Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a complex genetic disorder that derives from the loss of expression of imprinted genes in the chromosomal region 15q11-13.¹ PWS affects multiple neuroendocrine systems; its main features include short stature, hypogonadism, sleep abnormalities, intellectual disability, and behavioral disturbances.² Hyperphagia and morbid obesity starting in early childhood are hallmarks of this disease.²

PWS remains a life-limiting condition, with a mortality rate 3 times that of unaffected individuals in the general population. Leading causes of mortality are morbid obesity, respiratory diseases, cardiac failure, pulmonary embolism, and sudden death.²

The management of PWS requires a multidisciplinary approach. No cure for PWS is available, but various therapies aim to address the associated physical, cognitive, and behavioral challenges.²

Growth Hormone Therapy

Growth hormone (GH) replacement therapy with somatropin (sold as Genotropin^®, Omnitrope^®, and Norditropin^®, among others)³ was approved by the US Food and Drug Administration (FDA) for the treatment of PWS in 2000.² More than half of cases of PWS affecting children are characterized by GH deficiency. GH therapy is usually initiated if a PWS diagnosis is suspected, in patients as young as 3 months old.²

Read more about PWS diagnosis

The safety and efficacy of GH therapy have been reported, with no increased risk of diabetes, scoliosis, or central and obstructive apnea observed in children.¹ Benefits of its use in children include significant improvements in standard deviation scores for height, head circumference, and facial appearance; in adults, benefits include improvements in body composition, cognitive function, motor skills, muscle strength, and cardiac risk profile, in addition to a reduction in fatigue.^1,2

At the start of treatment, patients are often given recombinant human growth hormone (rhGH) at a dosage of 0.5 mg/m² per day, titrated up to 1.0 mg/m² per day, with monthly monitoring of insulin-like growth factor (IGF). The frequency of monitoring is reduced to biannual during long-term surveillance.² 

The patient should undergo screening for obstructive sleep apnea before and after treatment is started.²

Read more about somatropin

Treatment of Hypogonadism

Estrogen and progestin are routinely prescribed for adolescent female patients with PWS, even though more studies are needed to determine the ideal dose to achieve clinical endpoints.¹ Hypogonadism in female patients can be treated with low-dose estrogen delivered through transdermal patches for 2 years or until menarche.⁴ 

Testosterone can be given to male patients 15 to 16 years old with delayed or incomplete puberty; growth and skeletal maturation must be monitored. Human chorionic gonadotropic hormone (hCG) has been used to lower the position of the testicles although a significant number of patients may still need orchiopexy.⁴

Read more about PWS surgical management

Treatment of Hyperphagia and Obesity

Patients with PWS often have extreme, insatiable hunger. When not monitored, this can lead to the consumption of excessive food. Hyperphagia is considered the main cause of mortality and morbidity in PWS. Together with obesity, hyperphagia affects approximately 40% of children and adolescents and up to 98% of adults with PWS.² 

First-line therapies to manage hyperphagia and obesity in PWS include aggressive behavioral therapy along with nutritional counseling. These treatments often involve strict food surveillance and limitation, nutrition and caloric intake monitoring, and regular exercise.²

Even though no pharmacological therapies are available to address these conditions, various experimental therapies are under study with the goal of filling the gap in pharmacological treatment. Drugs under study include Topamax^® (topiramate), an antiepileptic drug and mood stabilizer; glucagon-like peptide (GLP-1) agonists; Contrave^® (naltrexone/bupropion); Alli^® or Xenical^® (orlistat); Meridia^® (sibutramine); and rimonabant.²

Read more about PWS experimental therapies

Management of Behavioral Disturbances

Patients with PWS often exhibit behavioral disturbances, such as cognitive rigidity, anxiety, mood disorders, and self-injury. Behavioral disturbances are typically addressed with selective serotonin reuptake inhibitors (SSRIs) and atypical neuroleptics.² Experimental drugs such as Wakix^® (pitolisant), a drug approved in Europe for the management of narcolepsy, and Pitocin^® (oxytocin) are also being studied for potential use in PWS.²

Read more about PWS clinical trials

References

1. Tauber M, Hoybye C. Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction. Lancet Diabetes Endocrinol. 2021;9(4):235-246. doi:10.1016/S2213-8587(21)00002-4.
2. Szabadi S, Sila Z, Dewey J, et al. A review of Prader-Willi syndrome. Endocrines. 2022;3:329-348. doi:10.3390/endocrines3020027
3. Scheimann A. Prader-Willi syndrome medication. Medscape. Updated August 27, 2021. Accessed July 16, 2023.
4. Fermin Gutierrez MA, Mendez MD. Prader-Willi syndrome. StatPearls [Internet]. Updated January 31, 2023. Accessed July 16, 2023.

Reviewed by Debjyoti Talukdar, MD, on 7/20/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.