Dampened surge in heart rate at respiratory event termination in children with Prader-Willi syndrome.

The analysis of individual cognitive profiles and the assessment of executive function components contributes to abetter understanding of the problems that children, adolescents, and adults with intellectual disabilities experience in coping with social demands. Characteristic profiles and abnormalities in executive functions in Down syndrome, fragileX syndrome, and Prader-Willi syndrome are described. These examples illustrate associations with psychological problems-so-called behavioral phenotypes-in children, adolescents, and adults with these genetic syndromes.

Prader–Willi syndrome (PWS) is a neuroendocrine disorder characterized by hypothalamic dysfunction, congenital hypotonia, abnormal growth trajectories, and impaired pubertal development, all of which contribute to a markedly increased risk of scoliosis, with a cumulative prevalence reaching up to 70–80% by skeletal maturity, significantly exceeding that of idiopathic scoliosis. Unlike idiopathic scoliosis, spinal deformity in PWS follows a distinct bimodal pattern, with critical vulnerability during infancy and a second acceleration during pubertal transition. Growth hormone (GH) therapy, a cornerstone of PWS management, substantially improves linear growth, body composition, and muscle strength, yet its relationship with scoliosis onset and progression remains a clinical challenge due to the potential for accelerated growth during critical developmental windows, which may unmask or exacerbate underlying spinal instability. Current scoliosis surveillance strategies in PWS are largely extrapolated from idiopathic scoliosis and fail to account for the unique neuroendocrine and biomechanical context of this syndrome. In particular, endocrine modifiers such as GH treatment status, growth velocity, hypogonadism, pubertal stage, body composition, and genotype-specific phenotypes are rarely integrated into structured monitoring protocols. In this narrative review, we synthesize epidemiological, mechanistic, and clinical evidence to elucidate the neuroendocrine and biomechanical pathways underlying scoliosis development in PWS, including the roles of hypotonia-related instability, altered vertebral growth modulation, and delayed epiphyseal maturation. We critically examine the dualistic effects of GH therapy, the impact of pubertal maturation, and genotype–phenotype associations as key determinants of scoliosis risk and progression. Building on this evidence, we propose an endocrine-informed, risk-stratified scoliosis monitoring framework that integrates growth dynamics, hormonal status, body composition, and spinal parameters to guide surveillance intensity, imaging strategies, and multidisciplinary referral. By shifting the focus from isolated curve detection to longitudinal, endocrine-guided surveillance, this review provides a clinically actionable model to optimize early identification and management of scoliosis in children and adolescents with PWS. This framework aims to support coordinated endocrine–orthopedic care and inform future prospective studies designed to refine outcome measures and ultimately improve long-term musculoskeletal and quality-of-life outcomes in this vulnerable population.

Hypercoagulability in Prader-Willi Syndrome: A case-control study exploring coagulation profiles and thrombotic risk.

Narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) are rare, chronic neurologic disorders of hypersomnolence. Narcolepsy type 1 results from the selective loss of orexin-producing neurons, leading to markedly reduced levels of orexin neuropeptides in the brain and CSF. NT2 shares some symptoms with the former but has no orexin deficiency. Both disorders manifest as a spectrum of debilitating symptoms, including excessive daytime sleepiness (EDS), cataplexy (NT1 only), fragmented nocturnal sleep, sleep paralysis, and hallucinations. Diagnosis is particularly challenging, especially in pediatric patients. We describe 7 pediatric patients presenting with complex narcolepsy phenotype of EDS or cataplexy with a diverse array of comorbid genetic, neurologic, and neuropsychiatric conditions. These cases illustrate the diagnostic challenges in differentiating "primary narcolepsy" from "narcolepsy because of a medical disorder" (e.g., Prader-Willi Syndrome) or "narcolepsy associated with autism spectrum disorder or very early-onset schizophrenia." The patients underwent a comprehensive diagnostic workup, including polysomnography, multiple sleep latency testing (performed after wash-out of concomitant medications), brain magnetic resonance imaging, CSF hypocretin-1 assay, and, in case of consistent clues, autoimmune, and genetic testing. Ensuring accurate and prompt narcolepsy diagnosis allows effective and patient-centered management.

Prader-Willi syndrome is a rare neuroendocrine genetic disorder that causes hypothalamic dysfunction, hyperphagia, and morbid obesity. Early diagnosis is critical to prevent life-threatening complications. This case report details the fatal outcome of a patient with late-diagnosed Prader-Willi syndrome, highlighting the consequences of diagnostic delay and management challenges in a low-resource setting. A 17-year-old Asian male individual with a known diagnosis of Prader-Willi syndrome (confirmed by multiplex ligation-dependent probe amplification at age 15 years) presented to the emergency department with acute respiratory distress, generalized edema, and decreased urinary output. His medical history was significant for premature birth, hyperphagia from early childhood, morbid obesity (body mass index 40.63 kg/m2), type 2 diabetes mellitus, hypertension, and social withdrawal. Despite a prior admission 3 months earlier, where he was stabilized with noninvasive ventilation, metformin, glucagon-like peptide-1 agonists, enalapril, and dietary planning, he was lost to follow-up. On readmission, he was in severe respiratory failure (SpO2 46% on room air) with acidosis. Physical examination revealed tachycardia, tachypnea, cyanosis, bilateral pitting pedal edema, and crepitations on lung auscultation. Investigations confirmed severe pneumonia, metabolic acidosis, and poorly controlled diabetes. Despite aggressive interventions, including mechanical ventilation and intravenous antibiotics, the patient suffered a fatal cardiorespiratory arrest. This case underscores that late diagnosis of Prader-Willi syndrome can lead to irreversible, fatal complications. A multidisciplinary management plan is insufficient without addressing profound socioeconomic and educational barriers that hinder its execution. The delay in diagnosis prevented life-changing interventions such as growth hormone therapy. This report emphasizes the need for early diagnosis and holistic, family centered care adapted to the patient's socioeconomic reality to prevent such adverse outcomes.

Schaaf-Yang syndrome and Prader-Willi syndrome are imprinting disorders that result from the disruption of paternally expressed genes within the 15q11-q13 region. Both conditions present with overlapping clinical features including developmental delay, hypotonia and endocrine abnormalities. Schaaf-Yang syndrome specifically results from heterozygous variants in the paternally expressed MAGEL2 gene. Because these variants are often de novo, determining that the variant is on the paternal allele is essential for a definitive diagnosis. Traditional methods, such as methylation-specific PCR, are labour-intensive, while it is challenging to phase variants separated by distances greater than the fragment length (~600 bp) using short-read sequencing. In this study, we used long-read Oxford Nanopore sequencing to perform trio-assisted phasing of a de novo MAGEL2, p.(Gln638Ter) variant identified in two unrelated probands referred for congenital hyperinsulinism genetic testing. Long reads spanning both the variant and informative parental heterozygous variants confirmed that the variant was on the paternal allele and was therefore pathogenic and causative of Schaaf-Yang syndrome and associated with hyperinsulinism in both individuals. Our findings demonstrate the clinical utility of long-read sequencing for enabling trio-assisted variant phasing in imprinting disorders, particularly when phenotypes are incomplete or overlapping. Our findings further highlight congenital hyperinsulinism as a rare but important feature associated with Schaaf-Yang syndrome.

Emergency Department Care for Patients With Prader-Willi Syndrome: A 2019-2021 National Emergency Department Sample Analysis.

We previously showed that hyperphagia affects quality of life of craniopharyngioma (CP) survivors. Characteristics of hyperphagia are unknown. This study aimed to characterize and quantify hyperphagia in CP survivors with and without hypothalamic obesity (HO). Forty caregivers responded to online questionnaires including the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) and Food Safe Zone (FSZ). Caregivers reported significantly more comorbidities in survivors with HO, with 82% presenting with hypothalamic syndrome. Survivors with HO had higher hunger, lower satiety, and higher food preoccupation. Hunger impacted many life aspects with more extreme manifestations described in the HO group. HQ-CT scores were significantly higher in survivors with HO with levels similar to Prader-Willi syndrome (PWS), and were associated with weight status, hunger levels and satiety. HO diagnosis, hyperphagia, and food preoccupation predicted HQ-CT scores. We found that caregivers of survivors with HO used many food safety tactics. FSZ scores were significantly higher in the HO group, associated with survivors’ hunger and satiety levels, HQ-CT, and food preoccupation scores. In conclusion, eating behaviors in CP survivors are on a spectrum of manifestations between normal eating behaviors to severe hyperphagia characteristic of PWS in survivors with HO, calling for early diagnosis in this population.

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with substantial comorbidity and early mortality. However, the epidemiologic burden on Asian populations, particularly in South Korea, remains poorly understood. This study evaluates the nationwide incidence, prevalence, mortality, comorbidities, and healthcare costs of PWS in South Korea. We conducted a retrospective, population-based cohort study using the Korean National Health Insurance Database from 2005 to 2021. Among 2,553 individuals with PWS-related diagnostic codes, 458 patients were included in the study based on predefined criteria incorporating growth hormone therapy (GHT) or methylation-specific PCR testing. Epidemiologic trends, comorbidities, intensive care unit (ICU) admissions, and healthcare expenditures were analyzed. The overall birth incidence was 6.8 per 100,000 live births, with a significant increase evident after 2016. The median age at diagnosis was 1.0 years, and GHT was initiated at a median age of 2.0 years. The all-cause mortality rate was 3.5%, with pneumonia being the leading cause of death. ICU admission occurred in 25.5% of patients, often during infancy. Intellectual disability and/or developmental delay was present in 68.6% of patients, and type 2 diabetes mellitus in 15.1%. The mean cumulative healthcare cost per patient exceeded 86 million Korean won. Comorbidity prevalence and annual medical costs increased steadily over time. This is the first nationwide study to quantify the long-term epidemiological and economic burden of PWS in South Korea. Our findings underscore the need for early diagnosis, integrated care models, and policy support for this complex population.

Initiation of GH therapy was not associated with a change in loop gain, suggesting that changes in ventilatory control are unlikely to contribute to the development of OSA in children with PWS. • Prader-Willi syndrome is associated with abnormal ventilatory control and increased risk of sleep-disordered breathing. • Growth hormone therapy may influence respiratory physiology but its effect on the stability of ventilatory control (loop gain) remains unclear. • In this cohort of children with Prader-Willi syndrome, growth hormone therapy did not alter loop gain despite inter-individual variability. • Our findings suggest that any sleep-disordered breathing that emerges following growth hormone therapy is likely driven by mechanisms other than altered loop gain.

Adult data indicate that hypogonadism is underdiagnosed and undertreated in Prader-Willi Syndrome (PWS). We aimed to describe the spectrum of pubertal development, and the diagnosis and treatment of hypogonadism in paediatric/adolescent patients with PWS. A retrospective cohort study of patients with PWS aged 6-18 years seen at an Australian tertiary paediatric centre between 1 January 1990 and 31 May 2025 (n = 65). Spontaneous puberty onset was achieved in 63% females aged ≥ 8 years and 68% males aged ≥ 9 years with onset at a median age of 10.3 [8.9-12.5] years in females and 12.3 [11.9-14.3] years in males. By last visit, hypogonadism was diagnosed in 77% of females (95% central aetiology, 5% unknown) and 88% of males (73% central aetiology, 27% primary/mixed) at a median age of 14.1 [13.1-15.8] years in females and 15.3 [14.1-15.6] years in males. Pubertal hormone replacement therapy was initiated in 80% females and 60% males, with no significant change in proportion of patients with behavioural/psychiatric issues post treatment. Median femoral neck bone mineral density showed age-adjusted z-score of -1.5 [-2.2 to -0.8] and height-adjusted of -0.9 [-1.6 to 0.3]. Despite approximately two-thirds of adolescents with PWS entering puberty spontaneously, the majority demonstrated hypogonadism before transitioning to adult care, emphasising the need for ongoing pubertal assessment in this population. Aetiology is predominantly central hypogonadism, but there can also be a component of primary hypogonadism. Longitudinal controlled studies are required to determine optimal detection of hypogonadism and timing of pubertal hormone replacement in PWS.

ObjectivesObesity management has limited oral pharmacotherapies. Bitter taste receptor (TAS2R) agonists may modulate hunger, satiety, and metabolism via gut-brain signaling. We evaluated denatonium acetate (DA), a gut-restricted TAS2R agonist, across preclinical and clinical settings, and explored its combination with sitagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor).MethodsIn mice transitioned to high-fat diet (HFD) or established with diet-induced obesity (DIO), we tested oral DA (20–80 mg/kg twice daily or 75 mg/kg once daily), a sitagliptin-formulated HFD, the combination, and subcutaneous tirzepatide, including a post-tirzepatide discontinuation phase, to assess weight trajectories and metabolic benefits. In randomized, placebo-controlled clinical studies, ARD-101 (oral DA) was evaluated in adults with obesity (200 mg twice daily for 28 days) and in healthy participants (single 800 mg).ResultsIn mice transitioned to HFD, DA reduced weight gain (up to 43.1%), decreased food intake, and improved glucose and lipid measures. In DIO mice, once-daily DA or sitagliptin-HFD prevented weight gain; the combination reduced body weight (−18.8%) with metabolic benefits. In a separate DIO mouse study, tirzepatide reduced weight by 23.7%. Following tirzepatide discontinuation, switching to DA plus sitagliptin-HFD limited weight regain comparable to continued tirzepatide. In adults with obesity, ARD-101 reduced weight versus placebo by 0.8 kg at Day 28 and 1.3 kg at end-of-study and decreased hunger and food cravings. It also altered gut hormone levels in healthy participants.ConclusionsGut-restricted TAS2R agonism warrants further study for hyperphagia in Prader–Willi syndrome, and in combination with DPP-4 inhibition for obesity.Clinicaltrials.gov numberNCT05121441.Integrated research application system (IRAS) number1011885.

Hyperphagia, overweight and obesity are frequent in people with rare neurodevelopmental disorders (NDDs). Prader-Willi syndrome (PWS) is a rare NDD with hyperphagia and hyperghrelinemia. To measure ghrelin levels, hyperphagia and caregiver burden in rare NDDs patients to understand pathophysiology and improve care. A single-visit, non-interventional, national, multicenter, cross-sectional study. Seven French reference centers for rare NDDs participated. 130 patients (43% children) with a rare genetic NDD (27 distinct conditions) were included. Their median age was 19.8 years. Three control groups were used for comparison: "PWS" (n=153), "Obese" (n= 49), and "Lean" (n=31) groups. The primary endpoint was ghrelin level (total, acylated (AG), unacylated (UAG)). The first secondary endpoint was hyperphagia questionnaire (HQ) scores. Median total ghrelin levels were 76.7 [22.2-1110.9] pg/mL; median AG levels were 33.7 [8.0-754.3] pg/mL; and median UAG levels were 44.2 [11.5-356.6] pg/mL, which were lower than the PWS group (p<0.001) and no different from the Obese group. The mean HQ total score was 26.3 [10-46] for children and 24.0 [11-52] for adults. The HQ total score was statistically higher in children with NDDs and lower in adults compared to PWS. The mean ZBI score was 37.8 [6-74] in children and 37.6 [2-76] in adults, and was positively correlated with the HQ total score. Ghrelin levels were normal in our study population. Hyperghrelinemia is a biomarker of PWS. Hyperphagia is more prevalent and severe in children with NDDs compared with PWS.

Prader-Willi Syndrome (PWS) is a rare genetic developmental disability. The syndrome is generally characterized by mild to moderate intellectual disability, various social/cognitive deficits, and behavioral challenges including rigidity, temper outbursts, and hyperphagia—an extremely overactive and insatiable appetite. Much of the current research being conducted today on PWS is focused on addressing the hyperphagia phenotype. However, there are several gaps in the current literature on the management of hyperphagia in Prader-Willi Syndrome. Firstly, there has still been relatively little success in managing hyperphagia as a behavioral phenotype, and many families must resort to trial and error in managing their child’s extreme food-seeking behaviors. This indicates that this population could benefit from a novel intervention to manage hyperphagic symptoms. Secondly, these interventions should be agency-respecting and therefore individual-centered, not caregiver-centered. Finally, group interventions have produced promising results but have yet to be implemented to manage hyperphagic behaviors. Individuals with PWS are in dire need of an effective intervention that aims to manage the severity of their hyperphagic behaviors. Through this project, I therefore hope to add to previous research findings regarding the efficacy of group interventions in PWS, with the added dimension of measuring the intervention’s effect on hyperphagia. In other words, this project will provide evidence for the efficacy of an online group intervention on the PWS symptom of hyperphagia. I expect that participants who receive the intervention will show a significant improvement in their hyperphagic behaviors.

Case ReportChildren with genetically or clinically confirmed PWS who underwent overnight PSG in our sleep laboratory between 2018 and 2025 were included in the study.The exclusion criteria were

The disproportionate burden of severe obesity in youth with special needs and the role of metabolic and bariatric surgery.

Severity and phenotype of sleep-disordered breathing in Prader-Willi syndrome compared to obstructive sleep apnea syndrome in children.

Abstract: According to OMIM and Orphanet databases, Schaaf-Yang syndrome (SYS) (OMIM: 615547, ORPHA: 398069) is a rare genetic disorder that shares certain clinical features with Prader-Willi syndrome (PWS), including hypotonia, developmental delay, and early-onset obesity. However, SYS often exhibits a more complex and variable phenotype. Missense variants in MAGEL2 have been reported only rarely, and their phenotypic spectrum appears milder and more variable than that of truncating mutations. Data on early-onset obesity as a dominant feature in such patients are limited. In this case report, we describe a child with mild phenotype (SYS) carrying the novel missense variant MAGEL2(NM_019066.5) :c.1265C>T (p.Pro422Leu) presenting with severe early-onset obesity and a comparatively neurodevelopmental phenotype. We present a case of a boy with neonatal hypotonia, diagnosed with (SYS) at age 9 years, with follow-up to age 11 years. The boy was born at 34+3 weeks of gestation with hypotonia, feeding difficulties, and a persistent ductus arteriosus that required surgical ligation in early infancy. In the following years, he developed severe early-onset obesity, already evident by age 2 despite multidisciplinary care. Genetic testing performed at age 9 years identified a novel missense variant (NM_019066.5)c.1265C>T in the MAGEL2 gene, which was not inherited from his mother, thereby confirming the diagnosis of (SYS). At the time of the most recent evaluation, at age 11 years, he remained under long-term follow-up. Clinical management over this period included endocrine therapy, cardiac surgery, physical rehabilitation, and dietary interventions, and despite the complexity of his condition, long-term stabilization of his BMI percentile was achieved with consistent non-pharmacological interventions. This case highlights the importance of early multidisciplinary investigation and intervention in SYS, particularly when obesity is the dominant feature. Effective long-term weight stabilization is possible through structured lifestyle management. Keywords: Schaaf-Yang syndrome, pediatric obesity, MAGEL2 mutation, hypothyroidism, developmental delay, physical activity

To enhance the diagnosis, management, and monitoring of Chinese children with chromosome 15q11-q13 duplication syndrome (dup15q) by analyzing their genetic and clinical characteristics. In this study, one Chinese prenatal case and 21 postnatal cases genetically diagnosed with dup15q syndrome underwent a detailed assessment of genetic and clinical characteristics. Most patients had normal prenatal (12/22, 54.5%) and neonatal (14/21, 66.7%) histories. Most symptoms were developmental delays (motor: 18/21, 85.7%; cognition: 13/21, 61.9%; language: 12/21, 57.1%). Other common features included autism spectrum disorder (ASD)-related behaviors (10/21, 47.6%) and seizures (7/21, 33.3%). Trisomy microduplications accounted for 54.5% (12/22), and tetrasomy microduplications accounted for 40.9% (9/22) of cases. We compared the phenotypic differences between the two groups using a composite score. One rare case of paternal duplication presented with early-onset obesity and tapered fingers resembling Prader-Willi syndrome (PWS). In addition, non-invasive prenatal testing (NIPT) detected int dup(15) in prenatal cases. Some patients with epilepsy were well controlled without anti-seizure drugs or monotherapy (3/7, 42.8%), while others had refractory epilepsy. Chinese children with dup15q exhibited high clinical heterogeneity, including multisystem developmental delays, ASD-related symptoms, and seizures. Phenotypic severity is influenced by multiple factors. NIPT may show positive findings, and chromosomal microarray analysis (CMA) combined with methylation analysis is important.