Case

The patient was the second-born male born of a 35-year-old mother. There was no family history of cardiomyopathy, hepatobiliary disease, or congenital disorders in his parents, elder sister, or other blood relatives. The mother was followed up at a local obstetrics and gynaecology clinic, and no abnormalities were noted until 35 weeks of gestation. On the fetal echocardiogram at the 37 weeks 2 days gestational checkup, fetal oedema, cardiac dysfunction, bilateral atrioventricular valve regurgitation, and cardiac enlargement, with the cardiothoracic area ratio increased by approximately 50%, were found for the first time (Figure 1a). The mother was transferred to a local perinatal hospital.

Figure 1.

Clinical images of the patient. ( a ) Fetal echocardiogram at 37 weeks 2 days of gestation. Subcutaneous oedema, pleural effusion, mitral and tricuspid regurgitation, arrows a–d, respectively, are seen. The cardiothoracic area ratio is about 50%. ( b ) Chest X-ray at birth. The cardiothoracic ratio is 65%. ( c )–( f ) Pathological autopsy findings. ( c ) Macroscopic examination of the heart. Thinned ventricular muscle. ( d ) Microscopic image of the heart. Hypoplasia of cardiomyocytes. ( e ) Macroscopic examination of the liver. The appearance is dark green. ( f ) Microscopic image of the liver. Bile duct hyperplasia and bile congestion are seen.

The fetus was diagnosed with cardiogenic fetal oedema and delivered the same day by emergency caesarean section. Birth weight was 3656 g (+3.1 SD), ^{Reference Itabashi, Miura, Uehara and Nakamura4} and Apgar scores were 5 and 8 at 1 and 5 minutes, respectively. Generalised oedema was noted, but no obvious body surface malformations were identified. Cyanosis was evident from birth, tracheal intubation and artificial ventilation were promptly started, and the patient was transferred to the neonatal ICU. A chest X-ray showed a cardiothoracic ratio of 0.65 (Figure 1b), and echocardiography showed bilateral atrioventricular valve regurgitation and pericardial effusion, with a left ventricular ejection fraction of 40%. No congenital cardiac structural abnormalities or arrhythmias were found, and he was diagnosed with congenital dilated cardiomyopathy. Treatment for heart failure, with catecholamine, milrinone, and furosemide, was started, but his condition gradually worsened, and he was transferred to our hospital for intensive care the day after birth.

On admission to our hospital, left ventricular ejection fraction on echocardiography was reduced to 20%. Blood tests showed abnormal biochemistry and coagulation findings that could be attributed to heart failure: TP 3.9 g/dL, Alb 2.6 g/dL, BUN 14.7 mg/dL, CRE 1.07 mg/dL, NT-pro-BNP 24,892 pg/µL, PT-INR 1.85, APTT 41.4%, fibrinogen 81 mg/dL, D-dimer 17.9 µg/dL, and FDP 45.6 µg/dl, as well as abnormally high ferritin of 2214 ng/mL. In contrast, hepatobiliary enzymes including bilirubin were generally within normal ranges. The next day, left ventricular ejection fraction decreased to 10%, and percutaneous cardiopulmonary support was initiated. At 7 days of age, continuous administration of epinephrine brought the left ventricular ejection fraction to 30%, and assisted circulation was terminated. Further improvement of left ventricular ejection fraction of 40% was observed at around 30 days of age. Nevertheless, ferritin and direct bilirubin values increased to a maximum of 19,447 ng/mL and 12.6 mg/dL, respectively, at the same time (Figs. S1, S2). At about 40 days of age, cardiac function worsened again, and the patient was considered non-viable. The patient was shifted to terminal care at age 53 days and died at age 61 days. On pathological autopsy, myocardial thinning and hypoplasia of ventricular myocytes were observed in the heart macroscopically and microscopically, respectively (Figure 1c, d). The liver was dark green in appearance, and microscopic evidence of bile congestion and bile duct hyperplasia was observed (Figure 1e, f). Prenatal tests for the cause of cardiomyopathy, including chromosomal abnormalities, metabolic and mitochondrial diseases, intrauterine infections, and maternal antibodies, such as anti-SS-A antibodies, showed no abnormal findings (Table S1). Virus isolation tests in pharyngeal mucus, urine, and stool were negative, ruling out acute myocarditis, although evaluation of the myocardium itself was not performed. After the patient’s death, a de novo variant of FHL2 (NM_001318895.3), c.391C>T, p.Arg131Cys, was identified by trio-exome sequencing and verified by Sanger sequencing (Figure 2a). Details of genetic testing are described in the Supplementary Information.

Figure 2.

Genetic testing results and information on FHL2. ( a ) Sanger sequencing of FHL2 in the patient and parents. The patient has de novo c.391C>T heterozygously. ( b ) The Arg131 residue of FHL2 is highly conserved in vertebrates.