Introduction

Prader-Willi syndrome (PWS) is a rare genetic disorder affecting various organs of the body, with an estimated occurrence of 1 in every 10,000 to 30,000 individuals. This condition is characterised by significant low muscle tone, feeding challenges during infancy, and a later inclination towards compulsive overeating, which can lead to obesity if eating behaviours are not addressed. Motor skills and language development are delayed, and all individuals have some level of cognitive impairment. Similar behaviours are often observed, with temper tantrums, stubbornness, and compulsive actions. 

Hypogonadism is a component of this disease, where the gonads (testes or testicles in men and ovaries in women) malfunction, leading to issues like underdeveloped genitals and often infertility. Growth hormone (GH) insufficiency causes decreased height, while common facial features, strabismus, and scoliosis are typical. Obesity increases the risk of both sleep problems and type II diabetes.¹ This article discusses the symptoms and methods of diagnosis of Prader-Willi Syndrome.

Symptoms

What are the symptoms of Prader-Willi Syndrome?

Signs and symptoms of Prader-Willi syndrome can differ from person to person and might gradually change as individuals progress from childhood to adulthood.

Infants

Common signs and symptoms that may be present from birth could include:

• Hypotonia (poor muscle tone): this is a key sign; babies may feel floppy or resemble rag dolls when held
• Distinct facial characteristics: children may be born with almond-shaped eyes, a long narrow head, a triangular mouth and, a thin upper lip
• Weakened sucking reflex: babies might experience a weakened sucking reflex due to reduced muscle tone. This can lead to feeding difficulties and contribute to failure to thrive
• Overall poor responsiveness: a baby may appear unusually tired, show poor responsiveness to stimuli, have difficulties waking up or have a weak cry
• Underdeveloped genitals: boys may have a small penis and small or undescended testes (cryptorchidism). Baby girls may also present with underdeveloped genitals

Early childhood to adulthood

In Prader-Willi syndrome, certain traits may appear early and last a lifetime, needing ongoing management. These traits may include:

• Food cravings and weight gain: consuming excessive amounts of food, leading to rapid weight gain, starting around the age of 2 years. Unusual food-seeking behaviours, such as food hoarding, or eating frozen food or even garbage, may emerge
• Underdeveloped sex organs: hypogonadism occurs when the testes in men or ovaries in women do not produce enough sex hormones, resulting in underdeveloped sex organs, delayed or incomplete puberty and, in nearly all cases infertility. Without intervention, women may not begin menstruating until their 30s or may never menstruate, and men may have limited facial hair and may never fully deepen their voices
• Poor growth and physical development: low levels of human growth hormone (HGH) contribute to short adult height, low muscle mass and high body fat. Other hormone-related concerns may include an underactive thyroid (hypothyroidism) or central adrenal insufficiency, where there is decreased secretion of adrenocorticotropin hormone (ACTH). This reduces cortisol production, making it difficult for the body to handle stress well
• Cognitive impairment: having a mild to moderate intellectual disability is a common characteristic of this syndrome. Even individuals who do not experience a significant intellectual disability have some learning difficulties
• Delayed motor development: toddlers with Prader-Willi syndrome often achieve physical movement milestones — for example, sitting up or walking — later than their peers
• Speech problems: speech is frequently delayed and ongoing difficulties with articulating words may persist into adulthood
• Behavioural problems: individuals with this syndrome either children or adults, may show traits of stubbornness, anger, control or manipulation. They may also experience obsessive-compulsive tendencies or repetitive behaviours, along with other mental health conditions such as anxiety and skin-picking
• Sleep disorders: individuals with the syndrome often have trouble sleeping, which can make them feel tired during the day and worsen their behaviour
• Other signs and symptoms: these may include small hands and feet, hip problems, scoliosis, reduced saliva flow, vision problems, problems regulating body temperature, a high pain tolerance, or reduced pigment (hypopigmentation) resulting in pale skin, hair or eyes

Diagnosis

How is Prader-Willi Syndrome diagnosed?

Prader-Willi syndrome is diagnosed using a series of highly specialised genetic tests. Chromosome tests, such as karyotypes, cannot reliably detect the genetic changes linked to the syndrome. The physical examination and history taking are vital in diagnosing and should come before genetic testing. Three major genetic changes can cause PWS, and all 3 types will show a positive DNA methylation analysis. The genetic tests are:

DNA Methylation Testing

Anyone suspected of having PWS should undergo a DNA methylation analysis. This test detects almost all (>99%) cases of PWS.

Fish

In the past, after a positive DNA methylation test, this evaluation was conducted to confirm whether the individual exhibits the deletion type which is the most prevalent. It is not the ideal initial test, as it will not detect the two other subtypes of PWS. Even if the test results are negative, the individuals could still have the syndrome.

Chromosome Microarray/Oligo-SNP array (OSA)

It is becoming the test of choice due to its ability to detect different chromosome deletions, even those smaller or "atypical" in size. It will also identify many cases of uniparental disomy 15 (UPD), another genetic type of PWS, which is when an individual inherits two copies of chromosome 15 from the same parent. It does not detect all cases of PWS, specifically those with imprinting defects.

Uniparental disomy (UPD) and imprinting defect testing

This is a specialised DNA test that examines DNA polymorphisms. It requires blood from the patient and both parents for accurate interpretation.²

Summary

Prader-Willi syndrome (PWS) is a rare genetic condition characterised by weak muscles, feeding difficulties, cognitive impairment, and a strong urge to overeat, leading to obesity. Symptoms typically appear shortly after birth and persist throughout life. The characteristic hyperphagia (overeating) usually emerges later in life, typically around age 2. Other common traits of the syndrome include underdeveloped sex organs, slow growth, learning challenges, delayed motor skills, speech and behavioural problems. Diagnosis involves specialised genetic tests such as DNA methylation analysis, which can detect almost all (>99%) cases of PWS. Further diagnostic tests could involve FISH and Chromosome Microarray/Oligo-SNP array.