The condition is named after Swiss physicians Andrea Prader and Heinrich Willi who, together with Alexis Labhart, described it in detail in 1956. An earlier description was made in 1887 by British physician .
Genomic imprinting errors:Loss of gene expression within paternally-inherited genes on 15q11.2-q13 chromosome results from errors in the genomic imprinting due to the following:
- Paternal deletion (70%)
- Maternal uniparental disomy (25%)
- Imprinting center defects: Microdeletions or epimutations on chromosome 15 accounts (remaining cases)
Most cases sporadic, but familial cases can present when paternal genes carry a microdeletion in the imprinting center inherited from his mother.
Mainly characterized by severe hypotonia with feeding difficulties in the first years of life. Global developmental delays, hyperphagia with a gradual development of morbid obesity at about 3 years of age. It is also recognizable by facial features, strabismus, and other musculoskeletal conditions.
Infantile hypotonia:Characteristic feature and found in nearly all PWS cases.
- Poor suck reflex producing feeding difficulties
- Decreased muscle mass, and strength
- Failure to thrive early in life, requiring to have special equipment for feeding or the need for gavage to improve the nutrition for an extended period
Dysmorphic facial features:
- Almond-shaped palpebral fissures
- Narrow frontal diameter
- Narrow nasal bridge
- Thin upper vermilion with downturned corners of mouth
- Enamel hypoplasia
- Small hands and feet (inapparent at birth, but can evolve slowly over time)
Developmental delays and behavioral issues:
- Motor developmental delay (present in majority of cases)
- Milestone acquisition double the usual age on average
- Language impairment typically seen
- Intellectual and learning disabilities: Can fluctuate but are usually more evident at the time the individual reaches school age
- Behavioral problems (varying degree, seen in almost all cases): Anxiety, obsessive-compulsive disorder, temper outbursts, and self-inflicted injuries
Growth hormone deficiency:M/C endocrinopathy reported in PWS. Deficient/subnormal IGF-1 seen with impairment in growth hormone secretion test and abnormal 24-hour growth hormone spontaneous secretion
- Short stature: Present since early childhood and appears in almost all cases in the second decade of life
- Growth deceleration
- Absent growth spurt during puberty
Hyperphagia and obesity:4 nutritional phases described, ranging from failure to thrive to obesity, which is the hallmark of PWS
- Phase 0: (In utero) decreased fetal movements and growth restriction
- Phase 1: Hypotonic but not obese infants
- Subphase 1a: Difficulty feeding with/without failure to thrive from birth to 15 months
- Subphase 1b: Steady growth at an average rate of weight gain
- Phase 2: Excessive weight gain begins
- Subphase 2a: Weight increases with no significant changes in calorie intake/appetite
- Subphase 2b: Weight increments associated with increased appetite and interest (median age of 4.5 years)
- Phase 3: Hyperphagia related to food-seeking behavior and lack of satiety (median age of 8 years)
- Phase 4: Insatiable appetite no longer present (only some patients reach this phase)
Hyperphagia that occurs in phase 3, in correlation with the food-seeking behavior, stealing of food or money for food, associated with the decrease of total caloric requirement, results in obesity. In Prader Willi syndrome, obesity is mainly central, in the abdomen, thighs, and buttocks, leading to significant complications with increased morbidity and mortality.
Hopogonatropic hypogonadism:Present in all cases
- Cryptorchidism (present in almost all male cases) and many require orchiopexy
- Short penis (average at birth, but length starts to fall to -2 SD later)
- Difficulty in urination while standing (due to smaller penile size and increase fatty pad over the pubic area)
- Delayed puberty
- Sleep disorders
- Thick viscous saliva
- High pain threshold
- Decreased vomiting
- Temperature instability
- DNA methylation testing: Mainstay of diagnosis to identify any defect in the parental imprinting on chromosome 15 (this test can detect > 99% of all affected individuals)
- Diagnosis can be made early in life at around 8.6 weeks of age (in developing countries) or even at 3.9 years of age (in centers of reference)
- Fluorescence in situ hybridization (FISH): Chromosome analysis to identify 15q11-q13
- Chromosomal microarray: Identify maternal disomy
- Thyroid function test: Essential to assess hypothyroidism, especially before initiating any growth hormone treatment
- Liver function tests and serum insulin-like growth factor-1 (IGF-1) to evaluate growth hormone deficiency.
- Fasting glucose levels and oral glucose tolerance test to investigate diabetes.
- Polysomnography (sleep study) to diagnose any sleep disorders.
- Dual X-ray absorptiometry (DXA scan) to assess bone mineralization and composition
Differential diagnosis:There are some other syndromes called Prader Willi like Syndrome (PWLS) that share some physical features with Prader Willi syndrome but differs on a genetic basis. Some clinical manifestations of PWLS are hypotonia, short stature, obesity, developmental delays.
- Growth hormone: Recommended as early as at the time of diagnosis, from 3 to 6 months old.. Patients can reach predicted final adult height if treated early.
- Human chorionic gonadotropic hormone (hCG): Lower the testicle position, although significant percentage of them still need orchiopexy.
- Testosterone: Approved for 15-16 years olds, with delayed/incomplete puberty, for puberty progression.
- Low-dose transdermal estrogen: Females may receive for hypogonadism for 2 years or until the time of menarche
Behavioral and cognitive strategies:Help patients understand the expectation and rules, schedules, the use of verbal cues, and to minimize compulsiveness and aggressiveness