Discussion

Noonan syndrome is an autosomal dominant disorder with a high percentage of affected individuals having cardiovascular involvement. Many Noonan syndrome-associated PTPN11 pathogenic variants increase signalling through the RAS-MAPK pathway, which can have downstream effects on growth factors that influence cellular proliferation, survival and differentiation (Fig 1). ^{Reference Roberts, Allanson, Tartaglia and Gelb1} These transcriptional effects can present with wide phenotypic variability which can often lead to a delay in diagnosis, as was seen in our first case. Atrioventricular canal defects can occur in up to 8% of patients with Noonan syndrome, and recent studies show an association with PTPN11 variants. ^{Reference Linglart and Gelb3,Reference Digilio, Romana Lepri and Dentici6} Severely unbalanced atrioventricular defects leading to a hypoplastic left heart syndrome variants, however, have only been described one time in the literature in a patient with a RAF1 mutation. ^{Reference Schulz, Fröber, Kraus and Schneider4} A better understanding of genotype–phenotype associations can lead to earlier diagnosis and improved care.

Figure 1.

Growth factors bind to a receptor. Through the docking protein GRB2, SOS1, and PTPN11 are recruited which promotes activation of RAS and MAP-K pathway. ERK can enter the nucleus and alter transcription which has downstream effects on cellular proliferation and differentiation. MEK inhibitors, like trametinib, can inhibit this pathway. Gene variants associated with Noonan syndrome are depicted in green.

In patients with Noonan syndrome and hypoplastic left heart syndrome, there are several important periprocedural considerations. At least 10% of Noonan syndrome patients will have lymphovascular disorders including thoracic duct abnormalities which can be unmasked by cardiac surgery and present as refractory chylothoraces or lymphatic pericardial effusions as was seen in patient 1. ^{Reference Linglart and Gelb3} Therefore, patients with Noonan syndrome may not tolerate the transition to Glenn or Fontan physiology which can increase venous congestion and exacerbate lymphatic disorders. Therefore, when anatomy permits, a patient with Noonan syndrome may benefit from biventricular repair or hybrid operative approach. Recently severe lymphovascular disorders have been successfully treated with trametinib, a RAS-MAPK pathway inhibitor, in a patient with the SOS1 variant of Noonan syndrome (Fig 1). ^{Reference Dori, Smith and Pinto7} This may be an important treatment adjunct for patients with Noonan syndrome that must proceed down the single ventricle pathway, but more studies will need to be done to determine its efficacy in patients with the PTPN11 mutation.

Noonan syndrome may also affect the haematologic system with up to 65% of patients with Noonan syndrome having bleeding diatheses, including factor deficiencies and qualitative platelet disorders. ^{Reference Artoni, Selicorni and Passamonti8} Patient 2 exhibited numerous haematologic complications including postoperative bleeding and early shunt thrombosis. Haematologic consultation to identify these coagulation disorders, therefore, is recommended prior to surgical intervention in patients with Noonan syndrome and could potentially improve perioperative outcomes. Haematologic malignancies and solid organ tumours can also occur frequently in Noonan syndrome from dysregulation of the RAS-MAPK pathway. ^{Reference Smpokou, Zand, Rosenbaum and Summar9} For example, 2.9% of patients with neuroblastoma have pathogenic PTPN11 variants, so screening for these and other commonly associated malignancies is an important consideration in the care and prognosis of these patients.

Given these factors that can complicate periprocedural care, prognosis of patients with Noonan syndrome and hypoplastic left heart syndrome is poor. Both patients in this series, as well as the only other patient reported in the literature, ^{Reference Schulz, Fröber, Kraus and Schneider4} suffered early death. Recently RAS-MAPK pathway inhibitors have been used to successfully manage lymphovascular complications and hypertrophic cardiomyopathy-related heart failure. ^{Reference Andelfinger, Marquis and Raboisson10} In the future, other similar targeted therapies may be developed for patients with the PTPN11-related Noonan syndrome. We hope that a better understanding of the genotype–phenotype association between PTPN11 variant Noonan syndrome and hypoplastic left heart syndrome variants may lead to earlier diagnosis, more informed decisions around periprocedural care, and the potential for earlier availability of targeted therapies.