This site complies with the HONcode standard for trustworthy health information:
verify here.

Central Adrenal Insufficiency, Pituitary and Neuroradiological Alterations in Prader-Willi

« Back to Volume 24, Issue 2, November 2008 - Table of Contents

Prader-Willi syndrome (PWS; OMIM 176270) is a genetic disorder caused by an alteration in the long arm of paternal chromosome 15 (by deletion, microdeletion, maternal uniparental disomy, mutation of imprinting centre, chromosomal rearrangement). PWS is characterized by a complex clinical picture (short stature, uncontrollable hyperphagia, obesity, hypogonadism) and growth hormone deficiency that seem to be a central hypothalamic/pituitary dysfunction.

The annual death rate of PWS patients is very high (3%). Many of these deaths are sudden and unexplained. Because most deaths occur during infections and PWS patients suffer from various hypothalamic insufficiencies, de Lind van Wijngaarden and colleagues investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Twenty-five children genetically confirmed PWS were randomly selected. Twelve patients had paternal deletion (63%), 6 had maternal disomy (32%), and one an imprinting center mutation (5%). Median age of patients with PWS was 9.7 years (range 3.7 to 18.6 years). All were treated with recombinant human growth hormone (rhGH). Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were also assessed on a different day at wake-up, 30 minutes after wake-up, at 1400 h, and at 2000 h. Fifteen patients (60%) showed an insufficient ACTH response at the metyrapone test. There was no significant difference in age, gender, genotype, and BMI SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions.

Moreover, Iughetti and colleagues retrospectively analyzed 91 patients with PWS (42 females, 49 males; age range 0.7 to 16.8 years) by cerebral MRI to determine whether there was any diminution in the anterior pituitary gland or other neuroradiological alterations. All subjects were genetically confirmed as PWS (58 microdeletions, 8 deletions, 28 maternal uniparental disomy). Of these 91 patients, MRI analysis showed a reduction in pituitary height (height <1 SD) in 45 patients (49.4%: 23 cases <2 SD; 20 males, 25 females) with 4 cases of empty sella, a complete absence of the posterior pituitary bright spot in 6 patients (6.6%) and other neuroradiological alterations in 10 patients (11%: 8 cases of ventricular enlargement, 2 cases of thin corpus callosum). Altogether, neuroradiological alterations were present in 61 of the 91 (67%) patients. No genotype-phenotype relationship was shown. These results of both de Lind van Wijngaarden and Iughetti indicate that CAI and neuroradiological alterations are more frequent in PWS patients than has been reported to date.

de Lind van Wijngaarden RF, Otten BJ, Festen DAM, et al. High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93:1649-54.

Iughetti L, Bosio L, Corrias A, et al. Pituitary height and neuroradiological alterations in patients with Prader-Labhart-Willi syndrome. Eur J Pediatr. 2008;167:701-2.

Editor’s Comment

These are very interesting observational studies, which provide important information for physicians who care for those with PWS. Strikingly, de Lind van Wijngaarden and colleagues reported 60% of PWS patients had CAI; the high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Because metyrapone blocks cortisol synthesis, it causes a sudden increased demand for ACTH production, a situation mimicking stress. Patients with an insufficient ACTH response during the metyrapone test are therefore considered as having CAI during stressful conditions such as infection and surgery. In view of the importance of an adequate function of the hypothalamus-pituitary-adrenal axis for survival, the high prevalence of CAI may be an explanation for the high death rate in PWS patients. In addition to CAI, the condition of acutely ill PWS patients is further compromised by an increase in those with sleep apnea and sudden death during upper respiratory infection. Therefore, de Lind van Wijngaarden and colleagues stated that PWS patients should be considered to have CAI during stress until proven otherwise with a metyrapone test and they recommended hydrocortisone treatment for PWS patients during stressful conditions including mild upper respiratory infections.

From these results, both neuroradiological alterations and CAI may relate mutually and may be important risk factors for a tendency of sudden, unexpected death in PWS patients. Further studies, including functional and longitudinal neuroradiological investigation, are needed to clarify these problems in PWS patients.

Yoshikazu Nishi, MD

« Back to Volume 24, Issue 2, November 2008 - Table of Contents

Last Updated: 6/12/2009