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ObjectivesHypoglycaemia is a common finding in the newborn and may be associated with hyperinsulinism (HI). Congenital HI is a rare cause of neonatal hypoglycaemia and is associated with severe neurodevelopmental impairment.1 Previous reports on neonatal HI focus on congenital HI rather than the more commonly presenting transient HI. The primary objective of this study is to describe a cohort of neonates with hyperinsulinism from a neonatal, rather than a supra-specialist perspective.MethodsWe conducted a service evaluation of the management of neonatal hyperinsulinism in a level 3 Neonatal Intensive Care Unit, over seven years (1/2015 – 12/2021). We collected demographic data, maternal health details, information regarding clinical care, associated conditions and follow-up. The cohort was subdivided into subgroups based on clinical severity, gestational age and growth. Clinical severity was defined as:(1) Severe: treated with diazoxide,(2) Moderately severe: clinically worrying HI without diazoxide,(3) Mild: biochemical evidence of HI without clinically worrying criteria.Results99 cases identified – Severe(n=20), Moderately-severe(n=30), Mild(n=49).77% were born locally. Hypoglycaemia was the primary reason for admission in 58% of locally born and 30% of transferred from other hospitals. 12% of infants were Large for gestational age (LGA), 35% Small for Gestational Age (SGA), 42% preterm (<37 weeks), and 17% had diabetic mothers. Birthweight z-score, gestational age, and maternal diabetes did not influence clinical severity.When exploring subgroups of clinical severity, age on diagnosis was lower in Mild infants, compared to Severe (p=0.008). Length of admission was longer for Severe and Moderate compared to Mild(p<0.001). Severe infants received a higher maximum strength of dextrose compared to Moderate and Mild(p<0.001). Glucose requirement on diagnosis was higher in Severe(9.0 ± 5.0mg/kg/min) and Moderate(7.4 ± 3.6mg/kg/min), compared to Mild (5.3 ± 2.3mg/kg/min)(p<0.001).Severe infants had not established full enteral feeds when started on diazoxide, with a mean glucose requirement of 13.2±4.8mg/kg/min. The Severe group achieved full enteral feeds on day 26±15, significantly later than the Moderate group (11±7, p<0.0001).ConclusionThis study highlights the diversity of infants with HI cared for in the NICU. SGA, LGA and preterm infants may be at increased risk from both HI and limited availability of alternative fuels.2 Management of HI is challenging, as the decision to treat with diazoxide is not straightforward and is influenced by multiple objective and subjective variables. Further research is needed into larger cohorts from different centres to explore the range of clinical practice, and long-term outcomes of this diverse group of infants.ReferencesMartino, Sartorelli, Gragnaniello, Burlina. Congenital hyperinsulinism in clinical practice: from biochemical pathophysiology to new monitoring techniques, 23 September 2022.Stanley, Thornton, De Leon. New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia, 10 March 2023.

Congenital adrenal hyperplasia (CAH), a genetic condition that disrupts cortisol synthesis, is associated with elevated androgen levels in females with CAH. Altered hormonal milieus have been linked to changes in brain structure, yet little is known about how CAH affects the cerebral cortex. Here, we investigated vertex-wise cortical thickness in 53 individuals with CAH (33 women and 20 men) and 53 sex- and age-matched controls (33 women and 20 men) using surface-based morphometry. There were no significant effects of biological sex and no significant diagnosis-by-sex interaction. However, there was a significant effect of diagnosis, with thinner cortices in various regions across the left and right lateral and medial surfaces in individuals with CAH compared to controls. These findings point to widespread cortical alterations in CAH, independent of sex, and extend prior evidence of structural brain variations in this endocrine disorder. The observed cortical thinning may result from multiple factors, including prenatally reduced cortisol levels, potential long-term consequences of postnatal glucocorticoid treatment, and ongoing physiological and psychosocial stressors.

Congenital Adrenal Hyperplasia (CAH) is a group of genetic disorders that affect the adrenal glands. CAH manifests in abnormal levels of cortisol and androgens and is accompanied by white matter alterations. However, no CAH study has specifically targeted the corpus callosum, the brain’s largest white matter fiber tract. To bridge that gap in the literature, we investigated callosal morphology in 53 individuals with CAH and 53 matched controls (66 women, 40 men). In addition to calculating areas for seven callosal subsections, we estimated the callosal thickness at 100 equidistant points. All statistical analyses were conducted while co-varying for age and total brain volume and applying corrections for multiple comparisons. There were no significant effects of biological sex and no significant group-by-sex interactions. However, there was a significant effect of group, both for area measures and thickness estimates, indicating smaller dimensions within the callosal splenium and isthmus in people with CAH. Our findings corroborate previous studies highlighting white matter alterations in CAH and may suggest that callosal integrity is compromised due to potentially adverse effects of glucocorticoids, a standard treatment for both men and women with CAH.

Background: Anogenital distance (AGD) is sexually dimorphic in rodents anil humans, being 2- to 2. 5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. Objective: This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. Materials and Methods: Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. Results: Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (± SD) at birth was 19.8 ± 6.1 mm in males and 9.1 ± 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex- dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r = 0.20, p = 0.001). Conclusion: We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.

Background Puberty in girls is occurring earlier worldwide with a declining trend over the recent decades, resulting in increased attention on the accompanying risks of psychosocial challenges and adverse health outcomes for the affected girls. Diverse mechanisms have been proposed as mediators of the tendency for earlier pubertal maturation, including a shift toward a more sedentary lifestyle and changes in dietary habits leading to childhood obesity. Several studies have demonstrated a potential association between the rise in childhood obesity prevalence and the decline in the age at which puberty begins. Increased insulin resistance is thought to play a role in this connection, and previous studies indicated that improved insulin sensitivity following either treatment with metformin or weight loss could delay pubertal progression in girls with overweight. Methods LIFE-MET is a randomized, placebo-controlled, four-arm, multicenter trial of girls ( n  = 80) with overweight and early puberty. Allocation to metformin or placebo will be double-blinded. Eligible girls will be randomly assigned to one of the four study arms: Metformin + lifestyle intervention ( N  = 20), Metformin alone ( N  = 20), Placebo + lifestyle intervention ( N  = 20), Placebo alone ( N  = 20). The intervention period is 6 months with a follow-up after an additional 6 months. The primary outcome is the change in bone age from baseline to 12 months, as a marker of pubertal progression. Secondary outcomes include changes in body composition, Tanner stage, fitness level, sex hormones, insulin resistance, and age at menarche. Discussion New strategies not only for the treatment but also for the prevention of both overweight and early puberty are needed. The LIFE-MET trial is a randomized controlled trial with a combination of lifestyle intervention including online, virtual reality training and a pharmacological intervention consisting of metformin and/or placebo, to our knowledge the first of its kind. We expect that this intervention will have a beneficial effect on both pubertal progression, daily physical activity level, and body composition. Additionally, a healthier body composition may have beneficial effects on long-term co-morbidities related to early puberty. Trial registration Clinical Trial Information System (CTIS): 2024-511009-50-00. Approved 04/30/2024. https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-511009-50-00 .

In a trial involving youths with new-onset type 1 diabetes, intensive glucose control with hybrid closed-loop therapy for 24 months did not preserve C-peptide secretion as compared with standard insulin therapy.

In a multicenter, randomized, crossover trial involving children 1 to 7 years of age with type 1 diabetes, a closed-loop system was compared with sensor-augmented pump therapy in random order. The closed-loop system improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in a hypoglycemic state.

Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard deviation score (SDS), and reductions in IS (p < 0.0001). Compensatory increases in AIR (p < 0.0001) were insufficient and resulted in reduced DI (p = 0.032). Children in the highest IGF-I SDS tertile at baseline were the least insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses after 1 year were positively related to AIR (r = 0.30, p = 0.007) and DI (r = 0.29, p = 0.005). Conclusion: In SGA children treated with a high GH dose for 1 year, baseline IGF-I levels were related to IS whilst gains in height and IGF-I responses were associated with insulin secretion. Defining heterogeneity in IGF-I in SGA children may be useful in predicting growth and metabolic response.

ObjectiveReports of hyperinsulinism typically focus on infants managed by highly specialised services. However, neonates with hyperinsulinism are initially managed by neonatologists and often not referred to specialists. This study aimed to characterise the diversity in presentation and management of these infants.SettingLevel 3 neonatal intensive care.PatientsNeonates with hyperinsulinism, defined as blood glucose <2.8 mmol/mL and insulin level >6 pmol/L.Design7-year retrospective study (January 2015–December 2021).Results99 cases were identified: severe—treated with diazoxide (20%), moderate—clinically concerning hyperinsulinism not treated with diazoxide (30%), mild—biochemical hyperinsulinism (50%). Birth weight z-score was −1.02±2.30 (mean±SD), 42% were preterm, but neither variable correlated with clinical severity. The severe group received a higher concentration of intravenous glucose (27±12%) compared with the moderate (15±7%) and mild (16±10%) groups (p<0.001). At diagnosis, the intravenous glucose intake was similar in the severe (7.43±5.95 mg/kg/min) and moderate (5.09±3.86 mg/kg/min) groups, but higher compared with the mild group (3.05+/2.21 mg/kg/min) (p<0.001). In the severe group, term infants started diazoxide earlier (9.9±4.3 days) compared with preterm (37±26 days) (p=0.002). The national congenital hyperinsulinism service was consulted for 23% of infants, and 3% were transferred.ConclusionsThis study highlights the diversity in clinical presentation, severity and prognosis of neonatal hyperinsulinism, irrespective of birth weight and gestational age. More infants were small rather than large for gestational age, and the majority had transient hyperinsulinism and were not referred to the national centre, or treated with diazoxide. Further research is required to understand the breadth of neonatal hyperinsulinism and optimal management.