Long-term effects of growth hormone (GH) treatment in young children with Prader-Willi syndrome (PWS) have never been compared with untreated age-matched controls with PWS, and it is unclear if starting GH in the first year of life is safe and more effective than starting GH in early childhood. We investigated the effects of long-term GH on body composition, anthropometrics and cognition in young children with PWS compared to untreated controls and assessed whether starting GH in the first year of life is optimal and safe. An open-label, prospective study was performed, comparing GH-treated children with untreated controls, and comparing children who started GH in the first year of life (subgroup A) with children who started between 2–5 years (subgroup C). A total of 82 GH-treated children with PWS and 22 age-matched controls with PWS were included. The main outcome measures were body composition, anthropometrics, IQ, and safety parameters. After 8 years, GH-treated children had significantly better body composition and were taller than age-matched controls. Subgroup A had a lower FM% trajectory during treatment than subgroup C and showed a greater and longer-term increase in the LBM index. After 8 years, subgroup A had a lower trunk/peripheral fat ratio (p = 0.043) and higher IQ (p = 0.043). No adverse effects of starting GH in the first year were found. Children with PWS who received long-term GH had a better body composition and growth than untreated age-matched controls and starting GH in the first year of life was optimal and safe.

BackgroundPrader-Willi syndrome (PWS) is associated with hypothalamic dysfunction. It has been reported that the HPA axis might show a delayed response during acute stress, and it is unknown whether the response of the HPA-axis during acute stress changes with age in children with PWS.AimTo investigate the HPA-axis response during an overnight single-dose metyrapone (MTP) test in children with PWS and to assess if the response changes with age, whether it is delayed and if it changes with repeated testing over time. In addition, we evaluated different cut-off points of ACTH and 11-DOC levels to assess stress-related central adrenal insufficiency (CAI).MethodsAn overnight single-dose MTP test was performed in 93 children with PWS. Over time, 30 children had a second test and 11 children a third one. Children were divided into age groups (0-2 years, 2-4 years, 4-8 years and > 8 years).ResultsMost children did not have their lowest cortisol level at 7.30h, but at 04.00h. Their ACTH and 11-DOC peaks appeared several hours later, suggesting a delayed response. When evaluated according to a subnormal ACTH peak (13-33 pmol/L) more children had an subnormal response compared to evaluation based on a subnormal 11-doc peak (< 200 nmol/L). The percentage of children with a subnormal ACTH response ranged from 22.2 to 70.0% between the age groups, while the percentage of a subnormal 11-DOC response ranged from 7.7 to 20.6%. When using the ACTH peak for diagnosing acute-stress-related CAI, differences between age groups and with repeated testing over time were found, whereas there was no age difference when using the 11-DOC peak.ConclusionEarly morning ACTH or 11-DOC levels are not appropriate to determine acute stress-related CAI in children with PWS, thus multiple measurements throughout the night are needed for an accurate interpretation. Our data suggest a delayed response of the HPA-axis during acute stress. Using the 11-DOC peak for the test interpretation is less age-dependent than the ACTH peak. Repeated testing of the HPA-axis over time is not required, unless clinically indicated.

Context Most patients with Prader-Willi syndrome (PWS) have a mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS. Objective To investigate the effects of 3 years GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood. Design Open-label, prospective study. Setting Dutch PWS Reference Center Methods Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by Developmental Behavior Checklist – Parents/caregivers (DBC-P). Results 46 young adults with PWS with a median age of 19 (IQR 17–21) years were investigated. Estimated mean (95% CI) total, verbal and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at start and 67 (64-71) after 3 years (p=0.30); Verbal IQ being 65 (62-68) and 66 (62-70), resp. (p=0.31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (p=0.42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (p=0.94) (P50). Conclusions Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.