Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2–3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin–melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (LEP, LEPR, POMC, and PCSK1) or autosomal dominant (MC4R, SH2B1, SIM1, GNAS) modes of inheritance. Other gene mutations in heterozygous states (MRAP2, MC3R, SRC1, KSR2) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies.

Background: Treatment with recombinant human growth hormone (rhGH) is approved for children born small for gestational age (SGA) who fail to show postnatal catch-up growth; however, optimizing its efficacy remains a challenge. Aim: to evaluate the impact of rhGH therapy on growth trajectory (GT) and adult height (AH) in SGA children and to identify factors influencing height gain (HG). Methods: A total of 49 SGA children (24 males, 25 females) without postnatal growth recovery and treated with rhGH were enrolled. Clinical and anthropometric data were collected at treatment initiation (T0), after 1 (T1) and 2 years (T2) of therapy, at pubertal onset (P0), during the first (P1) and second year (P2) of puberty, and at attainment of AH. Parameters included age, bone age, H, weight, BMI (all expressed as SDS), HG, and the difference between H and target height (Δ H-TH). Results: a significant increase in HG at all evaluated stages was observed (p < 0.05). The H-TH difference progressively decreased from T0, particularly until the first two years of puberty. Nevertheless, mean AH was -1.75 ± 0.63 SDS, and it was found to fall within the TH range in 86% of cases. Univariate and multivariate regression analysis revealed that age and H at T0 were independent predictors of HG. Conclusions: rhGH treatment has a positive impact on GT in children born SGA. Pubertal growth has a limited contribution in influencing AH of these patients. H and timing of treatment initiation significantly influence HG in SGA children. Early selection of patients for rhGH therapy could further improve their GT.

OBJECTIVE:Management of 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) in early infancy is challenging, with extent of variation in management unclear. DESIGN AND METHODS:Using the I-CAH Registry, we retrospectively reviewed management over the first 90 days of life of 154 infants with 21-OHD born in 2018-2023, across 33 centers in 18 countries. RESULTS:Of 154 infants (92 female, 62 male), 136 were diagnosed postnatally, with median (10th centile, 90th centile) presentation age of Day 4 (0, 20.8). At initial hospital discharge, median doses of hydrocortisone (HC), fludrocortisone (FC), and salt were 17 (11.4, 39.6) mg/m2/day, 100 (50, 200) mcg/day and 3.5 (1.6, 8.7) mmol/kg/day, and at Day 90 (D90) 14.5 (8.7, 24.1) mg/m2/day, 100 (50, 200) mcg/day, and 2.1 (1.0, 5.2) mmol/kg/day, respectively. Hyponatremia, hyperkalemia, and hypoglycemia were reported in 70.0%, 71.9%, and 13.0% of infants, respectively. At D90, hyponatremia and hyperkalemia were reported in 7.4% and 28.6%, respectively. At D90, BP measurements were recorded in 30.5%, amongst whom 31.9% had hypertension reported. Median total hospitalization duration over 90 days was 9 days (2, 24). Adrenal crises were associated with 40. 6% of hospitalization episodes. Percentages (males:females) of cases seen by a pediatric endocrinologist, psychologist, pediatric endocrine nurse specialist, and surgeon by D90 were 95.9% (58:84), 33.3% (9:35), 42.1% (20:36), and 23.8% (0:35), respectively. CONCLUSIONS:Contemporary management of CAH in early infancy varies considerably. Hypertension and hyperkalemia are frequently reported. Our data may help inform development of quality indicators for benchmarking CAH care in infancy.

The increasing prevalence of childhood obesity has been accompanied by an increase in consumption of ultra-processed foods (UPF), characterized by high energy density and low nutritional quality. Emerging evidence suggests that dietary patterns rich in UPF may contribute to low-grade systemic inflammation and early metabolic dysfunction in children and adolescents. Objective: This systematic review aimed to evaluate the association between UPF consumption and markers of inflammation and metabolic health in pediatric populations. Methods: A systematic literature search was conducted on PubMed in accordance with PRISMA guidelines. Observational and interventional studies evaluating UPF intake or diet-related inflammatory potential in children and adolescents (≤18 years) were included. Outcomes of interest included inflammatory biomarkers (e.g., C-reactive protein, interleukins, tumor necrosis factor-α) and metabolic parameters (e.g., insulin resistance, lipid profile, glucose metabolism). Results: A limited number of studies have directly assessed UPF consumption using the NOVA classification. Overall, these studies suggest a potential association between increased UPF intake and adverse metabolic outcomes, although findings on inflammatory markers remain inconsistent. A larger body of indirect evidence, including studies assessing dietary inflammatory indices and related dietary patterns, consistently supports a link between pro-inflammatory diets and increased inflammation and metabolic dysregulation in pediatric populations. Conclusions: Although direct evidence on UPF consumption remains limited, the available findings, supported by complementary indirect evidence, suggest a plausible relationship between UPF-rich diets, inflammation, and metabolic health in children and adolescents. Further well-designed studies are needed to clarify causality and improve the standardization of dietary assessment methods.

Galactosemia is an inborn error of galactose metabolism, characterized by the failure to metabolize galactose correctly due to enzyme deficiencies. Type I or classic galactosemia is the most severe form of galactosemia. The diagnosis is made by metabolic screening. Symptoms manifest from the first days of life and include feeding difficulties, vomiting, hypoglycemia, jaundice, and sepsis with E. coli. Long-term treatment consists of a strict galactose-free diet. However, patients may still develop endocrine complications, such as hypergonadotropic hypogonadism in females. We report the case of a 9.5-year-old girl with classic galactosemia who was diagnosed with hypergonadotropic hypogonadism at an early age. The clinical follow-up until the start of puberty induction therapy is described. We highlight the importance of a timely diagnosis of hypogonadism to avoid a delay in the timing of puberty induction, which could lead to the potential complications.

BackgroundChildhood obesity represents a major public health issue worldwide. Evidence showed the need to implement prevention strategies mainly focused on lifestyle habits. Sleep hygiene is a variable of great interest and this review systematically examined the effects of sleep duration in increasing childhood obesity riskMethodsA systematic literature review was conducted from December 2023 to February 2024. Study selection and data extraction procedures were performed in accordance with Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines and Statement, and risk of publication bias was assessed by the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies.ResultsOriginal works in English were eligible for review and eleven studies that met the inclusion criteria were included. Studies collected were heterogeneous in terms of duration, sample characteristics, hours of sleep manipulation, anthropometric and hematological parameters collected, therefore it was not possible to perform a meta-analysis. A narrative synthesis of the reported evidence highlighted the impact of sleep duration above all on food intake, eating habits and hormone levels and consequently on the risk of childhood obesity development.ConclusionThis finding suggests the need to consider sleep hygiene as a modifiable lifestyle habit like diet and physical activity, in order to early prevent childhood obesity. Poor sleep hygiene can significantly contribute to weight gain and exacerbation of metabolic disorders linked to childhood obesity. Although more rigorous studies are needed, clinicians need to be aware of the role of sleep hygiene in reducing childhood obesity risk.

Abstract Disclosure: A.K. Lucas-Herald: None. J. Bryce: None. M. Chen: None. C. Naotunna: None. M. Sepich: None. L. Tack: None. M. Cools: None. S. Poyrazoglu: None. E. Globa: None. M. Stancampiano: None. H.L. Claahsen-van der Grinten: None. T. Guran: None. Z. Yavas Abali: None. L. de Vries: None. S.E. Hannema: None. A. Guven: None. D. Janus: None. H.A. AlShaikh: None. L. Guazzarotti: None. G. Herrmann: None. U. Probst: None. N. Lenherr-Taube: None. D. Konrad: None. M.W. O’Reilly: None. M. Steigert: None. A. Ucar: None. M. Wasniewska: None. R. Coco: None. P. Holterhus: None. V.M. Schwitzgebel: None. S.F. Ahmed: None. Introduction: Males with XY Differences of Sex Development (DSD) may have an increased risk of high blood pressure and accelerated vascular ageing. It is not clear which individuals are most at risk of this. Methods: Data were obtained from centres using the International Disorders of Sex Development (I-DSD) Registry on boys and men with 46,XY DSD. Blood pressure (BP) readings were requested as well as information on risk factors for hypertension (birthweight, obesity, family history, associated malformations) as well as ongoing management of any high BP readings. Results: In total BP readings from 208 individuals with 46,XY DSD were available from 22 centres worldwide. Of these, the median (range) age at the time of the BP reading was 13 years (1, 54). In total 97 (47%) had a non-specific XY DSD; 37 (18%) had a disorder of gonadal development; 34 (16%) had a disorder of androgen synthesis; 23 (11%) had a disorder of androgen action; 14 (7%) had hypogonadotrophic hypogonadism; and 3 (1%) had a disorder of Müllerian development. There were 77 (37%) cases ≥16 years of age, of whom 7 (10%) were classified as hypertensive. The median systolic BP of those adults with an underlying DSD was 120 mmHg (90, 153). Of the 131 (63%) individuals <16 years of age, 25 (19%) had a BP > 95th centile for age and height. The median BP standard deviation score (SDS) of those children with an underlying DSD was 0.3 (-2, 3). Of the 25 children with a raised BP, 6 (24%) had a BP >99.8th centile and 19 (76%) had a BP >98th centile. Boys with disorders of gonadal development had the highest median BP SDS at 0.9, although this was not significantly different to any other condition. There were no differences in BP SDS at the time of the study according to gestation at birth, birthweight, type of underlying of condition or presence of obesity or a co-existing anomaly however BP SDS was significantly associated with age. Of the 32 with hypertension, 3 (9%) were treated with antihypertensives; 2 (6%) had an echocardiogram and none (0%) are reported to have had ambulatory blood pressure monitoring. Conclusions: Up to 20% of young people with XY DSD have a BP in the hypertensive range during childhood at clinic compared to approximately 5% reported global prevalence in children. Our findings suggest that routine BP measurements should be recommended in this group as well as investigation to determine whether this is true hypertension or secondary to clinic anxiety. Management of these individuals requires adherence to international guidelines to prevent future cardiovascular damage. More research into the underlying cause of this phenomenon is required. Presentation: 6/1/2024

BackgroundRett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that involves mainly girls and is the second most frequent cause of genetic intellectual disability. RTT leads to neurological regression between 6 and 18 months of life and could be associated with a variable neurological impairment. However, RTT affects not only neurological function but also wide aspects of non-neurological organs. Recent data showed that the endocrine system is often involved in RTT patients, including disorders of growth, bone health, thyroid, puberty onset, and weight abnormalities However, systematic data on endocrinopathies in RTT are scarce and limited.ObjectiveThis review aims to analyze the prevalence and type of endocrine comorbidities in RTT population, to allow a precocious diagnosis and appropriate endocrinological management.MethodsSystematic research was carried out from January 2000 to March 2024 through MEDLINE via PubMed, Scopus, and the Cochrane Library.ResultsAfter the selection phase, a total of 22 studies (1090 screened) met the inclusion criteria and were reported in the present review. Five studies were observational-retrospective, four were cross-sectional and case report or series, three were survey, prospective, and case-control, and finally one study for descriptive-transversal and longitudinal population-based study. The sample population consisted of multiethnic groups or single ethnic groups. The main endocrinopathies reported were malnutrition, bone alterations, and alterations of puberty onset.ConclusionsOur analysis shows that endocrinopathies are not rare in RTT patients. Therefore, in the context of a multidisciplinary approach, accurate screening and monitoring for endocrinopathies should be recommended in all RTT patients, to improve clinical practice, healthcare management, and, finally, patients’ quality of life.

Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype–phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible.

BACKGROUND:Disorders/Differences of sex development (DSD) are often due to disruptions of the genetic programs that regulate gonad development. The GATA-4 gene, located on chromosome 8p23.1, encodes GATA-binding protein 4 (GATA-4), a transcription factor that is essential for cardiac and gonadal development and sexual differentiation.CASE DESCRIPTION:A child with a history of micropenis and cryptorchidism. At 8 years of age, he came under our observation for an increase in sexual pubic hair (pubarche). The laboratory parameters and the GnRH test suggested a central precocious puberty (CPP). Treatment with GnRH analogs was started, and we decided to perform genetic tests for DSD. The NGS genetic investigation showed a novel and heterozygous variant in the GATA-4 gene.DISCUSSION:In the literature, 26 cases with 46,XY DSD due to the GATA4 gene were reported.CONCLUSION:The novel variant in the GATA-4 gene of our patient was not previously associated with DSD. This is the first case of a DSD due to a GATA-4 mutation that develops precocious puberty. Precocious puberty could be associated with DSD and considered a prelude to hypogonadism in some cases.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

PURPOSE:Turner syndrome (TS) is the most common sex chromosomal abnormality found in female subjects. It is a result of a partial or complete loss of one of the X chromosomes. Short stature is a hallmark of TS. Attainment of adult height (AH) within the normal range for height within the general female population represents the usual long-term goal of growth hormone (GH) treatment. The aim of this systematic review was to understand the efficacy of GH therapy on AH of patients with TS.METHODS:The literature review yielded for analysis 9 articles published from 2010 to 2021. Using the data from this literature search, the goal was to answer 5 questions: (1) What is the efficacy of GH on AH of girls with TS?; (2) Is AH influenced by the age at initiation of GH treatment?; (3) What is the optimal dose of GH to improve AH?; (4) Can the timing of either spontaneous or induced puberty influence AH?; and (5) Can the karyotype influence AH in patients with TS?FINDINGS:GH therapy and adequate dose could enable patients with TS to achieve appropriate AH compared with the possible final height without therapy. The greatest increase in height during GH therapy occurs in the prepubertal years, and if therapy is continued to AH, there is no further increase. Furthermore, karyotype did not show a predictive value on height prognosis and did not affect the outcome of GH administration or the height gain in girls with TS.IMPLICATIONS:Even if GH therapy is safe, close monitoring is indicated and recommended. Further evidence is needed to understand what other parameters may influence AH in patients undergoing GH therapy.

Systematic data on endocrinopathies in Rett syndrome (RTT) patients remain limited and inconclusive. The aim of this retrospective observational two-center study was to assess the prevalence of endocrinopathies in a pediatric population of RTT patients. A total of 51 Caucasian patients (47 girls, 4 boys) with a genetically confirmed diagnosis of RTT were enrolled (mean age 9.65 ± 5.9 years). The patients were referred from the Rett Center of two Italian Hospitals for endocrinological evaluation. All the study population underwent clinical and auxological assessments and hormonal workups. MeCP2 mutations were detected in 38 cases (74.5%), CDKL5 deletions in 11 (21.6%), and FOXG1 mutations in 2 (3.9%). Overall, 40 patients were treated with anti-seizure medications. The most frequent endocrinological finding was short stature (47%), followed by menstrual cycle abnormalities (46.2%), weight disorders (45.1%), low bone mineral density (19.6%), hyperprolactinemia (13.7%) and thyroid disorders (9.8%). In the entire study population, endocrinopathies were significantly more frequent in patients with MeCP2 mutations (p = 0.0005), and epilepsy was more frequent in CDKL5 deletions (p = 0.02). In conclusion, our data highlighted that endocrinopathies are not rare in RTT, especially in patients with MeCP2 deletions. Therefore, in the context of a multidisciplinary approach, endocrinological evaluation should be recommended for RTT patients.