Yael Lebenthal

Background: Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder characterized by absent or delayed puberty and infertility due to gonadotropin-releasing hormone deficiency. While loss-of-function variants in FGFR1 are the most commonly known genetic cause of CHH, diagnostic screening typically focuses on coding exons, potentially overlooking pathogenic variants in noncoding regions. Methods: We investigated 4 unrelated families with CHH. Family 1 included a mother and 3 daughters presenting with variable reproductive phenotypes and incomplete penetrance of anosmia; Family 3 consisted of a girl with CHH and anosmia; and Families 2 and 4 consisted of male patients who presented with CHH and anosmia. Genetic investigations were done using either exome or genome sequencing. Experimental characterization of the identified intronic variants was conducted using RNA extracted from peripheral blood mononuclear cells. Exome or genome sequencing–based haplotyping was performed for the recurring variant. Results: In Families 1 to 3, we identified a recurring heterozygous intronic variant in FGFR1: c.92-19G > A. RNA analysis confirmed that this variant generates a cryptic splice acceptor site, leading to the inclusion of 17 intronic nucleotides, resulting in a premature stop codon. Haplotype analysis revealed the variant occurred independently in each family. In Family 4, a distinct heterozygous intronic variant was identified in FGFR1, which was shown to cause intron 15 retention with premature termination. Conclusion: Our findings demonstrate that intronic variants in FGFR1 are a possible cause of CHH and can lead to diverse clinical phenotypes ranging from normosmic CHH to severe Kallmann syndrome, including significant presentation in female patients.

Aim: To explore changes in body composition in adolescents with obesity treated with glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) and their association with metabolic syndrome (MetS) components. Methods: This real‐world retrospective study included adolescents (12–18 years) with obesity who received multidisciplinary lifestyle‐based obesity care between 2020 and 2024. GLP‐1 RA therapy (liraglutide or semaglutide) was prescribed and dosed on an individualised basis. BMI and muscle‐to‐fat ratio (MFR) z ‐scores (by bioimpedance), and MetS components (glucose intolerance, hypertension, and dyslipidemia) were evaluated and compared with patients not receiving GLP‐1 RA at corresponding time points. Multivariable regression analyses adjusted for sex, age, physical activity, and length of follow‐up evaluated contributors for improvement in body composition. Results: Of 67 eligible adolescents, 41 (61.2%) received GLP‐1 RA therapy. The GLP‐1 RA‐treated group experienced greater improvements in BMI z ‐scores (−0.34 [−0.57, −0.07] vs. −0.07 [−0.17, 0.05], p < 0.001), and MFR z ‐scores (0.41 [0.12, 0.56] vs. 0.13 [0.01, 0.25], p = 0.007) compared to those without GLP‐1 RA therapy. GLP‐1 RA treatment duration was identified as the sole contributor to BMI and MFR z ‐score improvements ( R ² = 0.515, p < 0.001 and R ² = 0.231, p = 0.012, respectively). A 0.25‐unit decrease in BMI z ‐score and a 0.25‐unit increase in MFR z ‐score were associated with 2.8‐fold and 1.8‐fold higher odds of MetS component improvement, respectively. Conclusion: Adolescents with obesity under GLP‐1 RA therapy combined with lifestyle intervention demonstrated improvements in body composition and MetS components.

Context: Vosoritide, a C-type natriuretic peptide analogue, is the first approved therapy targeting the pathophysiology of achondroplasia. While clinical trials demonstrate efficacy, individuals with prior orthopedic surgeries are typically excluded, and real-world data remain limited. Objective: To evaluate real-world growth outcomes of vosoritide therapy in children with achondroplasia, including those with prior surgical interventions. Methods: This retrospective analysis included 25 children with achondroplasia (17 boys, age range 2.9-14.3 years) treated with vosoritide for a mean duration of 12.7 months at a multidisciplinary center. Z-scores were calculated using an AI-assisted growth assessment tool previously validated for children with achondroplasia. Δ z-scores for height, sitting height, arm span, and body mass index (BMI) were calculated from baseline to follow-up. Multiple linear regression analyses assessed predictors of response. Results: Mean height z-scores improved from −0.62 ± 1.09 to −0.24 ± 1.20 (P < .001). Mean arm span z-score increased from −1.28 ± 0.93 to -0.96 ± 0.91 (P = .007). Sitting height z-scores showed a non-significant trend toward improvement; BMI z-scores remained stable. Mean Δ height and Δ arm span z-score gains were +0.38 ± 0.45 and +0.32 ± 0.48, respectively. A subgroup analysis of 8 patients with vs 17 without prior limb-lengthening surgery showed no significant differences. Regression analyses adjusted for sex, age, BMI z-scores, and surgical history were likely underpowered to detect meaningful predictors of response. There were no serious treatment-related adverse events. Conclusion: Vosoritide therapy enhanced linear and appendicular growth in a real-world cohort of children with achondroplasia, including post-surgical patients. These findings align with clinical trial data and support the therapy's applicability across diverse clinical profiles.

Autism spectrum disorder (ASD) is more prevalent in transgender and gender‐diverse (TGD) individuals than in the general population, yet the specific developmental pathways within and clinical outcomes of this intersection are insufficiently understood. This study examined how ASD and sex assigned at birth (SAAB) are associated with gender‐related milestones, access to gender‐affirming consultation and care (GACC), and psychiatric outcomes. We reviewed electronic medical records for 786 TGD children and adolescents (aged 4–19 years) presenting to a national referral clinic between 2013 and 2025. Demographic, developmental, and psychiatric variables were analyzed across four ASD‐by‐SAAB groups using generalized linear models and logistic regressions, with Bonferroni‐adjusted post hoc comparisons ( α = 0.0083). ASD was documented in 9.7% of the cohort, with referrals of autistic TGD patients increasing significantly over time. Autistic patients presented with a distinct profile, characterized by higher socioeconomic position (SEP), intellectual giftedness, non‐binary gender identity, and an earlier stage of pubertal development at presentation. Crucially, while ages at gender‐related milestones were largely comparable between neurotypes, autistic assigned female at birth (AFAB) adolescents were significantly less likely to initiate puberty suppression or gender‐affirming hormones than their non‐autistic peers. Furthermore, higher SEP was associated with earlier clinical presentation only for non‐autistic youth. Autistic TGD patients exhibited a higher psychiatric burden, with an ASD diagnosis uniquely associated with elevated rates of anxiety, ADHD, and psychotropic medication use. These findings reveal a disparity between developmental synchrony and clinical access, underscoring the need for autism‐informed protocols to support equitable gender‐affirming care.

Aims: Adolescents with type 1 diabetes are at increased risk of impaired cognitive function, particularly in tasks requiring memory, attention, and executive functioning. Given the emerging evidence that excess adiposity may impair cognition through metabolic and inflammatory pathways, we investigated the association between body composition components and spatial navigation in adolescents with type 1 diabetes. Methods: In this observational study, 64 adolescents (39 boys, mean age 15.9 ± 2.2 years) with type 1 diabetes completed spatial navigation assessment by the Virtual Morris Water Maze Task (vMWMT) and underwent body composition assessment via bioelectrical impedance analysis. Glycaemic control was evaluated through HbA1c measurement and continuous glucose monitoring metrics. Associations between vMWMT outcomes (time‐to‐first move, time‐to‐platform, and path length) and body composition components [body mass index (BMI) and muscle‐to‐fat ratio (MFR) z‐scores] were analysed by sex‐stratified correlation and multivariable linear regression models. Results: Mean BMI z‐scores did not differ between sexes, whereas girls had lower muscle‐to‐fat ratio (MFR) z‐scores than boys (−0.60 ± 0.84 vs. 0.25 ± 1.00, p < 0.001). The boys' longer time‐to‐first move and time‐to‐platform were positively correlated with lower MFR z‐scores and higher HbA1c levels, greater time in marked hypoglycemia and in severe hyperglycemia and longer diabetes duration. Boys' diabetes duration predicted a longer time‐to‐first move ( B = 0.064, p = 0.009), while both diabetes duration and a lower MFR z‐score predicted a longer time‐to‐platform ( R ² = 0.457, p < 0.001). The girls' longer time‐to‐platform was positively correlated with higher BMI z‐scores. Their HbA1c levels at diabetes onset predicted longer time‐to‐first move ( B = −3.46, p = 0.018), and their relatively higher BMI z‐scores predicted longer time‐to‐platform ( B = 9.33, p = 0.022). Conclusions: Spatial navigation performance in adolescents with type 1 diabetes is influenced by body composition in boys and weight status in girls. Identifying and managing sex‐specific risk factors may help optimise cognitive function in adolescents with type 1 diabetes.

Introduction: Childhood-onset multifactorial dyslipidemia is associated with obesity and early cardiometabolic risk, yet weight status alone may not reflect abnormalities in body composition. We aimed to examine associations between body composition, physical activity, and cardiometabolic markers in this population. Methods: This observational study included 101 children (mean age 13.8 ± 3.2 years) referred to a tertiary lipid clinic. Body composition was assessed by bioelectrical impedance analysis. Individuals were stratified by fat mass z-score (p < 0.05). Fat mass z-score correlated with all cardiometabolic markers. In multivariable models, lower muscle-to-fat ratio (β = −15.0), lower physical activity (β = −3.1), and female sex (β = 9.9) were independently associated with higher diastolic blood pressure percentiles. Discussion: In pediatric multifactorial dyslipidemia, both adiposity and muscle-to-fat imbalance contribute to early cardiometabolic risk and may improve risk stratification.

Background: X-linked hypophosphatemic rickets (XLH) is a rare inherited metabolic bone disorder caused by excess fibroblast growth factor 23 (FGF23), leading to hypophosphatemia and rickets. Burosumab, a human monoclonal antibody targeting FGF23, was approved for the treatment of XLH in April 2018. By 2022, the FDA extended its approval to include children as young as six months of age. Objectives: To describe three infants with XLH who began burosumab therapy before one year of age and were monitored for at least one year. Design: Case series. Methods: Clinical outcomes, including anthropometric measures, skeletal outcomes (Rickets Severity Score [RSS], mechanical axis deviation [MAD], and neck-shaft angle [NSA]), and laboratory parameters, were assessed in a real-world setting. Results: Two patients demonstrated satisfactory linear growth, and one experienced growth faltering, possibly due to sleep-disordered breathing or phosphate imbalance. These patients received higher doses of burosumab than the current guideline recommendations for achieving treatment goals aimed at normalizing phosphate levels. The patient’s phosphate levels improved but did not normalize. Bone pain was not formally assessed, but parents reported improvements in their children’s conditions. Importantly, two patients with assessable mechanical axes demonstrated neutral mechanical axis deviations, indicating improved lower limb alignment and supporting the therapeutic efficacy of burosumab. All three patients had favorable RSS outcomes, and none developed long bone diaphyseal bowing or coxa vara following this early initiation of burosumab treatment. Conclusion: This case series demonstrated potential benefits of early initiation of burosumab treatment for XLH by showing improvements in growth, phosphate levels, and skeletal outcomes. Burosumab appears well tolerated in infancy, but further research is needed to refine dosing strategies and assess its long-term safety and therapeutic efficacy in young patients with XLH. Meticulous monitoring and individualized care are essential throughout treatment. Plain language summary: This case series followed three infants with X-linked hypophosphatemic rickets (XLH) who initiated burosumab treatment at 6 months of age, filling a significant knowledge gap in early intervention. Despite requiring higher-than-recommended dosing, burosumab demonstrated favorable outcomes in terms of growth parameters and skeletal development over a minimum one-year follow-up. Two patients maintained normal growth trajectories, whereas one experienced temporary growth faltering, which resolved after adenoidectomy. Importantly, neutral mechanical axis deviation was achieved, indicating effective prevention of lower limb deformities. No significant adverse effects were observed. Despite limitations such as a small sample size and short follow-up, these findings suggest that early burosumab therapy can improve outcomes in infantile XLH patients. Further research is needed to refine dosing protocols and assess long-term safety and efficacy in this young population.

Aims/hypothesis: Neuropsychological assessments and neuroimaging techniques have indicated impaired spatial working memory in adolescents with type 1 diabetes. We investigated the influence of diabetes-related factors on their spatial navigation performance. Methods: Spatial navigation performance on the virtual Morris water maze task (vMWMT) was evaluated in adolescents with type 1 diabetes and compared with that of healthy control adolescents of similar age and sex. Collected data on diabetes-related variables included disease duration, diabetic ketoacidosis (DKA) at diagnosis and continuous glucose monitoring (CGM) metrics during the 2 weeks preceding the assessment, with focus upon nocturnal values measured during the night before testing. Time to first move, time to platform and path length were measured in visible and hidden platform vMWMT stages. Results: The 74 study participants (age 15.6 ± 3.1 years, 45 boys) with type 1 diabetes demonstrated sex-specific patterns of spatial navigation, comparable with those observed in the healthy control group. Both the boys and girls had longer time to first move than the control groups in the visible platform stage, which assessed motor control ( p =0.036 and p =0.002, respectively). Test outcomes did not differ between the participants with and without type 1 diabetes in the hidden platform stages, which assessed spatial learning and memory. However, linear regression models adjusted for sex, age and DKA at diagnosis found that diabetes duration (β=0.464, p R ² =0.396, p =0.003), while nocturnal time spent in marked hypoglycaemia (β=0.397, p =0.002) predicted longer path length ( R ² =0.206, p =0.017). Conclusions/interpretation: Spatial navigation performance in adolescents with type 1 diabetes is influenced by both disease duration and recent glycaemic control. Glycaemic excursions, especially during the night, were shown to impair performance. Graphical