Sleep Apnea Evident in PWS Children, Even With Growth Hormone Use

Sleep apnea — repeat and extended pauses in breathing during sleep — is frequent in obese children, both those with simple obesity and children with Prader-Willi syndrome (PWS) who are not treated with growth hormone, a study suggests.

Children with PWS using growth hormone (GH) therapy and less prone to obesity, however, also showed a significant incidence of breathing disorders while asleep.

These findings indicate that sleep studies would be useful in supporting more personalized care for these children, the investigators said.

The study “Comparison of Frequency and Severity of Sleep-Related Breathing Disorders in Children with Simple Obesity and Paediatric Patients with Prader–Willi Syndrome,” was published in the Journal of Personalized Medicine

PWS is caused by the absence or loss of function of paternal genes located in chromosome 15, which control sleep, metabolism, appetite, and social behavior. Consequently, patients have an insatiable appetite and chronic overeating (hyperphagia), which can cause severe obesity.

Sleep-disordered breathing is known to be induced by obesity in individuals with PWS. Other disease-related factors known to increase the risk of obstructive sleep apnea (OSA) — when throat muscles intermittently relax and block, or obstruct, the airway during sleep — in PWS patients include the narrowing of upper airways, limited saliva, and hypertrophy (enlarged growth) of adenoids and tonsils.

Previous studies report that treating PWS children with GH can help to ease breathing disorders. Growth hormone treatment is widely used by these patients to improve growth, body composition, and muscle strength.

But how this therapy might influence breathing disorders during sleep is poorly understood. Studies into the risk of such disorders developing in obese children, both those with PWS and those with simple obesity, are also lacking.

A research team in Poland compared the frequency and severity of sleep-related breathing disorders (SRBDs) between children with obesity and those with PWS to assess the role of obesity and related metabolic issues — such as insulin resistance — in developing such disorders. (Insulin resistance refers to the incapacity of cells to respond properly to insulin and regulate sugar levels.)

Researchers also compared the frequency and severity of sleep-disordered breathing (SDB; a more general category that includes apnea) between PWS children being treated with GH and those who are not.

Their study included 30 children with simple obesity (mean age, 14.2), 17 PWS patients using GH (mean age, 8.9; GH used for mean of four years) and eight untreated PWS patients (mean age, 13).

Both body mass index — BMI, a measure of body fat — and BMI standard deviation (SD, which reflects how far BMI varies from an average value of children of the same age and sex) were measured. Only GH-treated PWS children had a normal BMI — a mean of 18.3 — compared with a mean BMI of 32.8 in the untreated PWS group.

Sleep-disordered breathing was assessed by determining the frequency of obstructive sleep apnea, central sleep apnea (CSA; due to the brain improperly signaling muscles used in breathing), and mixed apneas (a combination of brain-derived and obstructive factors). Parameters such as the apnea index (AI), hypopnea index — HI, measures repetitive episodes of airflow reduction — and the apnea-hypopnea index (AHI), which refers to the number of apneas or hypopneas recorded and is an indication of sleep apnea severity, were also measured.

Insulin resistance was determined by the oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance, or HOMA-IR. Insulin levels were assessed in all participants; in PWS patients on GH therapy, the team also determined the levels of insulin-like growth factor 1 (IGF1), a hormone that promotes normal bone and tissue growth.

Results showed that higher BMI-SD and AHI values correlated with more apnea and hypopnea in children with simple obesity. HI was also higher in these children and in PWS patients not using GH, compared with those treated with GH.

This “proves the high incidence of SRBDs in obese children, both with simple obesity and in the group of patients with PWS without rhGH [recombinant human GH] treatment,” the team wrote.

In PWS children using GH, an association was observed between BMI-SD and CSA, indicating that when BMI in these patients increasingly varies from the norm it may aggravate central sleep apnea despite growth hormone use, the researchers wrote.

These children also showed a trend toward higher CSA compared with both untreated PWS and simple obesity children. According to the researchers, such findings suggest that central sleep apnea does not improve with treatment with GH.

Children with PWS also had higher frequency of mixed apneas as compared with simple obesity children.

“Most of our patients with PWS, regardless of the rhGH treatment, presented moderate to severe AHI [apnea-hypopnea index]. Only three patients, all treated with rhGH, showed mild AHI,” the researchers wrote.

“Our study proves the high incidence of SRBDs in obese children, both with simple obesity and in the group of patients with PWS without rhGH treatment. However, also patients with PWS on the rhGH therapy, without obesity, showed significant SRBDs,” the researchers wrote.

Glucose and insulin levels were higher in children with simple obesity (130.9 mg/dL) and those with PWS not on GH (140.4 mg/dL), than in PWS children treated with GH (113.3 mg/dL).

Insulin resistance was also higher with simple obesity compared to PWS children using GH (3.6 vs. 2.3). Greater insulin resistance appeared to relate with worse AHI and AI in these two groups.

In three GH-treated PWS patients, IGF1 values exceeded the normal range. GH therapy is known to increase IGF1 levels, causing hypertrophy of adenoids and tonsils, the investigators noted.

This finding, they added, suggests that sleep-related breathing disorders should be monitored in PWS children under GH therapy, as these patients have specific risk factors for these disorders.

“This includes monitoring of any changes in breathing, particularly in sleep, and evaluation by [oxygen level measures and sleep studies], together with otorhinolaryngology [ear, nose, throat] assessment, within the first three to six months of rhGH treatment,” the researchers wrote.