What is Noonan syndrome?

What is Noonan Syndrome

Noonan syndrome is an autosomal dominant genetic disorder affecting approximately 1 in 1,000 to 2,500 live births, caused by mutations in genes of the RAS/MAPK signaling pathway, most commonly PTPN11 (50% of cases), and characterized by distinctive facial features, congenital heart defects (especially pulmonary stenosis), short stature, and an approximately 8-fold increased childhood cancer risk. 1

Genetic Basis and Molecular Pathophysiology

• Noonan syndrome results from pathogenic variants in genes encoding proteins of the RAS/MAPK pathway, with PTPN11 mutations accounting for nearly half of all cases 1
• Additional causative genes include SOS1 (13%), RAF1 (5%), RIT1 (5%), and less commonly KRAS, SOS2, NRAS, RRAS, RRAS2, MRAS, SPRED2, and LZTR1 (with rare recessive inheritance patterns for LZTR1 and SPRED2) 1
• Despite advances in molecular genetics, approximately 20-40% of patients still lack an identified genetic cause, making clinical diagnosis essential 2, 3
• The condition follows autosomal dominant inheritance with nearly complete penetrance, though most cases represent de novo mutations 3, 4

Cardinal Clinical Features

Facial Dysmorphisms

• Characteristic facial features include hypertelorism (widely spaced eyes), down-slanting palpebral fissures, low-set posteriorly rotated ears, ocular ptosis, broad neck with low posterior hairline, and webbed neck (pterygium colli) 1, 5
• The facial phenotype changes with age and shows variable expressivity, making diagnosis more challenging in mildly affected individuals 2, 6

Cardiovascular Abnormalities

• Pulmonary valve stenosis with valve dysplasia is the most common cardiac defect, occurring in approximately one-third of patients 5, 1
• Hypertrophic cardiomyopathy represents another major cardiac manifestation 1
• Pulmonary stenosis in Noonan syndrome shows lower success rates with balloon valvuloplasty compared to isolated pulmonary stenosis, often requiring surgical intervention 5
• Other cardiac defects include atrial septal defects and other structural abnormalities 1

Growth and Development

• Proportionate short stature is a cardinal feature, with growth abnormalities including failure to thrive in infancy 5, 1
• Relative or absolute macrocephaly is common 1
• Developmental delays and learning difficulties occur frequently, though severe intellectual disability is uncommon 1, 4

Additional Systemic Manifestations

• Chest wall deformities including pectus carinatum superiorly and pectus excavatum inferiorly 5, 4
• Cryptorchidism in males and disorders of pubertal timing 1, 4
• Lymphatic dysplasia and feeding problems in infancy 1, 3
• Bleeding diathesis requiring hematologic screening before any surgical procedures 5, 7
• Ophthalmologic abnormalities including ptosis, amblyopia, refractive errors, and strabismus (requiring evaluation) 5
• Sensorineural hearing loss in up to 40% of patients 5
• Renal structural anomalies 5

Cancer Risk and Surveillance Requirements

Overall Cancer Risk

• The relative childhood cancer risk is increased approximately 8-fold over the general population, though high relative risk translates to moderate absolute cancer risk due to low baseline pediatric cancer rates 1
• The cancer spectrum is broad and includes myeloid and lymphoblastic leukemia, rhabdomyosarcoma, neuroblastoma, and gliomas 1

Myeloproliferative Disorder (MPD)

• Specific PTPN11 variants (particularly codon 61 mutations and T73I) and certain KRAS mutations are associated with development of often self-limiting myeloproliferative disorder in infancy 1
• MPD can transform into juvenile myelomonocytic leukemia (JMML), though predictors for transformation versus self-resolution remain unclear beyond somatic events like monosomy 7 1

Recommended Surveillance Protocol

• Physical examination evaluating for hepatosplenomegaly and clinical concern for leukemia should occur every 3 months through age 1 year, then at every well-child visit until age 5 years 1
• No routine bloodwork is recommended for asymptomatic healthy children; obtain complete blood count only if the child is ill or has hepatosplenomegaly on examination 1
• If bloodwork is abnormal, immediate consultation with a hematologist experienced in MPD is required 1
• Brain tumor surveillance is not recommended unless clinical symptoms develop (cumulative risk <1%) 1

Diagnostic Approach

Clinical Diagnosis

• Diagnosis remains primarily clinical, based on a scoring system incorporating family history, facial features, cardiac defects, growth parameters, chest wall abnormalities, and other criteria 4, 3
• The van der Burgt scoring system from 1994 remains the established diagnostic framework 8

Genetic Testing Strategy

• Genetic confirmation should occur concurrently with cardiac evaluation, testing for mutations in PTPN11, SOS1, RAF1, RIT1, KRAS, and other RAS/MAPK pathway genes 5, 7
• If karyotype is normal but phenotype suggests genetic syndrome, proceed with targeted gene panel testing for Noonan syndrome genes 7
• Genetic diagnosis enables appropriate cancer surveillance protocols and informs family planning 5

Essential Initial Workup

• Immediate cardiology evaluation with echocardiography to assess for pulmonary stenosis, hypertrophic cardiomyopathy, and other structural abnormalities 5, 7
• Blood pressure measurement in all four extremities to screen for coarctation 7
• Height measurement and plotting on growth curves 7
• Hematologic screening before any surgical intervention 5, 7
• Ophthalmologic evaluation for ptosis, amblyopia, refractive errors, and strabismus 5
• Audiologic assessment for sensorineural hearing loss 5
• Renal ultrasound for structural anomalies 5
• Developmental assessment with early intervention services as needed 5

Management Considerations

Cardiac Management

• Intervention for pulmonary stenosis is generally indicated when resting gradient exceeds 40 mmHg 5
• Patients with dysplastic valves may require surgical rather than catheter-based intervention 5
• Coordinated multidisciplinary care through a medical home model is recommended 5

Growth Hormone Therapy

• Growth hormone treatment shows modest response in height gains, similar to that observed in Turner syndrome 2
• Presence of PTPN11 mutations may indicate reduced growth response to short-term growth hormone treatment 8

Critical Diagnostic Pitfalls

• Mildly affected patients often go undiagnosed due to lack of awareness among healthcare providers and variable phenotypic expression 6
• The changing phenotype with age makes recognition more difficult in older children and adults 2, 6
• Noonan syndrome must be distinguished from Turner syndrome in females with webbed neck; key differences include normal karyotype in Noonan syndrome, occurrence in both sexes, and different cardiac lesion patterns 7
• Some families resist diagnosis when features are mild and represent family traits, potentially delaying appropriate surveillance and management 6