DISCUSSION
We reported the first case of Noonan syndrome complicated with HCC. Noonan syndrome is a genetic multisystem disorder that involves mutations of genes encoding the proteins in the RAS-MAPK pathway [1-3]. PTPN11 is representative pathogenic gene of Noonan syndrome [1]. PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines [10]. Activating mutations in PTPN11 have been shown to be directly associated with the pathogenesis of Noonan syndrome and childhood leukemias [6, 13]. In Noonan syndrome patients with a pathogenic PTPN11 mutation, the risk of developing cancer is reported to be 3-5 times higher than that in the general population [7]. The loss of Shp2 promotes the development of HCC, suggesting that PTPN11 functions as a tumor suppressor in HCC tumorigenesis [10, 11]. PTPN11 was first identified as a proto-oncogene in leukemia [13]. However, most recent findings suggest that PTPN11 plays a tumor suppressor role in HCC [10, 11], implying its dual faces in tumorigenesis.
Although the defined pathogenesis of HCC in the present case was not confirmed, we considered that there were two possibilities. One possibility involves genetic abnormalities associated with Noonan syndrome. Because Noonan syndrome is associated with mutations in PTPN11 and/or genes encoding the RAS-MAPK pathway [1-3], these pathogenic variants may have caused HCC in the present case. PTPN11, which is mutated in Noonan syndrome, has tumor suppressor roles in HCC [10, 11]. Patients with Noonan syndrome seem to have an increased risk of developing HCC.
The other possible pathogenesis involves vessel abnormality and congestion. Chronic congestion due to heart failure is one of the pathogeneses of HCC [13]. The present case was complicated by hypertrophic cardiomyopathy, and mitral regurgitation. Furthermore, the patient had past history of surgery for an atrial septal defect. The patient also had a portal vein anomaly. It is known that increased venous pressure and decreased cardiac output and hepatic venous drainage result in sinusoidal dilatation around the central veins [13]. Finally, this may have caused liver cirrhosis and the development of HCC. Chronic congestion and/or vessel abnormality may be a reason for the development of HCC in this case.
One limitation of this case report is that gene mutation analyses of PTPN11 and/or RAS-MAPK pathway proteins were not performed. Because this is the only case report on Noonan syndrome complicated with HCC, it would be desirable to accumulate and analyze other cases. Although this is the only reported case of Noonan syndrome complicated with HCC and despite the relationship between these two diseases being unknown, the presence of RAS-MAPK pathway protein abnormalities and the development of HCC are clinically interesting.