Prenatal Phenotype of Children with Noonan Syndrome
Until recently, the various phenotypes of RASopathies were clinically diagnosed only after birth. However, we are now striving for the earliest possible diagnosis, sometimes even prenatally. Ultrasound examination of the fetus during screening tests, focusing on certain characteristic morphological changes, plays a crucial role in this. In the case of pathological findings on imaging methods, molecular genetic testing and monitoring of pregnancy in specialized centers are indicated.
Prevalence of RASopathies and Suspicious Signals
Noonan syndrome is one of the most common RASopathies. The so-called RASopathies form a group of syndromes caused by mutations in genes encoding individual components of the RAS/MAPK signaling pathway, which is responsible for cell proliferation, regulation, differentiation, and survival. The prevalence of RASopathies is estimated to be 1/700−1250 live births.
Common characteristics of RASopathies include facial dysmorphism, psychomotor retardation, a higher tendency for certain types of tumors, and especially cardiovascular abnormalities. Although each clinical syndrome has a unique phenotype, the individual units often overlap and suspicion of one syndrome can lead to the diagnosis of another type of RASopathy. Given the overlap of the mentioned clinical signs, genetic testing and molecular analysis are key for the final diagnosis.
Morphological Signs of Noonan Syndrome
The key morphological sign we focus on during congenital anomaly screening is called nuchal translucence (NT). This examination was originally designed for Down syndrome screening; however, later a correlation between pathological NT values and other chromosomal and structural abnormalities was found.
For Noonan syndrome, the leading sign is NT pathology. Besides that, we distinguish between major and minor fetal signs of Noonan syndrome. Major signs include enlargement of the jugular lymphatic sacs (probably due to defective development of the lymphatic vessels with impaired drainage), cystic hygroma, presence of effusion (whether localized, for example in the pericardium, chest, or abdomen, or overall under the image of fetal hydrops), cardiovascular abnormalities (especially pulmonary stenosis and hypertrophic cardiomyopathy), and polyhydramnios. Among morphological changes in the kidneys, the most common is dilation of the calyceal-pelvic system. Pathological NT value and 1 major sign are sufficient to suspect the presence of a RASopathy.
Minor signs supporting the possible diagnosis of Noonan syndrome include limb anomalies (syndactyly, short femurs), facial stigmatization (small nose, slanted forehead, brachycephaly, low-set ears), and some less typical heart defects (ventricular and atrioventricular septal defects or Fallot's tetralogy).
Heart Pathology in Noonan Syndrome
In RASopathies, it mainly involves defects of the pulmonary artery and the right ventricular outflow tract. Cardiac pathologies are the most clinically significant and prognostically limiting after overall stigmatization. Therefore, they are monitored prenatally and postnatally, and in hemodynamically significant defects, interventional solutions are indicated. For illustrative prognostic purposes, it is stated that hypertrophic cardiomyopathy diagnosed after 6 months of age without other symptoms has a survival rate of up to 95%, while cardiomyopathy detected in the first 6 months of life along with signs of heart failure has a survival rate of only about 30%.
Conclusion
We are able to diagnose RASopathies prenatally, mainly due to the established screening program during pregnancy. Morphologically, we focus particularly on assessing fetal nuchal translucence, polyhydramnios, effusions, and cardiac or kidney abnormalities. Heart defects are the earliest and most significant postnatal symptoms in RASopathies, but their prenatal diagnosis is still technically complicated and less successful.
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Source: Pavlíček J. Prenatal Phenotype of RASopathies. Czechoslovak Pediatrics 2020; 75 (4): 232−238.
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