Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Prader-Willi syndrome (PWS) is a genetic condition that causes small stature and obesity in affected children. With an incidence rate of 1 in every 15,000 live births, PWS is considered the most common cause of genetically determined obesity in children. Boys and girls of all races and ethnicities can be equally affected by this condition.1
PWS was first described in 1956 by 3 Swiss physicians: Andrea Prader, Alexis Labhart, and Heinrich Willi. In this first paper, they reported characteristics of 9 children with common clinical features of short limbs, short stature, decreased lean body mass, weak muscle tone at birth, low intelligence, early-onset obesity, and severe obesity.1
The genes responsible for PWS are located in a specific region of the long arm of chromosome 15 (15q11-q13). Human cells normally contain 1 maternally derived chromosome 15 and 1 paternally derived chromosome 15. The genes in the PWS region of chromosome 15 are usually only active on the paternally derived chromosome and inactive on the maternally derived chromosome 15. Inactivation or loss of these genes in the PWS region of the paternal chromosome 15 leads to a complete absence of activity of these genes.1 Inactivation of these genes can occur by paternal deletion, maternal uniparental disomy (UPD), or imprinting center defects.
PWS by Deletion
In nearly 70% of cases, the abnormality results from deletion of some genetic material in the PWS region of the paternal chromosome 15. These deletions are often so small that routine genetic tests are unable to detect these defects.1
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PWS by Maternal Uniparental Disomy
Uniparental disomy is the second most common mechanism, responsible for about 30% of cases. UPD is a condition in which both copies of a particular chromosome are abnormally derived from only 1 parent instead of 1 copy from each parent. In the UPD subtype of PWS, both copies of chromosome 15 are derived from the mother and no paternal chromosome 15 is present in the affected child.1
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PWS by Imprinting Defect
The third mechanism, responsible for 1% to 3% of cases, involves small genetic mutations in the PWS region of the paternal chromosome 15. Although the genetic materials are present in the PWS region, these genes are inactive due to the mutations.1
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Signs and Symptoms
After birth and in early infancy, PWS manifests with severe hypotonia, lack of appetite, and feeding problems. In early childhood, affected babies start eating excessively. If food intake is not regulated, morbid obesity develops. Developmental milestones are delayed. Patients who do not receive growth hormone supplements invariably suffer from growth impairment, leading to short stature. They also develop characteristic facial features. Strabismus and scoliosis are seen in some cases.2
In both sexes, sexual developmental abnormalities are common and characterized by hypogonadism, hypoplasia of genital organs, and impaired pubertal development. Infertility is seen in most cases. Language skills develop late along with variable levels of cognitive abnormalities. Behavioral abnormality is characterized by a distinctive combination of temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsiveness.2
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Identification of specific signs and symptoms of PWS requires a detailed clinical history along with a thorough examination. Clinical diagnostic criteria have been developed for the early detection of potential cases of PWS. However, confirmation of the diagnosis requires genetic testing. Genetic testing is also needed to identify if the disease has resulted from deletion, maternal UPD, or genetic imprinting.3
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Therefore, as a protocol, every newborn and young child presenting with unexplained hypotonia and feeding problems should undergo genetic testing for PWS. Techniques used for diagnostic confirmation of PWS include DNA methylation tests and fluorescence in situ hybridization (FISH). Recent advanced techniques like high-resolution chromosomal microarray are more sensitive and can identify even smaller chromosomal defects that are usually undetected by routine chromosomal analysis. Microarray utilizes several hundred thousand DNA probes covering the entire genome to detect small deletions or rearrangements in the 15q11-q13 region on chromosome 15. Imprinting defects and specific maternal disomy 15 subclasses can also be identified with this method.3
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Although the genetic defect responsible for PWS is incurable, the physical symptoms can be somewhat controlled by certain treatment regimens.4
Growth hormone supplementation with human growth factors, such as somatropin (sold as Genotropin®, Omnitrope®, and Norditropin®, among others), helps with growth and developing muscle mass. Sex hormone supplementation improves the symptoms of hypogonadism, assisting with the development of puberty progression. These hormones also help improve bone density.4,5
Muscle strength and motor coordination can be improved with exercise and physical therapy.4 Speech therapy is utilized to improve language skills in affected patients.6
Special feeding techniques and food formulations, if used properly from infancy, can help normalize growth. Continued use of a balanced, low-calorie diet, weight monitoring, external food restriction, and daily exercise aids in the normal growth of affected children as they age.2
Psychological and cognitive symptoms are managed with special education services. Children with PWS can realize their full capacity with proper support and treatment.4
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Prognosis and Complications
Predominant life-threatening complications of PWS are type 2 diabetes, heart failure, and other metabolic abnormalities resulting from morbid obesity. These complications can increase morbidity and early mortality in patients with PWS.7
However, normal life expectancy and quality of life can be achieved with the right treatment and proper support from family members and a care team of expert professionals. Living in a special group home under expert supervision may be necessary for some patients with severe intellectual and cognitive disabilities. Constant supervision of diet is compulsory for most patients to prevent overeating and excessive weight gain.7
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- Strong TV. What is Prader-Willi syndrome? A clear explanation of PWS symptoms, causes, diagnosis, genetics, treatments & research. Foundation for Prader-Willi Research. Accessed July 17, 2023.
- Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. October 6, 1998. Updated March 9, 2023. Accessed July 17, 2023.
- Prader-Willi syndrome. National Organization for Rare Disorders (NORD). Updated July 12, 2023. Accessed July 17, 2023.
- Kugler M. Prader-Willi syndrome symptoms and treatment. Verywell Health. Updated June 7, 2022. Accessed July 17, 2023.
- Fermin Gutierrez MA, Mendez MD. Prader-Willi syndrome. StatPearls [Internet]. Updated January 31, 2023. Accessed July 16, 2023.
- Speech and language therapy for the child with Prader-Willi syndrome. Prader-Willi California Foundation. Accessed July 17, 2023.
- Watson S. What is Prader-Willi syndrome? Symptoms, causes, diagnosis, treatment, and prevention. Everyday Health. Accessed July 17, 2023.
Reviewed by Kyle Habet, MD, on 7/20/2023.