Introduction

Prader-Willi syndrome is the most common genetic cause of morbid childhood obesity, affecting approximately 1 in every 15,000 births^1,2

This is a distinctive disorder, typically diagnosed from birth due to the weak muscles (hypotonia) leading to the hallmark “floppiness” of Prader-Willi babies and poor suckling which causes feeding difficulties. Key symptoms, including uncontrollable appetites (hyperphagia) and learning delays, typically appear before 8 years of age.³

Abnormal activity in the Hypothalamus, a critical brain region for producing hormones and regulating behaviour such as appetite and sleep, has been identified in individuals in Prader-Willi. The effect of this dysfunctional hypothalamus is still being researched but key hormone deficiencies have been identified in PWS, such as Growth Hormone (GH). Growth Hormone Therapy (GHT) is widely used in children with Prader-Willi syndrome to improve their muscle tone, reduce fat levels and improve their motor abilities such as walking.⁴

Understanding Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a complex genetic disorder caused by defects in the PWS “critical region” on chromosome 15. Individuals with PWS have distinct symptoms, including:

• Floppiness from birth due to weak muscle tone (hypotonia)
• Uncontrollable appetites (hyperphagia) typically lead to morbid childhood obesity
• Short stature 
• Under-developed genitals and delayed puberty (hypogonadism)
• Learning difficulties and intellectual disabilities
• Challenging behaviours including skin-picking and aggression

Whilst ongoing research aims to understand PWS and develop effective therapies for patients, clinical studies have highlighted hormone dysregulation that can partly explain the PWS symptoms. For example, Growth Hormone (GH) deficiencies can explain weakened muscle tone, short stature and learning difficulties in children with PWS.

Therapies aiming to address these hormone deficiencies to restore normal levels are believed to be a viable intervention; Growth hormone therapy is currently the gold standard for individuals with Prader-Willi syndrome.^3,4

Hormone deficiencies in Prader-Willi Syndrome

Hormone deficiencies are believed to be caused by abnormal activity in a part of the brain called the Hypothalamus which has a crucial role in producing hormones.⁴

Researchers have reported that Prader-Willi genes, such as MAGEL2 and NECDIN, have critical roles in the Hypothalamic-Pituitary axis. This axis produces hormones required for automatic bodily functions including appetite regulation. Functions such as appetite regulation and growth are abnormal and disrupted in individuals with Prader-Willi.

Researchers are hopeful that restoring normal hormone levels might be beneficial for patients, particularly in controlling dangerous food-seeking behaviour that increases the risk of morbid childhood obesity.^5,6

Growth Hormone (GH) deficiency

Growth hormone deficiency is found in approximately 74% of Prader-Willi patients. This hormone has an integral role in normal physical development. This hormone deficiency contributes to the weak muscles (hypotonia), increased body fat, short stature and learning delays found in children with PWS.³

Diagnosis of growth hormone deficiency

A physician can diagnose growth hormone deficiency in individuals with PWS.

• Physical examinations of the child: recording the height and length of their limbs
• Blood test: measuring levels of Growth Hormone and Insulin-like growth factor

Typically, a blood test is used. Low GH and insulin-like growth factor levels indicate that the individual has a deficiency and may benefit from Growth Hormone Therapy.⁷

Sex hormones: Testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH)

Deficiencies in sex hormones (testosterone, luteinizing hormone and follicle-stimulating hormone) are common in individuals with Prader-Willi syndrome and this leads to under-developed sexual organs and delayed puberty (hypogonadism).

Sex hormone deficiencies are believed to be caused by dysfunction in the hypothalamus and also the sexual organs (testes and ovaries). Sex differences have been noted for the presentation of hypogonadism in individuals with Prader-Willi.⁸

In a study, approximately 94% of individuals assigned female at birth (AFAB) with Prader-Willi syndrome presented with hypogonadism, such as small labia and severely delayed periods (between 13 and 34 years of age). If left untreated, the abnormally low levels of female sex hormones can increase the risk of osteoporosis.⁸

In a Dutch study, approximately 98% of individuals assigned male at birth (AMAB) with Prader-Willi syndrome had symptoms of hypogonadism, such as small penises, high-pitched voices and difficulty growing body hair.

Treatment with sex hormone therapy, such as testosterone replacement therapy, can be beneficial but challenging/aggressive behaviour means regular and effective administration of this therapy is difficult.⁹

Researchers believe that the mechanisms of Prader-Willi syndrome can result in infertility, with no reports of AMAB individuals fathering a child and just seven reports of AFAB individuals giving birth.⁸

Ghrelin dysregulation: the ‘hunger hormone’

Researchers are currently interested in understanding the role of a hormone called ghrelin, also known as, the “hunger hormone”. This hormone has a critical influence over whether we feel hungry and it’s a specific research avenue for PWS due to the hallmark feature of an uncontrollable appetite. 

In individuals with Prader-Willi syndrome, levels of ghrelin are increased which is believed to contribute to the uncontrollable food-seeking behaviour and appetite in this disease. However, researchers have also reported that ghrelin has roles in many pathways and can contribute to anxiety and abnormal metabolism in PWS.¹⁰

Consequently, researchers aim to understand this hormone better as it could be the key to effective therapeutic for individuals with Prader-Willi.

Clinical management of hormone deficiencies in PWS

Early diagnosis of Prader-Willi is key to ensuring individuals have the best quality of life possible as without early interventions, particularly dietary control and strict routines, the risk of morbid childhood obesity is high.¹

A multi-disciplinary approach is necessary to treat individuals with Prader-Willi. This includes but is not limited to:

• Cognitive behavioural therapy to improve mental health conditions
• Dietary interventions to assist with the increased risk of obesity
• Drug therapies to treat the consequences of hormone deficiencies

Growth hormone therapy

Growth hormone therapy was approved by the US Food and Drug Administration (FDA) in 2000 and it’s considered the gold standard drug therapy for children with PWS. It involves the injection of a synthetic growth hormone at least once a week until the individual has stopped growing. 

The direct benefits of this include:

• Increasing height
• Reducing body fat levels
• Strengthening muscles
• Improved stamina
• Improved bone health
• Improved weight distribution

It positively affects cognitive and behavioural development in children, for example improving the developmental delays often seen in babies with PWS such as speaking and walking milestones.¹¹

The Global PWS Registry reports on the widespread use of this therapy and notably highlights that 93% of individuals believe the drug has benefitted them.¹²

Sex hormone replacement

Some individuals with Prader-Willi syndrome may benefit from sex hormone therapy. Each individual should be assessed for their unique symptoms and needs. 

For example, AFAB individuals with PWS might be recommended hormone replacement therapy, such as oestrogen and progesterone, due to their increased risk of osteoporosis.⁸

AMAB individuals may benefit from sex hormone replacement therapy (testosterone), however, it can also lead to severely challenging and aggressive behaviour. Therefore, each individual’s case and the potential benefits and consequences should be considered before the administration of sex hormone replacement therapy.⁹

Promising research avenues 

There is a lot of exciting research in the PWS field, to ease the hallmark symptom of uncontrollable hunger (hyperphagia). Being unable to control eating not only has physical effects such as obesity, but it also causes feelings of anxiety and powerlessness in individuals with PWS. Therefore an effective drug is desperately needed to give individuals with PWS their freedom around food and to reduce the risk of morbid obesity.¹⁰

A promising ongoing Phase 3 clinical trial, called COMPASS PWS, is investigating the effectiveness and safety of a carbetocin nasal spray. This drug utilises the oxytocin pathway as it has a similar structure to oxytocin. Whilst this trial is ongoing, the Phase 2 results suggest it can significantly reduce hyperphagia in children with PWS. So, phase 3 results are eagerly anticipated.¹³

Summary

Prader-Willi syndrome is a complex disorder which affects multiple systems. It has distinct symptoms, such as weak muscle tone and uncontrollable appetites (hypotonia and hyperphagia).

Loss of the genes in the ‘PWS critical region’ causes abnormal hypothalamus activity. This abnormal hypothalamus activity leads to hormonal dysregulation such as: 

• Growth hormone deficiency
• Sex hormone deficiency (testosterone, luteinising hormone and follicle-stimulating hormone)
• Increased levels of ghrelin, the ‘hunger hormone’

These abnormal levels of hormones, particularly growth hormone deficiency, contribute to the symptoms of PWS. Therefore hormone therapies, such as growth hormone therapy, are recommended to improve the quality of life of individuals with PWS.

Researchers are still working to develop therapies that reduce the food-seeking behaviour and uncontrollable hunger in PWS.