What is the treatment plan for a patient with Noonan syndrome, considering potential cardiac issues, bleeding disorders, and increased cancer risk?

Management of Noonan Syndrome

Patients with Noonan syndrome require immediate cardiology evaluation, genetic testing with cancer surveillance protocols, hematologic screening before any procedures, and coordinated multidisciplinary monitoring for cardiac, oncologic, bleeding, developmental, and growth complications. 1

Immediate Cardiac Evaluation and Management

Cardiology assessment is the first priority because pulmonary stenosis—the most common cardiac defect occurring in approximately one-third of patients—shows lower success rates with balloon valvuloplasty in Noonan syndrome compared to isolated pulmonary stenosis. 1, 2

• Initial echocardiography should assess for pulmonary stenosis, hypertrophic cardiomyopathy, septal defects, and left-sided lesions. 1, 2
• Cardiac catheterization may be necessary when echocardiography is insufficient to determine severity or optimal intervention timing. 1
• Intervention is generally indicated when the resting gradient exceeds 40 mmHg, though patients with dysplastic valves often require surgical rather than catheter-based intervention. 1
• For mild pulmonary stenosis (gradient <30 mmHg), follow-up with physical examination, echocardiography-Doppler, and ECG should occur at 5-year intervals in asymptomatic patients. 3
• RAF1 mutations can present with atrial septal defects and ventricular septal defects in addition to the typical hypertrophic cardiomyopathy, requiring comprehensive structural assessment. 4

Genetic Testing and Cancer Surveillance

Genetic confirmation should occur concurrently with cardiac evaluation because specific mutations determine cancer surveillance protocols and prognosis. 1

• Mutations in PTPN11, SOS1, RAF1, RIT1, and other RAS/MAPK pathway genes cause Noonan syndrome, with PTPN11 accounting for over 50% of cases. 1, 2
• Specific PTPN11 or KRAS mutations (particularly codon 61, T73I, or T58I) confer high risk for juvenile myelomonocytic leukemia (JMML) and require surveillance with physical examination (assessing spleen size) and complete blood count with differential every 3-6 months until age 5 years. 5, 1
• Up to 10% of patients with PTPN11 or KRAS mutations develop transient myeloproliferative disease in infancy that resembles JMML; while generally self-resolving, it can cause significant morbidity and mortality or progress to frank JMML. 5
• Patients with PTPN11 or SOS1 mutations have increased risk of B-cell acute lymphoblastic leukemia, most with high hyperdiploidy. 5
• The 2024 Clinical Cancer Research guidelines recommend updated surveillance for RASopathies given advances in targeted therapies that can improve outcomes for both low-grade and malignant neoplasms. 5

Hematologic Assessment

Hematologic screening must be performed before any surgical intervention because bleeding diathesis occurs in Noonan syndrome and can cause significant perioperative complications. 1, 6

• Evaluate platelet function, coagulation studies, and factor levels to identify specific bleeding disorders. 6
• Lymphatic anomalies including chylothorax and protein-losing enteropathy occur in approximately 20% of cases and require specific management. 7
• In severe lymphatic disorders refractory to conventional treatment, MEK inhibition with trametinib has shown complete resolution of symptoms and remodeling of the lymphatic system in case reports. 7

Additional Essential Evaluations

Comprehensive screening for associated comorbidities should be completed at diagnosis:

• Ophthalmologic evaluation for ptosis, amblyopia, refractive errors, and strabismus. 1
• Audiologic assessment for sensorineural hearing loss, which occurs in up to 40% of patients. 1
• Renal ultrasound to screen for structural renal anomalies. 1
• Developmental assessment for learning difficulties with arrangement of early intervention services as needed. 1
• Growth monitoring for failure to thrive and proportionate short stature, which are cardinal features. 1

Coordinated Long-Term Care

The American Heart Association recommends children with structural heart defects receive coordinated multidisciplinary care through a medical home model. 1

• Regular cardiology follow-up with frequency determined by severity of cardiac lesions (5-year intervals for mild pulmonary stenosis with gradient <30 mmHg). 3
• Oncology surveillance based on specific genetic mutation identified. 5, 1
• Monitor for development of new symptoms including exercise intolerance, changes in murmur character, or signs of right ventricular dysfunction. 3
• Increase follow-up frequency if pulmonary stenosis gradient increases to >30 mmHg (every 2-5 years) or if symptoms develop. 3

Critical Pitfalls to Avoid

• Do not delay cardiac evaluation—pulmonary stenosis in Noonan syndrome requires different management than isolated pulmonary stenosis. 1
• Do not proceed with surgery without hematologic screening—unrecognized bleeding disorders cause preventable perioperative complications. 1
• Do not skip genetic testing—specific mutations determine cancer surveillance intensity and inform family planning. 1
• Do not assume mild cardiac disease is benign—significant progression can occur before symptoms develop, requiring regular follow-up even with mild findings. 3
• Do not overlook lymphatic complications—these can be life-threatening but may respond to MEK inhibition when conventional therapy fails. 7