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Incidence

The incidence of Prader-Willi syndrome is 1 in 16,000-25,000 live births.

Clinical Characteristics

Pattern of manifestations including neonatal hypotonia and hypogonadism with later hyperphagia, obesity, and mental disability. A characteristic appearance may develop with almond-shaped palpebral fissures, down-turned corners of the mouth, small hands and feet. Consensus diagnostic criteria have been formulated for Prader-Willi syndrome. Major criteria of neonatal/infantile hypotonia, infantile feeding problems, excessive weight gain between ages 1-6 years, compatible facial features, hypogonadism, global developmental delay/mental disability, hyperphagia and food obsession, and appropriate deletion/mutation in the chromosome 15q13q15 region. Minor criteria include decreased fetal movement; unstable, stubborn or oppositional behavior; sleep apnea (poor sleep due to breathing difficulties); short stature; hypopigmentation; small hands and feet; strabismus (wandering eye); thick saliva; problems with speech articulation; and skin picking. Deletion or uniparental disomy of chromosome 15 is the keystone of diagnosis, provided the clinical features are compatible. Decreased fetal movement due to fetal hypotonia (low muscle tone) and a propensity for breech positioning are common in pregnancy. After birth, the infant is sufficiently hypotonic that a muscle disorder may be considered. The consequent weak suck and poor feeding often produces a \\\\\\\"failure to thrive\\\\\\\" picture until the change to overeating occurs. Between ages 1 and 4 years, there is a transformation from growth failure to obesity caused by a voracious appetite. Abnormal eating behaviors include stealing food, nocturnal foraging for food, eating inappropriate foods, and binge eating. Morbid obesity may ensue that causes a shortened life span in Prader-Willi syndrome because of cardiopulmonary disease. Behavior problems dominate the management of Prader-Willi syndrome. Sleep disorders are common, with 50-90% of patients having daytime sleepiness. Although frequent snoring and a narrow upper airway occur in these patients, abnormal brain regulation of sleep is as common as obstruction to night-time breathing. Violent outbursts, temper tantrums, obsessive-compulsive behavior, rigidity, manipulation, and stubbornness are common. Older children and adults exhibit depression and a \\\\\\\"refusal-lethargy syndrome\\\\\\\" of hyperactivity, refusal of food and drink, and urinary/fecal soiling of their clothes. Skin picking with skin infections or scarring and recurrent nasal bleeding may reflect the obsessive-compulsive and oppositional aspects of the syndrome. Spontaneous psychoses unrelated to other physical or behavioral problems have been reported in Prader-Willi syndrome, but their prevalence is not known. Developmental delay is most obvious in motor milestones, with sitting at an average age of 12-13 months, walking at 24-30 months, and riding a tricycle at 4.2 years. Cognitive functions that are independent of hypotonia are less severely delayed, with single words appearing at 21-23 months and sentences at a mean of 3.6 years. Articulation defects are common and the speech often has a nasal quality. Reading is a relative strength, with mathematics and social interactions being weaknesses. Performance in solving mazes or codes was substantially above verbal performance that required auditory processing; this profile may explain the clinical impression that many Prader-Willi patients enjoy puzzles. Over 40% of patients have a global IQ that is above 70 and in the borderline or normal range. Poor performance in school often reflects specific learning disabilities, distractibility, or behavioral problems.

Precipitants

none

Provocation Tests

none

Diagnostic Procedures

Chromosome and DNA diagnosis demonstrating microdeletion of band 15q13q15 (~60% of patients), maternal origin of both chromosomes 15 (uniparental disomy, ~25%), or defective DNA methylation (~5%). The latter test is positive for all three categories. Most cytogenetic laboratories offer fluorescent in situ hybridization (FISH) analysis for the characteristic Prader-Willi deletion as a routine service. If a deletion is not detected in a patient with typical features, then DNA analyses for the origin of the number 15 chromosomes or for abnormal methylation patterns are available in some laboratories. If DNA analysis indicates that both chromosomes 15 are of maternal origin, then a diagnosis of Prader-Willi syndrome owing to uniparental disomy is established. For the 5-10% of patients who have Prader-Willi syndrome without deletion or uniparental disomy, DNA testing to demonstrate abnormal structure of the father\\\\\\\'s chromosome 15 can be performed. This latter \\\\\\\"DNA methylation\\\\\\\" analysis can be used as a comprehensive test when it is available, since deletion or uniparental disomy patients will also have abnormal DNA methylation results. Rare children who meet diagnostic criteria may not have positive testing by any of the three methods-these children may have mutations in one of the genes that cause Prader-Willi syndrome.