Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Prader-Willi syndrome (PWS) is a rare genetic disorder that affects the metabolic, nervous, endocrine, and musculoskeletal systems. It is caused by deletions or alterations of genes located on chromosome 15 at 15q11.2-q13.1
The various clinical features of PWS include hyperphagia leading to obesity, severe hypotonia, feeding and growth problems, hypogonadism, distinctive facial features, hypopigmentation, and cognitive and behavioral problems. Scoliosis and hip dysplasia may also occur in children with PWS.1
First Description of PWS in the Medical Literature
In 1864, John Langdon Down, a British physician widely recognized for his description of a syndrome that now bears his name,2 first reported the physical characteristics of a woman that met the criteria for PWS.3 He used the term polysarcia (Greek polys, “many”; sarx, “flesh”) to describe obesity — the predominant feature of the condition.3
Down listed features that met the 1993 major criteria for PWS3,4:
- Development of gross obesity at age 7 years
- Narrow forehead, rhomboidal facial features, and pouting lips
- Lack of menstruation and pubic hair, low libido, and a small uterus and ovaries at autopsy
- Voracious appetite with aggressive food-seeking behaviors, including lying and stealing to obtain food
- Serious cognitive impairment and learning difficulties
Down also listed features that met the 1993 minor criteria for PWS3,4:
- Short stature
- Temper outbursts, stubbornness, manipulative behavior, thieving, and lying
- Dyspnea, problems breathing at night (most likely indicating sleep apnea), and excessive daytime sleepiness
- Small hands and feet
- Poor articulation
He also described the unusual skill sets of this woman, who excelled at jigsaw puzzles, embroidery, and all types of handiwork.3
In 1861, before Down’s comprehensive description of the patient who met the clinical criteria for PWS, another physician, Hopkins, provided an incomplete description.3,5
Read more about PWS signs and symptoms
1956 Foundational Description of PWS
In 1956, the Swiss doctors Andrea Prader, Heinrich Willi, and Alexis Labhart described the phenotypic characteristics of the condition now named for them in a case series of 9 children with the disorder. They reported the following clinical characteristics1,6,7:
- Abnormal growth
- Small hands and feet
- Short stature
- Early onset of childhood obesity
- Hypotonia from birth
- Insatiable hunger
- Extreme obesity and very low lean body mass
- Intellectual disabilities
- Cryptorchidism in males
Read more about PWS clinical features
Discovery of the Genetic Etiology of PWS
In 1981, David Ledbetter and colleagues published a seminal paper in The New England Journal of Medicine in which they reported deletions of a particular region of chromosome 15 as the genetic cause of PWS.1,8
In their paper, they described their difficulties in discovering the origin of PWS, stating that an autosomal-recessive pattern of inheritance had been proposed. They also mentioned the 1976 work of Hawkey and Smithies. They reported a patient with PWS who had an abnormal karyotype, with a Robertsonian translocation within chromosome 15. They established that similar translocations involving D-group chromosomes (chromosomes 13-15) had previously been described, indicating that the short arm of chromosome 15 was involved in an unbalanced translocation that resulted in PWS.8
Ledbetter and colleagues went on to discover that translocations were a rare cause of PWS and that deletions of genetic material on chromosome 15 were the predominant cause of the condition.8
Read more about PWS genetics
The research of Ledbetter and colleagues was confirmed in 1984 by Japanese scientists who performed a high-resolution chromosome analysis of 14 children with PWS and 5 infants with suspected PWS. The Japanese scientists selected the PWS patients for inclusion in their study based on clinical features, such as hypotonia, cognitive impairment, short stature, hypogonadism, peculiar distinctive facial expression, and obesity. They described a Robertsonian translocation in only 1 infant among the entire cohort; however, they identified an affected region on chromosome 15 in all of the patients that was confined to the sub-band 15q11.2, suggesting that deletions of this band were very frequent among patients with PWS.9
These findings sparked interest in continued research into the genetic etiology of PWS, which subsequently resulted in descriptions of the various molecular genetic subtypes of PWS.9
Read more about PWS types
As understanding of the genetic etiology of the condition advanced, a paradigm shift occurred regarding the clinical diagnosis of PWS. The major and minor criteria developed in 1993 by consensus are now only useful for developing a clinical suspicion that leads to genetic testing, as this now definitively confirms a diagnosis of PWS.4,10
Read more about PWS diagnosis
- Scheimann A. Prader-Willi syndrome: practice essentials. Medscape. Updated August 27, 2021. Accessed July 28, 2023.
- Van Robays J. John Langdon Down (1828 – 1896). Facts Views Vis Obgyn. 2016;8(2):131-136.
- Ward OC. Down’s 1864 case of Prader-Willi syndrome: a follow-up report. J R Soc Med. 1997;90(12):694-696.
- Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91(2):398-402.
- Hopkins ID. A case of polysarcia. Buffalo Med Surg J. 1861;1:114-15.
- What is Prader-Willi syndrome? Foundation for Prader-Willi Research. Accessed July 27, 2023.
- Prader A, Labhart A, Willi H. [A syndrome characterized by obesity, short stature, cryptorchidism, and oligophrenia following a myotonia-like condition in infancy]. [Article in German.] Schweizerische Medizinische Wochenschrift. 1956; 86:1260.
- Ledbetter DH, Riccardi VM, Airhart SD, Strobel RJ, Keenan BS, Crawford JD. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. 1981;304(6):325-329. doi:10.1056/NEJM198102053040604
- Fukushima Y, Niikawa N, Kuroki Y. The Prader-Willi syndrome and interstitial deletion of chromosome 15: high-resolution chromosome analyses of 14 patients with the Prader-Willi syndrome and of 5 suspected infants. Jpn J Human Genet. 1984;29:1-6. doi:10.1007/BF01876751
- Gunay-Aygun M, Schwartz S, Heeger S, O’Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics. 2001;108(5):e92. doi:10.1542/peds.108.5.e92
Reviewed by Debjyoti Talukdar, MD, on 7/29/2023.