What are the clinical features of Noonan syndrome?

Clinical Features of Noonan Syndrome

Noonan syndrome is characterized by distinctive facial dysmorphisms, short stature, developmental delays, congenital heart defects (most commonly pulmonary valve stenosis with dysplasia), hypertrophic cardiomyopathy, and increased cancer risk. 1

Craniofacial Features

The facial dysmorphisms are cardinal diagnostic features and include: 1

• Hypertelorism (widely spaced eyes) with down-slanting palpebral fissures 1, 2
• Low-set, posteriorly rotated ears with characteristic shape 1, 2
• Ocular ptosis (drooping eyelids) 1, 2
• Webbed neck (pterygium colli) with low posterior hairline 1, 2, 3
• Micrognathia (small jaw) 2

These facial features are age-dependent and may be more subtle in adults, making early recognition critical. 4, 5

Growth and Development

• Proportionate short stature is nearly universal, affecting growth velocity throughout childhood 1, 2, 5
• Relative or absolute macrocephaly (large head size) 1
• Failure to thrive in infancy with feeding difficulties 1, 4
• Developmental delays and learning difficulties of variable severity, though intelligence is often normal 1, 6

Cardiovascular Manifestations

Cardiac involvement occurs in 50-80% of patients and represents a major source of morbidity: 4, 7

• Pulmonary valve stenosis (most common, occurring in approximately one-third of patients), typically with valve dysplasia 1, 2
• Hypertrophic cardiomyopathy 1, 6
• Other structural defects including atrial septal defects and ventricular septal defects 2, 4

The dysplastic nature of pulmonary stenosis in Noonan syndrome shows lower success rates with balloon valvuloplasty compared to isolated pulmonary stenosis, often requiring surgical intervention. 2

Thoracic and Skeletal Features

• Chest wall deformities including pectus carinatum (superior) and pectus excavatum (inferior) 1, 2
• Broad chest with widely spaced nipples 4
• Hyperelastic skin 1

Genitourinary Abnormalities

• Cryptorchidism (undescended testes) in males 1, 4
• Disorders of pubertal timing including delayed puberty 1, 6
• Structural renal anomalies requiring ultrasound screening 2

Hematologic Features

• Bleeding diathesis affecting coagulation, requiring screening before any surgical procedures 2, 3, 4
• Lymphatic anomalies including lymphedema 1, 4

Sensory and Ophthalmologic Features

• Sensorineural hearing loss in up to 40% of patients 2
• Ocular anomalies including amblyopia, refractive errors, and strabismus 2, 4

Malignancy Risk

The relative childhood cancer risk is increased approximately eightfold over the general population. 1 The spectrum includes: 1

• Myeloproliferative disorder (MPD) and juvenile myelomonocytic leukemia (JMML), particularly with specific PTPN11 or KRAS mutations 1
• Acute lymphoblastic leukemia 1
• Rhabdomyosarcoma 1
• Neuroblastoma 1, 2
• Gliomas (including dysembryoplastic neuroepithelial tumors) 1

Genetic Basis and Inheritance

Noonan syndrome is autosomal dominant (with rare exceptions of recessive LZTR1 or SPRED2 variants) with an estimated prevalence of 1 in 1,000 to 2,500 live births. 1, 7

Causative genes include: 1, 6

• PTPN11 (approximately 50% of cases)
• SOS1 (13%)
• RAF1 (5%)
• RIT1 (5%)
• Less commonly: KRAS, NRAS, BRAF, MAP2K1, RRAS, RRAS2, MRAS, SOS2, LZTR1, SPRED2

All encode proteins in the RAS-MAPK signaling pathway, explaining the overlapping phenotypes with other RASopathies. 1, 6

Critical Diagnostic Pitfall

Despite genetic advances, approximately 20-40% of clinically diagnosed cases lack an identified genetic mutation, making Noonan syndrome frequently a clinical diagnosis. 4, 5 The phenotype shows variable expressivity and changes with age, requiring familiarity with age-specific presentations. 4, 5, 6