What Is Prader-Willi Syndrome?

Prader-Willi syndrome (PWS) has autosomal dominant inheritance (inherited from even one affected parent) and affects both sexes equally. Thus, the lifetime risk of being affected if one parent is affected is 50 percent.

PWS is caused by genetic abnormalities in an unstable region on chromosome 15, disrupting gene expression regulation. 

During early fetal development, genetic changes responsible for PWS occur in a section of the chromosome known as the Prader-Willi critical region (PWCR).

Three specific chromosomal changes

1. Deletions: Deletion in one area of the paternal chromosome 15 causes the loss of function of multiple genes in the majority (75 percent) of PWS cases. 
2. Maternal uniparental disomy: Typically, a child inherits two copies of chromosome 15, one from each parent. In 20 percent of cases, a child with PWS has two copies of chromosome 15 from the mother and none from the father.
3. Imprinting center defect: Genes in PWCR on the chromosome that originated from the mother are inactivated due to a process known as “imprinting,” which affects whether the cell can “read” a gene in five percent of cases.

Most cases of PWS are not inherited, particularly those caused by a deletion in the paternal chromosome 15 or by maternal uniparental disomy.  

Affected people typically have no history of the disorder in their family. Rarely, a genetic change responsible for PWS can be inherited.

Prader-Willi syndrome can cause a wide range of symptoms that affect a child’s physical, psychological, and behavioral development.

A child with PWS may have distinctive facial features such as:

• Almond-shaped eyes
• A triangular mouth or turned-down mouth
• Narrow forehead
• Small hands and feet
• Thin upper lip
• Underdeveloped genitalia
• Poor muscle tone, which may cause a weak sucking reflex
• Sleepiness and difficulty waking up
• Poor response to stimulation and weak crying

An older child may present with symptoms that include:

• Food cravings and weight gain
• Short height stature and poor muscular mass 
• Undeveloped sex organs (both gender)
• Incomplete or delayed puberty
• Mild to moderate cognitive and intellectual impairment
• Learning disabilities
• Behavioral problems such as temper outbursts and stubbornness
• Compulsive behavior such as picking at the skin
• Speech problems
• Hypothyroidism (an underactive thyroid)
• Adrenal insufficiency
• High risk of osteoporosis

Prader-Willi syndrome (PWS) is typically diagnosed based on clinical symptoms, and a blood test is ordered to confirm the diagnosis.

The diagnostic criteria used to diagnose PWS include:

Major criteria (each criterion scores 1 point)

• Characteristic facial features such as almond-shaped eyes, a down-turned mouth, a narrow distance between the temples, and a thin upper lip
• Delayed developmental milestones
• Feeding problems or failure to thrive in infancy
• Hypogonadism (underactive sex hormones)
• Floppy baby at birth
• Rapid weight gain between one and six years of age

Minor criteria (each criterion scores 1 point)

• Decreased fetal movements and infantile lethargy
• Eyes and vision problems, including squint and short-sightedness
• Pale skin, hair, and eye color 
• Narrow hands with a straight ulnar border
• Short height
• Skin picking
• Sleep disturbance or sleep apnea

Investigations

• Methylation analysis: Encompasses all the major genetic subtypes of PWS
• Fluorescence in situ hybridization: Used to identify PWS caused by deletion

Currently, there is no treatment for Prader-Willi syndrome (PWS). However, people with PWS may benefit from early diagnosis and supportive management to improve their quality of life. 

Although treatment varies depending on symptoms, most children with PWS are managed in the following ways:

• A pediatrician may recommend a high-calorie formula or specific feeding techniques and monitor the child's progress to help them gain weight.
• Human growth hormone therapy promotes proper development, improves muscular tone, and reduces body fat. 
• Hormone replacement treatment is initiated when the child reaches puberty to help lower the risk of osteoporosis. 
• Undescended testicles may require surgery.
• Sleep disorder treatment may help with daytime sleepiness and behavioral issues.
• A dietitian can assist in developing a nutritious, low-calorie diet to help manage weight while maintaining sufficient nutrition.
• Supplemental vitamins or minerals may be required to ensure balanced nutrition. 
• Increasing physical activity and exercise aids in weight management and physical development.
• Because behavioral problems associated with PWS can disrupt life at school, social relationships, and family life, it is important for children with the condition to have support from their family and friends and professional support.
• Counseling can help people and their families cope with the emotional aspects of the disease.