What is the recommended management and treatment plan for a patient with Noonan syndrome?

Management and Treatment of Noonan Syndrome

Patients with Noonan syndrome require lifelong multidisciplinary surveillance focused on cardiac complications, malignancy screening (particularly myeloproliferative disorders in infancy and leukemia throughout childhood), growth monitoring, and management of developmental delays, with specific protocols varying by genetic mutation. 1

Genetic Confirmation and Risk Stratification

• Molecular genetic testing should be pursued to confirm diagnosis and identify the specific causative mutation (PTPN11, SOS1, RAF1, RIT1, LZTR1, KRAS, SOS2, NRAS, RRAS, RRAS2, MRAS, or SPRED2), as this directly impacts malignancy risk and surveillance intensity 1, 2
• PTPN11 and KRAS mutations confer the highest risk for myeloproliferative disease (MPD), occurring in up to 10% of affected infants 1
• PTPN11 and SOS1 mutations specifically increase risk for B-cell acute lymphoblastic leukemia (B-ALL) with high hyperdiploidy 1
• Approximately 61% of clinically diagnosed cases can be molecularly confirmed; the remainder are diagnosed clinically based on phenotypic features 2, 3

Malignancy Surveillance Protocol

Infancy Through Age 5 Years (High-Risk Period for MPD)

• Physical examination with specific evaluation for hepatosplenomegaly and clinical signs of leukemia every 3 months through age 1 year, then at every well-child visit until age 5 years 1
• Complete blood count (CBC) should be obtained only if the child is ill or hepatosplenomegaly is detected on examination—routine bloodwork in asymptomatic healthy children is not recommended 1
• If CBC abnormalities are identified, immediate consultation with a hematologist experienced in myeloproliferative disorders is required 1
• MPD in Noonan syndrome is typically transient and self-resolving but can cause significant morbidity and mortality; rare cases progress to frank juvenile myelomonocytic leukemia (JMML) 1

Childhood Through Adolescence

• Continue clinical surveillance for signs of leukemia (B-ALL, AML, JMML) at routine healthcare visits, as the relative childhood cancer risk is approximately eightfold higher than the general population 1
• The spectrum includes myeloid and lymphoblastic leukemia, rhabdomyosarcoma, neuroblastoma, and glioma 1
• No routine brain imaging is recommended for asymptomatic patients 1

Cardiac Management

Initial Evaluation and Ongoing Monitoring

• Two-dimensional echocardiography with Doppler, chest x-ray, and ECG are required for initial cardiac evaluation 1
• Pulmonary valve stenosis is the most common cardiac defect; three morphological types exist: typical dome-shaped valve, dysplastic valve (frequent in Noonan syndrome with poor mobility and myxomatous thickening), and unicuspid/bicuspid valve 1
• Hypertrophic cardiomyopathy occurs in Noonan syndrome and requires specific surveillance distinct from sarcomeric HCM 1

Pulmonary Stenosis Surveillance

• For asymptomatic patients with peak instantaneous valvular gradient by Doppler <30 mm Hg: follow-up physical examination, echocardiography-Doppler, and ECG every 5 years 1
• For asymptomatic patients with gradient >30 mm Hg: echocardiography-Doppler every 2-5 years 1
• Stenosis is classified as mild (<30 mm Hg), moderate (30-50 mm Hg), or severe (>50 mm Hg) 1
• Cardiac catheterization should be reserved exclusively for percutaneous intervention, not diagnostic purposes 1

Hypertrophic Cardiomyopathy Considerations

• The nomenclature "Noonan syndrome with cardiomyopathy" or "Noonan syndrome with LV hypertrophy" is preferred over "Noonan hypertrophic cardiomyopathy," as this distinguishes it from sarcomeric HCM 1
• Noonan syndrome with cardiomyopathy is caused by mutations in RAS/MAPK pathway genes, not sarcomere protein genes 1

Growth and Endocrine Management

• Short stature is a cardinal feature requiring growth parameter monitoring at every visit 1, 4, 2
• Endocrinology consultation for growth hormone evaluation and potential treatment should be considered for significant growth deficiency 2

Developmental and Neurological Assessment

• Variable cognitive deficits occur; approximately one-third of patients have intellectual disability 1, 4, 3
• Developmental screening and early intervention services should be implemented as needed 2
• Neurological examination at each visit focusing on developmental milestones and cognitive function 4

Ophthalmologic Surveillance

• Comprehensive ophthalmologic examination should be performed early in childhood, as 97% of patients have some visual defect 5
• Common findings include: hypertelorism (74%), strabismus (48%), refractive errors (61%), amblyopia (33%), ptosis (48%), prominent corneal nerves (46%), and nystagmus (9%) 5
• Fundal changes occur in 20% including optic nerve head drusen, optic disc hypoplasia, colobomas, and myelinated nerves 5
• Approximately 47% require non-surgical treatment and 16% require surgery for strabismus or ptosis 5

Additional Multisystem Surveillance

• Cryptorchidism screening in males, as this is a common feature 1, 4, 2
• Bleeding diathesis evaluation if clinical bleeding occurs, as coagulation abnormalities can occur 6
• Lymphatic dysplasia monitoring for lymphedema 4, 2
• Skeletal assessment for chest deformities (pectus excavatum, pectus carinatum) and scoliosis 1, 4
• Ectodermal features including sparse/coarse hair, sparse eyebrows, and skin abnormalities 6, 3

Critical Management Pitfalls

• Do not perform routine screening brain MRI in asymptomatic patients—imaging should be symptom-directed 1
• Do not obtain routine CBC in healthy, asymptomatic infants without hepatosplenomegaly, as this leads to unnecessary testing and anxiety 1
• Restenosis after percutaneous valvuloplasty is more common if residual gradient >30 mm Hg remains post-procedure 1
• Family members may have subtle manifestations and should be evaluated if a mutation is identified, as penetrance is variable 6
• The dysplastic pulmonary valve type has poor mobility and marked myxomatous thickening without commissural fusion, making it less amenable to balloon valvuloplasty than the typical dome-shaped valve 1

Genetic Counseling

• Noonan syndrome is inherited in an autosomal dominant pattern with variable penetrance 4, 2, 3
• First-degree relatives should be evaluated for subtle features and offered genetic testing if a pathogenic variant is identified in the proband 6
• Approximately 50% of cases represent de novo mutations 2