System-based intervention	Clinical issue	Timing of intervention	Comments
Auditory	Hearing loss	Hearing tests in infancy and/or at diagnosis	—
		Annual hearing test throughout childhood
Cardiovascular	Congenital heart defects	At the time of diagnosis and regular follow-up with cardiologist	Cardiac consultation, echocardiography, and electrocardiography
		Children and adults without heart disease on initial evaluation should have cardiac reevaluation every five years
Dental	Dental malocclusion	Oral examination by primary care physician at each visit	—
		Dental referral between one and two years of age, with annual dentist visits thereafter
Dermatologic	See Table 1 for common skin findings	Referral as indicated	—
Developmental	Behavioral disorders, developmental delay, learning difficulties, mild intellectual disability, speech disorders	Development assessment annually (beginning in second half of first year of the patient's life or at diagnosis)	If screening results are abnormal, consider appropriate intervention
		Baseline neuropsychologic assessment at primary school entry
Endocrine	Delayed puberty, hypothyroidism, short stature	Referral as indicated	Endocrine evaluation for growth hormone therapy to treat short stature and hormone therapy for delayed puberty
Gastroenterologic	Feeding difficulties	Referral as indicated	Appropriate therapeutic intervention as needed (e.g., swallowing study, speech therapy, reflux studies)
Genetic	To confirm diagnosis, genetic counseling and genotype–phenotype correlation	Referral as indicated	—
Growth	Failure to thrive, short stature, slow growth	At the time of diagnosis, three times a year for the first three years, then annually	Monitor and plot growth on Noonan syndrome age-based growth charts
Hematologic	Increased bleeding tendencies (factor deficiency, quantitative or qualitative platelet defect)	Baseline coagulation screen at diagnosis or after six to 12 months of age if screening was initially performed during infancy or whenever diagnosis is made	If bleeding symptoms:
				First-tier: Baseline coagulation screen (complete blood count, prothrombin time, activated partial thromboplastin time)
				Second-tier (in consultation with hematologist): Specific factor assay and platelet function studies
Lymphatic	Lymphatic vessel dysplasia, hypoplasia, or aplasia	Referral as indicated	Refer patients with lymphedema to lymphedema clinic (contact National Lymphedema Network; http://www.lymphnet.org/)
Metabolic	Failure to thrive Inadequate weight gain	Referral as indicated	Dietary assessment and nutrition intervention
Neurologic	Arnold-Chiari malformation, craniosynostosis, headaches, hydrocephalus, seizures	Referral as indicated	Physician should have a low threshold for investigating neurologic symptoms (electroencephalography, magnetic resonance imaging of the brain)
Ocular	Dysmorphic findings, vision problems	Detailed eye examination in infancy and/or at diagnosis	—
		Eye reevaluation as indicated if abnormal or every two years thereafter
Pregnancy	Congenital heart defects, effusion, hydrops fetalis, increased nuchal translucency, polyhydramnios, renal anomalies	Per obstetrician's recommendation	Chorionic villus sampling or amniocentesis for diagnosis if indicated
			Fetal ultrasonography and echocardiography
Renal	Renal anomalies (e.g., pyeloureteral stenosis, hydronephrosis)	Renal ultrasonography at the time of diagnosis	Increased risk of urinary tract infection if structural anomaly found, consider antibiotic prophylaxis and evaluation by nephrologist
Reproductive	Female fertility normal8; male fertility problems related to defective spermatogenesis caused by cryptorchidism or gonadal dysfunction due to impaired Sertoli cell function	Orchiopexy if testes undescended by one year of age	Fertility clinic evaluation in males
Skeletal	Pectus deformity of sternum, spinal abnormality	Annual examination of chest and back	If screening abnormal, consider radiography of the spine
Surgical and anesthesia risk	Increased risk of complications due to a cardiac disorder, increased bleeding tendency, or craniofacial and/or vertebral anomalies	Referral as indicated	See cardiovascular, hematology, and skeletal management recommendations