2026-07-29 | Challenges in managing endocrine and metabolic dysfunction in a child with Prader-Willi syndrome and medulloblastoma.
Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by severe hyperphagia, early-onset obesity, developmental delay, behavioral disturbances, and multiple endocrine dysfunctions. Clinical management is especially challenging when complicated by central nervous system tumors, which can further exacerbate hypothalamic dysfunction with consequent endocrine and metabolic complications. We present a clinically complex case of a girl with genetically confirmed PWS who developed medulloblastoma, requiring neurosurgical resection, craniospinal radiotherapy, and chemotherapy. Subsequent management was complicated by severe obesity, insulin resistance with impaired glucose tolerance, central hypothyroidism, adrenal insufficiency, and progressive neurological decline with severe obstructive sleep apnea. Key clinical challenges highlighted include the cautious re-initiation of growth hormone therapy post-oncological treatment, carefully balancing its metabolic and growth benefits, alongside multidisciplinary strategies to manage severe obesity-related endocrine and metabolic dysfunction. This case describes the co-existence of PWS and medulloblastoma, highlighting important clinical considerations that may inform management strategies and optimize outcomes in similarly complex situations.
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2026-07-23 | Carbetocin Nasal Spray for the Treatment of Hyperphagia in Prader-Willi Syndrome: Results From the Randomized, Placebo-Controlled, Phase 3 Compass PWS Study.
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. The oxytocinergic system represents one of the key neural circuits that is dysfunctional in PWS, making it an attractive therapeutic target. The oxytocin analog carbetocin has a longer half-life and greater receptor selectivity than oxytocin and showed therapeutic potential in the phase 3 CARE-PWS study (ClinicalTrials.gov NCT03649477) based on nominally significant improvements in hyperphagia and anxiousness with the 3 times daily (TID) 3.2-mg dose of intranasal carbetocin over placebo. The phase 3 placebo-controlled COMPASS PWS study was conducted to confirm the potential benefit observed with carbetocin in the CARE-PWS study. In the 12-week COMPASS PWS study (ClinicalTrials.gov NCT06173531), 175 participants were randomized 1:1 to carbetocin 3.2 mg TID nasal spray (n = 85) and placebo (n = 90). The primary efficacy endpoint was the change from baseline at week 12 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Secondary efficacy endpoints were the change in the Clinical Global Impression-Severity (CGI-S) score for PWS, and in the CGI-S for hyperphagia in PWS score from baseline at week 12, the CGI-Change for PWS score at week 12, and the percentage of participants with a treatment response (defined as improvement from baseline ≥8 points) based on the HQ-CT at week 12. Exploratory efficacy endpoints included the change from baseline at week 12 in scores for the PWS Anxiousness and Distress Behaviors Questionnaire. The least squares mean change (standard error) from baseline at week 12 in the HQ-CT was -4.8 (0.8) and -5.1 (0.8) in the carbetocin and placebo groups, respectively; the treatment difference of 0.3 (95% confidence interval: -1.8, 2.4; P = 0.79) was not statistically significant. There was no separation between carbetocin and placebo for any secondary or exploratory endpoint. The most frequently reported treatment-emergent adverse events in the carbetocin-treated participants were headache (n = 6 [7.2%]) and pyrexia (n = 5 [6.0%]). Carbetocin nasal spray did not demonstrate efficacy compared with placebo for hyperphagia in PWS in the 12-week COMPASS PWS study.
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2026-07-23 | Prader Willi Syndrome with Maternal Uniparental Disomy Mutation in a 7-year- old Nigerian girl- A Case Report.
Prader-Willi Syndrome (PWS) is one of the earliest cases of human genetic imprinting of parental origin involving chromosome 15, with an incidence of 1:10000-30000 per live births. Symptoms of PWS are erratic, beginning early in life with difficulty in feeding and failure to thrive and evolving into new characteristics such as obesity as age advances. Reported here is a case of a 7-year-old girl who presented at the pediatric endocrinology clinic with a 4-year history of progressive weight gain, voracious appetite, snoring during sleep, and poor academic performance. She had feeding difficulties, growth failure, and delayed developmental milestones in the first year of life. This was managed with a fortified diet till she was 3 years of age, when she started eating voraciously and was gaining weight increasingly. Medical history, characteristic facial appearance, and anthropometry measurements at presentation were suggestive of Prader-Willi Syndrome, which was confirmed with DNA analysis. She is currently on dietary modification and planned exercises, and she lost 3 kg over a period of eight months. She is also receiving assisted learning both at school and at home. Prader-Willi syndrome should be considered in a child with initial growth failure that subsequently translates into progressive weight gain following excessive eating and cognitive impairment. Early commencement of lifestyle intervention could help in reducing excessive weight gain. This case confirms limited awareness and insufficient recognition of this rare clinical syndrome. To our knowledge, this is the first genetically confirmed case of PWS in Nigeria.
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2026-07-08 | Integrated multi-platform genetic profiling reveals dual molecular pathology in 46, XY disorders of sex development through NR5A1 Haploinsufficiency and maternal chromosome 15 UPD.
Dual molecular diagnoses involving concurrent monogenic variants and imprinting disorders are increasingly recognized in complex phenotypes, yet systematic approaches to elucidate such convergence remain limited. We report a 46,XY proband with disorders of sex development (DSD), global developmental delay, and clinical features suggestive of Prader-Willi syndrome (PWS). We performed whole-exome sequencing (WES) to identify sequence-level variants. Upon detection of copy-neutral loss of heterozygosity (CN-LOH), we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to assess imprinting status and performed single-nucleotide polymorphism (SNP) microarray to characterize the extent and allelic architecture. WES identified a maternally inherited heterozygous deletion spanning exons 2-7 of NR5A1, classified as likely pathogenic based on its predicted loss-of-function impact on this dosage-sensitive transcription factor. WES also detected a 13.95 Mb CN-LOH at 15q21.1q21.3. MS-MLPA revealed a methylation profile consistent with maternal uniparental disomy of chromosome 15 (UPD(15)), confirming PWS. SNP microarray detected a larger 32.7 Mb CN-LOH across 15q14-q21.3. The combined data support maternal UPD(15) involving mixed heterodisomy and isodisomy, likely arising from meiotic nondisjunction followed by trisomy rescue. An integrated genomic strategy resolved dual etiologies-NR5A1 haploinsufficiency and maternal UPD(15)-underlying complex neurodevelopmental and reproductive features. Demonstrating how integrated analysis of sequence variation, epigenetic regulation, and genome-wide allelic architecture can uncover coexisting monogenic and imprinting mechanisms, this case highlights a diagnostic strategy warranting further evaluation in broader cohorts.
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2026-07-02 | Correlations between endocrine-metabolic characteristics and body fat distribution, appetite, growth, and memory in children with Prader-Willi syndrome.
To explore the correlations between endocrine-metabolic characteristics and body fat distribution, appetite, growth, and memory in children with Prader-Willi Syndrome (PWS). Forty-six children with PWS and forty-six with simple obesity were studied, alongside a healthy control group. Researchers measured physical development, hyperphagia, memory, hormone levels, and lipid profiles. They compared endocrine-metabolic differences across groups and examined correlations between these indicators and body fat, appetite, growth, and memory in children with PWS. The PWS group presented overweight, growth retardation, increased body fat, elevated hyperphagia scores and reduced memory scores relative to simple obesity and healthy control groups, with distinct plasma metabolic and endocrine profiles (higher ghrelin, Triglycerides [TG], Total Cholesterol [TC], Low-Density Lipoprotein Cholesterol [LDL-C], Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] and C-peptide; lower Insulin-like Growth Factor-1 [IGF-1], Triiodothyronine [T3], Thyroxine [T4], Thyroid-Stimulating Hormone [TSH] and High-Density Lipoprotein Cholesterol [HDL-C]). Correlation analyses confirmed positive associations of ghrelin, cortisol, and HOMA-IR with Fat Mass Index (FMI); of cortisol and HOMA-IR with hyperphagia score; of TSH, TG, HOMA-IR, and C-peptide with Body Mass Index (BMI); and of IGF-1 and T3 with memory score, as well as negative associations of IGF-1 with FMI and hyperphagia score; of HDL-C with BMI; and of ghrelin with memory score (all p < 0.05). Children with PWS present major endocrine-metabolic abnormalities associated with abnormal body fat, hyperphagia, growth retardation, and memory impairment, which help clarify multisystem damage in hereditary obesity and guide targeted clinical interventions.
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