Noonan Syndrome

Noonan Syndrome

Noonan syndrome (NS) is the most common of the RASopathies, a group of genetic disorders caused by germline mutations in genes of the RAS/MAPK signalling pathway. This pathway is crucial for cell growth and differentiation. The syndrome has variable expressivity and penetrance, meaning the presentation can range from subtle to severe, and not all individuals with a mutation will show the same features.

While the karyotype is typically normal, it is still an essential part of the initial diagnostic work-up to exclude conditions such as Turner syndrome, given the overlapping phenotypic features. The term ‘Pseudo-Turner’ is outdated and should be avoided due to its pejorative and misleading nature.

 

Genetics and Diagnosis

  • Autosomal Dominant Inheritance: NS is usually inherited in an autosomal dominant pattern with a 50% chance of transmission to offspring. Approximately 60% of cases are due to a de novo mutation.

  • Genetic Heterogeneity: Over 15 genes have been implicated in NS. The most common mutations are in PTPN11 (50%), followed by SOS1, RAF1, RIT1, and KRAS. The specific gene mutation can influence the phenotype; for example, PTPN11 mutations are more strongly associated with pulmonary stenosis and a higher risk of leukaemia, while SOS1 mutations are linked to milder features.

  • Diagnostic Confirmation: Molecular genetic testing is the gold standard for diagnosis. However, a negative result does not rule out NS as new genes continue to be discovered and a small percentage of cases remain genetically undiagnosed.

 

Clinical Features

The clinical presentation of NS is a developmental continuum. Features can be subtle at birth and become more pronounced with age.

 

Antenatal and Neonatal Period

Non-specific antenatal findings may include increased nuchal translucency, polyhydramnios, hydrops fetalis, or cystic hygroma. Neonatally, feeding difficulties and poor weight gain are common.

 

Characteristic Phenotype

The distinctive facial features evolve with age and can include:

  • Wide-set, down-slanting eyes (hypertelorism) with droopy eyelids (ptosis) and epicanthic folds.

  • Low-set, posteriorly rotated ears with a thickened helix.

  • Relatively large head with a broad forehead.

  • A short, webbed neck with a low posterior hairline.

  • Broad chest with widely spaced nipples.

 

Systemic Manifestations

  • Cardiovascular: Approximately 80% of individuals have congenital heart defects. The most common is pulmonary valve stenosis (~40%), often dysplastic. Hypertrophic cardiomyopathy (HCM) occurs in 10-20% and is a leading cause of mortality. Coarctation of the aorta is less common but can occur.

  • Growth: Short stature is a cardinal feature. Many children experience growth delay and failure to thrive.

  • Haematological: Easy bruising or bleeding is common, affecting up to 89% of patients, often due to factor XI deficiency or platelet dysfunction.

  • Skeletal: Pectus carinatum or pectus excavatum, kyphosis/scoliosis, and cubitus valgus are common.

  • Neurodevelopmental: Learning difficulties and intellectual disability are variable but common, affecting up to half of all individuals. Recent research highlights a higher prevalence of neurodevelopmental conditions such as ADHD and features of Autism Spectrum Disorder (ASD).

  • Urogenital: Cryptorchidism affects up to 80% of males and carries a risk of infertility if untreated. Renal anomalies are also seen.

  • Ophthalmic and Auditory: Strabismus (squint) is frequent. Hearing issues, particularly sensorineural hearing loss, are also common.

  • Lymphatic: Lymphoedema, particularly of the extremities, is a frequent finding.

 

Investigations and Management

A multidisciplinary approach is essential for optimal care, involving clinical geneticists, paediatric cardiologists, endocrinologists, and other specialists.

 

Recommended Investigations at Diagnosis

  • Karyotype to exclude chromosomal abnormalities.

  • Molecular genetic testing for confirmation.

  • Echocardiogram (ECHO) and ECG to assess for cardiac defects and a baseline for future monitoring.

  • Hearing and vision assessments.

  • Renal tract ultrasound.

  • Coagulation profile to screen for coagulopathies.

  • Developmental assessment.

 

Management and Recent Developments

  • Cardiac Management: All patients require a comprehensive cardiac assessment at diagnosis. The Noonan Syndrome Guideline Development Group (DYSCERNE, 2010) suggests annual ECHO until age 3, and then at ages 5 and 10. Lifelong follow-up with a cardiologist is recommended, particularly for those with HCM or a history of valvular intervention.

    • Recent Developments: Novel treatments are emerging. Studies have shown that MEK inhibitors (e.g., trametinib) can reverse hypertrophic cardiomyopathy in severe cases in infants with specific gene mutations, offering a promising therapeutic avenue.

  • Growth Hormone Therapy: Recombinant human growth hormone (rhGH) is licensed for use in NS in the UK and can significantly improve final adult height. NICE guidelines recommend it for children with NS and a height below the 2.5th centile. Treatment is typically started around age 4-5 years and continued until the end of growth.

  • Undescended Testes: Orchidopexy is recommended for male infants with cryptorchidism if the testes have not descended by 12 months to improve fertility potential and reduce the risk of testicular cancer.

  • Neurodevelopmental Support: Early intervention is critical. An Education, Health and Care (EHC) plan should be considered for children with learning or behavioural difficulties.

  • Multidisciplinary Team: The importance of a coordinated multidisciplinary team has been emphasised in recent UK research. A recent study from Loughborough University highlighted the need for improved healthcare coordination and mental health support for families of children with NS.

  • Genetic Counselling: This is crucial for all families to understand the inheritance pattern and recurrence risks, including the possibility of germline mosaicism for de novo mutations.