The History of Prader-Willi syndrome

By Nelson Tang

What is Prader- Willi syndrome? This essay will answer various questions such as what it is and the signs and symptoms associated with it. It will also take a look at the history of the disorder and what has changed since its discovery and the advancements made in the field along with what we further understand about it. Moreover, it will discuss how it was discovered and who were the people behind it. Lastly, it will talk about Andrea Prader, Alexis Labhart, and Heinrich Willi in regards to who they were and their contributions and relationship to Prader-Willi syndrome.

Prader-Willi syndrome is a genetic disorder that occurs roughly in 1 out of every 10,000 to 30,000 births and is the result of a number of genetic abnormalities. Therefore, it is a rare disease that affects males and females equally, while some have claimed it to be one of the most common genetic pathologies. [2]. It is a spectrum disorder meaning that it will vary from person to person in terms of the symptoms or severity. What causes Prader-Willi syndrome to manifest in an individual? This is due to a lack of chromosome 15 in the 5q11.2-q13 region with the genes in this region only being active in the chromosome that came from the father.

This genetic defect can happen for three different reasons. One of these reasons include the deletion or lack of chromosome 15, which accounts for about 60% of all cases. Another reason is the inheritance of two chromosome 15s from the mother and none from the father, which is referred to as maternal uniparental disomy (UPD) and accounts for about 35% to 40% for all cases. Lastly, there is an imprinting defect, which causes chromosome 15 to be inactive despite being present and this only accounts for 1% to 3% of all cases. [4].

Due to the rarity of this disorder, diagnosis are difficult to assess and make at times. It requires extensive testing such as by cytogenetic examination. In the molecular diagnostics of the syndrome, there are the FISH method (fluorescence in situ hybridization), DNA methylation analysis and DNA sequencing. Lastly, there is also the prenatal diagnosis. Therefore, there is a close monitoring between infancy and toddler years. Depending on the age, there are different levels of testing as those who are older require higher points when it comes to their diagnosis such as 8 points for those who are above the age of 3. [2].

What are the signs and symptoms of Prader-Willi syndrome? One of the most common signs is the behavior changes. Individuals with this syndrome exhibit mood changes, aggressive behavior, tantrums, irritability, compulsive behavior, and poor social interaction as tendency only increases with age. Little flexibility is shown in behavior and there is a reluctance to accept any kind of change to daily routines. Studies also show that about 20% of patients display behaviors that are typical of those with autism spectrum disorders. Articulation disorder, a higher pain threshold, disturbances in thermoregulation, and sleep problems are other symptoms that may appear.

Furthermore, there are certain physical characteristics such as dysmorphic features, which include a narrow face, almond-shaped eyelid fissures, small mouth, thin upper lip, or downward corners of the mouth. There is also hypogonadism where in boys, they have smaller testicles, a smaller penis and a poorly developed scrotum. In girls, there is cryptorchidism, which results in a small clitoris, hypoplastic labia minora. Other physical defects may include floppy skin, low muscle tone, poor suck reflex, short stature, smaller hands or feet, and hypopigmentation in hair or skin. There is also the shift from little weight gain during infancy to rapid weight gain shortly after during the second year. During the second year of life, there are also eating disorders and increased appetite. [2]. Symptoms seem to be due to dysfunction of a hypothalamus. The hypothalamus is a small endocrine organ located at the base of the brain. And plays a crucial role in many of our bodily functions. Such responsibilities it has include the  regulation of hunger and satiety, body temperature, pain, sleep-wake balance, fluid balance, emotions, and fertility. [4].

Currently, there are no known cures for Prader-Willi syndromes, but there are several ways in managing the condition. One of the first steps is a strict dietary intake based on the individual's height and weight. This is a way to counter the rapid weight gains or unusual eating. Diet and weight are things that need to be regularly monitored and regulated. Developmental services and educational support can help with mobility, motor functions, speech, and learning. Hormonal and surgical treatments, therapy, and medicine can also be used as well. [3]. Lastly, there is physical activity to counter weight gain and lower the risks of obesity. With exercise, it can lead to increased energy levels and muscle mass, which increases mobility and motor functions. 

However, this should all be done under the supervision of a physiotherapist due to low muscle tone. Through these treatments and methods, one’s quality of life can be improved.

Prior to the discovery, it is noted that John Langdon Down who discovered what we know as Down syndrome also described the first patient who had Prader-Willi syndrome in 1887. Down described this girl having mental impairment, short stature, hypogonadism, and obesity as he  attributed these symptoms to polysarcia.[1]. Prader-Willi syndrome was discovered by three people: Andrea Prader, Alexis Labhart, and Heinrich Willi; who were Swiss doctors. In 1956, they conducted clinical trials leading to the discovery.  It involved the examination of the characteristics of nine children who were part of the trial. Based on observations, there were a number of common characteristics defined in their initial report. This included small hands and feet, abnormal growth and body composition (small stature, very low lean body mass, and early-onset childhood obesity), hypotonia (weak muscles) at birth, insatiable hunger, extreme obesity, and intellectual disability. [4]. With more clinical trials being conducted over time, the results and findings have shown to vary between different age groups starting with the neonatal group, which had hypotonia with poor suck. Ages one month to two years displayed hypotonia with poor appetite and suck in the neonatal period, and developmental delay. Ages two to six years displayed hypotonia with a history of poor suck and developmental delay. Ages six to 12 years displayed a history of hypotonia with poor suck (hypotonia often persists),developmental delay, excessive eating with central obesity if uncontrolled externally. Ages 13 years and onward displayed cognitive impairment, usually mild intellectual disability,excessive eating and hyperphagia with central obesity if uncontrolled externally and hypothalamic hypogonadism or typical behavioral findings.[3]. In 1981, Dr. Ledbetter was able to identify the deletions located between bands 15q11 and 15q13 where he determined it to be the site of  Prader-Willi syndrome. [1]. Thanks to the discovery, further research and development has been built upon their findings and work leading to a better understanding of the disorder. With more advocacy, it can lead to more funding and research into one day finding a cure.

References:

[1]. Ann Scheimann, MD. “Prader-Willi Syndrome.” Practice Essentials, Pathophysiology, Epidemiology, Medscape, 3 May 2024, emedicine.medscape.com/article/947954-overview?form=fpf. Accessed 27 June 2024. 

[2]. Drabik, Marta, et al. “Management of Prader-Labhart-Willi Syndrome in Children and in Adults, with Particular Emphasis on the Treatment with Recombinant Human Growth Hormone.” Pediatric Endocrinology, Diabetes, and Metabolism, U.S. National Library of Medicine, 2022, www.ncbi.nlm.nih.gov/pmc/articles/PMC10226360/. 

[3]. Driscoll, Daniel J. “Prader-Willi Syndrome.” GeneReviews® [Internet]., U.S. National Library of Medicine, 2 Nov. 2023, www.ncbi.nlm.nih.gov/books/NBK1330/. 

[4]. Fpwr. “What Is Prader-Willi Syndrome?” What Is Prader-Willi Syndrome, www.fpwr.org/what-is-prader-willi-syndrome#causes.