Laura Chioma

Background: Differences of sex development (DSD) are a group of congenital conditions characterized by atypical development of genital structures. The diagnosis is complex and involves clinical, hormonal, and genetic evaluations. Objective: To describe the clinical profile, diagnosis, and management of patients with DSD, with particular attention to genetic diagnosis. Study design: Retrospective study from a tertiary care pediatric hospital in Italy. Methods: 420 patients with DSD referred to the Endocrine Unit of Bambino Gesù Children’s Hospital in Rome, Italy, between 2016 and 2023 were included. Results: 75 patients had a 46,XY karyotype, 135 had a 46,XX karyotype, and 210 had chromosomal mosaicism. In our group of pediatric DSD patients, 21/420 patients were born from pregnancies induced with assisted reproduction techniques (ICSI/FIVET). Of these 21 patients, 5 had sex chromosome mosaicism. Using next-generation sequencing (NGS), we identified three new genetic variants: one in the AR gene, one in the NR5A1 gene, and one in the SRY gene. The use of NGS significantly improved the diagnostic yield, and a definitive diagnosis was reached in 84.76% of the entire cohort. Conclusions: This study highlights the challenges in the management of patients with DSD from early recognition to treatment and follow-up. A multidisciplinary approach is essential for a comprehensive evaluation of these conditions and to understand the role and clinical significance of the genetic variants.

CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.

Excess body weight has been considered beneficial to bone health because of its anabolic effect on bone formation; however, this results in a poor quality bone structure. In this context, we evaluated the involvement of circulating extracellular vesicles in the impairment of the bone phenotype associated with obesity. Circulating extracellular vesicles were collected from the plasma of participants with normal weight, as well as overweight and obese participants, quantified by flow cytometry analysis and used to treat mesenchymal stromal cells and osteoblasts to assess their effect on cell differentiation and activity. Children with obesity had the highest amount of circulating extracellular vesicles compared to controls. The treatment of mesenchymal stromal cells with extracellular vesicles from obese participants led to an adipogenic differentiation in comparison to vesicles from controls. Mature osteoblasts treated with extracellular vesicles from obese participants showed a reduction in differentiation markers in comparison to controls. Children with obesity who regularly performed physical exercise had a lower circulating extracellular vesicle amount in comparison to those with a sedentary lifestyle. This pilot study demonstrates how the high amount of circulating extracellular vesicles in children with obesity affects the bone phenotype and that physical activity can partially rescue this phenotype.

Purpose Constitutional delay of growth and puberty (CDGP) represents the most frequent cause of delayed puberty in males, sharing some clinical features with growth hormone deficiency (GHD) and isolated hypogonadotropic hypogonadism (IHH). Short-term induction therapy (SIT) has been approved for the induction of puberty in CDGP. We aim to investigate the efficacy of SIT with transcutaneous testosterone gel (TTG) or intramuscular testosterone therapy (IMTT) in a cohort of CDGP subjects, compared to clinical observation. Furthermore, we aim to evaluate the role of SIT as a diagnostic tool to differentiate CDGP from GHD and IHH subjects. Methods The retrospective study included 246 male subjects with delayed puberty. The study population was divided into three groups: TTG, IMTT, and control group (CNT). Results At 6 months observation, height velocity (HV) was significantly increased in both treated groups compared to CNT group, particularly higher in TTG than IMTT group. A significant testicular enlargement was revealed in both CNT and TTG group compared to IMTT group. Furthermore, LH value was significantly greater in TTG compared to IMTT group. IGF-1 values after SIT rose significantly in both treated groups compared to CNT group. Moreover, almost all GH provocative tests performed after SIT showed a normal GH response. Conclusion SIT with TTG appears to be more effective to induce growth spurt, better tolerated and with a more physiological effect on pubertal induction compared to IMTT in CDGP population. Finally, TTG might be a useful tool in the diagnostic work up to discriminate CDGP from GHD or IHH.

Background: Male hypogonadism may be associated with micropenis and cryptorchidism in newborn, absent or incomplete pubertal development when it occurs during childhood. During puberty, androgen replacement therapy plays a pivotal role in subjects with hypogonadism to induce sexual maturation, growth acceleration, anabolic effects on fat-free mass growth increasing muscle strength, directly and indirectly on the attainment of peak bone mass in young men. Moreover, in newborns with congenital hypogonadism, androgen therapy could be effective to increase genital size. Summary: Testosterone replacement therapy (TRT) represents the cornerstone of the management of hypogonadism in boys. During puberty, replacement therapy needs to be modulated with gradual dosing increase to better mimic the physiologic pubertal development. Currently, intramuscular testosterone (T) esters (in particular testosterone enanthate) and subcutaneous T pellets are the only formulations approved by the US Food and Drug Administration for delayed puberty, while no preparation is approved for long-term use in the adolescent age. Several new T formulations (as transdermal, nasal, subcutaneous, and oral formulation) are recently developed to improve the pharmacokinetic profile and to ease the administration route increasing patient compliance in adult males with hypogonadism. All these formulations are not approved for pediatric age, although some of them are used as “off-label” regimens. This special issue is aimed to illustrate new T formulations and their potential role as replacement therapy in the pediatric population, as well as to highlight investigational areas to contribute to health care improvement in these patients. Key Messages: Despite the lack of evidence-based guidelines regarding the choice of T formulation in the pediatric population, new formulations appear to have a potential role for TRT in adolescent age. They have been designed for adult age with a little flexibility of dosage, although a few formulations may be attractive for pubertal induction and penile enlargement thanks to their greater flexibility and easing of administration. On the other hand, long-acting and stable formulations could meet post-pubertal needs, increasing TRT compliance in a critical phase as the adolescent age. Further controlled, long-term safety, and efficacy studies for all these new T formulations within the pediatric population are needed.

Epidemic obesity is the most important risk factor for prediabetes and type 2 diabetes (T2D) in youth as it is in adults. Obesity shares pathophysiological mechanisms with T2D and is likely to share part of the genetic background. We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Genotyping of 42 SNPs established by genome-wide association studies for T2D, FG and FI was performed in 1660 Italian youths aged between 2 and 19 years. We defined GRS for T2D, FG and FI and tested their effects on glycaemic traits, including FG, FI, indices of insulin resistance/beta cell function and body mass index (BMI). We evaluated causal relationships between obesity and FG/FI using one-sample Mendelian randomization analyses in both directions. GRS-FG was associated with FG (beta = 0.075 mmol/l, SE = 0.011, P = 1.58 × 10−11) and beta cell function (beta = −0.041, SE = 0.0090 P = 5.13 × 10−6). GRS-T2D also demonstrated an association with beta cell function (beta = −0.020, SE = 0.021 P = 0.030). We detected a causal effect of increased BMI on levels of FI in Italian youths (beta = 0.31 ln (pmol/l), 95%CI [0.078, 0.54], P = 0.0085), while there was no effect of FG/FI levels on BMI. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.

Constitutional delay of growth and puberty (CDGP) treatment include observation or therapy with intramuscular testosterone (IMTT). No data are available about transdermal testosterone gel (TTG). The aim of our study was to analyze the use of TTG in males with CDGP.