Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with a characteristic trajectory. Infants display hypotonia, poor social and feeding skills, and high risk of choking, which have been shown to improve after oxytocin (OT) treatment. Our aim is to demonstrate the efficacy of intranasal OT treatment administered in the postnatal critical period on infant feeding skills and document its long-term effects. We enrolled 52 infants with PWS (median age 2.2 months) in a European double-blind randomized placebo-controlled study. Infants were randomly assigned in a 1:1 ratio to either 4 IU/day of OT or placebo for a 4-week evaluation of efficacy. A second randomization in each group was performed. Infants in the placebo group were randomized into 4 weeks of OT followed by 4 weeks of placebo or 8 consecutive weeks of OT. Those in the OT group were randomized into additional 4 weeks of OT followed by 4 weeks of placebo or 8 consecutive weeks of placebo. Infants were followed-up to 26 weeks from baseline. Feeding skills were evaluated using Neonatal Oral-Motor Scale (NOMAS) as primary endpoint and videofluoroscopy of swallowing study (VFSS) as key secondary endpoint. Subsequently, 40 infants included in France (OT-exposed cohort) participated in a new study to document long term safety of OT treatment and to compare them with an unexposed cohort (n = 24) at about 3 years of age. Prevalence and severity of comorbidities of the disorder were compared between the two cohorts. OT was well tolerated. At 4 weeks, NOMAS normalization rates were similar between OT and placebo, but OT yielded a higher VFSS responder rate (53.3

Introduction: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls.Methods: Longitudinal study in 134 children with PWS and 157 healthy controls, from The Netherlands, France and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored.Results: The AG/UAG ratio was in the first years of life lower in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p=0.114), while the UAG levels decreased from 290 pg/ml in phase 1a to 137 pg/ml in phase 2b (p<0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p= 0.012).Conclusions: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia.

STUDY QUESTION:What is the long-term outcome of individuals born with bilateral testicular regression (BTR) in relation to its underlying etiology? SUMMARY ANSWER:Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal, especially in those with a suspected genetic etiology (i.e. heterozygous DHX37 variants) or a micropenis at birth. WHAT IS KNOWN ALREADY:BTR is a rare and poorly understood condition. Although a vascular origin has been postulated, heterozygous missense variants in DHX37 have been attributed to the phenotype as well. How these various etiologies impact the clinical phenotype, gonadal histology and outcome of BTR remains unclear. STUDY DESIGN SIZE DURATION:For this cross-sectional study, individuals with BTR were recruited in eight Belgian pediatric endocrinology departments, between December 2019 and December 2022. A physical exam was performed cross-sectionally in all 17 end-pubertal participants and a quality of care questionnaire was completed by 11 of them. Exome-based panel testing of 241 genes involved in gonadal development and spermatogenesis was performed along with a retrospective analysis of presentation and management. A centralized histological review of gonadal rests was done for 10 participants. PARTICIPANTS/MATERIALS SETTING METHODS:A total of 35 participants (33 with male, 1 with female, and 1 with non-binary gender identity) were recruited at a mean age of 15.0 ± 5.7 years. MAIN RESULTS AND THE ROLE OF CHANCE:The median age at presentation was 1.2 years [0-14 years]. Maternal gestational complications were common (38.2%), with a notably high incidence of monozygotic twin pregnancies (8.8%). Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp and p.Arg308Gln) were found in three participants. No other (likely) pathogenic variants were found. All three participants with a DHX37 variant had a microphallus at birth (leading to female sex assignment in one), while only six of the remaining 31 participants without a DHX37 variant (19.4%) had a microphallus at birth (information regarding one participant was missing). Testosterone therapy during infancy to increase penile growth was more effective in those without versus those with a DHX37 variant. The three participants with a DHX37 variant developed a male, female, and non-binary gender identity, respectively; all other participants identified as males. TRT in incremental doses had been initiated in 25 participants (median age at start was 12.4 years). Final height was within the target height range in all end-pubertal participants; however, 5 out of 11 participants (45.5%), for whom stretched penile length (SPL) was measured, had a micropenis (mean adult SPL: 9.6 ± 2.5). Of the 11 participants who completed the questionnaire, five (45.5%) reported suboptimal understanding of the goals and effects of TRT at the time of puberty induction. Furthermore, only 6 (54.5%) and 5 (45.5%) of these 11 participants indicated that they were well informed about the risks and potential side effects of TRT, respectively. Histological analysis of two participants with DHX37 variants suggested early disruption of gonadal development due to the presence of Müllerian remnants in both and undifferentiated gonadal tissue in one. In eight other analyzed participants, no gonadal remnants were found, in line with the BTR diagnosis. LIMITATIONS REASONS FOR CAUTION:The limitations of this study include the relatively small sample size (n = 35) and the few individuals with DHX37 variants (n = 3). Furthermore, data on the SPL were often missing, due to this being undocumented or refused by participants. WIDER IMPLICATIONS OF THE FINDINGS:TRT provides adequate statural growth, even when initiated in late adolescence, thus providing time for physicians to explore the patients' gender identity if needed. However, sufficient and understandable information regarding the effects and side effects of TRT is required throughout the management of these patients. SPL remains suboptimal in many individuals and could be improved by TRT during infancy to mimic the physiological mini-puberty. An environmental origin in some participants is supported by the high incidence of gestational complications (38.2%) and by the three monozygotic twin pregnancies discordant for the BTR phenotype. Individuals with a heterozygous DHX37 variant have a more severe phenotype with severely restricted penile growth until adulthood. Histological analysis confirmed DHX37 as a gonadal development, rather than a BTR-related, gene. STUDY FUNDING/COMPETING INTERESTS:Funding was provided by the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) and by Ghent University Hospital under the NucleUZ Grant (E.D.B.). M.C. and E.D.B. are supported by an FWO senior clinical investigator grant (1801018N and 1802220N, respectively). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER:N/A.

Objectives To improve adult height in pubertal girls with a poor height prediction, treatment with growth hormone (GH) can be used in combination with a gonadotropin releasing hormone agonist (GnRHa), to delay closure of the growth plates. However, there are few studies to support this practice, and they show conflicting results. The objective of this trial is to assess the safety and efficacy of this combination treatment in early pubertal girls with a short predicted height, in comparison with matched controls. Design, patients, and methods We designed an open-label, multicenter, interventional case-control study. Early pubertal girls with predicted adult height (PAH) below -2.5 SDS, were recruited in tertiary care centers in Belgium. They were treated for four years with GH and GnRHa. The girls were followed until adult height (AH) was reached. AH vs PAH, AH vs Height at start, and AH vs Target Height (TH) were evaluated, as well as safety parameters. Control data were assembled from historical patient files or from patients who preferred not to participate in the study. Results Sixteen girls with mean age ( ± SD) at start of 11.0 years (± 1.3) completed the study protocol and follow-up. Their mean height ( ± SD) increased from 131.3 ± 4.1 cm (-2.3 ± 0.7 SDS) at start of treatment to 159.8 ± 4.7 cm (-1.1 ± 0.7 SDS) at AH. In matched controls, height increased from 132.3 ± 4.2 cm (-2.4 ± 0.5 SDS) to 153.2 ± 3.4 cm (-2.1 ± 0.6 SDS) (p<0.001). AH surpassed initial PAH by 12.0 ± 2.6 cm in treated girls; and by 4.2 ± 3.6 cm in the controls (p<0.001). Most treated girls reached normal adult height (>-2SD) (87.5%) and 68.7% reached or superseded the target height (TH), which was the case in only a minority of the controls (37.5% and 6.2%, respectively) (p= 0.003 and 0.001). A serious adverse event possibly related to the treatment, was a fracture of the metatarsals. Conclusion A four-year GH/GnRHa treatment in early pubertal girls with a poor PAH seems safe and results in a clinically relevant and statistically significant increase in AH compared with matched historical controls. Clinical trial registration ClinicalTrials.gov , identifier NCT00840944.

Background: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.

Obesity is the most prevalent chronic disease worldwide. The negative impacts of weight excess and obesity are considerable at the individual and collective levels, spreading across physical, menta...

• Nutrition is one of the principal regulators of circulating IGF-I. Many mechanisms are involved in the nutritional regulation of IGF-I. • Both energy and protein are critical to the regulation of serum IGF-I concentrations. After fasting, adequate energy and protein are necessary for restoration of serum IGF-I, but energy may be somewhat more important than protein. While a low intake of protein is able to increase IGF-I in the presence of adequate energy, there is a threshold requirement of energy below which optimal protein intake fails to raise IGF-I after fasting. • The decline of serum IGF-I during dietary restriction is independent of diet-induced alterations in pituitary GH secretion. In severe dietary restriction (fasting), a marked decrease in the number of liver somatogenic receptors suggests that a GH receptor defect is involved in the decline of serum IGF-I. In protein restriction, the decline of serum IGF-I results from a postreceptor defect in GH action at the hepatic level. • Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression results from both transcriptional and posttranscription mechanisms. • Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs. • The molecular mechanisms leading to the decline of IGF-I in catabolic stress seem to be similar to those operational in food deprivation. • Nutrients may also control the biological action of IGF-I, either directly or indirectly, through changes in IGFBPs.

Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward-seeking behaviour and the sleep/wake cycle. Prader-Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food-seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.

Objective: Several criteria for first-year growth response (FYGR) to growth hormone (GH) treatment have been proposed. We explored which FYGR criteria predicted best the final height outcome after GH treatment in prepubertal children with GH deficiency (GHD).Design and methods: Height data of 129 GHD children (83 boys) who attained adult height and had been treated with GH for at least 4 consecutive years with at least 1 year before pubertal onset, were retrieved from the Belgian GH Registry. The FYGR parameters were: (1) increase in height (ΔHt) SDS, (2) height velocity (HV) SDS, (3) ΔHV (cm/year), (4) index of responsiveness (IoR) in KIGS prediction models, (5) first-year HV SDS based on the KIGS expected HV curve (HV KIGS SDS), (6) near final adult height (nFAH) prediction after first-year GH treatment. Poor final height outcome (PFHO) criteria were: (1) total ΔHt SDS <1.0, (2) nFAH SDS <−2.0, (3) nFAH minus midparental height SDS <−1.3. ROC curve analyses were performed to define the optimal cut-off for FYGR parameters to predict PFHO. Only ROC curves with an area under the curve (AUC) of more than 70% were further analyzed.Results: Twelve, 22 and 10% of the children had respectively a total ΔHt SDS <1, nFAH SDS <−2, and nFAH minus midparental height SDS <−1.3. The AUC's ranged between 73 and 85%. The highest AUC was found for first-year ΔHt SDS to predict total ΔHt SDS <1, and predicted nFAH SDS to predict nFAH SDS <−2. The currently used FYGR criteria had low specificities and sensitivities to detect PFHO. To obtain a 95% specificity, the cut-off value (and sensitivity) of FYGR parameters were: ΔHt SDS <0.35 (40%), HV SDS <−0.85 (43%), ΔHV <1.3 cm/year (36%), IoR <−1.57 (17%), HV KIGS SDS <−0.83 (40%) to predict total ΔHt SDS <1; predicted nFAH SDS (with GH peak) <−1.94 (25%), predicted nFAH SDS (without GH peak) <−2.02 (25%) to predict nFAH SDS <−2. At these cut-offs, the amount of correctly diagnosed poor final responders equals the amount of false positives.Conclusion: First-year growth response criteria perform poorly as predictors of poor final height outcome after long-term GH treatment in prepubertal GHD children.

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

Our aim was to analyze a cohort of patients with childhood-onset growth hormone deficiency (GHD) to evaluate if there is some correlation between the response to GH treatment during childhood and adulthood, respectively. This was an observational retrospective monocentric cohort study of 47 patients treated with GH during childhood and adulthood. Changes in growth parameters during childhood were compared with the increase of IGF-I z-score and other indexes of GH response (body composition, lipid profile) after 1 year of treatment in adulthood. The only significant positive correlation was observed between final growth velocity during the last year of childhood GH treatment and increase in IGF-I z-score in GH-treated adults (r=0.592, p=<0.01). No correlation was observed between growth-promoting effects of GH as child and metabolic changes induced by GH as adult. We also observed a negative correlation between weight at the end of childhood GH treatment and the IGF-I response during first year of treatment in adults (r=-0.335, p <0.05). No significant positive correlation could be observed between the main parameters that evaluate response to GH treatment in children and adults. However, the final growth velocity, which may be considered as one of the main criteria of end of GH treatment in children, was identified as parameter that could predict future response to GH treatment in adulthood.

Summary Objective Despite lymphocytic or autoimmune infundibuloneurohypophysitis ( INH ) is an increasingly recognized aetiology in children with central diabetes insipidus (CDI); clinical data on epidemiology (clinical evolution, predisposing factors, complications), diagnosis and management of this entity are limited and mostly based on published case reports. The aim of this study was to gain a broader insight in the natural history of this disease by analysing the clinical presentation, radiological pituitary stalk changes, associated autoimmunity and hormonal deficiencies in children with CDI and a self‐limiting or transient stalk thickening ( ST ), diagnosed as autoimmune infundibuloneurohypophysitis, during the last 15 years in four Belgian university hospitals. Design and Patients The medical files of nine CDI patients with a ST at initial presentation and no signs of Langerhans cell histiocytosis or germinoma at presentation and/or during follow‐up of more than 1.5 years were reviewed. Results Age at presentation ranged from 3 to 14 years. Two patients had a positive family history of autoimmunity. Three children presented with associated growth failure, two with nausea and one with long‐standing headache. Median maximal diameter of the stalk was 4.6 mm (2.7‐10 mm). Four patients had extra‐pituitary brain anomalies, such as cysts. One patient had central hypothyroidism, and another had a partial growth hormone deficiency at diagnosis. Within a mean follow‐up of 5.4 (1.5‐15) years, stalk thickening remained unchanged in two patients, regressed in one and normalized in six children. CDI remained in all, while additional pituitary hormone deficiencies developed in only one patient. Conclusions In this series of children INH with CDI as initial presentation, CDI was permanent and infrequently associated with anterior pituitary hormone deficiencies, despite a frequent association with nonstalk cerebral lesions.

The cover image, by J. Schaefers et al., is based on the Original Article Clinical presentation and outcome of children with central diabetes insipidus associated with a self-limited or transient pituitary stalk thickening, diagnosed as infundibuloneurohypophysitis, DOI: 10.1111/cen.13362.

Background: The aim of our study was to determine the influence of routine ketone monitoring on hyperglycemic events (HE) and ketosis in youngsters with type 1 diabetes (T1D). Methods: Our single-site, controlled and randomized study was conducted on children and adolescents with T1D outside of remission phase. During two crossover periods of 6 months, patients ( n = 22) experiencing HE tested ketones alternatively with a blood ketone meter or urine ketone test strips and gave their opinion on screening methods after completion of clinical trial. Moreover, we evaluated levels of awareness of ketone production in a series of 58 patients and sometimes parents via a multiple-choice questionnaire. Results: Based on self-monitoring data, patients experienced a mean of 4.8 HE/month (range 0–9.3). Patients performed accurate ketone tests more frequently during urine (46%) than during blood-testing (29%) periods ( p < 0.05); while globally, 50% of ketone tests were inaccurate (i.e. without HE). Ketosis occurred significantly more often during urine (46.4%) than during blood (14.8%) monitoring ( p = 0.01), although no episodes of diabetic ketoacidosis (DKA) were noticed. Duration of hyperglycemia was not different whether patients measured ketones or not, suggesting that ketone monitoring did not affect correction of glycemia. Patients evaluated blood monitoring more frequently as being practical, reliable, and useful compared with urine testing. Scores in the awareness questionnaire were globally low (36.8%) without difference between patients and their parents. Conclusions: Although our study shows differences in outcomes (e.g. accurate use, detection of ketosis) of urine versus blood ketone monitoring, these did not affect the occurrence of HE. Whereas ketone monitoring is part of standardized diabetes education, its implementation in daily routine remains difficult, partly because patient awareness about mechanisms of ketosis is lacking.

In a written survey with a low response rate, GH treated SGA girls were found to have the lowest HQoL. Females and children with the lowest height gain GH appear most at risk for presenting the lowest HQoL under GH therapy. The potential benefit of growth hormone (GH) therapy on health-related QOL (HQoL) of children with short stature related to GH deficiency (GHD) or smallness for gestational age (SGA) has not been well documented. We therefore assessed potential disease and treatment related predictors for a poor HQoL in GH treated children. Children with male gender, SGA disorder, greater height deficit and poor height gain were expected to be at risk.. The QoLISSY questionnaire a cross-culturally developed height specific instrument was sent by mail to 157 children with idiopathic GHD and 219 non-syndromic SGA children, between 8 and 18 years old, being treated for at least one year with GH for short stature ( height SDS < -2.5) at a Belgian GH treatment center. The questionnaires were filled out by the child. Response rate was 20.5%. Clinical and growth data were retrieved from the BESPEED database for GH treated children. 3. Results

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS.