Adrenal function and mortality in children and adolescents with Prader–Willi syndrome attending a single centre from 1991–2009

We read with great interest the paper by de Lind van Wijngaarden et al. in the Journal for Clinical Endocrinology and Metabolism regarding the high prevalence of central adrenal insufficiency (CAI) in patients with Prader–Willi syndrome (PWS), defined as an adrenocorticotrophic hormone (ACTH) level of <33 pmol/l (<8Æ3 mU/l) at 7Æ30 am. following the single-dose administration of metyrapone 30 mg/kg at 11Æ30 pm. the previous evening. The rationale of the metyrapone stimulation test is that the acute inhibition of cortisol synthesis by inhibition of 11b-hydroxlyase mimics the stress situation and causes a sudden increased demand for ACTH production. The authors reported that the ACTH response was insufficient in 15 of 25 (60%) randomly selected PWS outpatients (median age 9Æ7 years) with values of 14–26 vs 49–76 pmol/l in the subnormal and normal groups, respectively. They concluded that the high percentage of CAI might explain the high rate of sudden death in these patients, particularly during infection-related stress, and advised consideration of treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test. The same group suggested in a subsequent paper that the children diagnosed with CAI on the above-mentioned criteria had a higher central apnoea index and lower average overnight SaO2 before metyrapone (20 children/13 with CAI) and a greater increase in obstructive apnoea index than non-CAI children after metyrapone (10 children/6 with CAI). However, the greater increase in central apnoea index in children with CAI after metyrapone did not reach significance owing to the low number of patients. These findings have important implications for PWS management; instituting emergency steroid cover has major logistical consequences, while steroid treatment could exacerbate the existing tendency towards obesity in PWS. Since 1991, we have held a dedicated PWS clinic at the Royal Hospital for Sick Children in Glasgow. In the light of the paper by de Lind van Wijngaarden et al., we decided to examine retrospectively pituitary-adrenal axis function in subjects attending our clinic. We therefore conducted a case-note review of all patients in whom pituitary testing was carried out and cortisol responses to hypoglycaemia, via the insulin tolerance test (ITT) or synthetic ACTH (1-24ACTH), were noted. The maximum stimulated cortisol level at any time after insulin or 1-24ACTH was recorded, and values of <500 nmol/l were considered suggestive of adrenal insufficiency according to current evidence. We also collected details concerning patient mortality. Of the 70 patients who have attended the Glasgow clinic since its inception in 1991 until 2009, 25 (19M:6F) have undergone anterior pituitary stimulation testing, median (range) age 7Æ16 (0Æ43–16Æ27) years. Fifteen patients received insulin (0Æ15 l/kg) as part of an ITT while 10 received 1-24ACTH, six standard dose (250 lg) and four low dose (1 lg), and their data are shown in the Fig. 1. Median (range) basal and peak cortisol results were 328 (105–851) nmol/l and 915 (479–1481) nmol/l, respectively. There was no statistical difference between hypoglycaemia-induced or 1-24ACTH-induced basal (P = 0Æ64) or peak values of cortisol (P = 0Æ72). Only one patient of 25 (4%) showed a peak cortisol <500 nmol/l in response to hypoglycaemia, with a value of 479 nmol/l. Details of the seven patient deaths in our clinic at the median (range) age of 25Æ3 (14Æ8–40Æ8) years are shown in Table 1. Two of the seven deaths occurred in tested patients, and the remaining five occurred in untested patients. Four patients had type 2 diabetes. One patient, a boy aged 14 years, died from complications of portal hypertension unrelated to PWS. The other six deaths were all in