Prader-Willi Syndrome

Prader-Willi syndrome is a multisystem genetic disorder characterized by delayed psychomotor development, intellectual disability, and behavioral issues. It is a very rare disease that causes various severe physical and mental problems in the patient, who, even with treatment, cannot achieve full independence.

Symptoms

The symptoms of Prader-Willi syndrome are present from birth, although they vary from person to person and progress depending on the stage of life:

• Fetal and neonatal period:
• Decreased fetal movements.
• Abnormal positioning of the fetus’s hands and feet.
• Excessive accumulation of amniotic fluid.
• Hypotonia: muscle weakness in the baby, especially in the central axis of the body.
• Poor sucking reflex due to hypotonia.
• Weak or absent crying.
• Lack of response to stimulation.
• Dystonia: involuntary muscle contractions.
• Underdeveloped genitals: the penis, scrotum, clitoris, and labia are smaller than usual. Cryptorchidism (undescended testicles) may occur.
• Distinctive facial features: almond-shaped eyes, narrow forehead at the temples, downturned mouth, and thin upper lip.
• Thick and reduced salivation.
• Infancy and early childhood:
• Delayed growth and weight gain.
• Delayed psychomotor development and language acquisition.
• Low muscle mass and high body fat percentage.
• Hypopigmentation: light-colored hair, skin, and eyes.
• Hyperphagia: insatiable appetite and uncontrolled food intake, with a lack of satiety. This can lead to abnormal and obsessive behaviors related to food.
• School-age period:
• Obesity.
• Short stature.
• Small hands and feet.
• Strabismus, myopia, or other vision problems.
• Scoliosis: curvature of the spine.
• Sleep disorders: insomnia, frequent awakenings, apneas, and daytime hypersomnia.
• High pain tolerance, which can lead to self-injury.
• Compulsive skin picking.
• Altered temperature sensitivity.
• Adolescence and adulthood:
• Cognitive impairment: learning difficulties and speech articulation problems.
• Hypogonadism: little or no production of sex hormones, leading to delayed or incomplete puberty and, in most cases, infertility.
• Obsessive-compulsive traits.
• Stereotypies: repetitive behaviors.
• Behavioral problems: tantrums, stubbornness, manipulative behavior, intolerance to change.
• Difficulties in social relationships and emotional regulation.
• Mental health disorders: patients may develop symptoms of anxiety, depression, bipolar disorder, psychosis, or phobias.

Causes

Prader-Willi syndrome is caused by the absence of expression of paternal genes in the 15q11-q13 region of chromosome 15. This lack of expression can result from:

• Deletion or loss of the 15q11-q13 region on the paternal chromosome. This is the most common cause.
• Maternal uniparental disomy: both copies of chromosome 15 are inherited from the mother.
• Mutations or defects in the paternal genes that prevent their expression. This is very rare.

This genetic alteration leads to dysfunction in the hypothalamus, the brain region responsible for regulating processes such as body temperature, hunger, mood, sleep, and the release of several pituitary hormones, such as growth hormone and gonadotropins. Disruption of hypothalamic function results in the hallmark symptoms of the syndrome.

It is important to note that Prader-Willi syndrome is a genetic disorder but is generally not hereditary. Instead, it is caused by a spontaneous genetic defect that occurs during conception or shortly thereafter. The risk of recurrence within the family is extremely low.

Risk Factors

In theory, Prader-Willi syndrome can be inherited: if a parent has the syndrome due to the deletion of the relevant region on chromosome 15, there is a 50% chance of passing the affected chromosome to the fetus, resulting in the disorder. However, this is extremely rare, as individuals with Prader-Willi syndrome are typically not fertile.

Complications

One of the main sources of severe complications in patients with Prader-Willi syndrome is obesity, which results from hyperphagia, hypotonia, and hormonal deficiencies. Obesity is a major risk factor for developing type 2 diabetes and cardiovascular, respiratory, or liver diseases, which can significantly reduce life expectancy. Additionally, difficulties in regulating body temperature and a high pain tolerance—both characteristics of the syndrome—can hinder and delay the diagnosis of injuries or other conditions, increasing their potential risk.

Growth hormone and sex hormone deficiencies can lead to osteoporosis, a reduction in bone density that makes bones weak and prone to fractures. In very rare cases, hypothalamic dysfunction can also lead to adrenal insufficiency, a failure of the adrenal glands to produce cortisol, aldosterone, testosterone, adrenaline, and noradrenaline. Acute adrenal insufficiency is a medical emergency that has been associated with early mortality in Prader-Willi syndrome.

Cognitive, emotional, and behavioral disorders also interfere with patients’ social relationships, academic performance, and work life, significantly limiting their independence and quality of life.

Prevention

Prader-Willi syndrome cannot be prevented. However, if one has a child with the syndrome, it is recommended to seek genetic counseling before having more children.

What specialist treats Prader-Willi syndrome?

The complexity of Prader-Willi syndrome requires a highly specialized multidisciplinary team composed of doctors in neurology, endocrinology, pediatrics, psychiatry, psychology, and other fields.