What is the recommended diagnostic work‑up and management for a pediatric patient with Noonan syndrome?

Diagnostic Work-Up and Management for Pediatric Noonan Syndrome

Initial Diagnostic Approach

For a child with suspected Noonan syndrome, establish the diagnosis through clinical evaluation focusing on characteristic facial dysmorphisms (hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears), cardiac defects, and short stature, then confirm with molecular genetic testing of RAS-MAPK pathway genes. 1

Clinical Diagnostic Features

• Facial features: Examine for hypertelorism with down-slanting palpebral fissures, ocular ptosis, low-set posteriorly rotated ears, and broad neck with low posterior hairline 2
• Cardiac abnormalities: Most commonly pulmonary valve stenosis with dysplasia and hypertrophic cardiomyopathy 1
• Growth parameters: Document proportionate short stature and relative macrocephaly on standard growth curves 2
• Developmental assessment: Evaluate for motor and cognitive delays at each visit 2

Genetic Testing

• Molecular confirmation: Order multigene RAS-MAPK pathway panel testing, which identifies pathogenic variants in approximately 80% of cases 3
• Common genes: PTPN11 accounts for nearly 50% of cases, with other genes including SOS1, RAF1, RIT1, LZTR1, KRAS, SOS2, NRAS, RRAS, RRAS2, MRAS, and SPRED2 1
• Inheritance pattern: Autosomal dominant with approximately 50% arising from de novo mutations 3

Comprehensive Initial Work-Up

Cardiac Evaluation (Critical for Morbidity/Mortality)

Obtain transthoracic echocardiography at diagnosis as the first-line imaging modality to evaluate for pulmonary valve stenosis and hypertrophic cardiomyopathy. 4, 2

• Echocardiographic assessment: Measure maximum diastolic wall thickness in all LV segments, evaluate LV diastolic function with pulsed Doppler, tissue Doppler velocities, pulmonary vein flow velocities, and pulmonary artery systolic pressure 4
• Right ventricular evaluation: Assess for characteristic increased right ventricular free wall thickness and hypertrophy 4
• Left atrial assessment: Measure left atrial size and volume 4
• Advanced imaging: Consider cardiac MRI when echocardiographic images are suboptimal or to better characterize hypertrophy extent and evaluate for aortic dilatation 4

Cancer Surveillance Protocol

Implement structured cancer surveillance starting at birth or diagnosis, as childhood cancer risk is increased approximately eightfold over the general population. 1

Myeloproliferative Disorder (MPD) Surveillance

• Physical examination: Evaluate 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
• Laboratory testing approach: Do NOT obtain routine bloodwork in asymptomatic children; only obtain CBC if the child appears ill or has hepatosplenomegaly on examination 1, 2
• Abnormal results: If bloodwork is abnormal, immediately consult a hematologist with expertise in MPD 1
• Risk context: Specific PTPN11 variants are associated with MPD, which can be self-limiting but may transform to JMML 1

Brain Tumor Surveillance

• No routine imaging: Brain tumor risk is less than 1%; surveillance is NOT indicated unless clinical symptoms develop 1, 2

Other Malignancies

• Broad cancer spectrum: Increased risk for myeloid and lymphoblastic leukemia, rhabdomyosarcoma, neuroblastoma, and glioma 1
• Annual physical examination: Perform yearly physical examination by general physician starting at birth or diagnosis 1

Ongoing Management

Growth and Endocrine Management

• Growth monitoring: Plot height, weight, and head circumference at every well-child visit on standard growth curves 2
• Growth hormone therapy: Consider for short stature, though response may vary by genotype (PTPN11 mutations may indicate reduced response) 5, 6
• Pubertal assessment: Monitor for delayed puberty and hypogonadism, particularly in males 5

Cardiovascular Follow-Up

• Serial echocardiography: Perform regular follow-up echocardiography to monitor for recurrent stenosis in patients with pulmonary valve stenosis 4
• HCM monitoring: For patients with hypertrophic cardiomyopathy, comprehensive evaluation of LV diastolic function is essential, as restrictive filling patterns indicate higher risk for adverse outcomes 4
• Blood pressure monitoring: Check yearly starting at birth or diagnosis to screen for pheochromocytoma (≤5% risk) and consider renal artery stenosis if hypertensive 1

Otolaryngologic Care

• Early ENT involvement: Consider early otolaryngology referral, as eustachian tube dysfunction, hearing loss, and speech delay are common 7
• Speech therapy: Arrange for articulation deficiency and language delay as needed 7
• Otitis media management: Monitor for recurrent otitis media requiring pressure equalization tubes 7

Developmental Support

• Multidisciplinary approach: Coordinate care with genetics, cardiology, oncology, neurology, and other subspecialties as clinically indicated 3
• Developmental monitoring: Assess milestones at each visit, noting any motor or cognitive delays 2

Special Considerations for LZTR1 Variants

For children with heterozygous LZTR1 variants, implement schwannomatosis surveillance starting at age 15-19 years with baseline brain and spine MRI, then every 2-3 years. 2

• Avoid early brain imaging: Do not perform routine brain MRI surveillance in asymptomatic young children with LZTR1 Noonan syndrome, as brain tumor risk is less than 1% 2
• Pain monitoring: Monitor for chronic neuropathic pain patterns 2

Critical Pitfalls to Avoid

• Do not obtain routine CBCs: This is a common error; bloodwork should only be obtained if the child is symptomatic or has hepatosplenomegaly 1, 2
• Do not miss cardiac evaluation: Cardiac abnormalities are a major source of morbidity and mortality; echocardiography at diagnosis is mandatory 4, 2
• Do not perform routine brain imaging: Unless symptomatic, brain tumor surveillance is not indicated given the low (<1%) risk 1, 2
• Do not overlook genetic counseling: Offer counseling to discuss inheritance patterns, recurrence risks, and family testing 2