INTRODUCTION
Noonan syndrome is a genetic multisystem disorder characterized by
distinctive facial features, developmental delay, learning difficulties,
short stature, congenital heart disease, renal anomalies, lymphatic
malformations, and bleeding difficulties [1-3]. The mutations that
cause Noonan syndrome alter genes encoding proteins with roles in the
RAS-MAPK pathway, leading to pathway dysregulation [1-3]. Noonan
syndrome was first characterized by Jacqueline Noonan, who reported nine
patients with pulmonary valve stenosis, small stature, hypertelorism,
mild intellectual disability, ptosis, undescended testes, and skeletal
malformations [4]. Noonan syndrome is an autosomal dominant,
variably expressed, multisystem disorder with an estimated prevalence of
1 in 1,000 to 2,500 [5]. In the RAS-MAPK signaling pathway,
molecular genetic testing identifies a pathogenic variant in PTPN11 in
50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1
in 5% each, and KRAS in <5% [1].
Several hematological cancers have been reported in patients with Noonan
syndrome, particularly during childhood, including juvenile
myelomonocytic leukemia, acute myelogenous leukemia, and B-cell acute
lymphoblastic leukemia [6]. A large study of a cohort of 297 Dutch
patients with Noonan syndrome and a pathogenic PTPN11 mutation
calculated that the risk of cancer was increased 3-5 times in comparison
to the general population [7].
It is reported that expression of PTPN11/Shp2 is elevated in human
hepatocellular carcinoma (HCC), and that its levels were even higher in
metastatic foci [8]. PTPN11 is representative pathogenic gene of
Noonan syndrome [1]. PTPN11, which encodes tyrosine phosphatase
Shp2, is a critical gene mediating the cellular responses to hormones
and cytokines [9]. The loss of Shp2 promotes the development of HCC,
suggesting that PTPN11 functions as a tumor suppressor in HCC
tumorigenesis [10, 11]. As a result, there seems to be a
relationship between abnormality of PTPN11 and/or RAS-MAPK signaling
pathway in Noonan syndrome and HCC. However, there have been no previous
case reports of Noonan syndrome complicated with HCC.
We herein report the case of a patient with Noonan syndrome complicated
with HCC. To our knowledge, this represents the first reported case of
Noonan syndrome complicated with HCC.
CASE
PRESENTATION
A 19-year-old man consulted our department after hepatic hyperechoic
lesions were incidentally pointed out by screening ultrasound. There
were no associated symptoms. He had a history of Noonan syndrome. He
showed distinctive facial features, as well as developmental delay,
mental retardation, funnel chest, hypertrophic cardiomyopathy, mitral
regurgitation, and renal anomalies. He had received surgery for an
atrial septal defect at 5 years of age, cryptorchidism at 7 years of
age, and scoliosis at 19 years of age. His height and weight were 150 cm
and 35 kg, respectively.
The laboratory data at the first visit were as follows: red blood cell
count (RBC), 314×104/μL; hemoglobin (Hb), 14.5 g/dL;
white blood cell count (WBC), 5,500/μL; platelet count (Plt),
13.9×104/μL; prothrombin time (PT), 71 %; PT-INR,
1.16; total protein (TP), 6.2 g/dL; albumin (Alb), 3.4 g/dL; total
bilirubin (T-Bil), 2.6 mg/dL; direct bilirubin (D-Bil) 0.1 mg/dL;
aspartate aminotransferase (AST) 25 U/L; alanine aminotransferase (ALT)
23 U/L; lactate dehydrogenase (LDH) 154 U/L; alkaline phosphatase (ALP),
344 U/L; γ-glutamyltransferase (γ-GT), 40 U/L; blood urea nitrogen
(BUN), 14 mg/dL; creatinine (Cr), 0.53 mg/dL and C-reactive protein
(CRP), 0.01 mg/dL. The patient was negative for both hepatitis B surface
antigen and hepatitis C virus antibody. His alpha-fetoprotein (AFP),
serum des-gamma-carboxy prothrombin (DCP), carcinoembryonic antigen
(CEA), and carbohydrate antigen 19-9 (CA19-9) values were all within the
normal ranges.
Abdominal computed tomography (CT) revealed that the portal vein seemed
to be interrupted at the liver hilum and flow to the inferior vena cava
merging with the hepatic vein (Figure 1a ). The liver parenchyma
showed poor contrast and the intrahepatic portal vein was unclear in the
portal phase (Figure 1b ). The irregular parenchyma disappeared
at the late phase (Figure 1c ). At the lower margin of segment
6, the tumor showed enhancement from the margin, with staining continued
until the late phase (Figure 1d, e ). This tumor showed high
signal intensity on T2-weighted magnetic resonance imaging (MRI)
(Figure 1f ). We considered that the findings reflected a
diagnosis of hemangioma. Superparamagnetic iron oxide (SPIO)-enhanced
MRI revealed another tumor in segment 4. This tumor showed low signal
intensity after SPIO enhancement, while the central portion showed high
intensity (Figure 2a ). We considered that this tumor was focal
nodular hyperplasia (FNH). Similar lesions were also observed in the
liver. We considered that the portal vein and vessel abnormalities
associated with Noonan syndrome had caused multiple sites of hyperplasia
in the liver. Because it was difficult for the patient to remain still
for a long time due to mental retardation,
gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid
(EOB)-enhanced MRI were not performed in the initial evaluation.
The FNH-like lesion in segment 4 gradually grew (Figure 2b, c ).
On EOB-MRI, this lesion showed faint staining in the early phase, was
unclear in the portal phase and showed central low intensity in the
hepatocyte phase (Figure 2d, e, f ). A similar lesion was
observed in segment 7 (Figure 3a, b ). On an SPIO-MRI scan
performed 2 years after the first visit, the lesion was 16 mm in
diameter. This tumor also gradually grew; however, the growth rate was
slow (Figure 3c, d, e ). During the course, hypervascular areas
were observed in the tumor of segment 7 in the arterial phase, while
washout was observed in the late phase. Although the serum DCP level was
within normal range until 3 years from first visit, it was elevated to
116 mAU/mL at 4 years from the first visit and then gradually increased.
We hypothesized this tumor contained the HCC component.
Surgical resection, transarterial chemoembolization, and radiation
therapy were considered. Because of the patient’s mental retardation and
portal vein abnormality, supportive care was selected. The hepatic tumor
gradually grew and reached 12×16 cm diameter at 7 years from the first
visit. Obstructive jaundice developed as a complication of tumor
progression. The laboratory data at this time were as follows: RBC,
314×104/μL; Hb, 10.1 g/dL; WBC, 22,000/μL; Plt,
18.4×104/μL; PT, 81 %; PT-INR, 1.06; TP, 6.5 g/dL;
Alb, 3.3 g/dL; T-Bil, 34.8 mg/dL; D-Bil, 28.1 mg/dL; AST, 82 U/L; ALT,
24 U/L; LDH, 199 U/L; ALP, 185 U/L; γ-GT, 67 U/L; BUN, 67 mg/dL; Cr,
2.27 mg/dL and CRP, 3.67 mg/dL. AFP was 14.9 ng/mL, and DCP was 42,771
mAU/mL
The patient died of liver failure due to tumor progression in the 7th
year after the first visit. Autopsy revealed that liver tumor was HCC.
The portal vein was interrupted at the liver hilum and flowed directly
into the hepatic vein (Figure 4a ). Microscopic evaluation of
the tumor revealed well to moderately differentiated HCC (Figure
4b ). Part of the tumor cells showed foamy cytoplasm and contained fat
droplets (Figure 4c ). Histological examination of the
background liver showed cholestasis, fibrosis around the portal vein and
central vein, and ductular proliferation (Figure 4d ).