High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome

CONTEXT: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained. OBJECTIVE: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. DESIGN: 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 assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h. SETTING: The study was conducted in a pediatric intensive care unit. PATIENTS: Patients included 25 randomly selected PWS patients. MAIN OUTCOME MEASURE: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h. RESULTS: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index 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. CONCLUSIONS: Strikingly, 60% of our 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. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test.     

Activity related energy expenditure in children and adolescents with Prader-Willi syndrome

OBJECTIVE: To measure activity related energy expenditure in Prader-Willi syndrome (PWS) corrected for body size. SUBJECTS: 17 PWS subjects (10 females, seven males, age 7.5-19.8 y) and 17 obese controls, matched for gender and bone age. MEAUREMENTS: Basal metabolic rate (BMR) was measured by ventilated hood and average daily metabolic rate (ADMR) was measured with doubly labelled water. Activity induced energy expenditure (AEE) was calculated as 0.9ADMR -BMR. Activity related energy expenditure was corrected for body size using the following measures: AEE per kg body weight (AEE/kg), ADMR/BMR (PAL), and the residual of the regression of ADMR on BMR (rADMR). Group differences were analyzed by analysis of covariance adjusting for bone age, fat mass (FM) and gender. RESULTS: ADMR, AEE and PAL were lower (P < 0.01) in the PWS group compared with the control group (7.14 +/- 1.72, 1.07 +/- 0.69 and 1.33 +/- 0.15 MJ/day compared with 9.94 +/- 2.64, 2.56 +/- 1.03 and 1.55 +/- 0.12 MJ/day respectively). The variance of AEE/kg and PAL was significantly explained by gender and PWS, while AEE was additionally explained by FM. The variance of rADMR was explained by PWS and not by FM or gender. CONCLUSION: Activity related energy expenditure is decreased in PWS compared with controls adjusted for bone age, FM and gender.     

Evaluation of adrenal function using the human corticotrophin-releasing hormone test, low dose Synacthen test and 9am cortisol level in children and adolescents with central adrenal insufficiency

Background The insulin tolerance test (ITT) has become less popular in paediatrics because of the risks associated with hypoglycaemia. Human corticotrophin‐releasing hormone (hCRH) test results correlate with the ITT and may be an acceptable method to test for central adrenal insufficiency (CAI). Simpler tests, such as the low dose Synacthen test (LDST) and 9am cortisol, have also been proposed. Objective To compare the ability of the hCRH test, LDST, 9am cortisol level and 24‐h cortisol profiles to diagnose CAI in a paediatric population. Design and setting A cross‐sectional study in a tertiary paediatric endocrine clinic. Participants Thirty‐one children and adolescents (aged 2·3–18·3 years) with CAI risk factors had an hCRH test, LDST, 9am cortisol and 24‐h cortisol profile performed. Results Of 23 patients with confirmed CAI (hCRH peak cortisol < 400 nmol/), 19 failed the LDST (peak cortisol < 267 nmol/l, i.e. 10th percentile for controls). Nineteen would have failed based on the 10th percentile cut point for 9am cortisol (< 140 nmol/l). Using receiver operating characteristic (ROC) curve coordinates, a 9am cortisol < 108 nmol/l was sensitive (83%) and specific (99%) for CAI. The 9am cortisol levels measured on two occasions were repeatable (94%) and correlated (r = 0·83, P = 0·01). All eight adrenally sufficient patients (hCRH peak cortisol ≥ 400 nmol/l) passed the LDST. Seven had normal 9am cortisol (≥ 140 nmol/l). The 24‐h cortisol area under the curve (AUC) for these patients was within the 10th–90th percentiles for control subjects’ AUC. The peak cortisol to hCRH and LDST were correlated (r = 0·88, P = 0·01), with no difference between the peaks (mean difference –5·3 nmol/l, P = 0·69). Conclusions In children with CAI risk factors, the diagnosis can be made if unstressed 9am cortisol is < 108 nmol/l. As cortisol levels > 381 nmol/l are highly suggestive of normal hypothalamic–pituitary–adrenal (HPA) function, stimulation testing need only be performed if 9am cortisol is 108–381 nmol/l. The LDST should be interpreted cautiously because mild CAI may be missed. When stimulation results are marginal, 24‐h cortisol profiles can provide reassurance of normal cortisol status.     

Primary adrenal insufficiency in children

Primary adrenal insufficiency is a rare pediatric condition, which can be presented as chronic or acute forms, especially during stress. The clinical features are unspecific and include weakness, nausea and vomiting, abdominal pain and diarrhea, arterial hypotension, hypoglycemia and dehydration. The etiology can be acquired such as infectious, hemorrhagic and drug-induced disorders, or be dependent on a genetic origin, such as congenital adrenal hyperplasia, Addisons disease, congenital adrenal hypoplasia, adrenoleucodystrophy, or deposit disorders of the adrenal gland. The familial history, presence of consanguinity, adjacent diseases and associate factors, should be considered to confirm the diagnosis. Laboratory investigation includes cortisol, ACTH and the determination of the steroidogenic precursors. The ACTH stimulation test is performed in intermediate conditions. Adrenal auto-antibodies quantitation and molecular studies can be helpful to confirm specific diseases. A substitutive glucocorticoid and mineralocorticoid therapy should be started as soon as the diagnosis is confirmed. The treatment aimed to control the symptoms with the smaller dose that can allow an adequate growth and pubertal development.     

Drug-induced sleep endoscopy in children with Prader-Willi syndrome

Purpose

Review drug-induced sleep endoscopy (DISE) findings in children with Prader-Willi syndrome (PWS) and correlate the patterns of airway collapse with apnea-hypopnea index (AHI) and body mass index (BMI).

Methods

A total of nine children with PWS underwent DISE. DISE findings were recorded using the VOTE classification system. The relationship between different patterns of airway collapse with AHI and BMI was analyzed.

Results

The majority of children with PWS were found to have multilevel obstruction (six out of nine children, 66.6 %). The velum was the most common site of obstruction (nine out of nine children, 100 %). All of the patients had positional obstructive sleep apnea (OSA). Patients with partial or complete anterior-posterior tongue base collapse were associated with a significantly higher AHI (P = 0.016) compared to patients with no anterior-posterior tongue base collapse. Apart from tongue base collapse, no other patterns of airway collapse showed a consistent association with AHI in our results. No patterns of airway collapse showed a significant association with BMI in our study.

Conclusions

In our study, partial or complete anterior-posterior tongue base collapse was associated with higher AHI values in children with PWS. Therefore, careful attention should be addressed to the management of tongue base collapse. Positional therapy could be a potential treatment for patients with PWS since it may alleviate the severity of tongue base collapse.

     

Cushing's syndrome and adrenal insufficiency in pregnancy

During pregnancy, major changes of the corticotroph axis activity are observed. The placenta synthetizes Corticotropin-Releasing Hormone (CRH) and pro-opio-melanocortin (POMC), and the plasma levels of both peptides are highly increased during pregnancy. The cortisol plasma levels are two-fold elevated compared to the levels observed in non pregnant women. This increase in cortisol level is mainly due to the doubling of the Cortisol Binding Globulin (CBG). Untreated Cushing's syndrome during pregnancy is associated with a high maternal as well as fetal morbidity (hypertension, preeclampsia, diabetes mellitus, premature birth.). Adrenocortical tumors are the major cause of Cushing's syndrome diagnosed in pregnancy. The treatment of hypercortisolism during pregnancy required a multidisciplinary approach by highly specialized teams. Adrenal insufficiency is rarely diagnosed during pregnancy. Untreated adrenal failure is associated with a high maternal and fetal morbidity and mortality. On the other hand, steroid replacement therapy appropriately monitored during pregnancy is associated with a very favorable outcome in pregnant women with adrenal insufficiency. During labor steroid replacement therapy should be adapted as for any surgical procedure.     

Metabolic syndrome in children with Prader-Willi syndrome: The effect of obesity

Background and aims

Prader-Willi syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status.

Methods and results

A cross-sectional study was performed in 109 PWS children aged 2-18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2.Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p = 0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p = 0.001) and high triglycerides (7% vs 23% and 16%, p = 0.026). Frequency of altered glucose metabolism was not different among groups (2% vs 10% and 5%), but type 2 diabetes (four cases) was present only in obese PWS. Non-obese PWS showed lower insulin and HOMA-index respect to obese PWS and obese controls (p ≤ 0.017). Overall MS frequency in PWS was 7.3%. None of the non-obese PWS showed MS compared with 16% of obese PWS and controls (p < 0.001). When obesity was excluded from the analysis, a significantly lower frequency for clustering of ≥2 factors was still found in non-obese PWS (p = 0.035).

Conclusion

Non-obese PWS showed low frequency of MS and its components, while that observed in obese PWS was very close to those of obese controls, suggesting the crucial role of obesity status. Prevention of obesity onset remains the most important goal of PWS treatment. Early identification of MS could be helpful to improve morbidity and mortality in such patients.     

Primary adrenal insufficiency and primary antiphospholipid syndrome

Primary adrenal insufficiency (PAI) is a rare complication of antiphospholipid syndrome (APS). The hypercoagulable state in the APS may lead to adrenal vein thrombosis and subsequently to hemorrhagic necrosis of the adrenal glands. This complication of APS is important to recognize because it may be fatal if untreated. We describe one case of PAI and primary APS, with magnetic resonance studies consistent with hemorrhagic necrosis of the adrenal glands.     

Adenotonsillectomy for obstructive sleep apnea in children with Prader-Willi syndrome

The aim of our study was to evaluate the efficacy of adenotonsillectomy for the treatment of obstructive sleep apnea syndrome (OSA) in pediatric patients with Prader-Willi syndrome (PWS), and to describe the postoperative complications. Five patients (4 males; median age, 4.4 years; range, 1.6-14.2 years) were studied. All patients underwent an overnight cardiorespiratory sleep study. All patients had adenotonsillar hypertrophy (ATH), and two were also obese. The preoperative obstructive apnea/hypopnea index (AHI; median and range) was 12.2 (9.0-19.9) events/hr; the mean oxygen saturation was 95 (79-96)%; the nadir oxygen saturation was 71 (58-78)%; and the oxygen desaturation index (ODI) was 15.8 (11.4-35.9) events/hr. Preoperatively, patients were classified as having moderate to severe OSA. A second sleep study, performed 16 (3-43) months after adenotonsillectomy, showed a significant decrease in AHI (P = 0.009) and ODI (P = 0.009). Mean and nadir oxygen saturation did not differ significantly postsurgery (P = 0.188, P = 0.073, respectively). Four out of five children showed at least one postoperative complication. Difficult awakening from anesthesia, hemorrhages, and respiratory complications requiring reintubation and/or supplemental oxygen administration were observed. In conclusion, patients with PWS and OSA who underwent adenotonsillectomy showed a significant decrease in AHI and number of oxygen desaturations.     

Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome

OBJECTIVE Adrenal insufficiency (Al) is a well known complication of AIDS. However, the clinical and biochemical features of Al in HIV infected patients have not been extensively studied. DESIGN A restrospective clinical study. PATIENTS We reviewed clinical records of 74 AIDS patients with clinical and/or biochemical indications of Al who underwent Synacthen testing in order to determine adrenocortical function during a 5-year period. MEASUREMENTS AI was diagnosed when Cortisol levels failed to rise above 496 nmol/l at any time during the test. Cortisol was measured by RIA. RESULTS Sixteen patients (22%) were diagnosed with Al. Most were young males and all of them had a known risk factor, principally I.v. drug users. The main complaint was fatigue. Hyponatraemia or hyperkalaemia were uncommon. All of them were severely immuno-suppressed, with AIDS-defining conditions from at least 6 months before the diagnosis of Al, and had been diagnosed with at least one disease that has been reported to produce Al in AIDS patients. Survival was poor. Thirteen of these patients (81%) died within 6 months. Basal cortisol levels were lower than 275 nmol/l in 75% of patients with Al but in only 2% of the group of 58 patients who had normal adrenal responses to Synacthen. CONCLUSIONS Adrenal insufficiency features in AIDS patients with advanced disease, without specific findings and with a history of previous opportunistic diseases. Basal cortisol values at 0830 h lower than 275 nmol/l are highly suggestive of adrenal insufficiency in patients with AIDS.     

Annuloplasty in children and young adolescents with severe rheumatic mitral insufficiency

Eleven patients aged 8 to 15 years underwent measured asymmetrical annuloplasty for severe mitral regurgitation in the years 1961 through 1966. They had had a total of 20 attacks of acute rheumatic fever. The intervals between the last attack of acute rheumatic fever and operation ranged from 2 to 8 years. The criteria for surgery were congestive failure and progressive cardiac enlargement. Using the hydraulic formula of Gorlin, a mitral annuloplasty was tailored to the size of each patient so that insufficiency was eliminated without producing hemodynamically significant stenosis. In this group of 11 children there has been one death. The majority of our 11 patients reacquired murmurs of mitral regurgitation. Satisfactory results, however, are not dependent on complete hemodynamic correction. All patients have improved remarkably and have sustained this improvement up to 7 years. These results suggest that mitral annuloplasty should be the operation of choice in children with severe mitral regurgitation.     

青春期多囊卵巢综合征肾上腺雄激素合成与胰岛素抵抗的关系

目的探讨青春期多囊卵巢综合征（PCOS）患者肾上腺雄激素合成与胰岛素抵抗（IR）的关系。方法选取体重正常的PCOS患者33例，肥胖PCOS57例；15例年龄匹配的健康女性为正常对照（NC）。研究对象均作OGTT，并行ACTH兴奋试验测定0min及ACTH兴奋后60min时血皮质醇、17α-羟孕酮（17-OHP）、去氢表雄酮（DHEA）。结果肥胖PCOS患者FIns、2hIns及HOMA-IR高于体重正常的PCOS患者，而促黄体激素低于后者（P〈0．05及P〈0．01）。ACTH兴奋试验结果显示体重正常及肥胖PCOS组的17—OHP0、17—OHP60、17—OHP净增值（△17-OHP）、DHEA0、DHEa60。均高于NC组（P〈0．05及P〈0．01）。肥胖PCOS组ACTH兴奋后17—OHR60、DHEA60及净增值均显著高于体重正常PCOS组（P〈0．05及P〈0．01）。相关分析示体重正常PCOS组HOMA-IR仅与BMI相关，而肥胖PCOS组HOMA-IR与BMI、17—OHP60、△17-OHP、DHEA60、△DHEA呈正相关（P〈0．05及P〈0．01）。结论青春期PCOS患者存在肾上腺雄激素合成亢进并对ACTH反应性增强，肥胖PCOS患者肾上腺雄激素的合成可能与IR有较为密切的关系。