Noonan Syndrome (Not Just) in the Pediatric Cardiologist's Office
Noonan Syndrome (NS) is a genetically determined disease associated with a high prevalence of (not just) congenital heart defects. When is it necessary to consider it in a cardiologist's office, where to refer the patient if suspected, and how to proceed if the diagnosis is confirmed?
Introduction
Noonan Syndrome is a relatively common genetically determined disease with a prevalence of 1/1000–2500 live births. The inheritance is usually autosomal dominant. The clinical picture is variable, with most patients exhibiting facial dysmorphia (triangular-shaped face, ptosis of the eyelids, low-set ears, hypertelorism, and a wider neck). Other symptoms may include short stature, congenital heart defect (pulmonary valve stenosis, atrial or atrioventricular [AV] septal defect, etc.) or cardiomyopathy, abnormalities of the lymphatic system, skeleton, and urogenital tract, mild mental retardation, or cryptorchidism.
NS belongs to the so-called RASopathies - diseases caused by germline mutations in the genes of the RAS/MAPK signaling pathway. A number of causal genes have been identified so far, the most common cause being missense mutations in the PTPN11 gene (up to 60% of cases), SOS1, RAF1, or KRAS. The diagnosis can thus be confirmed molecularly genetically in 70–75% of patients.
Cardiovascular Manifestations
According to current knowledge, congenital heart defects, cardiomyopathy, or their combination occur in up to 90% of patients with NS. Some may be clinically silent at the time of diagnosis or may manifest later in life (especially hypertrophic cardiomyopathy). Cardiovascular involvement also belongs to the diagnostic criteria for establishing the clinical diagnosis of NS.
Pulmonary Valve Stenosis
Pulmonary stenosis is the most common congenital heart defect in patients with NS (up to 70%). According to studies, this defect in children is conditioned by NS in up to 6% of cases (most commonly by a mutation in the PTPN11 gene). Approximately 60% of cases are mild stenoses, 10% are moderately severe, and 30% are hemodynamically significant. Mild stenosis usually does not progress and does not require intervention during the patient's life. Conversely, patients with more severe stenosis require intervention in 50–100% of cases. In 65% of cases, percutaneous balloon valvuloplasty fails, and the defect must be resolved by surgical valvulotomy. Additional associated heart defects that may require intervention are common in all patients regardless of the severity of the stenosis.
Atrioventricular (AV) Septal Defect
AV septal defects are observed in up to 15% of children with NS. The most common cause is again a mutation in the PTPN11 gene. The typical form is the partial defect (primum atrial septal defect along with a cleft in the anterior leaflet of the mitral valve), while the complete defect is rare.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy affects 10–30% of patients with NS. According to studies, up to 30% of children with this diagnosis also have NS. These children also have a worse prognosis – within one year, up to 20% of children die or undergo heart transplantation (compared to 14% with hypertrophic cardiomyopathy not conditioned by NS). The higher mortality is due to the younger age at manifestation and the higher incidence of heart failure. A concentric form of hypertrophy with obstruction of the left ventricular outflow tract is more common.
Recommendations for Practice
If patients with pulmonary valve stenosis show even mild signs of facial dysmorphia or have other associated cardiac or extracardiac defects typical for NS, they should be referred for genetic counseling to consider molecular genetic testing. The same should be considered for children with a newly diagnosed AV septal defect (especially if it is present in multiple family members) or hypertrophic cardiomyopathy.
For all patients with newly diagnosed NS, an ECG and echocardiographic examination are indicated. For patients with a normal finding, cardiological examination should be repeated every 5 years (even in adulthood) considering the risk of late manifestation of hypertrophic cardiomyopathy. Patients with a congenital heart defect or hypertrophic cardiomyopathy should be monitored individually based on the severity of the findings.
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Source: Klásková E. Noonan Syndrome from a Pediatric Cardiologist's Perspective. Czech-Slovak Pediatrics 2020; 75 (4): 227–231.
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