An Obese Female with Prader-Willi Syndrome and Daytime Sleepiness

Abstract

An obese 13-year-old female with Prader-Willi syndrome (PWS) was referred for evaluation of excessive daytime sleepiness. She was a resident of a group home for persons with PWS allowing for dietary management and a regimented schedule. Her daily wake time was 06:30 and bedtime was 21:00. The patient had a tonsillectomy and adenoidectomy at age 5 years for obstructive sleep apnea and had never been treated with growth hormone. A nighttime attendant at the group home reported that the patient rarely snored and never was noted to have breathing pauses. The patient reported falling asleep rapidly and remembered few awakenings during the night. She was not difficult to awaken in the morning before breakfast. However, the patient was noted to be very sleepy throughout the day and would nap frequently if not prompted to wake up and become more active. There were no clear-cut episodes of cataplexy. Previous testing had shown the patient to have intelligence slightly below the lower limits of normal. Physical examination: BMI 29; HEENT–Mallampati 2 with absent tonsils; neck circumference of 13 inches. The patient had almond shaped eyes and small hands and feet. Polysomnography TST 465 minutes Sleep efficiency 96% Sleep latency 5 minutes REM latency 15 minutes Total Arousal Index 9.4 (/hour) Respiratory Arousal index 0.5 (/hour) AHI 0.9 (/hour) REM AHI 1.9 (/hour) PLM Index 0 (/hour) Sleep stages (% TST)     Stage N1 6%     Stage N2 54%     Stage N3 20%     Stage R 20% View it in a separate window What is the cause of this patient's daytime sleepiness? Answer: Narcolepsy due to Medical Condition The Prader-Willi syndrome (PWS) is a genetic disorder in which genes on the paternal chromosome 15 are missing or unexpressed. The genes are “imprinted,” meaning corresponding genes on the maternal chromosome 15 are not expressed. A minority of cases occur from maternal uniparental disomy (both of the 15th chromosomes are maternal). PWS is characterized by short stature, hyperphagia, obesity, hypothalamic-pituitary dysfunction, and sleep disorders. Hypotonia and feeding difficulties are common in the neonatal period. In infancy, patients have a failure to thrive and developmental delay. Strabismus may also occur. Starting around age 2 to 4 years, PWS individuals exhibit hyperphagia and excessive weight gain, which can result in morbid obesity. Due to hypogonadotrophic hypogonadism they have delayed puberty. Abnormal growth hormone secretion results in short stature, a low bone density, and reduced muscle mass. The characteristic appearance of PWS patients includes a high narrow forehead, almond shaped eyes, down-turned lips, a prominent nasal bridge, and small hands and feet. Scoliosis is common (up to 80%). Intelligence is variable but is usually in the low normal to mild to moderately decreased range. Patients with the PWS may have excessive daytime sleepiness from a number of sleep disorders including sleep apnea, narcolepsy, or as a manifestation the PWS itself.1 Sleep related breathing disorders associated with PWS are common and include both obstructive and central apnea and hypoventilation.2–5 The frequency of obstructive apnea in studies of PWS patients varies widely (0–100%) and this likely represents patient selection. Risk factors for OSA in PWS patients other than obesity or tonsillar hypertrophy include facial dysmorphism, hypotonia, and sticky secretions. Of interest, one recent study5 of a group of 53 PWS children with a relatively normal BMI (median 17.7 kg/m2) found a median apnea + hypopnea index (AHI) of 5.4/hour with most events being central apneas. Treatment of PWS patients with growth hormone (GH) can improve body composition (greater muscle mass and lower percentage fat) and increase height.6 However, sudden death has been reported in a few patients in the first few months of growth hormone treatment.6 The deaths often occurred during an upper respiratory tract infection and some of the patients were morbidly obese. Of note, one death was noted in a patient with a normal pretreatment sleep study. One theory is that GH treatment by increasing insulin-like growth factor (IGF) caused adenotonsillar hypertrophy with worsening of upper airway narrowing. Miller and coworkers4 performed sleep studies in 25 PWS patients before and after 6 weeks of growth hormone treatment. All patients had both obstructive and central events before treatment. Sixteen patients had a lower apnea + hypopnea index (AHI) at 6 weeks, with improvement in both central and obstructive events in most patients. Six patients had a higher AHI after GH treatment, and those patients also developed tonsillar hypertrophy. Another study5 found no change in the AHI at 6 months after GH treatment, although one patient died unexpectedly during an upper respiratory tract infection. A definite link between sleep apnea and sudden death in PWS following GH treatment has not been proven. However, those patients with morbid obesity, untreated obstructive sleep apnea, concurrent respiratory infections, or hypoventilation are probably not good candidates for GH treatment. Excessive daytime sleepiness in patients with PWS can occur early in life and can cause significant problems for the patients. A short nocturnal REM latency and MSLT findings of a short sleep latency and two or more sleep onset REM periods have been reported in PWS patients without sleep apnea.1 Such patients are considered to have narcolepsy due to a medical disorder also termed symptomatic or secondary narcolepsy.7 Cataplexy has been reported in some patients with PWS8 but a reliable history is often difficult to elicit. Some patients with PWS without sleep apnea also have daytime sleepiness but do not meet diagnostic criteria for narcolepsy. In these cases, sleepiness is likely a manifestation of the PWS itself. Hypothalamic dysfunction might be suspected as the cause of daytime sleepiness in PWS given other manifestations of the disorder such as hyperphagia and growth hormone secretion dysfunction. Nevsimolva et al9 studied 4 PWS patients without cataplexy (2 with excessive sleepiness) and found a reduced CSF level of hyopocretin 1 (about 60% of the control group level). However, Fronczek and coworkers10 did not find a decrease in hypocretin neurons in PWS patients compared to age matched controls. Thus, some abnormality in the hypocretin system could be involved in the causation of daytime sleepiness of PWS. However, the exact nature of the dysfunction and the role of the hypocretin system in producing daytime sleepiness in PWS remain to be determined. The current patient was not felt to have cataplexy. The nocturnal sleep study showed no evidence of sleep apnea, but the REM latency was significantly decreased. A MSLT was performed following the nocturnal sleep study. The MSLT findings included a mean sleep latency of 3.4 minutes (severe sleepiness) and REM sleep was present in 3 of the 5 naps. On the basis of these results the patient was diagnosed with narcolepsy due to a medical condition (PWS).