PWS

Prader-Willi Syndrome (PWS)

PWS is a complex, multisystem neurodevelopmental genetic disorder caused by the absence of paternally expressed genes on chromosome 15q11-q13. It is a classic example of genomic imprinting, where the expression of a gene depends on its parental origin.

  • Genetic Mechanisms:

    • Paternal Deletion: The most common cause (~70% of cases), where a section of the paternal chromosome 15 is deleted.

    • Maternal Uniparental Disomy (UPD): (~25% of cases) The child inherits two copies of chromosome 15 from the mother and none from the father.

    • Imprinting Centre Defects: A rare cause (~1-2% of cases) where the paternal genes are present but not activated.

This is distinct from Angelman syndrome, which results from a similar genetic change on the same chromosomal region but of maternal origin.

 

Clinical Manifestations

The clinical presentation of PWS is biphasic, with different features dominating at different ages.

  • Neonatal and Infancy:

    • Severe Hypotonia: This is a hallmark feature, often leading to a “floppy” baby with a weak cry and poor reflexes.

    • Feeding Difficulties: The hypotonia affects the suck reflex, causing poor feeding and failure to thrive. Nasogastric tube feeding is often required.

    • Delayed Milestones: Gross motor milestones like sitting and walking are typically delayed.

  • Early Childhood:

    • Onset of Hyperphagia: This is the most challenging feature, a pathological, unrelenting drive to eat. It typically emerges between ages 2 and 8.

    • Obesity: If not strictly controlled, hyperphagia leads to rapid, dangerous weight gain and morbid obesity.

    • Dysmorphic Features: Small hands and feet and short stature are characteristic. Other features may include a narrow forehead, almond-shaped eyes, and a thin upper lip.

  • Older Children and Adolescence:

    • Learning and Behavioural Difficulties: Intellectual disability (usually mild) and significant behavioural issues, including temper outbursts, stubbornness, and obsessive-compulsive traits like skin-picking, are common.

    • Endocrine Issues:

      • Hypogonadism: Undescended testes in boys and underdeveloped genitalia in both sexes. Puberty is often incomplete or delayed.

      • Adrenarche: Girls may experience premature adrenarche.

      • Growth Hormone Deficiency (GHD): This is a key finding and contributes to short stature and poor body composition.

 

Recent Developments and Management Updates

Recent guidance emphasizes a proactive, multidisciplinary approach to management from the point of diagnosis.

  • Diagnosis: Early diagnosis is crucial. DNA methylation analysis is now the preferred initial test as it can detect all three genetic subtypes and confirm the diagnosis without the need for parental samples.

  • Medical Management:

    • Growth Hormone (GH) Therapy: Current NICE guidance in the UK supports the use of recombinant human growth hormone (somatropin) for children with PWS. It is not just for height; GH therapy has been shown to improve body composition by increasing muscle mass and reducing fat, improve muscle strength, and increase energy levels, which in turn encourages physical activity.

    • Endocrine Support: Hormone replacement therapy (e.g., testosterone for males, oestrogen/progesterone for females) is used to induce and complete puberty and improve bone mineral density.

    • Management of Hyperphagia: This remains the cornerstone of care. It requires a highly structured, controlled food environment from early childhood. The Prader-Willi Syndrome Association UK (PWSA UK) provides excellent resources and guidelines on food security and dietary management.

  • Clinical Trials: While a cure is not yet available, a number of clinical trials are ongoing, particularly in the US and EU. These often focus on novel drug therapies to control hyperphagia, such as DCCR (diazoxide choline controlled release), which recently received FDA approval in the US for this indication. While some UK trials have been initiated for other potential therapies, the DCCR trials highlight a new frontier in pharmacological intervention for the core symptoms of PWS.

  • Complications: Paediatricians should screen for and manage common complications:

    • Obesity-related: Type 2 diabetes, cardiovascular issues.

    • Respiratory: Obstructive sleep apnoea (often requiring overnight CPAP). A sleep study is recommended following diagnosis.

    • Orthopaedic: High risk of scoliosis, requiring regular screening.

    • Psychological: Mental health support is vital for managing behavioural and mood disorders.