Clinical characteristics: Prader-Willi syndrome (PWS) is characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. 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). A distinctive behavioral phenotype (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Characteristic facial features, strabismus, and scoliosis are often present.

Diagnosis/testing: PWS is a contiguous gene syndrome due to abnormal DNA methylation within the Prader-Willi critical region (PWCR) at 15q11.2-q13. The diagnosis and molecular cause can be identified in a proband by simultaneous DNA methylation analysis and oligo-SNP combination array (OSA). DNA methylation analysis identifies maternal-only imprinting within the PWCR. OSA can identify the molecular cause in those with a 15q11.2-q13 deletion, imprinting center deletion, and uniparental isodisomy and segmental isodisomy. In individuals with maternal-only imprinting identified on DNA methylation analysis and a normal OSA, DNA polymorphism analysis can be used to distinguish uniparental heterodisomy from an imprinting defect by epimutation.

Management: Treatment of manifestations: In infancy, special nipples or nasogastric tube feeding to assure adequate nutrition. 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 (maintain BMI z score <2); encourage physical activity. Developmental services and educational support; hormonal and surgical treatments can be considered for cryptorchidism; growth hormone therapy to normalize height, increase lean body mass and mobility, and decrease fat mass; endocrine management of sex hormone replacement at puberty; treatment for those with precocious puberty, type 2 diabetes, and hypothyroidism; urgent evaluation for those with acute gastrointestinal manifestations; topiramate or N-acetylcysteine as needed for skin picking; standard treatment for neurobehavioral and ophthalmologic manifestations, sleep issues, scoliosis, hip dysplasia, and seizures; modafinil may be helpful for daytime sleepiness; calcium and vitamin D supplementation to avoid osteoporosis; sex steroid therapy, growth hormone, or bisphosphonates for low bone density; products for dry mouth and frequent dental hygiene; social work support and care coordination. In adulthood, a residential facility for individuals with PWS that helps regulate behavior and weight management may prevent morbid obesity, and growth hormone may help to maintain muscle mass.

Surveillance: Monitor development, growth, skin, sleep issues, and family needs at each visit. Assess testicular position annually in males; assess glycosylated hemoglobin and/or glucose tolerance test in adolescents and those with obesity or rapid weight gain; and assess free thyroxine and TSH every six to 12 months. Assess for central adrenal insufficiency as needed; monitor height, weight, and BMI monthly in infancy, every six months until age ten years, and then annually. Assess for behavioral issues annually after age two years, and for psychosis annually in adolescent and adults. Assess for vision issues and sleep issues annually; sleep study prior to starting growth hormone therapy and four to eight weeks after starting growth hormone therapy. Clinical examination for scoliosis at each visit when child can sit independently; spine x-rays annually in those with clinical findings of scoliosis or obesity; DXA scan every two years beginning in adolescence. Assess for new seizures or monitor those with seizures at each visit. Dental evaluations every six months or more frequently in those with dental issues.

Genetic counseling: Individuals with PWS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration. The vast majority of families have a recurrence risk of less than 1%. However, certain etiologies involve a recurrence risk as high as 50%, and a scenario with a risk of almost 100%, though very unlikely, is theoretically possible. Reliable PWS recurrence risk assessment therefore requires identification of the genetic mechanism of PWS in the proband (i.e., a 15q deletion, UPD 15, or an imprinting defect) and parental testing to discern the presence of a predisposing genetic alternation (e.g., a parental chromosome rearrangement or paternal heterozygosity for an imprinting center deletion). Once the causative genetic mechanism has been identified in the proband, prenatal testing for PWS is possible.