Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a rare, inherited chromosomal disorder arising from deletion or disruption of genes in the proximal arm of chromosome 15. It was first described in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, and Guido Fanconi of Switzerland. It occurs in 1 of 10,000–16,000 live births.

Mothers with prior experience of normal pregnancies report distinctly delayed onset of labor and reduced fetal activity during the pregnancies involving Prader-Willi children. PWS is characterized at birth by the lack of spontaneous movements, excessive daytime sleepiness perhaps arising from a primary hypothalamic dysfunction, and protective reflexes. Babies display little interest in feeding and their ability to suck is weak or absent. They will take longer to attain the ability to walk, talk, sit, and stand. Children will go on to develop symptoms of muscular hypotonia (weak muscle tone) and asphyxia. Distinctive facial features also identify a child with the syndrome; these include a narrow face, almond-shaped eyes, small-appearing mouth, a thin upper lip with down-turned corners of the mouth, and full cheeks. The child's eyes may cross (strabismus). A frequent feature generally overlooked is thick saliva at the edges of the mouth. Patients also tend to be relatively insensitive to pain.

Between ages 1–6, the child with PWS suddenly develops a tremendous interest in food, and starts overeating (hyperphagia). The brain regions associated with satiety response in those with PWS is delayed and insensitive to food intake. This leads to severe disturbances of appetite regulation, including delayed meal termination and early return of hunger after a meal, leading to abnormal body mass composition and obesity; this in turns leads to increased cardiovascular morbidity and mortality. Unlike individuals with common obesity who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Ghrelin is an endogenous 28-amino acid ligand in the stomach for the growth hormone (GH) secretagogue receptor; it stimulates appetite and causes obesity in animal models and in humans when given in pharmacological doses. PWS is the most common genetic cause of obesity. Patients also have reduced lean body mass and increased fat mass and GH deficiency.

PWS children are generally well behaved; however, they have been known to display spontaneous outbursts of aggressive behavior, and this disorder has also been associated with obsessive-compulsive disorder. Patients may develop symptoms of mental retardation, cognitive deficits, learning problems, and behavioral difficulties.

It has been suggested that a contributing factor to the reduced neurocognitive and psychosocial performance is due to the high prevalence of obstructive sleep apnea syndrome in these patients; this is where [Page 1409]repetitive upper airways collapse during sleep, resulting in hypoxia and sleep fragmentation.

Patients have endocrine problems including reduced or absent secretion of sex hormones (hypogonadism); they have combined hypothalamic (low leutinizing hormone) and peripheral (low inhibin B and high follicle stimulating hormone) hypogonadism, possibly due to a primary defect in sertoli or germ cell maturation or an early germ cell loss. During adolescence, males may have a smaller penis and may have undescended testis. Secondary sexual characteristics such as pubic hair and breast development in females may not develop as well. Growth spurt in patients is also delayed and thus patients tend to have a shorter stature.

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