Cardiovascular System Affection in Children with Noonan Syndrome

Cardiovascular System Affection Determines Prognosis

Main clinical symptoms in children with Noonan syndrome include short stature, typical facial dysmorphia (ptosis of the eyelids, epicanthus, low-set ears, broad forehead, short neck, depressed nose, etc.), chest deformities (pectus carinatum/excavatum), mental retardation, cryptorchidism, lymphatic system dysplasia, and cardiovascular abnormalities. These can be diagnosed in up to 80% of children with this disease, mainly including pulmonary stenosis, hypertrophic cardiomyopathy, and atrioventricular septal defect. Heart involvement often determines the morbidity and mortality of these patients. Moreover, it is classified among the so-called major diagnostic criteria.

• Hypertrophic cardiomyopathy is generally very rare in childhood, thus its finding often leads to suspicion of a genetic defect and diagnostic establishment. Compared to children with idiopathic familial hypertrophic cardiomyopathy, children with Noonan syndrome generally have a worse prognosis, and the affliction is often detected earlier. At the time of diagnosis, some of them already show signs of heart failure, which causes death in up to 25% of patients in infancy.
• Up to 40% of children with Noonan syndrome have varying degrees of pulmonary stenosis. This is otherwise rare in the general pediatric population, with a prevalence of around 0.05%.
• Noonan syndrome and generally RASopathies are also associated with atrioventricular septal defect responsible for left-to-right shunt. However, it is often transient and less hemodynamically significant (compared to children with Down syndrome).

Abnormal EKG Findings Are Not Specific

Changes in EKG findings in patients with Noonan syndrome are also classified among the major diagnostic criteria, although they are not specific to individual heart defects. They are visible in over 60% of cases. They include right deviation of the heart axis, abnormal R/S wave ratio in the left precordial leads (low R waves in the left precordium and deep S waves in the right precordium), abnormal Q waves, and broadened QRS complex.

Is There a Correlation Between Genotype and Cardiovascular Phenotype?

Studies suggest a correlation between specific mutations and cardiovascular system involvement: 

• Missense mutation of the PTPN11 gene is most commonly associated with pulmonary stenosis or atrioventricular septal defect. Hypertrophic cardiomyopathy, on the other hand, is less common.
• Mutation of the RAF1 gene is associated with hypertrophic cardiomyopathy in 80–95% of cases.
• In the case of MEK1 gene mutation, the incidence of pulmonary stenosis is nearly 100%.

Recommended Cardiological Monitoring

Regular follow-up with a cardiologist is absolutely essential for patients with Noonan syndrome. They represent a population with extremely increased cardiovascular risk. As mentioned above, cardiological findings also determine any potential premature morbidity and mortality of patients. Therefore, it is crucial to detect cardiovascular system involvement as early as possible. All children with newly diagnosed Noonan syndrome should undergo both EKG and echocardiographic examination.

The follow-up should ideally be lifelong, at intervals of at least 5 years. Hypertrophic cardiomyopathy, being a progressive condition, can manifest later in life. Given the low prevalence of the disease, it is recommended that cardiological monitoring be conducted in specialized tertiary centers.

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Source: Klásková E. Cardiovascular System Affection in Children with Noonan Syndrome. Webinar: The Child with Noonan Syndrome in Clinical Practice, December 9, 2020. Available at: www.prolekare.cz/videa/webinar-dite-se-syndromem-noonanove-v-klinicke-praxi-125249