Discussion
To date, only few studies regarding the perinatal findings in Noonan syndrome have been described in medical literature. In the prenatal period, the most common clinical characteristics that have been reported are lymphatic anomalies, such as increased nuchal translucency, pleural effusions, cystic hygroma, hydrops fetalis. Long bones <5° centile have been described in almost half of cases. Other common prenatal findings in NS are: polyhydramnios, macrosomia (defined as abdominal circumference >90th centile), occipital-frontal circumference >90th centile, congenital heart defects. Arrhythmias have been reported only once in medical literature.
Regarding neonatal findings, cardiovascular anomalies, such as structural heart defects, valvular dysplasia, hypertrophic cardiomyopathy are the most common features. Lymphatic dysplasia, birth weight and occipital-frontal circumference >90th centile, renal defects and hypotonia are anomalies frequently described in infants affected by NS. 10
During the prenatal period our patient showed specific findings of NS: increased nuchal translucency, right caliectasis, polyhydramnios, abdominal circumference and occipital-frontal circumference > 90th centile, hydrops fetalis.
At birth other anomalies became evident, such as length >97th centile, long fingers and toes, megalencephaly, and Wolff-Parkinson-White syndrome (WPW). Those characteristics are not typical of Noonan syndrome. Wolff-Parkinson-White syndrome has never been associated with Noonan syndrome.
WPW syndrome is characterized by the presence of an accessory atrioventricular pathway, which bypasses the normal atrioventricular conduction. This pathway leads to a ventricular pre-excitation, causing palpitations, syncope, ventricular fibrillation and even sudden cardiac death. 11, 12
Recently, variants in the PI3K-AKT pathway have been described to be associated with overgrowth syndromes (PIK3CA-Related Overgrowth Spectrum, PROS), such as Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP, MIM # 602501) and Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-1 (MPPH, # MIM 603387), but also Congenital lipomatous asymmetric overgrowth, epidermal naevi, skeletal and spinal anomalies syndrome (CLOVES, # MIM 612918), as well as hemimegalencephaly and isolated macrodactyly. 13 For this reason, the analysis of a panel of genes involved in the PI3K/AKT/mTOR pathway was performed from a saliva sample of our patient and the gene panel testing came back negative. Since PROS shows phenotypic variability and it is mostly caused by somatic PI3KCA mutations, it could be important to follow the child over time, in order to monitor the onset of other signs related to PROS. It could be interesting to perform the analysis of a panel of genes involved in the PI3K-AKT pathway in other tissues as well. Indeed, it cannot be excluded that PIK3CA mutant cells might exert growth-promoting effects on adjacent or distant cells by signal propagation of secreted biomolecules or exosomes.