PRADER-WILLI sindrome
GeneReviews PWS
Clinical characteristics
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Diagnosis/testing
Consensus clinical diagnostic criteria are accurate, but the mainstay of diagnosis is DNA methylation testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR) on chromosome 15; this testing determines whether the region is maternally inherited only (i.e., the paternally contributed region is absent) and detects more than 99% of affected individuals. DNA methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially in those who have atypical findings or are too young to manifest sufficient features to make the diagnosis on clinical grounds.
Management
Treatment of manifestations: In infancy, special nipples or enteral tube feeding to assure adequate nutrition; physical therapy may improve muscle strength; hormonal and surgical treatments can be considered for cryptorchidism. In childhood, strict supervision of daily food intake based on height, weight, and body mass index (BMI) to provide energy requirements while limiting excessive weight gain (keeping BMI Z score <2 or better) and encouraging physical activity. Growth hormone replacement therapy to normalize height, increase lean body mass and mobility, and decrease fat mass. Evaluation and treatment of sleep disturbance per the general population. Educational planning should be instigated and speech therapy provided if needed. Firm limit-setting to manage behavioral problems; serotonin reuptake inhibitors are helpful for most teenagers and adults. Replacement of sex hormones at puberty produces adequate secondary sexual characteristics. N-acetylcysteine or topiramate may help reduce skin picking. Modafinil has been successful in treating daytime sleepiness in many children. In adulthood, a group home for individuals with PWS that regulates behavior and weight management may prevent morbid obesity, and growth hormone may help to maintain muscle bulk.
Prevention of secondary complications: Weight control to avoid development of type 2 diabetes mellitus; calcium and vitamin D supplementation to avoid osteoporosis; if osteoporosis develops, consider treatment with a bisphosphonate.
Surveillance: Infants should be screened for strabismus; routine monitoring of height, weight, and BMI to assure appropriateness of exercise program and diet; annual testing for hypothyroidism.
Other: No medications are currently known to aid in controlling hyperphagia, although several are under investigation.
Genetic counseling
PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15 and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region. The risk to sibs is typically less than 1% if the affected child has a deletion or uniparental disomy, up to 50% if the affected child has an imprinting defect, and up to 25% if a parental chromosome translocation is present. Prenatal testing is possible for pregnancies at increased risk if the underlying genetic mechanism is known.
