Neurofibromatosis type 1 (NF1) presenting with dichotomous pubertal presentation: A case series.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a mutation in the NF1 gene, which is located on chromosome 17q11.2, which encodes for a protein known as "Neurofibromin", which acts as an inhibitor of oncogene RAS. This gene mutation causes tumours to grow on nerves which results in other systemic abnormalities such as skin changes, bone and eye abnormalities, hormonal imbalances, and diversity in achievement of puberty with neurologic complications. NF1 has a wide variety of associations in context with puberty. It is important to determine the cause of precocious and delayed puberty in order to establish an early treatment plan, to lead a successful prognosis, and decrease complications. The case reports of two patients presenting with dichotomous pubertal variation in association with NF1 are presented.

Identification of Environmental Compounds That May Trigger Early Female Puberty by Activating Human GnRHR and KISS1R.

There has been an alarming trend toward earlier puberty in girls, suggesting the influence of an environmental factor(s). As the reactivation of the reproductive axis during puberty is thought to be mediated by the hypothalamic neuropeptides kisspeptin and gonadotropin-releasing hormone (GnRH), we asked whether an environmental compound might activate the kisspeptin (KISS1R) or GnRH receptor (GnRHR). We used GnRHR or KISS1R-expressing HEK293 cells to screen the Tox21 10K compound library, a compendium of pharmaceuticals and environmental compounds, for GnRHR and KISS1R activation. Agonists were identified using Ca2+ flux and phosphorylated extracellularly regulated kinase (p-ERK) detection assays. Follow-up studies included measurement of genes known to be upregulated upon receptor activation using relevant murine or human cell lines and molecular docking simulation. Musk ambrette was identified as a KISS1R agonist, and treatment with musk ambrette led to increased expression of Gnrh1 in murine and human hypothalamic cells and expansion of GnRH neuronal area in developing zebrafish larvae. Molecular docking demonstrated that musk ambrette interacts with the His309, Gln122, and Gln123 residues of the KISS1R. A group of cholinergic agonists with structures similar to methacholine was identified as GnRHR agonists. When applied to murine gonadotrope cells, these agonists upregulated Fos, Jun, and/or Egr1. Molecular docking revealed a potential interaction between GnRHR and 5 agonists, with Asn305 constituting the most conservative GnRHR binding site. In summary, using a Tox21 10K compound library screen combined with cellular, molecular, and structural biology techniques, we have identified novel environmental agents that may activate the human KISS1R or GnRHR.

Exposure to Per- and Polyfluoroalkyl Substances and Timing of Puberty in Norwegian Boys: Data from the Bergen Growth Study 2.

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants with endocrine-disruptive properties. Their impact on puberty in boys is unclear. In this cross-sectional study, we investigated the association between PFAS exposure and pubertal timing in 300 Norwegian boys (9-16 years), enrolled in the Bergen Growth Study 2 during 2016. We measured 19 PFAS in serum samples and used objective pubertal markers, including ultrasound-measured testicular volume (USTV), Tanner staging of pubic hair development, and serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone. In addition to logistic regression of single pollutants and the sum of PFAS, Bayesian and elastic net regression were used to estimate the contribution of the individual PFAS. Higher levels of the sum of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) were associated with later pubertal onset according to USTV (age-adjusted odds ratio (AOR): 2.20, 95% confidence interval (CI): 1.29, 3.93) and testosterone level (AOR: 2.35, 95% CI: 1.34, 4.36). Bayesian modeling showed that higher levels of PFNA and PFHxS were associated with later pubertal onset by USTV, while higher levels of PFNA and perfluoroundecanoic acid (PFUnDA) were associated with later pubertal onset by testosterone level. Our findings indicate that certain PFAS were associated with delay in male pubertal onset.

[Diagnosis and treatment of class â ¡ malocclusion in adolescents].

Class Ⅱ malocclusion is one of the factors inducing poor appearance and occlusal dysfunction in adolescents, which affects their physical and mental development. The success of treatment in correction class Ⅱ malocclusion in adolescents is dependent on the appropriate choice of therapy timing and methods, because of multifaceted causes. And puberty represents an essential period for development improvement. In the meantime, precise risk prevention and management are also conducive to the enhance treatment outcomes. A comprehension of the diagnosis, therapy, and risk control of adolescents class Ⅱ malocclusion will be discussed.

Use of puberty-blocking hormones for gender dysphoria in New Zealand: descriptive analysis and international comparisons.

AIM: To investigate use of puberty-blocking hormones (gonadotropin-releasing hormone analogues [GnRHa]) for gender dysphoria in New Zealand. Specifically, to describe demographic characteristics and time trends in the prevalence and incidence of prescribing, and to calculate cumulative incidence (proportion) of first prescribing of GnRHa for gender dysphoria in order to make valid international comparisons. METHOD: The national Pharmaceutical Collection was used to identify all dispensing from 2006 to 2023 to those aged <18, by sex/gender and age. Cumulative incidence of first prescriptions between ages 12 and 17 (which largely excludes prescribing for other indications) was calculated and compared with the Netherlands and England and Wales. RESULTS: In New Zealand, prescription of GnRHa for gender dysphoria started around 2011; prevalence of use increased to 2014, then more steeply to 2022, followed by a decline. Incidence data show the decline started from 2021. New Zealand, compared to the Netherlands (which started prescribing in the 1990s), had 1.7 times the cumulative incidence of first prescriptions by 2018. Compared to England and Wales up to 2020, New Zealand had 3.5-6.9 times the cumulative incidence. CONCLUSION: The high rate of prescribing for probable gender dysphoria in New Zealand, and the decline after 2021, require further investigation.

Sibling relatedness and pubertal development in girls and boys: A population-based cohort study.

PURPOSE: To investigate the association between sibling relatedness and pubertal development in girls and boys. METHODS: This cohort study consisted of 10,657 children from the Puberty Cohort, Denmark. Information on sibling relatedness was obtained by self-report. Information on pubertal markers was obtained half yearly from age 11 and throughout puberty. Mean age difference at attaining pubertal markers was estimated using interval-censored regression models according to sibling relatedness (full, half and/or step siblings; half and/or step siblings; no siblings; relative to full siblings). RESULTS: Girls with both full, half and/or step siblings (-1.2 (CI 95 %: -2.5; 0.1) months), only half- and/or stepsiblings (-2.2 (CI 95 %: -3.7; -0.7) months), and no siblings (-5.5 (CI 95 %: -8.5; -2.5) months) entered puberty earlier than girls with full siblings. Boys with full, half and/or step siblings (-1.4 (CI 95 %: -2.7; -0.1) months), only half and/or step siblings (-1.2 (CI 95 %: -3.0; 0.6) months), and no siblings (-4.5 (CI 95 %: -8.8; -0.3) months) entered puberty earlier than boys with full siblings. CONCLUSIONS: Children with sibling relatedness other than full siblings entered puberty earlier than their peers with full siblings even after adjustment for parental cohabitation status, childhood body mass index and childhood internalizing and externalizing symptoms.

Geneenvironment interaction between phthalate exposure and pubertal genetic polymorphisms on blood pressure variability in children: Exploring the moderating effects of lifestyle behaviours.

Phthalates (PAEs) are synthetic compounds extensively employed in consumer products. Blood pressure (BP) in children can vary, the degree of visit-to-visit BP variability (VVV) is at least partially independent of BP. The interactions between PAEs exposure, pubertal-related genetic susceptibility and lifestyles on childhood VVV are not investigated. This study utilized data from a cohort collected from Oct 2017-2020 in Xiamen, China. Seven urine PAE metabolites were measured. The long-term VVV was characterized employing the standard deviation (SD) and average real variability. We constructed a genetic risk score (GRS) of pubertal-related genes and healthy lifestyle scores. Exposed to high levels of mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (OR=1.43, 95 %CI=1.07, 1.92) and mono-2-ethyl-5-oxohexyl phthalate (OR=1.36, 95 % CI=1.01, 1.83) was related to increased SBP-SD, and the OR for high SBP-SD related to high GRS was 1.38 (95 % CI=1.02, 1.85). Compared to participants who had low GRS and low MEHHP exposure, participants exhibiting high GRS and MEHHP levels were more likely to experience high SBP-SD (OR=2.00, P<0.05). Individuals exhibiting low GRS, low MEHHP levels, and adhering to healthy lifestyles were associated with the least probability of experiencing high SBP-SD (OR=0.31, P<0.05). Increased PAEs exposure could elevate childhood systolic VVV, and exacerbated the adverse impact of pubertal-related genetic susceptibility on the high VVV of SBP; however, healthy lifestyles might alleviate these adverse effects. Promoting healthy lifestyles and reducing PAEs exposure for preventing elevated BP variability among children is important, especially for individuals with greater genetic susceptibility to early pubertal onset. ENVIRONMENTAL IMPLICATION: Blood pressure (BP) in children can vary, as a noninvasive, inexpensive and applicable method, the extent of visit-to-visit variability (VVV) is at least partially independent of BP. The interactions between phthalates (PAEs) exposure, variants of puberty-related genes and lifestyles on VVV are not investigated. Increased childhood systolic VVV might be associated with PAEs exposure, with the associations more pronounced combined with pubertal genetic susceptibility. Yet, healthy habits could partly eliminate such adverse effects. Our study underscores the importance of advocating for healthy lifestyles and reducing exposure to PAEs, especially among individuals with high genetic susceptibility to early puberty onset.

Coming of age in war: Early life adversity, age at menarche, and mental health.

Armed conflict and forced migration (ACFM) represent a set of extreme environments that are increasingly common for children and adolescents to experience. Adolescence may constitute a sensitive period (puberty and psychoneurological maturation) through which ACFM adversity leaves a lasting mark. Adolescence has become a focal point for analysis and intervention as it relates to the effects of early life adversity on puberty, linear growth, and mental health. Research in public health and psychological science suggests early life adversity (ELA) may accelerate puberty, heightening risks for mental health disorders. However, it is not well substantiated whether ACFM-derived adversities accelerate or delay relative pubertal timing. Secondly, ACFM provides salient context through which to probe the relationships between nutritional, psychosocial, and demographic changes and their respective impact on puberty and mental health. We conducted a narrative review which 1) examined constructions of early life adversity and their proposed influence on puberty 2) reviewed empirical findings (n = 29 studies, n = 36 samples) concerning effects of ACFM ELA on age at menarche and 3) discussed proposed relationships between early life adversity, puberty, and mental ill-health. Contrary to prior research, we found war-derived early life adversity was more consistently associated with pubertal delay than acceleration and may exert counterintuitive effects on mental health. We show that ELA cannot be operationalized in the same way across contexts and populations, especially in the presence of extreme forms of human stress and resilience. We further discuss the ethics of puberty research among conflict-affected youth.

Regional brain structural network topology mediates the associations between white matter damage and disease severity in first-episode, Treatment-naïve pubertal children with major depressive disorder.

Puberty is a vulnerable period for the onset of major depressive disorder (MDD) due to considerable neurodevelopmental changes. Prior diffusion tensor imaging (DTI) studies in depressed youth have had heterogeneous participants, making assessment of early pathology challenging due to illness chronicity and medication confounds. This study leveraged whole-brain DTI and graph theory approaches to probe white matter (WM) abnormalities and disturbances in structural network topology related to first-episode, treatment-naïve pediatric MDD. Participants included 36 first-episode, unmedicated adolescents with MDD (mean age 15.8 years) and 29 age- and sex-matched healthy controls (mean age 15.2 years). Compared to controls, the MDD group showed reduced fractional anisotropy in the internal and external capsules, unveiling novel regions of WM disruption in early-onset depression. The right thalamus and superior temporal gyrus were identified as network hubs where betweenness centrality changes mediated links between WM anomalies and depression severity. A diagnostic model incorporating demographics, DTI, and network metrics achieved an AUROC of 0.88 and a F1 score of 0.80 using a neural network algorithm. By examining first-episode, treatment-naïve patients, this work identified novel WM abnormalities and a potential causal pathway linking WM damage to symptom severity via regional structural network alterations in brain hubs.

Do body esteem and quality of life scores change with puberty signs or precocious puberty treatment?

OBJECTIVES: Body esteem (BE) and quality of life (QOL) of girls aged 9-11 years may change depending on their puberty. We aimed to examine The Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) and the Body Esteem for Adolescents and Adults Scale (BESAA) for children. METHODS: The groups were determined as those whose puberty signs had not yet started (Group 1), those having with breast development stage 3 and/or larger (Group 2), and those who had received gonadotropin-releasing hormone agonist (GnRHa) treatment for at least 6 months (Group 3). RESULTS: A total of 145 girls (Group 1: 41, Group 2: 56, Group 3: 48), were included. The PedsQL scores of the Group 1 was higher than Group 2 (78.5 ± 10.3 vs. 70.1 ± 14.2; p=0.008). The PedsQL scores of the Group 1 was higher but not statistically different from Group 3 (78.5 ± 10.3 vs. 74.2 ± 14.3; p=0.401). The PedsQL scores of Group 2 was not statistically different from Group 3 (p=0.354). There was no statistical difference in BESAA scores between groups (p=0.291). Group 1's PedsQL Health and Activity subscale score was higher than Group 2 (p=0.002). CONCLUSION: The QOL of the girls with PP was found to be lower than their healthy peers. Health and Activity-related QOL scores were found to be lower in the untreated group, indicating that girls with PP were probably significantly disturbed by their puberty-related physical development at the onset of the disease.

Minipuberty in Daughters of Women with Hypothyroidism during Pregnancy.

Minipuberty is a term describing transient postnatal activation of the hypothalamic-pituitary-gonadal axis, likely playing an important role in the postnatal growth of female genital organs and breasts. Unlike infant boys, there are no data concerning the impact of gestational hypothyroidism on the course of minipuberty in infant girls. Therefore, the aim of the current study was to investigate the reproductive axis and genital organs in daughters of women with thyroid hypofunction during pregnancy. The study population included three matched groups of infant girls: offspring of women with thyroid hypofunction non-substituted or inadequately treated during gestation (group 1), descendants of women adequately substituted throughout pregnancy (group 2), and daughters of healthy women (group 3). Salivary concentrations of estradiol, progesterone, 17-hydroxyprogesterone, and androgens (testosterone, androstenedione, and dehydroepiandrosterone sulfate) and urine levels of gonadotropins were measured monthly from month 1 to month 6, once every two months between postnatal months 6 and 12, and once every three months between postnatal months 12 and 18. During each visit, we also determined ovarian volume, uterine length, and breast diameter. Concentrations of FSH, LH, and estradiol were lowest in group 1, and this group was also characterized by the shortest detection period for gonadotropins and estradiol. These differences were paralleled by differences in ovarian volume, uterine length, and breast diameter. There were no differences between groups 2 and 3 in levels of both hormones and in the size of the measured structures. The obtained results seem to indicate that non-substituted or inadequately substituted hypothyroidism during pregnancy may impair the course of minipuberty in the female offspring.

"Sexual Development": Timing Puberty in German Enlightenment Medicine (1778-99).

From the mid-eighteenth century onward, French vitalists started to re-theorize the bodily clock of maturation. Archaic notions of precocity as an ill omen and ancient constructions of sexual timing as ethnic markers now acquired an increasingly physiological profile. Regulatory conceptions of sexual and psychosexual "development" widely animated German literature in the closing decades of the century. Here is evidence of new interdisciplinary problematizations of pubescence (Mannbarkeit) as the coordination in time of the mental apparatus (Seele, Character) and the sex drive (Geschlechtstrieb). New developmental-physiological frames for sexual maturity and psychosexuality readily extended to the fate of Nationalcharacter, sponsoring various roundtables concerning etiological questions.

À partir du milieu du XVIIIe siècle, les vitalistes français ont commencé à théoriser à nouveau l'horloge corporelle de la maturation. Les représentations archaïques de la précocité, considérée comme un mauvais présage, et les anciennes constructions du calendrier sexuel, perçues sous l'angle des marqueurs ethniques, ont acquis un profil de plus en plus physiologique. De fait, les conceptions réglementaires du « développement ¼ sexuel et psychosexuel ont largement animé la littérature allemande au cours des dernières décennies du XVIIIe siècle. On y trouve des preuves de nouvelles problématisations interdisciplinaires de la puberté (Mannbarkeit) en tant que coordination dans le temps de l'appareil mental (Seele, Character) et de la libido (Geschlechtstrieb). Les nouveaux cadres développementaux et physiologiques de la maturité sexuelle et de la psychosexualité ont également influencé le Nationalcharacter, qui a parrainé diverses tables rondes sur les questions étiologiques.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Neurobiological characteristics associated with gender identity: Findings from neuroimaging studies in the Amsterdam cohort of children and adolescents experiencing gender incongruence.

This review has been based on my invited lecture at the annual meeting of the Society for Behavioral Neuroendocrinology in 2023. Gender incongruence is defined as a marked and persistent incongruence between an individual's experienced gender and the sex assigned at birth. A prominent hypothesis on the etiology of gender incongruence proposes that it is related to an altered or less pronounced sexual differentiation of the brain. This hypothesis has primarily been based on postmortem studies of the hypothalamus in transgender individuals. To further address this hypothesis, a series of structural and functional neuroimaging studies were conducted in the Amsterdam cohort of children and adolescents experiencing gender incongruence. Additional research objectives were to determine whether any sex and gender differences are established before or after puberty, as well as whether gender affirming hormone treatment would affect brain development and function. We found some evidence in favor of the sexual differentiation hypothesis at the functional level, but this was less evident at the structural level. We also observed some specific transgender neural signatures, suggesting that they might present a unique brain phenotype rather than being shifted towards either end of the male-female spectrum. Our results further suggest that the years between childhood and mid-adolescence represent an important period in which puberty-related factors influence several neural characteristics, such as white matter development and functional connectivity patterns, in both a sex and gender identity specific way. These latter observations thus lead to the important question about the possible negative consequences of delaying puberty on neurodevelopment. To further address this question, larger-scale, longitudinal studies are required to increase our understanding of the possible neurodevelopmental impacts of delaying puberty in transgender youth.

Genetic and non-genetic factors in prediction of early pubertal development in Chinese girls.

Objective: The objective of this study is to develop a combined predictive model for early pubertal development (EPD) in girls based on both non-genetic and genetic factors. Methods: The case-control study encompassed 147 girls diagnosed with EPD and 256 girls who exhibited normal pubertal development. The non-genetic risk score (NGRS) was calculated based on 6 independent biochemical predictors screened by multivariate logistic regressions, and the genetic risk score (GRS) was constructed using 28 EPD related single-nucleotide polymorphisms (SNPs). Area under receiver operator characteristic curve (AROC), net reclassification optimization index (NRI) and integration differentiation index (IDI) were used to evaluate the improvement of adding genetic variants to the non-genetic risk model. Results: Overweight (OR=2.74), longer electronic screen time (OR=1.79) and higher ratio of plastic bottled water (OR=1.01) were potential risk factors, and longer exercise time (OR=0.51) and longer day sleeping time (OR=0.97) were protective factors for EPD, and the AROC of NGRS model was 83.6% (79.3-87.9%). The GRS showed a significant association with EPD (OR=1.90), and the AROC of GRS model was 65.3% (59.7-70.8%). After adding GRS to the NGRS model, the AROC significantly increased to 85.7% (81.7-89.6%) (P=0.020), and the reclassification significantly improved, with NRI of 8.19% (P= 0.023) and IDI of 4.22% (P <0.001). Conclusions: We established a combined prediction model of EPD in girls. Adding genetic variants to the non-genetic risk model brought modest improvement. However, the non-genetic factors such as overweight and living habits have higher predictive utility.

Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta.

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1-16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.