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Objective: This study assessed the effect of 1‐year administration of diazoxide choline extended‐release tablet (DCCR) on hyperphagia and other complications of Prader‐Willi syndrome (PWS). Methods: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open‐label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ‐CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. Results: DCCR administration resulted in significant improvements in HQ‐CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ‐CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment‐emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). Conclusions: DCCR administration to people with PWS was well tolerated and associated with broad‐ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families. [ABSTRACT FROM AUTHOR]

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0–18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0–4 and 0–16 years. HCH‐specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials. [ABSTRACT FROM AUTHOR]

Context: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. Objective: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. Methods: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. Results: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P=.198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P=.012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P=.029; fat mass; P=.023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P=.037) and secondary end points were all improved (CGI-I; P=.015; Caregiver Global Impression of Change; P=.031; fat mass; P=.003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). Conclusion: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that children with Prader-Willi syndrome (PWS) and obstructive sleep apnoea syndrome (OSAS) have hypercapnia for higher proportion of total sleep time (TST) than non-syndromic children with similar obstructive apnoea-hypopnoea index (OAHI).Design: Cross-sectional study.Setting: Two tertiary care hospitals.Patients: Patients with PWS and non-syndromic children with snoring who underwent polygraphy and were of similar age, body mass index (BMI) z-score and OAHI.Main Outcome Measure: The two groups were compared regarding %TST with transcutaneous CO2 (PtcCO2) >50 mm Hg. The interaction between PWS diagnosis and OSAS severity (OAHI <1 episode/h vs 1-5 episodes/h vs >5 episodes/h) regarding %TST with PtcCO2 >50 mm Hg was tested using multiple linear regression.Results: 48 children with PWS and 92 controls were included (median age 2.3 (range 0.2-14.1) years vs 2.2 (0.3-15.1) years; BMI z-score 0.7±1.9 vs 0.8±1.7; median OAHI 0.5 (0-29.5) episodes/h vs 0.5 (0-33.9) episodes/h; p>0.05). The two groups did not differ in %TST with PtcCO2 >50 mm Hg (median 0% (0-100%) vs 0% (0-81.3%), respectively; p>0.05). However, the interaction between PWS and OSAS severity with respect to duration of hypoventilation was significant (p<0.01); the estimated mean differences of %TST with PtcCO2 >50 mm Hg between children with PWS and controls for OAHI <1 episode/h, 1-5 episodes/h and >5 episodes/h were +0.2%, +1% and +33%, respectively.Conclusion: Increasing severity of upper airway obstruction during sleep in children with PWS is accompanied by disproportionately longer periods of hypoventilation when compared with non-syndromic children with similar frequency of obstructive events. [ABSTRACT FROM AUTHOR]

Background: Kisspeptin is a hypothalamic neuropeptide playing a physiological role in human reproduction. Genetic over-activation of kisspeptin causes precocious puberty in children. Concentrations of circulating kisspeptin are low in adults. The concentrations of plasma kisspeptin in boys and girls have not been studied previously. Methods: Blood was obtained from 51 children and 63 adults. Plasma samples were analysed using radioimmunoassay. Children were aged 2-18 years, and attending hospital for a medically requested blood test unrelated to reproductive development. Data on pubertal status were not collected due to ethical reasons. Results: Mean plasma kisspeptin was significantly higher in children when compared with adults (mean plasma kisspeptin in pmol/L: 12.3±0.9, adults; 40.9±3.3, children, P<0.001 vs. adults). Overall mean concentrations of plasma kisspeptin were not significantly different between sexes (mean plasma kisspeptin in pmol/L: 39.5±3.2, boys; 44.3±6.3, girls, P=0.48). In both sexes, concentrations of plasma kisspeptin increased with age to peak concentrations between 9 and 12 years of age, before decreasing beyond 12 years of age to adulthood. Plasma kisspeptin concentrations were highly significantly elevated in both girls and boys aged 9-12 when compared with adults (mean plasma kisspeptin in pmol/L: 59.5±18.3, girls, P<0.01 vs. adult women; 43.8±6.2, boys, P<0.001 vs. adult men). Conclusions: We report that circulating kisspeptin is elevated in both boys and girls when compared with adults. Furthermore both boys and girls may have distinct, age-dependent concentrations of circulating kisspeptin. Further studies may determine if plasma kisspeptin could be used as a clinically useful biochemical marker of reproductive development in children. [ABSTRACT FROM AUTHOR]