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OBJECTIVES: To describe the response of thyroid-stimulating hormone (TSH) to thyroid-releasing hormone in children and adolescents with Prader-Willi syndrome (PWS), and to compare TSH and total thyroxine (TT4) concentrations measured on neonatal screening for congenital hypothyroidism in children with PWS and controls. STUDY DESIGN: All participants had genetically confirmed PWS. The TSH responses to thyroid-releasing hormone, free thyroxine (fT4), and free triiodothyronine (fT3) were measured in 21 subjects (14 females and 7 males; mean age, 6.4 years). Capillary TT4 was measured on neonatal screening samples from 23 subjects with PWS (14 females and 9 males), each of whom was matched for birth weight and sex with 4 anonymized controls. RESULTS: One subject with PWS had tertiary hypothyroidism. TSH level increased from 1.37 mU/L at baseline to 39.6 mU/L at 20 minutes, 47.2 mU/L at 40 minutes, 44.5 mU/L at 60 minutes, and 47.2 mU/L at 120 minutes. fT4 concentration was 6.3 pmol/L, and fT3 concentration was 4.6 pmol/L. In the other 20 subjects, mean TSH level was 1.9 mU/L (range, 0.8-4.2 mU/L) at baseline and 21.8 mU/L (range, 10.0-46.7 mU/L) at 20 minutes (peak). Mean fT4 concentration (10.4 pmol/L; range, 8.2-13.5 pmol/L) was in the lower one-third of the normal range in 18 subjects, and mean fT3 concentration (6.1 pmol/L; range, 4.8-8.4 pmol/L) was above the median in 13 subjects. In neonates, mean TSH level was 3.1 mU/L (range, 0.4-10.0 mU/L) in subjects with PWS versus 3.3 mU/L (range, 0.0-7.0 mU/L) in controls, and mean TT4 in subjects with PWS was 111% (range, 17%-203%) that of controls (P = not significant). CONCLUSION: Thyroid function was normal in our newborn subjects. In older children, frank hypothyroidism was found in only 1 of our 21 subjects. Thus, levothyroxine treatment should not be routinely prescribed to youth with PWS.

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OBJECTIVES: To determine which biological or clinical variables may predict cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation following supraphysiological doses of glucocorticoids in children. STUDY DESIGN: This retrospective study included all patients who underwent ACTH testing (1 µg) between October 2008 and June 2010 at the Sainte-Justine University Hospital Center, Montreal, after supraphysiological doses of glucocorticoids. RESULTS: Data from 103 patients (median age, 8.0 years; range, 0.6-18.5 years; 57 girls) were analyzed, revealing growth deceleration in 37% and excessive weight gain in 33%. Reasons for glucocorticoid treatment included asthma (n = 30) and hematologic (n = 22), dermatologic (n = 19), rheumatologic (n = 16), and miscellaneous (n = 16) disorders. The following information was recorded: duration of glucocorticoid treatment (median, 374 days; range, 5-4226 days); duration of physiological hydrocortisone replacement (median, 118 days; range, 0-1089 days); maximum daily (median, 200 mg/m(2)/day; range, 12-3750 mg/m(2)/day) and cumulative (median, 16 728 mg/m(2); range, 82-178 209 mg/m(2)) doses, in hydrocortisone equivalents; and interval since the last dose (median, 43 days; range, 1-1584 days). Sixty-two patients (58%) exhibited a normal response (ie, peak cortisol >500 nmol/L) to ACTH stimulation. Peak cortisol level was not related to sex, prior morning cortisol level, duration of treatment, or cumulative glucocorticoid dose; 28% of the patients with normal baseline cortisol levels nevertheless demonstrated a subnormal response to ACTH. CONCLUSION: Given the absence of clinical or biological predictors of the cortisol response to ACTH after suppressive doses of glucocorticoids, physicians have only 2 options: (1) empirically advocate glucocorticoid stress coverage during 18 months after cessation of high-dose glucocorticoid treatment; or (2) perform serial ACTH testing in all such patients until a normal peak cortisol level is attained.

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OBJECTIVES: To search for evidence of acute adrenal failure linked to inappropriate use of stress management protocols. STUDY DESIGN: Patients followed up for primary adrenal insufficiency (n = 102) or secondary adrenal insufficiency (n = 34) between 1973 and 2007 were included. All hospitalizations, both urgent (n = 157) and elective (n = 90), were examined. We recorded clinical evidence of acute adrenal failure, parental management before admission, and details of glucocorticoid prescription and administration in the hospital setting. RESULTS: For urgent hospitalizations, subgroup and time period did not influence the percentage of patients hospitalized (primary adrenal insufficiency 45%; secondary adrenal insufficiency 38%; P = .55). The use of stress glucocorticoid doses by parents increased significantly after 1997 (P < .05), although still only 47% increased glucocorticoids before hospitalization. Stress doses were more frequently administered on arrival in our emergency department after 1990 (P < .05); patients with signs or symptoms of acute adrenal failure decreased to 27% after 1997 (P < .01). Twenty-four percent of all hospitalizations were marked by suboptimal adherence to glucocorticoid stress protocols, with rare but significant clinical consequences. CONCLUSIONS: In spite of an increased use of glucocorticoid stress dose protocols by parents and physicians, patients remain at risk of morbidity and death from acute adrenal failure. This risk may be minimized with conscientious application of stress protocols, but other patient-specific risk factors may also be implicated.

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OBJECTIVE: To assess the effectiveness of growth hormone (GH) treatment of children with Prader-Willi syndrome (PWS) in clinical practice. STUDY DESIGN: This was a review of 23 patients with PWS (14 males, 9 females) under age 18 years, 10 of whom (5 males, 5 females) had been treated with GH for periods between 0.1 and 5.5 years. All of these patients had a GH level < 5.5 microg/L on 2 GH stimulation tests. RESULTS: In the 8 patients treated with GH for more than 1 year, median height velocity was 8.6 cm/year (range, 2.0 to 14.5 cm/year) during the first year, greater than that in the no-GH group (5.5 cm/year [range, 0.8 to 7.0 cm/year]) (P < .05). The evolution of body mass index (BMI) was similar in both groups, however (GH group: 3.1 standard deviation score [SDS; range, -2.5 to +6.7] at GH initiation and 3.3 SDS [range, -0.4 to +8.9] at last visit; no-GH group: 3.2 SDS [range, -0.3 to +6.4] at first visit and 2.6 SDS [range, -0.1 to +6.4] at last visit). In 3 patients treated with GH, sequential body composition analysis by dual-energy X-ray absorptiometry revealed no benefit. In both groups, stabilization or diminution of BMI was more often observed in children of highly educated parents. Two of the 10 patients treated with GH developed obstructive sleep apnea (OSA) 1 to 2 months after starting GH, 1 of whom died (reported previously). CONCLUSIONS: GH therapy in children with PWS in the clinical setting did not lead to any discernible improvement in BMI or body composition and appeared to be associated with OSA. Regardless of GH therapy, parental education was associated with better outcome.

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In 4 boys with Prader-Willi syndrome, 3 of whom had cryptorchidism, penile length and plasma testosterone levels at 5 to 10 weeks of life were normal. We suggest that cryptorchidism reflects decreased abdominal pressure rather than hypogonadism, which develops later from progressive degeneration of gonadotropin-releasing hormone neurons.

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A 4-year-old boy with Prader-Willi syndrome died suddenly while asleep on day 67 of growth hormone treatment. During treatment, snoring had worsened. Autopsy showed multifocal bronchopneumonia. This case and two others recently published suggest that growth hormone may be associated with obstructive apnea, respiratory infection, and sudden death in this condition.

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