Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a rare genetic disorder with an incidence of 1 in 30,000 live births. PWS is caused by a lack of expression of imprinted genes of the paternally derived chromosome 15q11-q13. It is characterized by severe hypotonia in the newborn period. Children and adolescents have hyperphagia and weight gain and most have morbid obesity.

Siobhan T. Pittock, M.D., of the Division of Pediatric Endocrinology, Department of Pediatric and Adolescent Medicine, at Mayo Clinic, says: "Patients with PWS require care from multiple subspecialists from infancy through adulthood. The endocrinologist is frequently involved in management of several specific areas, such as growth, obesity, and hypogonadism. We also need to be aware of other complications of PWS, which include osteoporosis, sleep-disordered breathing, and sudden death."

Growth

Short stature in patients with PWS is caused by growth hormone (GH) deficiency and an inadequate pubertal growth spurt. Dr. Pittock explains: "The mean spontaneous adult height in individuals with PWS is 5 feet 4 inches in men and 4 feet 11 inches in women.

"The treatment of short stature in PWS patients with GH deficiency was approved by the US Food and Drug Administration in 2000. GH deficiency treatment for these children not only increases final height, but also improves lean body mass, strength and agility, motor development, and bone mineral density.

"The diagnosis of GH deficiency in adults with PWS is difficult because of a lack of reference ranges for the severely obese population. Several short-term studies in adult patients with PWS suggest that GH treatment improves lean body mass, bone density, and sense of well-being."

Obesity

PWS is associated with hypotonia in infancy, leading to poor feeding and poor weight gain. The poor feeding usually resolves by 1 to 2 years of age. When children reach 3 to 4 years of age, they have marked hyperphagia and decreased satiety.

Dr. Pittock adds: "When unrestricted, children with PWS consume 3 times the calories of age-matched controls. The cause of this hyperphagia is unknown but is likely due to a combination of factors that include:

• Abnormalities in satiety response in corticolimbic regions (seen on functional imaging studies)
• Neuroanatomical abnormalities in the hypothalamus (seen at postmortem examinations)
• Elevated levels of ghrelin (which is orexigenic)
• Low levels of the anorexigenic pancreatic polypeptide

"Marked obesity results from the poor satiety, reduced resting energy expenditure, and reduced physical activity. Despite their obesity, patients with PWS have relatively low rates of hyperlipidemia, diabetes mellitus, and hypertension."

Dr. Pittock continues: "Treatment of obesity in PWS is particularly challenging in the face of aggressive food-seeking behaviors, developmental delay, and behavioral problems. Pharmacologic treatment of obesity in PWS has not been effective. Restrictive bariatric surgery procedures in small numbers of patients have not resulted in sustained weight reduction. Bariatric surgery in these patients is also associated with unacceptably high morbidity and mortality rates and a high rate of gastric dilatation and perforation related to ongoing poor satiety. Environmental control still offers the best chance for weight management."

Hypogonadism

Central hypogonadism is found in both males and females with PWS. The hypogonadism in males is complicated by primary testicular dysfunction. Dr. Pittock explains: "Most PWS patients need hormonal treatment for induction, promotion, or maintenance of puberty. With this treatment, we try to mimic the normal timing and tempo of puberty. Oral or transdermal estrogen preparations are used for girls; transdermal or intramuscularly administered testosterone preparations are used for boys.

"Hypogonadism is common in adulthood. Aromatization of androgens in excess adipose tissue results in estrogen levels in women that are not as low as expected. Low blood sex hormone-binding levels in men result in a higher proportion of total testosterone as bioavailable testosterone.

There are no controlled studies on appropriate sex hormone replacement for adults with PWS. Pregnancies have been described in several women with PWS. No paternity has been reported in males."

Osteoporosis

The factors that contribute to osteoporosis in patients with PWS include hypogonadism, GH deficiency, and poor muscle tone with decreased muscle activity. Dr. Pittock highlights: "Adolescence represents a crucial time in bone mass accrual. We try to optimize bone health by:

• Ensuring appropriate calcium and vitamin D intake
• Encouraging weight-bearing exercise
• Correcting deficient levels of GH and sex steroids

"Low or decreasing bone mineral density in adults may also warrant GH and sex steroid replacement."

Sleep-disordered breathing

There have been multiple reports of sudden death in children with PWS. Most of these deaths occurred during sleep and in the context of an apparently mild respiratory illness. Patients with PWS are obese and therefore are at risk for obstructive sleep apnea.

Dr. Pittock points out: "One study of 53 prepubertal children with PWS showed an average apnea hypopnea index (AHI) of more than 4 (reference, <1). When studied during respiratory illness, the AHI was even higher, at 36.5. Studies were performed before and after the initiation of GH therapy and no differences in AHI were seen. Therefore, although sleep-disordered breathing may predispose to sudden death in PWS patients, it does not appear to be exacerbated by GH therapy.

"We recommend maintaining insulinlike growth factor-1 levels within the reference range to decrease the risk of adenotonsillar hypertrophy, which could potentially worsen obstructive sleep apnea. We also recommend that all of our patients with PWS have sleep evaluations performed and follow up with a sleep specialist both before and after initiation of GH therapy. Many benefit from the use of a continuous or bilevel positive airway pressure device."

Adrenal dysfunction

Not every PWS-related death can be attributed to sleep-disordered breathing. Because several deaths have occurred during minor illnesses, the question of adrenal insufficiency has been raised.

Dr. Pittock explains: "Several studies have shown normal results on baseline tests of adrenal function but a lack of normal response to dynamic testing (eg, metyrapone stimulation test). Those patients who had a subnormal response to metyrapone also had a higher AHI, suggesting a possible additive effect.

"Large studies have yet to be performed to validate this finding. However, since these children are at high risk for sudden death and the risk of stress dosing of corticosteroids is low, we frequently suggest stress doses of hydrocortisone during times of intercurrent illnesses."