Fatal heart failure caused by severe pulmonary regurgitation, tricuspid regurgitation and late-onset mitral stenosis in an adult patient with Noonan syndrome: a case report

The patient was born at 39 weeks of gestation and delivered by Cesarean section due to polyhydramnios. She was 3295 g at birth. Although short stature and abnormal facial features such as depressed nose, deeply grooved philtrum, and macroglossia were recognized at birth, the signs were not associated with any particular diagnosis. At 1 year of age, she was diagnosed with pulmonary valve stenosis. At 5 years of age, a balloon valvuloplasty for severe PS was performed; however, it was not sufficient to reduce the pressure gradient of PS (from 80 mmHg to 50 mmHg). At 6 years of age, surgical valvuloplasty to enlarge the annulus and reconstruct the right ventricular outflow tract was performed, which resulted in the disappearance of the PS pressure gradient. She was followed-up at our hospital yearly. Although echocardiogram showed mild PR, her clinical condition was good without specific medical treatment. When she was a high school student, she discontinued regular medical follow-up, and started studying abroad at 18 years of age. She occasionally experienced transient leg edema during this time. At 21 years of age, she developed dyspnea, edema, and abdominal bloating. She returned to Japan; thereafter, she required an emergency hospitalization. She was diagnosed with acute decompensated heart failure, which was mainly right-sided heart failure due to severe PR and TR. It was thought that PR had been subclinically exacerbated after the surgical valvuloplasty, resulting in right-ventricular volume overload. She was also diagnosed with protein-losing enteropathy associated with abnormalities in lymphatic drainage. Echocardiography showed no evidence of HCM, MS, or PS recurrence. Cardiac catheterization revealed a normal cardiac index of 3.9 L/min/m², and a normal estimated mitral valve area of 4.13 cm²/m². On the basis of the history of PS and characteristic physical features including short stature, webbed neck, and hypertelorism, she was clinically diagnosed with NS for the first time. A chromosomal study showed 46XX with no abnormality of chromosome 12. The patient refused genetic testing. She was successfully treated with a loop diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, and aldosterone inhibitor. After discharge, she resumed regular follow-up at the local hospital. Although the symptoms of heart failure, such as dyspnea and edema, persisted with a New York Heart Association class of II these symptoms could be controlled with oral medical treatment. There were no records regarding the follow-up echocardiographic findings at the local hospital. At 25 years of age, she was admitted to the local hospital again for massive ascites and marked edema and was referred to our hospital. Her height was 107 cm and her weight was 33 kg. She had a body temperature of 36.8 °C, blood pressure of 90/50 mmHg, regular pulse rate of 125 beats/min, respiratory rate of 18 breaths/min, and oxygen saturation of 95% without oxygen administration. On physical examination, she exhibited jugular venous distention at her neck, and systolic and diastolic regurgitant murmur at the left sternal border. Her breath sounds were decreased, and she had abdominal distention with no tenderness and significant leg edema. Laboratory data upon hospitalization are shown in Table 1. Chest radiography showed heart enlargement with cardiothoracic ratio of 63%, pulmonary edema, and bilateral pleural effusion (Fig. 1). Electrocardiogram showed sinus tachycardia with right axis deviation. Echocardiogram showed enlargement of the right-side heart with displacement of the ventricular septal wall, as well as severe PR, TR, and severe MS with a mean pressure gradient of 10 mmHg and mild thickening of the mitral valve leaflets (Figs. 2, 3, 4, 5 and 6, Additional file 1: Video 1, Additional file 2: Video 2, Additional file 3: Video 3, Additional file 4: Video 4). Since diastolic function based on the early diastolic mitral septal annular velocity was normal, it was unlikely that the patient had restrictive cardiomyopathy or constrictive pericarditis. Cardiac catheterization revealed a mean pulmonary artery pressure of 49 mmHg, a mean pulmonary artery wedge pressure of 33 mmHg, a left ventricular end-diastolic pressure of 24 mmHg, a low cardiac index of 1.9 L/min/m², and confirmed severe MS with an estimated mitral valve area of 0.81 cm²/m². Coronary arteries were intact. There was no evidence of rheumatic change or infectious endocarditis; the etiology of the late-onset MS was uncertain. Computed tomography of the chest and abdomen showed massive ascites as well as plural effusion and atelectasis in the right lung. On the basis of these findings, she was diagnosed with heart failure of both sides, which was mainly caused by severe PR and TR after surgical valvuloplasty for PS as well as the late-onset severe MS with uncertain etiology. Moreover, her abdominal ultrasonogram findings, including irregular external contour, enlarged left liver lobe, and splenomegaly, indicated that she had developed cirrhosis. This was thought to be associated with long-standing right-side heart failure, because of the negative viral or other hepatitis screening. Results of the analysis of ascites and plural effusion were consistent with a pure transudate. Thus, excessive fluid of the chest and abdomen was considered to have been caused by the chronic right-side heart failure in addition to the severe hypoalbuminemia associated with advanced cirrhosis and protein-losing enteropathy. In addition to the abdominal and chest drainage, fluid management using furosemide, tolvaptan, and carperitide was successfully performed. We discussed a treatment strategy with surgeons, including mitral valve replacement, tricuspid valvuloplasty, and right ventricular outflow tract reconstruction; however, considering the patient’s low left ventricular function, cirrhosis, very low albumin level, and atelectasis caused by the long-standing pleural effusion, surgical options were considered to be extremely high risk. In addition, transcatheter cardiac intervention could not be performed in Japan at that time. Therefore, we continued the optimal medication treatment as well as the occasional abdominal cavity drainage for recurrent ascites. Unfortunately, after repeated hospitalizations for ascites and edema, she died of decompensated heart failure 2 years later.

Parameter	Recorded value	Standard value
White blood cell count	10.5 × 10^3 /L	3.40–7.30 × 10^3 /L
Red blood cell count	3.98 × 10^6 /L	3.62–4.99 × 10^6 /L
Hemoglobin	11.7 g/dL	11.7–15.1 g/dL
Hematocrit	36.5%	34.1–45.3%
Platelet	407 × 10^3 /L	160–327 × 10^3 /L
C-reactive protein	0.60 mg/dL	≦0.20 mg/dL
Total protein	3.5 g/dL	6.4–8.4 g/dL
Albumin	1.8 g/dL	3.9–5.2 g/dL
Total bilirubin	0.23 mg/dL	0.2–1.0 mg/dL
Aspartate aminotransferase	19 U/L	12–35 U/L
Alanine aminotransferase	13 U/L	6–33 U/L
Lactate dehydrogenase	226 U/L	114–243 U/L
Alkaline phosphatase	274 U/L	120–362 U/L
γ-glutamyltranspeptidase	57 U/L	3–54 IU/L
Creatinine	0.20 mg/dL	0.30–1.10 mg/dL
Sodium	137 mEq/L	138–150 mEq/L
Potassium	4.4 mEq/L	3.6–5.0 mEq/L
Glucose	99 mg/dl	98–109 mg/dl
B-type natriuretic peptide	39.1 pg/mL	< 18.4 pg/mL
Total cholesterol	156 mg/dL	125–220 mg/dL
Glucose	102 mg/dL	65–110 mg/dL
Thyroid stimulating hormone	3.647 μIU/mL	0.350–4.940μIU/mL
Free-T3	1.97 pg/mL	1.71–3.71 pg/mL
Free-T4	0.87 ng/dL	0.70–1.48 ng/dL
Type IV collagen 7S	9.2 ng/mL	< 6.0 ng/mL
Hyaluronic acid	97 ng/mL	< 50 ng/mL
Prothrombin time	12.4 s	10.2–14.0 s