Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare, genetic disorder that affects multiple organ systems throughout the patient’s lifespan.¹ Several clinical features manifesting in 2 classic, distinctive nutritional stages may raise the suspicion of PWS. Stage 1, which occurs during infancy, is characterized by failure to thrive, hypotonia, and a poor sucking reflex for feeding. Stage 2 begins in early childhood and is characterized by hyperphagia that leads to obesity in later childhood.²

Researchers have subdivided the 2 classically described stages into 5 main phases, with subphases in phases 1 and 2, for a total of 7 phases²:

• Phase 0: occurs in utero and is characterized by decreased fetal movement and growth restriction
• Phase 1a: occurs between birth and age 15 months and is characterized by hypotonia and difficulty feeding with or without failure to thrive (FTT)
• Phase 1b: is characterized by steady growth along a growth curve and weight increasing at a normal rate; usually begins at a median age of 9 months (range of initial transition to this phase, 5 to 15 months)
• Phase 2a: manifests at a median age of approximately 2 years (quartile range: 20 to 31 months) and is characterized by weight gain without changes in appetite or caloric intake
• Phase 2b: begins at a median age of approximately 4.5 years (quartile range: 3 to 5.25 years) and is characterized by weight gain accompanied by an increased interest in food
• Phase 3: manifests at a median age of approximately 8 years (quartile range: 5 to 13 years) and is characterized by hyperphagia, lack of satiety, and aggressive food-seeking behaviors
• Phase 4: occurs in some adults with PWS when an insatiable appetite is no longer present and they are able to feel full

Dysmorphic Characteristics

Children with PWS may have characteristic dysmorphic features that are evident shortly after birth and become increasingly prominent with age, including^1,3:

• Almond-shaped eyes^1,3,4
• Narrow bifrontal diameter^1,3,4 
• Narrow nasal bridge³
• Dolichocephaly³ 
• Thin upper lip and downturned angles of the mouth^1,3 
• Production of thick and abundant saliva¹
• Small hands and feet^1,3,4
• Short stature due to low levels of growth hormone^1,3,4
• Unusually fair hair, skin, and eyes^3,4

Read more about PWS signs and symptoms

Neonatal Axial Hypotonia

Most infants with PWS present with marked hypotonia and are often described as “floppy babies.” Neonatal axial hypotonia is associated with lethargy, decreased movement, weak crying, and poor reflexes, especially a poor sucking reflex that may lead to FTT.¹ 

Failure to Thrive

Failure to thrive during infancy due to a poor sucking reflex and difficulty feeding may or may not develop in individuals with PWS.⁵ Some researchers propose that the development of FTT despite adequate caloric intake during PWS nutritional phase 1a may be caused by a high metabolic rate or malabsorption of nutrients.² 

Read more about PWS pathophysiology

Hyperphagia

Hyperphagia, or increased appetite and chronic overeating, leading to morbid obesity is a characteristic of PWS that becomes increasingly noticeable during early childhood.^3,4 Children with PWS exhibit an excessive interest in food, seek extra food, and become angry or frustrated when denied food.³

Children with PWS are unable to control their urges for food or food intake, so this aspect of daily living must be managed for them.³

Mental Health/Emotional Issues

Individuals with PWS are more likely to become anxious or stressed. The inability to access food is a particular trigger for difficult behaviors, such as^1,3:

• Temper tantrums involving shouting, crying, and screaming
• Acting out physically
• Difficulty adapting to changes in routine or environment, resulting in frustration or argumentative behavior
• Repeatedly asking the same questions (verbal perseverance)
• Stubbornness
• Skin picking
• Obsessive-compulsive features, particularly involving food

Neurobehavioral problems become more severe as individuals with PWS age and their body mass index (BMI) increases; however, the problems may diminish in older adults. The most severe behavioral and psychiatric problems develop during adolescence and early adulthood, including depression, bipolar disorder, and psychosis.⁶ Psychosis affects approximately 5% to 10% of young adults with PWS.^1,7

In addition to bipolar disorder, cycloid psychosis may be a comorbid feature of PWS. Cycloid psychosis is defined as episodes of psychosis with rapid full recovery between episodes.⁸

Individuals with PWS display a range of psychosis-risk symptoms, including cognitive disorganization (63.1%), unusual beliefs (38.6%), and suspiciousness (33.3%). The risk for the development of psychosis or psychosis-risk symptoms correlated significantly with sleep disturbance, nap frequency, sleep duration, daytime dysfunction, and sleep quality.⁹

Potential Axis I psychiatric disorders that may manifest in patients with PWS include¹⁰:

• Impulse control disorder
• Organic personality disorder
• Oppositional defiant disorder
• Dysthymic disorder
• Depressive disorder
• Attention-deficit/hyperactivity disorder
• Obsessive-compulsive disorder

Some patients with PWS may also exhibit self-mutilating behaviors.¹⁰

Read more about PWS care team

Gastrointestinal Issues

PWS may result in gastrointestinal issues, such as chronic constipation, stomach problems, dysphagia, and choking. Hypotonia compromises the entire gastrointestinal system in people with PWS. Because food transit times are much slower than normal, individuals with PWS are at risk for impaction, necrosis, perforation of the colon, and sepsis. Higher pain thresholds complicate the issue as those with PWS may not feel pain or be aware of any gastrointestinal problems.¹¹

Gastroparesis, or decreased gastric motility, may further contribute to gastrointestinal issues.¹² Despite slower gastric motility and emptying (which typically results in feelings of early satiety¹³), individuals with PWS do not process the message that the stomach is full, so they do not experience satiety. The resultant overstretching, distension, stomach rupture, or necrosis of stomach tissues may have life-threatening consequences. Constipation, often seen in PWS, may contribute to gastroparesis.¹²

Read more about PWS complications

Skeletal Problems

Skeletal problems common in PWS include scoliosis, hip dysplasia, diminished cervical lordosis, increased cervicothoracic kyphosis, and osteopenia/osteoporosis, which increases susceptibility to fractures.¹⁰ 

Severe scoliosis may require surgical intervention with spinal fusion, whereas less severe curvatures can be managed with bracing. Surgical intervention may also be required to treat fractures.¹⁰

Read more about PWS surgical management

Delayed Speech

The attainment of language milestones may be delayed in infants with PWS. They often begin to speak at approximately 2 years of age, reaching this milestone at twice the normal age.¹

Developmental Delay

Global development, particularly gross motor development, is often delayed in PWS, with milestones often achieved at twice the normal age (such as sitting at 12 months and walking at 24 months).¹ Children with PWS have problems with short-term memory, mild-to-moderate intellectual impairment, and learning disabilities that require extra support at school.^3,4

Skin Picking

One of the compulsive behaviors that manifests in many individuals with PWS is persistent skin picking, usually the skin of the face, hands, or arms.^1,3,4 Scratching, tweezing, piercing, or pulling at the skin may result in open sores, scars, and an increased risk of infection.³  

Sleep Disorders

Approximately half of individuals with PWS demonstrate rapid eye movement (REM) sleep disorders that may be phenotypic variations of narcolepsy or be caused by a generalized 24-hour state of hypoarousal.^14,15 REM sleep disturbances include¹⁴:

• Periods of REM sleep at sleep onset
• Increased arousals during REM sleep
• REM sleep during daytime naps
• Significantly increased total REM sleep
• Decreased REM latency
• Decreased duration of non-REM sleep stage N3

Sleep problems are extremely prevalent in PWS; central or obstructive sleep apnea, insomnia, excessive daytime sleepiness, narcolepsy, and cataplexy are becoming increasingly recognized and diagnosed in this patient population. Sleep disorders influence behavior, cognition, health, and quality of life for individuals with PWS, requiring prompt diagnosis and intervention.¹⁴

Read more about PWS diagnosis

Hypogonadism/Hypogenitalia

Hypothalamic dysfunction in PWS results in deficiencies of growth hormone and thyroid-stimulating hormone, central adrenal insufficiency, and hypogonadism. Hypotonia and hypogonadism are typically the first observable manifestations of hypothalamic dysfunction during infancy.¹

Males with PWS may have a penis and/or hypoplastic scrotum that is small with poor rugation and hypopigmentation. Unilateral or bilateral cryptorchidism is present in 80% to 90% of male infants with PWS and may require surgical intervention via orchidopexy.^1,16

In females with PWS, genital hypoplasia is often overlooked, but the clitoris and labia, particularly the labia minora, are small from birth.¹ 

Read more about PWS treatment

References

1. Elena G, Bruna C, Benedetta M, Stefania DC, Giuseppe C. Prader-Willi syndrome: clinical aspects. J Obes. 2012;2012:473941. doi:10.1155/2012/473941
2. Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi syndrome. Am J Med Genet A. 2011;155A(5):1040-1049. doi:10.1002/ajmg.a.33951
3. Symptoms – Prader-Willi syndrome. NHS. Published October 23, 2017. Accessed July 12, 2023.
4. Prader-Willi syndrome. MedlinePlus. Accessed July 12, 2023. 
5. Fermin Gutierrez MA, Mendez MD. Prader-Willi syndrome. StatPearls [Internet]. Updated January 31, 2023. Accessed July 12, 2023. 
6. Serious mental health problems in Prader-Willi syndrome. Foundation for Prader-Willi Research. Accessed July 12, 2023.
7. Steinhausen HC, Eiholzer U, Hauffa BP, Malin Z. Behavioural and emotional disturbances in people with Prader-Willi syndrome. J Intellect Disabil Res. 2004;48(1):47-52. doi:10.1111/j.1365-2788.2004.00582.x
8. Singh D, Sasson A, Rusciano V, Wakimoto Y, Pinkhasov A, Angulo M. Cycloid psychosis comorbid with Prader-Willi syndrome: a case series. Am J Med Genet A. 2019;179(7):1241-1245. doi:10.1002/ajmg.a.61181
9. O’Hora KP, Zhang Z, Vajdi A, et al. Neurobehavioral dimensions of Prader-Willi syndrome: relationships between sleep and psychosis-risk symptoms. Front Psychiatry. 2022;13. doi:10.3389/fpsyt.2022.868536
10. Kroonen LT, Herman M, Pizzutillo PD, MacEwen GD. Prader-Willi syndrome: clinical concerns for the orthopaedic surgeon. J Pediatr Orthop. 2006;26(5):673-679. doi:10.1097/01.bpo.0000226282.01202.4f
11. Gastroenterology. PWSA Victoria. Accessed July 12, 2023.
12. Larsen C. Understanding gastric motility and gastroparesis in PWS. Prader-Willi Syndrome Association USA. Published September 2, 2021. Accessed July 12, 2023.
13. Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut. 2019;68(12):2238-2250. doi:10.1136/gutjnl-2019-318712
14. Duis J, Pullen LC, Picone M, et al. Diagnosis and management of sleep disorders in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(6):1687-1696. doi:10.5664/jcsm.9938
15. Vgontzas AN, Bixler EO, Kales A, et al. Daytime sleepiness and REM abnormalities in Prader-Willi syndrome: evidence of generalized hypoarousal. Int J Neurosci. 1996;87(3-4):127-139. doi:10.3109/00207459609070832
16. Eiholzer U, l’Allemand D, Rousson V, et al. Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart-Willi syndrome. J Clin Endocrinol Metab. 2006;91(3):892-898. doi:10.1210/jc.2005-0902

Reviewed by Debjyoti Talukdar, MD, on 7/21/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

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.