Patients: A total of 328 subjects (171 with GHD, 154 with idiopathic short stature, and three with SHOX deficiency)., Results: In subjects with isolated GHD, MPHD was diagnosed in seven (4.2%) after a mean of 35.4 months (range, 9.4 to 68.0). Sex, age at diagnosis, duration of GH, and peak stimulated GH levels were not associated with developing MPHD. Among subjects with an MRI abnormality, 13.9% developed MPHD (OR, 6.3; 95% CI, 1.2 to 33.7). In the entire cohort, three subjects (0.9%) developed dysglycemia, and no subject had persistently abnormal liver or renal function tests., Conclusions: There is a limited role for routine biochemical screening for MPHD in children with idiopathic isolated GHD or for adverse effects in otherwise healthy children. Routine biochemical screening for MPHD should be limited to those with an abnormal MRI.

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI's ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post-pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Competing Interests: All authors have read and understood the BMJ policy on declaration of interests and have nothing to declare.

Objective: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes., Research Design and Methods: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring., Results: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac., Conclusions: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/aims: To examine characteristics, including mental health comorbidities, among adolescents presenting to a transgender clinic and to compare these data to previous reports., Methods: Retrospective chart review among youth seen at The Hospital for Sick Children between January 2014 and June 2016. Demographic data, clinical characteristics, and mental health comorbidities were assessed. Baseline and repeat blood work were also examined., Results: Charts from 203 adolescents aged 12-18 years were reviewed (156 assigned female at birth [AFAB] (77%) aged 16.3 ± 1.63 years, 47 assigned male at birth [AMAB] aged 16.1 ± 1.70 years). There was no statistically significant difference between gender groups except for Tanner stage (AFAB, mean 4.42 ± 0.8 and AMAB, mean 4.03 ± 1.1, p = 0.040). Individuals from racial/ethnic minority populations were under-represented compared to the background population. Self-report and baseline psychological questionnaires showed high levels of gender dysphoria, mood disorders, and suicidal ideation, with higher levels of anxiety detected on questionnaires among AFAB (p = 0.03). Laboratory abnormalities identified on baseline and repeat testing were minor; on cross-sex hormones, hemoglobin levels increased slightly in AFAB (p = 0.002, highest = 166 g/L) and decreased among AMAB (p = 0.02, lowest = 132 g/L)., Conclusion: Our study supports an evolving demographic trend with more AFAB than AMAB youth now presenting to gender clinics. The data also corroborate studies indicating that extensive laboratory testing may not be a necessary part of caring for these youths. Why more AFAB are now presenting to clinic and racial/ethnic minorities are underrepresented is not clear, but these trends have important implications for clinical care and warrant further study., (© 2018 S. Karger AG, Basel.)

Objectives: Clinical practice guidelines (CPG) provide evidence-based recommendations for patient care but may not be optimally applied in clinical settings. As a pilot study, we evaluated the impact of a computerized, point-of-care decision support system (CDSS) on guideline knowledge and adherence in our diabetes clinic., Methods: iSCREEN, a CDSS, integrated with a province-wide electronic health record, was designed based on the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Evaluation data were gathered by retrospective chart review and clinician questionnaire prior to and after implementation of iSCREEN. Records of patients with type 1 diabetes, 14 to 18 years of age, were assessed for appropriate screening for complications and comorbidities., Results: To assess guideline adherence, 50 charts were reviewed at 2 time periods (25 before and 25 after launch of iSCREEN). Results revealed improved frequency of appropriate screening for diabetic nephropathy (p=0.03) and retinopathy (p=0.04), accompanied by a decrease in under- and overscreening for these outcomes. To assess guideline knowledge, 58 surveys were collected (31 prior to and 27 after the launch of iSCREEN) from care providers in the field of pediatric diabetes. There was a trend toward improved guideline knowledge in all team members (p=0.06)., Conclusions: Implementation of a de novo CDSS was associated with improved rates of appropriate screening for diabetes-related complications. A trend toward improvement in health professionals' knowledge of the guidelines was also observed. Evaluation of this point-of-care computerized decision support tool suggests that it may facilitate diabetes care by optimizing complication screening and CPG knowledge, with the potential for broader implementation., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri-puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: While optimal blood glucose control is known to reduce the long-term complications associated with type 1 diabetes mellitus, adolescents often struggle to achieve their blood glucose targets. However, their strong propensity toward technology presents a unique opportunity for the delivery of novel self-management interventions. To support type 1 diabetes self-management in this population, we developed the diabetes self-management app bant, which included wireless blood glucose reading transfer, out-of-range blood glucose trend alerts, coaching around out-of-range trend causes and fixes, and a point-based incentive system., Objective: The primary objective was to evaluate bant 's effect on hemoglobin A 1c (HbA 1c ) through a randomized controlled trial (RCT). Secondary measures (eg, self-monitoring of blood glucose [SMBG]) were also collected to assess bant 's impact on the self-management behaviors of adolescents with type 1 diabetes., Methods: We enrolled 92 adolescents into a 12-month RCT, with 46 receiving usual care and 46 receiving usual care plus bant. Clinical outcome data were collected at quarterly research visits via validated tools, electronic chart review, glucometer downloads, and semistructured interviews. App satisfaction was assessed at 6 and 12 months, and at trial end, users ranked bant components based on perceived usefulness. Mobile analytics captured frequency of blood glucose uploads, which were used to categorize participants into high, moderate, low, or very low engagement levels., Results: Linear mixed models showed no changes in primary and secondary clinical outcomes. However, exploratory regression analysis demonstrated a statistically significant association between increased SMBG and improved HbA 1c in the intervention group. For a subgroup of bant users taking SMBG ≥5 daily, there was a significant improvement in HbA 1c of 0.58% (P=.02), while the parallel subgroup in the control arm experienced no significant change in HbA 1c (decrease of 0.06%, P=.84). Although app usage did diminish over the trial, on average, 35% (16/46 participants) were classified as moderately or highly engaged (uploaded SMBG ≥3 days a week) over the 12 months., Conclusion: Although primary analysis of clinical outcomes did not demonstrate differences between the bant and control groups, exploratory analysis suggested that bant may positively impact the use of SMBG data and glycemic control among youth. The next generation of bant will aim to remove barriers to use, such as deploying the app directly to personal devices instead of secondary research phones, and to explore the utility of integrating bant into routine clinical care to facilitate more frequent feedback. Future evaluations of mHealth apps should consider more robust research tools (eg, ResearchKit) and alternative RCT study designs to enable more rapid and iterative evaluations, better suited to the nature of rapidly evolving consumer technology., Trial Registration: ClinicalTrials.gov NCT01899274; https://clinicaltrials.gov/ct2/show/NCT01899274 (Archived by WebCite at http://www.webcitation.org/6qWrqF1yw)., (©Shivani Goyal, Caitlin A Nunn, Michael Rotondi, Amy B Couperthwaite, Sally Reiser, Angelo Simone, Debra K Katzman, Joseph A Cafazzo, Mark R Palmert. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 19.06.2017.)

Purpose: Pediatric residents must know how to perform pubertal examinations. The initial objective of this study was to evaluate pediatric resident knowledge and comfort related to the pubertal examination and to determine whether and why these examinations are avoided. The subsequent objective was to develop and assess a learning module (LM) addressing identified education gaps., Methods: A learning needs assessment (LNA) was administered to residents in four Canadian pediatric training programs. Identified themes and knowledge gaps were used to develop an online, case-based LM. A randomized assessment of the LM was conducted among residents from nine training programs across Canada., Results: Sixty-four residents completed the LNA. About 52% reported discomfort introducing the pubertal examination, 50% reported a lack of confidence related to the examination, and 56% reported having avoided a warranted examination. Ninety-seven residents participated in the LM assessment. The baseline results were similar to those from the LNA in terms of discomfort, lack of confidence, and avoidance related to pubertal examinations. However, the intervention group showed improvement on a knowledge assessment compared with control group (p < .001). Confidence levels also improved in the intervention group LM (p < .01). Most residents (95%) stated they found the LM to be useful., Conclusions: Residents report being uncomfortable with and avoiding the pubertal examination and have significant knowledge gaps. The online, case-based LM used in this study improved the knowledge and confidence related to this aspect of pediatric care and may be an effective adjunct to pediatric training., (Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty., (Copyright © 2016 by the American Academy of Pediatrics.)

Delayed puberty (DP) is defined as the lack of pubertal development by an age that is 2-2.5 SDs beyond the population mean. Although it generally represents a normal variant in pubertal timing, concern that DP could be the initial presentation of a serious underlying disorder has led to a diagnostic approach that is variable and may include tests that are unnecessary and costly. In this review, we examine available literature regarding the recommended diagnostic tests and aetiologies identified during the evaluation of youth with DP. We view this literature through the prism of the seemingly otherwise well adolescent. To provide further clinical context, we also evaluate the clinical and laboratory data from patients seen with DP in our centre over a 2-year period. The literature and our data reveal wide variability in the number of tests performed and raise the question of whether tests, other than gonadotropins, obtained in the absence of signs or symptoms of an underlying disorder are routinely warranted. Together this information provides a pragmatic rationale for revisiting recommendations calling for broad testing during the initial diagnostic evaluation of an otherwise healthy adolescent with DP. We highlight the need for further research comparing the utility of broader screening with a more streamlined approach, such as limiting initial testing to gonadotropins and a bone age, which, while not diagnostic, is often useful for height prediction, followed by close clinical monitoring. If future research supports a more streamlined approach to DP, then much unnecessary testing could be eliminated., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Neonates born to mothers with Graves' disease are at risk for significant morbidity and mortality and need to be appropriately identified and managed. Because no consensus guidelines regarding the treatment of these newborns exist, we sought to generate a literature-based management algorithm. The suggestions include the following: (1) Base initial risk assessment on maternal thyroid stimulating hormone (TSH) receptor antibodies. If levels are negative, no specific neonatal follow-up is necessary; if unavailable or positive, regard the newborn as "at risk" for the development of hyperthyroidism. (2) Determine levels of TSH-receptor antibodies in cord blood, or as soon as possible thereafter, so that newborns with negative antibodies can be discharged from follow-up. (3) Measurement of cord TSH and fT4 levels is not indicated. (4) Perform fT4 and TSH levels at day 3 to 5 of life, repeat at day 10 to 14 of life and follow clinically until 2 to 3 months of life. (5) Use the same testing schedule in neonates born to mothers with treated or untreated Graves' disease. (6) When warranted, use methimazole (MMI) as the treatment of choice; β-blockers can be added for sympathetic hyperactivity. In refractory cases, potassium iodide may be used in conjunction with MMI. The need for treatment of asymptomatic infants with biochemical hyperthyroidism is uncertain. (7) Assess the MMI-treated newborn on a weekly basis until stable, then every 1 to 2 weeks, with a decrease of MMI (and other medications) as tolerated. MMI treatment duration is most commonly 1 to 2 months. (8) Be cognizant that central or primary hypothyroidism can occur in these newborns., (Copyright © 2016 by the American Academy of Pediatrics.)

Growth and pubertal timing differ in boys and girls. Variants in/near LIN28B associate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response to Lin28b perturbation have been detected in mice, and overexpression of Lin28a has been shown to alter pubertal timing in female mice. To investigate further how Lin28a and Lin28b affect growth and puberty in both males and females, we evaluated Lin28b loss-of-function (LOF) mice and Lin28a gain-of-function (GOF) mice. Because both Lin28a and Lin28b can act via the conserved microRNA let-7, we also examined let-7 GOF mice. As reported previously, Lin28b LOF led to lighter body weights only in male mice while Lin28a GOF yielded heavier mice of both sexes. Let-7 GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). Male Lin28b LOF and male let-7 GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and female Lin28a GOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation by Lin28a, Lin28b, and let-7, in which Lin28b and let-7 can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans., (© 2016 Society for Endocrinology.)

Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.

Background: Mild or borderline congenital hypothyroidism [often referred to as mild neonatal hyperthyrotropinemia (MNH)] is characterized by an abnormal newborn screen (NBS), followed by mildly elevated TSH and normal FT4 on confirmatory testing. This condition is increasingly observed, but data regarding optimal management are limited., Objective: Examine the use of routine technetium thyroid scanning (TS) in the management of MNH., Methods: Retrospective study of infants with MNH between 2000 and 2011. We assessed the clinical course of infants with MNH according to TS results; as a comparator, infants with classic congenital hypothyroidism (CH) were analysed in parallel., Results: We identified 69 infants (52% boys) with MNH and 164 (34% boys) with classic CH. TS results were divided into four subgroups: no uptake in 7% of MNH vs 24% of classic CH (P < 0·01), decreased uptake/anatomical abnormalities in 39% vs 46% (p = NS), increased uptake in 35% vs 26% (p = NS) and normal uptake in 19% vs 4% (P < 0·01). In MNH, neither NBS-TSH, confirmatory TSH and FT4, mean LT-4 treatment doses and number of dose escalations, nor post-treatment FT4 and TSH differed among the four subgroups. In contrast, clinical features in infants with classic CH differed among the subgroups. Among MNH infants who reached 3 years of age, trial-off treatment was successful in 6 of 11 (55%) with no apparent difference in success rates among TS subgroups., Conclusions: The information provided by TS during evaluation of MNH does not predict clinical course; obtaining these scans in infants with MNH may not be an effective use of healthcare resources., (© 2015 John Wiley & Sons Ltd.)

Purpose of Review: This article overviews advances in the genetics of puberty based on studies in the general population, describes evidence for sex-specific genetic effects on pubertal timing, and briefly reviews possible mechanisms mediating sexually dimorphic genetic effects., Recent Findings: Pubertal timing is highly polygenic, and many loci are conserved among ethnicities. A number of identified loci underlie both pubertal timing and related traits such as height and BMI. It is increasingly apparent that understanding the factors modulating the onset of puberty is important because the timing of this developmental stage is associated with a wider range of adult health outcomes than previously appreciated. Although most of the genetic effects underlying the timing of puberty are common between boys and girls, some effects show sex-specificity and many are epigenetically modulated. Several potential mechanisms, including hormone-independent ones, may be responsible for observed sex differences., Summary: Studies of pubertal timing in the general population have provided new knowledge about the genetic architecture of this complex trait. Increasing attention paid to sex-specific effects may provide key insights into the sexual dimorphism in pubertal timing and even into the associations between puberty and adult health risks by identifying common underlying biological pathways.

Context: Delayed puberty (DP) is a common issue and, in the absence of an underlying condition, is typically self limited. Alhough DP seems to be heritable, no specific genetic cause for DP has yet been reported. In contrast, many genetic causes have been found for idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder characterized by absent or stalled pubertal development., Objective: The objective of this retrospective study, conducted at academic medical centers, was to determine whether variants in IHH genes contribute to the pathogenesis of DP., Subjects and Outcome Measures: Potentially pathogenic variants in IHH genes were identified in two cohorts: 1) DP family members of an IHH proband previously found to have a variant in an IHH gene, with unaffected family members serving as controls, and 2) DP individuals with no family history of IHH, with ethnically matched control subjects drawn from the Exome Aggregation Consortium., Results: In pedigrees with an IHH proband, the proband's variant was shared by 53% (10/19) of DP family members vs 12% (4/33) of unaffected family members (P = .003). In DP subjects with no family history of IHH, 14% (8/56) had potentially pathogenic variants in IHH genes vs 5.6% (1 907/33 855) of controls (P = .01). Potentially pathogenic variants were found in multiple DP subjects for the genes IL17RD and TAC3., Conclusions: These findings suggest that variants in IHH genes can contribute to the pathogenesis of self-limited DP. Thus, at least in some cases, self-limited DP shares an underlying pathophysiology with IHH.

Background: It has been recommended that basal luteinising hormone (LH) levels be used as the initial test to identify cases of central precocious puberty (CPP) in children. However, in clinical practice, gonadotropin-releasing hormone (GnRH) stimulation tests are frequently still used., Objective: To assess the diagnostic utility of a single LH to identify CPP in girls, as a means to safely reduce GnRH stimulation testing rates., Design: Retrospective analysis of patients referred for GnRH stimulation between August 2007 and December 2010, with prospective 12-month follow-up of GnRH stimulation testing rates post implementation of management algorithm., Patients: 57 girls (6.2 ± 2.1 years) with early signs of puberty., Main Outcome Measure: Ability of basal LH to predict clinical pubertal progression, 6 months following the GnRH stimulation test., Results: Pubertal progression occurred in 18 patients. All patients with a basal LH level ≥ 0.3 IU/L had subsequent pubertal progression, while 39 of 41 patients with a basal LH ≤ 0.2 IU/L did not progress, resulting in 100% specificity (95% CI 92% to 100%) and 90.5% sensitivity (69.6% to 98.8%). Using the locally derived algorithm, GnRH stimulation testing was redirected to patients with pubertal progression that was discordant with basal LH data. Post intervention, there was a 75% reduction in GnRH stimulation testing without comprising the rate of diagnosis of CPP., Conclusions: Our results confirm the diagnostic utility of basal LH levels in the diagnosis of CPP and demonstrate that dissemination and interpretation of local data may facilitate change in clinical practice, resulting in streamlined patient care and cost savings.

All reproductively competent adults have gone through puberty. While key genes and signaling pathways that lead to the onset of sexual maturation are known, the molecular mechanisms that determine when an individual enters puberty are only beginning to be understood. Both genetic and environmental factors determine the timing of puberty. New advances in understanding how environmentally sensitive, yet highly heritable developmental processes are regulated have come from the field of epigenetics. Of note, studies investigating the epigenetic control of the onset of puberty suggest that epigenetic repression of key inhibitory loci may play a fundamental role in the initiation of puberty. Current technologies that not only read out the DNA sequence, but also determine how the DNA is modified in response to the environment, promise new insight into how puberty is regulated, including the identification and understanding of gene regulatory networks that control the biological pathways affecting pubertal timing. Here we review the findings to date and discuss how epigenetic investigation can further our understanding of this fundamental aspect of human development., (© 2014 S. Karger AG, Basel.)

Objective: To examine a large population of infants with mild neonatal hyperthyrotrophinaemia (MNH) and determine prevalence, clinical characteristics and treatment history., Methods: Retrospective study of infants with MNH followed at The Hospital for Sick Children between 2000 and 2011. MNH was defined by an abnormal newborn screen followed by thyroid-stimulating hormone (TSH) between 5 and 30 mU/l and normal free T4 (FT4) on confirmatory tests., Results: Mild neonatal hyperthyrotrophinaemia represented 22·3% of patients (103/462; 60 boys, 43 girls) within our clinic. Incidence increased from two of 20 in 2000 to 31 of 74 cases in 2010. Seventy eight percent of patients started L-thyroxine (initial dose: 8·3 ± 2·5 mcg/kg). The treated group had higher confirmatory TSH levels (P = 0·001) and had undergone thyroid scintigraphy more often (P = 0·0001) compared with the nontreated group. Evidence of overtreatment was detected in 45% of thyroid function tests obtained during treatment. Among the treated infants who had reached 3 years of age, 45% (N = 14) underwent a trial-off medication. Compared with those not trialled-off therapy, these infants were less likely to have had dose escalations during treatment (P = 0·001). The trial-off treatment was successful in 50% of cases. In the subset of infants with confirmatory TSH >10 mU/l, trial-off therapy was successful in 40%. None of the assessed variables predicted success of trial-off therapy., Conclusions: Mild neonatal hyperthyrotrophinaemia is an increasingly common diagnosis. It is more common in males and is often transient, but predictors of success of trial-off therapy were not identified. Further studies are needed to determine optimum L-thyroxine dosing and to determine whether treatment improves neurocognitive outcomes., (© 2013 John Wiley & Sons Ltd.)

The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference--fundamental to the biological definition of sex--is inequality of X chromosome dosage. Studies of Turner Syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haploinsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used whole-brain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sex-hormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups., (Published by Elsevier Inc.)

Recent human and rodent brain imaging studies have shown that the shape of the brain can be changed by experience. These mesoscopic alterations in neuroanatomy are hypothesized to be driven by changes at the level of neuronal processes. To examine whether the shape of the brain changes rapidly, we used MRI to examine changes in the volume of the hippocampus across the 4-6 day estrous cycle in the female mouse. It is well known that changing steroid levels across the cycle influence dendritic spine maturation and alter synapse density in the hippocampus; our results show that the estrous cycle is associated with approximately 2-3% changes in hippocampal volume as seen by high-resolution ex-vivo MRI. Changes in hippocampal volume are, moreover, associated with a switch between hippocampal and striatal based navigation strategies in solving the dual choice T-maze in the same mice. A second experiment, using in-vivo MRI, suggests that these changes in hippocampal volume can occur over a 24 hour period. In summary, we show that the brain is highly plastic at a mesoscopic level of resolution detectable by MRI, that volumetric increases and decreases in hippocampal volume follow previously established patterns of changes in neuropil, and that these changes in volume predict changes in cognition., (© 2013.)