Central adrenal insufficiency screening with morning plasma cortisol and ACTH levels in Prader-Willi syndrome.

OBJECTIVES: Prader-Willi syndrome (PWS) is a complex genetic disorder with severe hypotonia, failure to thrive, childhood obesity, hypogonadism/hypogenitalism and learning/behavioral problems with endocrine-related growth and other hormone deficiencies. The prevalence of central adrenal insufficiency (CAI) using dynamic testing ranges from rare to 60%. We compared routine morning plasma cortisol (MPC) and ACTH levels in large cohorts of PWS and control children to address CAI. METHODS: Retrospective analysis of MPC and ACTH levels was undertaken in 128 PWS growth hormone (GH)-treated children under medical care before considering dynamic testing for CAI and 128 non-syndromic control children with short stature evaluated for GH deficiency. RESULTS: The average MPC level in PWS was 9.7 ± 3.7 µg/dL with no difference in age, gender or PWS genetic subtype and 13.4 ± 5.7 µg/dL in the control group. MPC levels were significantly lower (p < 0.05) in PWS but in the normal range. The morning plasma ACTH level in the PWS group was 22.1 ± 8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. CONCLUSIONS: MPC levels in PWS are normal and comparable with control children, without evidence or increased risk of CAI. Lower but normal MPC levels were seen in PWS and suggestive of reduced local regeneration of cortisol from cortisone in adipose tissue by the GH-IGF-I system. Hence, MPC measures alone or in combination with ACTH should be considered for initial screening for CAI in PWS but prior to dynamic testing.

Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome.

BACKGROUND: Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS. METHOD: This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant. RESULTS: Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment. CONCLUSION: Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition.

Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment.

Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.