Introduction to Noonan Syndrome

Noonan Syndrome (NS) is a genetic disorder characterized by distinctive facial features, short stature, congenital heart defects, and various other signs and symptoms. It is a relatively common condition, with an estimated incidence of 1 in 1,000 to 1 in 2,500 live births. NS is part of the RASopathies, a group of developmental disorders caused by germline mutations in genes encoding components of the RAS/MAPK signaling pathway.

Clinical Features of Noonan Syndrome

Craniofacial Features

• Broad forehead
• Hypertelorism (widely spaced eyes)
• Downward slanting palpebral fissures
• Low-set, posteriorly rotated ears with a thick helix
• High arched palate
• Micrognathia (small lower jaw)
• Short, webbed neck with low posterior hairline

Cardiovascular Abnormalities

• Pulmonary valve stenosis (50-60% of cases)
• Hypertrophic cardiomyopathy (20% of cases)
• Atrial septal defects
• Ventricular septal defects

Growth and Endocrine Issues

• Short stature (final adult height typically below the 3rd percentile)
• Delayed puberty
• Growth hormone deficiency in some cases

Skeletal Abnormalities

• Pectus excavatum or carinatum
• Scoliosis
• Cubitus valgus (increased carrying angle of the elbow)

Neurological and Developmental Issues

• Mild intellectual disability (25% of cases)
• Learning difficulties
• Motor delays
• Speech and language delays

Hematological Abnormalities

• Bleeding disorders (easy bruising, prolonged bleeding time)
• Thrombocytopenia
• Factor XI deficiency

Other Features

• Cryptorchidism in males
• Lymphatic abnormalities
• Increased risk of certain malignancies (e.g., juvenile myelomonocytic leukemia)

Diagnosis of Noonan Syndrome

Diagnosis of Noonan Syndrome is based on a combination of clinical features and genetic testing. The van der Burgt criteria are commonly used for clinical diagnosis:

Major Criteria

• Typical facial dysmorphology
• Pulmonary valve stenosis, hypertrophic cardiomyopathy, or ECG typical of NS
• Height <3rd percentile
• Pectus carinatum/excavatum
• First-degree relative with definite NS
• All three of: developmental delay, cryptorchidism, and lymphatic dysplasia

Minor Criteria

• Suggestive facial dysmorphology
• Other cardiac defect
• Height <10th percentile
• Broad thorax
• First-degree relative with suggestive NS
• One of: developmental delay, cryptorchidism, or lymphatic dysplasia

Definitive NS: 1 major + 2 minor criteria or 2 major criteria or 3 minor criteria

Genetic Testing

Molecular genetic testing can confirm the diagnosis. The following genes are associated with NS:

• PTPN11 (50% of cases)
• SOS1 (10-15% of cases)
• RAF1 (5-10% of cases)
• RIT1 (5% of cases)
• KRAS, NRAS, BRAF, and others (rare)

Management of Noonan Syndrome

Management of Noonan Syndrome is multidisciplinary and focuses on addressing the various clinical features and complications:

Cardiovascular Management

• Echocardiogram at diagnosis and regular follow-up
• Surgical intervention for severe pulmonary stenosis or hypertrophic cardiomyopathy
• Cardiac medications as needed

Growth and Endocrine Management

• Regular growth monitoring
• Growth hormone therapy in cases of documented GH deficiency or to improve final height
• Puberty induction if necessary

Developmental and Educational Support

• Early intervention services
• Speech and language therapy
• Occupational and physical therapy
• Special education support as needed

Hematological Management

• Coagulation studies and platelet function tests
• Hematology consultation for bleeding disorders
• Avoid aspirin and other antiplatelet drugs

Skeletal Management

• Orthopedic evaluation for scoliosis and chest wall deformities
• Surgical intervention if necessary

Other Management Considerations

• Ophthalmological evaluation
• Audiological assessment
• Dental and orthodontic care
• Genetic counseling for family planning

Genetics of Noonan Syndrome

Noonan Syndrome is an autosomal dominant disorder caused by mutations in genes involved in the RAS/MAPK signaling pathway. The genetic basis includes:

Major Genes and Their Frequencies

• PTPN11 (50%): Encodes SHP-2 phosphatase
• SOS1 (10-15%): Encodes a guanine nucleotide exchange factor
• RAF1 (5-10%): Encodes a serine/threonine kinase
• RIT1 (5%): Encodes a RAS-like protein
• KRAS, NRAS, BRAF, MAP2K1, SHOC2, CBL, and others (rare)

Inheritance Pattern

Autosomal dominant with complete penetrance and variable expressivity. About 60% of cases are de novo mutations.

Genotype-Phenotype Correlations

• PTPN11 mutations: Associated with pulmonary stenosis and bleeding disorders
• SOS1 mutations: Often associated with ectodermal features
• RAF1 mutations: Higher incidence of hypertrophic cardiomyopathy
• RIT1 mutations: Increased risk of hypertrophic cardiomyopathy and perinatal abnormalities

Genetic Testing Strategies

• Multi-gene panel testing for RASopathy-associated genes
• Sequential single-gene testing based on clinical features
• Whole exome sequencing in cases where panel testing is negative