Adiponectin levels in prepubertal children with Prader-Willi syndrome before and during growth hormone therapy

CONTEXT: Children with Prader-Willi syndrome (PWS) may have obesity and an abnormal body composition with a high body fat percentage, even if they have a normal body weight. Adiponectin has been inversely related to obesity and insulin resistance. OBJECTIVE: The objective of the study was to evaluate in prepubertal PWS children the following: 1) adiponectin levels, body composition, carbohydrate metabolism, and triglyceride levels; 2) associations between adiponectin and body composition, carbohydrate metabolism, and triglycerides; and 3) effects of GH treatment on these outcome measures. PATIENTS: Twenty prepubertal PWS children participated in the study. INTERVENTION: The subjects were randomized into a GH treatment group (n=10, 1 mg/m2.d) and a non-GH-treated control group (n=10). MAIN OUTCOME MEASURES: At baseline, after 1 and 2 yr of GH treatment, fasting levels of adiponectin, glucose, insulin, and triglycerides were assessed. Body composition and fat distribution were measured by dual energy x-ray absorptiometry. RESULTS: PWS children had significantly higher median (interquartile range) adiponectin levels [17.1 mg/liter (13.9-23.2)] than healthy sex- and age-matched controls [11.8 mg/liter (9.7-12.5), P<0.005]. Body fat percentage was significantly higher than 0 sd score [1.8 sd score (1.5-2.1), P<0.001]. Adiponectin levels were inversely related to triglyceride levels (r=-0.52, P=0.03). There was a tendency to an inverse relation with body fat percentage and body mass index, but no correlation with fasting insulin or glucose levels, the insulin to glucose ratio, or homeostasis model assessment index. During GH treatment, adiponectin levels increased significantly and did not change in randomized controls. CONCLUSION: Adiponectin levels were increased, and inversely associated with triglyceride levels, in prepubertal, not overweight PWS children, although they had a relatively high body fat percentage. During GH treatment, adiponectin levels further increased, whereas no change was found in the controls, which is reassuring with respect to the development of insulin resistance during GH treatment.     

Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment

BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, obesity and short stature. Several endocrine abnormalities have been described, including GH deficiency and hypogonadotrophic hypogonadism. Published data on thyroid hormone levels in PWS children are very limited. OBJECTIVE: To evaluate thyroid function in children with PWS, before and during GH treatment. DESIGN/PATIENTS: At baseline, serum levels of T4, free T4 (fT4), T3, reverse T3 (rT3) and TSH were assessed in 75 PWS children. After 1 year, assessments were repeated in 57 of the them. These children participated in a randomized study with two groups: group A (n = 34) treated with 1 mg GH/m(2)/day and group B (n = 23) as controls. RESULTS: Median age (interquartile range, IQR) of the total group at baseline was 4.7 (2.7-7.6) years. Median (IQR) TSH level was -0.1 SDS (-0.5 to 0.5), T4 level -0.6 SDS (-1.7 to 0.0) and fT4 level -0.8 SDS (-1.3 to -0.3), the latter two being significantly lower than 0 SDS. T3 level, at 0.3 SDS (-0.3 to 0.9), was significantly higher than 0 SDS. After 1 year of GH treatment, fT4 decreased significantly from -0.8 SDS (-1.5 to -0.2) to -1.4 SDS (-1.6 to -0.7), compared to no change in untreated PWS children. However, T3 did not change, at 0.3 SDS (-0.1 to 0.8). CONCLUSIONS: We found normal fT4 levels in most PWS children. During GH treatment, fT4 decreased significantly to low-normal levels. TSH levels remained normal. T3 levels were relatively high or normal, both before and during GH treatment, indicating that PWS children have increased T4 to T3 conversion.     

Prader-Willi syndrome and growth hormone treatment

Prader Willi syndrome (PWS) is a hypothalamo-hypophyseal disorder associated with eating disorders, morbid obesity and behavioural troubles. A deletion of a segment of paternal chromosome 15 is the more frequent cause of PWS. The syndrome is associated with increased morbidity (sleep apnea, increased cardio-vascular risk) and mortality (mainly due to respiratory infectious diseases). GH secretion is usually decreased. GH treatment induces height gain, positive body composition changes and improves psychomotor development. Obstructive apnea was described in case of rapid increase in the dose of GH. Corticotroph deflciency, warranting treatment in stress situations could also take part in the high mortality rate of these patients.     

Sleep-related breathing in children with mucopolysaccharidosis

Summary   Background: The mucopolysaccharidoses (MPSs), a group of genetic lysosomal storage disorders, are associated with significant morbidity. Secondarily to specific associated anatomical abnormalities, MPS is associated with sleep disordered breathing (SDB), specifically obstructive sleep apnoea (OSA) that may confer additional morbidity. Few studies have examined SDB in children with MPS using full polysomnography (PSG) and thus the exact prevalence and severity of SDB is unknown. Further, successful treatments for SDB in this population have not been explored. Objectives: This study evaluated both SDB and the efficacy of treatments offered to children with MPS using PSG data. Patients and methods: A retrospective chart review was conducted on all children with MPS and a history of suspected OSA who were referred to the Hospital for Sick Children, Toronto. Both baseline and follow up treatment PSG data were analysed. PSG data recorded included obstructive apnoea-hypopnoea index (OAHI) and central apnoea index (CAI). Results: Fourteen patients (10 male) underwent a baseline PSG. Three of 14 children on ERT were excluded from the main analyses. The median (range) baseline parameters of the population (n = 11) were recorded. The age was 5.2 years (0.8–17.8) and the body mass index (BMI) was 19.9 (13.7–22.2). The OAHI was 6.6 (0.0–54.8); the CAI was 0.6 (0.0–2.6). Seven of 11 (64%) had evidence for OSA and 3/7 children were classified as having severe OSA (OAHI > 10). Of these, 5/7 children underwent treatment for OSA with 3/5 children showing a significant reduction in their OAHI. Further, the 2 patients on ERT therapy with OSA were also both successfully treated. Conclusions: Children with MPS have a high prevalence of significant OSA and thus should be carefully screened for OSA using full polysomnography and treated accordingly. Competing interests: None declared     

The impact of growth hormone/insulin-like growth factor-I axis and nocturnal breathing disorders on cardiovascular features of adult patients with Prader-Willi syndrome

CONTEXT: Adult patients with Prader-Willi syndrome (PWS) are prone to develop obesity, GH deficiency (GHD), and their related complications, with cardiopulmonary failure explaining more than half of PWS fatalities. OBJECTIVE AND STUDY PARTICIPANTS: This study was undertaken to examine the effect of GHD and sleep breathing disorders on cardiovascular risk factors and heart features of 13 PWS (age 26.9 +/- 1.2 yr) and 13 age-, gender-, and body mass index-matched obese individuals (age 26.2 +/- 0.8 yr). RESULTS: Compared with controls, PWS patients had lower GH response to arginine+GHRH, IGF-I levels, triglycerides, total and LDL-cholesterol, insulin, and insulin resistance measured by a homeostatic model approach. Dual-energy x-ray absorptiometry, abdominal computed tomography scans, and polysomnography revealed a greater fat mass, similar abdominal fat, but greater sleep breathing disorders in PWS than obese subjects. Echocardiography showed no systolic or diastolic alteration, although PWS had lower left ventricle (LV) mass (135.7 +/- 7.7 vs. 163.5 +/- 8.4 g, P < 0.05) and near significantly lower values of LV end-diastole diameter (P = 0.08), compared with obese controls. Baseline radionuclide angiography documented comparable values of systolic and diastolic values between groups. However, adrenergic stimulation with dobutamine caused a lower increase of LV ejection fraction (71.9 +/- 1.9 vs. 76.3 +/- 1.2%, P < 0.05) and heart rate (103 +/- 6.9 vs. 128 +/- 2.8 beats/min, P < 0.05) in PWS than obese individuals. By multivariate analysis, nocturnal oxygen desaturation and IGF-I levels were main significant predictors of LV mass and heart rate in PWS patients. CONCLUSIONS: PWS differs from simple obesity by a healthier metabolic profile, impaired nocturnal breathing, decreased heart geometry, and systolic and chronotropic performance. GHD and the predictive role of IGF-I on structural and functional heart parameters suggest a GH/IGF-I-mediated control of cardiac risk in PWS.     

Sleep-related breathing disorders in facioscapulohumeral dystrophy

Purpose

Severe manifestations of facioscapulohumeral dystrophy (FSHD) may be associated with sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and nocturnal hypoventilation (NH), but prevalence data are scarce. In patients with respiratory muscle weakness, detection of NH can be facilitated by transcutaneous capnometry, but respective data derived from FSHD patients have not yet been published.

Methods

We collected sleep studies and capnometry recordings from 31 adult patients with genetically confirmed FSHD who were admitted to our sleep laboratory for first-ever evaluation of sleep-related breathing. Indications for admission included non-restorative sleep, morning headache, or excessive daytime sleepiness. In addition, sleep studies were initiated if symptoms or signs of respiratory muscle weakness were present. Thirty-one subjects with insomnia served as controls for comparison of respiratory measures during sleep.

Results

In the FSHD group, 17/31 (55%) patients showed OSA and 8 (26%) had NH. NH would have been missed in 7/8 patients if only oximetry criteria of hypoventilation had been applied. Capnography results were correlated with disease severity as reflected by the Clinical Severity Score (CSS). Non-invasive ventilation (NIV) was started in 6 patients with NH and 3 individuals with OSA. Nocturnal continuous positive airway pressure was administered to 2 patients, and positional therapy was sufficient in 4 individuals. In patients initiated on NIV, nocturnal gas exchange already improved in the first night of treatment.

Conclusions

SDB is common in adult patients with FSHD complaining of sleep-related symptoms. It may comprise OSA, NH, and most often, the combination of both. Sleep-related hypercapnia is associated with disease severity. Transcutaneous capnometry is superior to pulse oximetry for detection of NH.

     

Sleep-related breathing disorders in patients with pulmonary hypertension

BACKGROUND: Cheyne-Stokes respiration (CSR) and central sleep apnea (CSA) are common in patients with left-heart failure. We investigated the hypothesis that sleep-disordered breathing is also prevalent in patients with right ventricular dysfunction due to pulmonary hypertension (PH). METHODS: We studied 38 outpatients (median age, 61 years; quartiles, 51 to 72) with pulmonary arterial hypertension (n = 23) or chronic thromboembolic PH (n = 15). New York Heart Association (NYHA) class was II to IV, and median 6-min walk distance was 481 m (quartiles, 429 to 550). In-laboratory polysomnography (n = 22) and ambulatory cardiorespiratory sleep studies (n = 38) including pulse oximetry were performed. Quality of life and sleepiness by the Epworth sleepiness score were assessed. RESULTS: The median apnea/hypopnea index was 8 events/h (quartiles, 4 to 19), with 8 central events (quartiles, 4 to 17), and 0 obstructive events (quartiles, 0 to 0.3) per hour. Seventeen patients (45%) had > or = 10 apnea/hypopnea events/h. Comparison of 13 patients with > or = 10 CSR/CSA events/h with 21 patients with < 10 CSR/CSA events/h (excluding 4 patients with > or = 10 obstructive events/h from this analysis) revealed no difference in regard to hemodynamics, NYHA class, and Epworth sleepiness scores. However, patients with > or = 10 CSR/CSA events/h had a reduced quality of life in the physical domains. Ambulatory cardiorespiratory sleep studies accurately predicted > or = 10 apnea/hypopnea events/h during polysomnography in patients who underwent both studies (area under the receiver operating characteristic curve, 0.93; SE +/- 0.06; p = 0.002). The corresponding value for pulse oximetry was 0.63 +/- 0.14 (p = not significant). CONCLUSIONS: In patients with PH, CSR/CSA is common, but obstructive sleep apnea also occurs. Sleep-related breathing disorders are not associated with excessive sleepiness but affect quality of life. They should be evaluated by polysomnography or cardiorespiratory sleep studies because pulse oximetry may fail to detect significant sleep apnea.     

Sleep-related breathing disorders and cardiovascular disease

Sleep-related breathing disorders, ranging from habitual snoring to the increased upper airway resistance syndrome to sleep apnea, are now recognized as major health problems. The majority of patients have excessive daytime sleepiness and tiredness. Neuropsychological dysfunction results in poor work performance, memory impairment, and even depression. Until recently, the coexistence of cardiovascular and cerebrovascular diseases with sleep-related breathing disorders was thought to be the result of shared risk factors, such as age, sex, and obesity. However, in the past 5 years several epidemiologic studies have demonstrated that sleep-related breathing disorders are an independent risk factor for hypertension, probably resulting from a combination of intermittent hypoxia and hypercapnia, arousals, increased sympathetic tone, and altered baroreflex control during sleep. Sleep apnea may lead to the development of cardiomyopathy and pulmonary hypertension. Early recognition and treatment of sleep-related breathing disorders may improve cardiovascular function.     

Short-term effects of growth hormone on sleep abnormalities in Prader-Willi syndrome

CONTEXT: GH was approved for Prader-Willi Syndrome (PWS) in 2000. Fatalities in individuals with PWS soon after beginning GH treatment prompted concern about GH worsening sleep apnea. OBJECTIVE: We sought to determine whether GH affects sleep apnea in individuals with PWS. DESIGN: Twenty-five patients with PWS had overnight polysomnography (PSA) at baseline and 6 wk after starting GH. SETTING: The study was conducted in a sleep lab using a standardized procedure. PATIENTS: The patients studied had genetically confirmed PWS. MAIN OUTCOME MEASURES: PSA results were analyzed for frequency and severity of central and obstructive apnea/hypopnea events and total apnea/hypopnea index. RESULTS: As a group, GH improved apnea/hypopnea index by a mean of 1.2 events per hour (P = 0.02) and central events by a median of 1.7 events per hour (P < 0.001). Fourteen patients had improvement in obstructive events by a mean of 1.7 events per hour. Six patients had worsening of obstructive events on GH. Four of these patients had upper respiratory tract infections at the time of the second PSA and had tonsil/adenoid hypertrophy on otorhinolaryngological evaluation. Two patients with high serum IGF-I levels had increased obstructive events. CONCLUSIONS: Most of our PWS patients had improvement after short-term GH treatment, but 32% had worsening of sleep disturbance. A subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Because it is difficult to predict who will worsen with GH, patients with PWS should have PSA before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections. Otorhinolaryngological evaluation is warranted if sleep apnea worsens on GH. IGF-I levels should be monitored, with the goal being physiological levels.     

Sleep and breathing in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder, with hypotonia being the predominant feature in infancy, and developmental delay, obesity, and behavioral problems becoming more prominent in childhood and adolescence. Children with this disorder frequently suffer from excessive daytime sleepiness and have a primary abnormality of the circadian rhythm of rapid eye movement sleep. They also have primary abnormal ventilatory responses to hypoxia and hypercapnia, and these abnormalities may be exacerbated by obesity. Children with PWS are at risk of a variety of abnormalities of breathing during sleep, including obstructive sleep apnea and sleep-related alveolar hypoventilation. Clinical evaluation should include a careful history of sleep-related symptoms and assessment of the upper airway and lung function. Polysomnography should be considered for those with symptoms suggestive of sleep-disordered breathing. Treatment options depend on the underlying problem, but may include behavioral interventions, weight control, adenotonsillectomy, and nocturnal ventilation.     

Sleep-related breathing disorders in obese patients presenting with acute respiratory failure

INTRODUCTION: The study was conducted to assess the clinical and polysomnographic characteristics of patients with sleep-related breathing disorders who presented to the intensive care unit (ICU) with acute respiratory failure and the practicability of performing polysomnography for such patients. MATERIAL AND METHODS: We analyzed clinical presentation, cause of admission to the ICU, ICU course and outcome of 11 subjects with acute respiratory failure who were diagnosed to have sleep disordered breathing based on polysomnography between October 1999 and January 2003. Subjects were compared to 11 patients with obstructive sleep apnea syndrome matched to each subject using body mass index, age and apnea hypopnea index measured at the time of diagnosis (matched comparison group). Repeated arterial blood gases and polysomnography were done for 8 subjects compliant to treatment 6-8 months after discharge from ICU. RESULTS: The reason for ICU admission for all subjects was hypercapnic respiratory failure. pH and daytime PaO2 were significantly lower in studied subjects compared to the matched comparison group while awake daytime PaCO2 was significantly higher. Subjects had frequent episodes of hypoventilation. Follow up arterial blood gases and polysomnography 6-8 months after treatment (non-invasive ventilation) in compliant subjects showed significant improvement in all blood gases parameters. CONCLUSIONS: Early polysomnography (or portable cardio-respiratory monitoring) allows accurate diagnosis and institution of the appropriate ventilation method Further studies should assess the evolution of respiratory drive in patients with sleep disordered breathing and hypercapnia under therapy (non-invasive ventilation).