Prader-Willi Syndrome

What is Prader-Willi Syndrome?

This diagram points out some effects associated with Prader-Willi Syndrome. Insatiable hunger results in obesity, incomplete sexual development and infertility as an adult, almond shaped eyes and misalignment of the eyes, down turned mouth, behavioral problems and small hands

Prader-Willi Syndrome is a Chromosomal Abnormality of the structural sort. In the particular case of Prader Willi Syndrome (PWS) the q 11-13 region of chromosome 15 is deleted or unexpressed.  As a result, functioning of a brain structure called the hypothalamus is compromised.  PWS affects one in every 12,000-15,000 people and occurs equally among both sexes and across races.  The genes associated with PWS normally are expressed only from a region of chromosome 15 inherited from the father, the genes from the mother are inactivated.  If the material donated from the father is compromised via deletion or inactivation then the individual experiences the effects demonstrated in the picture at left.

Individuals with PWS have incomplete sexual development and are infertile as adults.  Hypothalamic dysfunction is thought to be the basis for many of the phenotypic features, such as short stature and hypogonadism. Hypogonadism presents as undescended testicles, small testes, and decreased scrotal rugae in males and small labia minora and clitoris in females. Puberty typically is delayed or incomplete and adults are infertile.

How Does Prader-Willi Syndrome Occur

a) deletion of PWS region of Chromosome 15 inherited from father; 70% of cases b) both chromosome 15s are inherited from mother; 25% of cases c) methylation of PWS region of Chromosome 15 inherited from father

Individuals affected with PWS either have a deletion or inactivation on chromosome 15 or inherit two copies of this chromosomal region from the mother.  A random deletion in the q12 band of chromosome 15 is contributed by the father and observed in 70% of PWS cases.  Inactivation or imprinting defect account for 5% of PWS cases.

Uniparental disomy occurs when both copies of chrosome 15 in the offspring come from the mother.  As a consequence of translocation, nondisjunction in meiosis I causes an unequal splitting of chromosome 15, yielding a zygote with either two copies or no copies of the chromosome.  This can explain why the father may not donate a copy of chromosome 15 and the mother may donate two copies of chromosome 15.  The PWS region of chromosome 15 is inherited from the father and inactivated in material donated by the mother even if there are two copies.  Uniparental disomy occurs in 25% of PWS cases.

Common Traits and Causes

Common features of Prader-Willi Syndrome

Common traits of PWS are as follows:

  • Characteristic facial features: almond shaped eyes, thin upper lip, Strabismus (lazy eye), down turned mouth
  • feeding problems during infancy
  • Hypogonadism
  • low levels of testosterone and estrogen
  • low muscle tone
  • rapid weight gain
  • insatiable appetite and resulting obesity
  • small stature
  • small hands and feet
  • behavioral difficulties (learning disability, low-normal inteligence to moderate mental retardation)

The major symptoms of PWS are the result of hypothalamic disturbances.

the defect in chromosome 15 leads to a malfunctioning hypothalamus

It has recently been shown that 20% of PWS patients have a complete absence of the posterior pituitary bright spot after magnetic resonance imaging (MRI).  The hypothalamus normally registers feelings of hunger and satiety as well as secretion of pituitary hormones related to sexual development which will be discussed in the next section .  While it is not known exactly what genes are effected by the absence of the PWS area of chromosome 15 it is believed that expression of the neuroendocrine peptides, vasopressin and oxytocin, on the supraoptic nucleus and paraventricular nucleus of the hypothalamus is compromised.  This indicates that proper signaling is compromised to the extent that individuals with PWS never feel full and explains why obesity is the biggest issue that these individuals face.

Sexual Development

The deletion of the PWS region of chromosome 15 causes a disturbance in hypothalamus function.  The function of the pituitary is compromised in these individuals because its function is dependent on the function of the hypothalamus.

In terms of sexual development; decreased levels of sexual hormones result in undescended testes in boys, hypoplastic external genitalia in both sexes, delayed or incomplete pubertal development, infertility in men and infertility in all but a few cases in women.  Testosterone levels are low in males while estradiol, Leutenizing hormone (LH), and Follicle Stimulating Hormone (FSH) levels in women are low.  Decreased levels of FSH and LH being secreted by the neurohypophysis is due to decreased levels of GNRH being secreted by the hypothalamus.  GnRH levels are low due to abnormal functioning of nerve cells in the hypothalamus.

In males the leydig cells are induced to secrete testosterone by FSH and LH.  Testosterone then induces development of the penis, scrotum, epeidiymis, vas deferens and seminal vesicle.  In individuals with PWS, there is no or little FSH and LH being released from the neurohypophysis and therefore the leydig cells do not release enough testosterone.  As a result, masles with PWS experience incomplete development in these structures which is evident in the picture above.  Low FSH and LH levels also lead to defective sperm development resulting in infertility.

In women with PWS, low levels of FSH and LH cause the granulosa cells located in the follicle to produce lower concentrations of Estrogen than normal.  Hypoplasia or absence of labia minora and/or clitoris may result from these lower concentrations of estrogen

Psychology and Behavioral Effects

Behavioral characteristics in PWS include excessive interest in food, skin picking, difficulty with a change in routine, temper tantrums, obsessive and compulsive behaviors, and mood fluctuations; these behaviors tend to increase through the teens, 20’s and 30’s.  Individuals with PWS typically have intellectual disabilities that range from borderline to mild/moderate mental retardation.

Treatment with psychotropic medications such as antidepressants, antipsychotics, appetite suppressants, and others have shown limited effectiveness in controlling excessive hunger and psychological issues.  Cognitive behavioral interventions along with speech-language therapy, and management of food related issues have proven most effective in treating the most severe behavioral characteristics.


Prader-Willi Syndrome Translocated Chromosome

Although there are published consensus clinical criteria for the diagnosis of PWS, genetic testing has become the standard because it detects nearly 100 percent of persons with PWS, is highly specific, and can diagnose PWS earlier than would be possible based on clinical criteria.  There are four main genetic tests that can be performed: high resolution chromosomal analysis, fluroescence in situ hybridization, DNA methylation test and DNA polymorphism studies.

High Resolution Chromosomal Analysis (examination under microscope) Large deletions and other chromosome abnormalities such as translocations and extra chromosomes Small deletions, uniparental disomy (UPD), Imprinting mutations Widely available
The following are classified as molecular tests:
(Stands for: Fluorescence In Situ Hybridization,
Deletions of all sizes UPD
Imprinting mutations,
Which parent each chromosome 15 came from
Widely Available
DNA polymorphism studies
(done to detect uniparental disomy)
Which parent each chromosome 15 came from  Can also detect some deletions. Imprinting mutations,
Some deletions
Not widely available
DNA methylation test
(confirms or rules out PWS as a diagnosis, with over 99% accuracy)
The imprinting pattern in region 15a11-q13(in PWS there is only a maternally inherited pattern) Which form (molecular class) of PWS the child has: deletion, UPD, or imprinting mutation. Not widely available


Although there is no cure for Prader-Willi syndrome (PWS), there are interventions that can significantly help individuals with PWS lead healthier lives. An example is growth hormone (GH) therapy to increase stature, decrease obesity, and increase muscle mass and capacity for physical activity.  Additionally, sex hormone therapy (testosterone in men and estrogen in women)  encourages development of secondarysexual characteristics as well as improvements in bone mineral content and bone mineral density.

Testosterone levels are usually low and testosterone replacement beginning early in adolescence is often helpful. Normal levels of testosterone are needed to preserve bone mass and prevent osteoporosis. Testosterone replacement also increases muscle mass and strength. In older males with a small penis, a short course of testosterone can be given to improve appearance and size.  Most females with PWS do not have regular menstrual cycles and if they do menstruate, may have early menopause. Hypoplasia of the labia and/or clitoris in teenage females is common. The use of estrogen replacement therapy for women with PWS is not well established but may help preserve bone mass and reduce osteoporosis.

Prader-Willi Syndrome Explained by MayoClinic


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