Hydrops fetalis is characterized by abnormal fluid accumulation in two or more fetal compartments, such as pericardial effusion, pleural effusion, ascites, or generalized edema of 5 mm [1]. They are classified into immune and non-immune types, with non-immune hydrops fetalis (NIHF) accounting for more than 85% of the cases [1,2].

NIHF may result from a wide range of causes, including hematological, infectious, chromosomal, vascular, and cardiac disease [1,3]. Cardiac causes account for approximately 15% to 20% of NIHF cases and include structural heart disease, cardiomyopathy, arrhythmias, and vascular anomalies [2,3]. Cardiomyopathies, although less common than structural heart defects, can lead to impaired cardiac function, pericardial effusion, and in severe cases, cardiac tamponade [4].

Genetic testing plays an important role in identifying the underlying causes of neonatal cardiomyopathy. Titin (TTN), which encodes the giant sarcomeric protein titin, is essential for myocardial elasticity and contraction. Mutations in TTN have been implicated in various forms of cardiomyopathy, including dilated and arrhythmogenic right ventricular cardiomyopathy [5-7]. Given its structural role in the sarcomeres, pathogenic TTN variants can lead to myocardial dysfunction, thereby increasing the risk of pericardial effusion and hydrops fetalis [8].

Here, we report the case of a preterm infant with NIHF and cardiac tamponade, in whom a heterozygous TTN gene mutation was identified. This case highlights the utility of genetic screening for neonates with unexplained NIHF and cardiac dysfunction.

The baby was a male infant delivered via cesarean section at 29 weeks and 2 days of gestation with a birth weight of 1,430 g. The mother, a primipara with no notable medical history, underwent routine outpatient follow-up. At 13 weeks and 6 days of gestation, she was transferred to Daegu Catholic University Medical Center because of a subchorionic hemorrhage. Subsequent prenatal ultrasonography showed gradual hematoma resolution, the presence of a single umbilical artery, and no fetal hydrops signs. There was a 15-hour premature membrane rupture before delivery, followed by persistent contractions and fetal deceleration, leading to a cesarean section due to fetal distress. After birth, the infant did not respond to stimulation and had a heart rate below 60 beats per minute (bpm), oxygen saturation (SpO₂) of 60%, and generalized cyanosis. Endotracheal intubation was performed, followed by prophylactic surfactant administration and positive-pressure ventilation. Despite these measures, no significant improvement was observed, and chest compressions were initiated. After 1 minute of chest compression, the heart rate increased to 150 bpm, with weak crying and improved skin color. The infant was then admitted to the neonatal intensive care unit. The Apgar scores were 3 at 1 minute and 8 at 5 minutes. Generalized edema was observed, and mechanical ventilation was initiated; vital signs subsequently stabilized (blood pressure, 55/29 mm Hg; heart rate, 136 bpm, SpO₂ 96%). A peripherally inserted central catheter line was placed, and chest radiography confirmed that the catheter tip was at the T1–T2 level within the superior vena cava.

Five hours after birth, the preterm infant developed sudden bradycardia (heart rate <70 bpm), SpO₂ of 60%, and pallor. Chest radiography revealed no pneumothorax but revealed mild edema (Figure 1). Transthoracic echocardiography (TTE) showed impaired left ventricular (LV) function without pericardial effusion. Epinephrine administration was initiated to support cardiac function.

Two hours later, the infant experienced another bradycardic episode: heart rate 70 bpm, SpO₂ 50%, and unmeasurable blood pressure. Chest radiography revealed no pneumothorax but showed progressive cardiomegaly (Figure 2). Emergency TTE revealed a 17 mm pericardial effusion and severely reduced cardiac function, leading to a cardiac tamponade diagnosis (Figure 3).

Pericardiocentesis was performed under echocardiographic guidance using a subcostal approach to drain 15 mL of the transudative fluid. No bacteria were detected in fluid cultures. Vital signs of the infant stabilized after the procedure.

On the following day, TTE showed a patent ductus arteriosus, an atrial septal defect (ASD), an 8 mm pericardial effusion, and reduced LV function, with no other structural anomalies (Figure 4). Despite ventilator support, the SpO₂ remained low. Chest computed tomography was performed to assess pulmonary anomalies but revealed only pleural effusion. Abdominal ultrasonography showed ascites. Infection and metabolic workups, including toxoplasma, rubella, cytomegalovirus, herpes simplex virus, syphilis (TORCH) screening, parvovirus B19, thyroid hormone testing, autoantibody (anti-Ro/La) testing, and fungal and parasitic evaluations, were unremarkable. Inborn errors in metabolic screening and chromosomal analysis also revealed no abnormalities.

The infant was managed conservatively for NIHF, inotropes were administered during hypotensive episodes, and fluid restriction was applied based on input/output monitoring. Serial TTEs were performed to monitor the cardiac function, pericardial effusion, pleural effusion, and ascites. On day 27, TTE revealed residual pericardial effusion (2.3 mm), whereas the ascites and pleural effusion resolved. The ductus arteriosus closed spontaneously. No retinopathy of prematurity or necrotizing enterocolitis was observed. Brain magnetic resonance imaging showed a grade 2 germinal matrix hemorrhage on the right side.

Owing to the baby’s history of pericardial effusion, cardiac tamponade, and decreased LV function, a cardiomyopathy panel using next-generation sequencing (NGS) was performed for the infant and parents. Two heterozygous TTN mutations (c.13898A>T and c.27856G>T) were identified in the infants. The father had no TTN variants, whereas the mother carried c.13898A>T but was asymptomatic with a normal echocardiogram. The c.27856G>T mutation is presumed to be pathogenic.

At 10 months old, follow-up TTE showed ASD closure, mild pericardial effusion (1–2 mm), and decreased cardiac function (fractional shortening 25%–26%, ejection fraction 54–57%). The infant gained appropriate weight without any clinical symptoms. At 15 months of age, neurological development, including muscle tone, was within the normal range.

Hydrops fetalis is defined as abnormal fluid accumulation in at least two fetal compartments. It usually presents as subcutaneous edema with effusion in two or more serous cavities [1]. Hydrops fetalis is classified into immune and NIHF, with more than 85% of all hydrops fetalis cases caused by non-immune causes [1,9]. The causes of NIHF include cardiac etiology, infectious diseases, hematologic disorders, structural congenital anomalies, single-gene disorders, and metabolic disorders. In 15% to 20% of NIHF cases, the cause is unknown [1,3,9,10].

Cardiovascular disorders that cause NIHF can be divided into four categories: (1) structural heart disease; (2) cardiomyopathies; (3) fetal arrhythmias; and (4) vascular disorders [3]. Right-sided structural heart disease and supraventricular tachycardia are common in fetal arrhythmias [3]. Cardiomyopathy cases associated with NIHF that we reviewed are few worldwide, and there have been no reports in Korea. Among these, there have been five NIHF reports caused by LV noncompaction cardiomyopathy. These cases are usually diagnosed during prenatal testing for fetal edema and decreased cardiac function. At birth, LV dysfunction develops, and heart failure progresses. Inotropic agents such as dopamine and dobutamine, along with diuretics, are administered. If the symptoms improved, digoxin, enalapril, and furosemide were administered. The prognosis is poor, with three out of five infants not surviving [10-12].

In NIHF caused by heart problems, the main mechanisms are increased right atrial pressure and volume overload. These factors decrease the ventricular contractility and result in pericardial effusion. This causes an increase in the ventricular filling pressure, which can lead to cardiac tamponade. When cardiac tamponade occurs, the venous return is impaired, ventricular filling pressure increases, and cardiac output is impaired, causing hemodynamic collapse. In this patient, cardiac tamponade occurred due to severe pericardial effusion, and emergency pericardiocentesis was performed via a subcostal approach under echocardiographic guidance [4]. Subsequently, pericardial effusion persisted on TTE, and cardiac contractility decreased; therefore, a genetic test was performed.

Gene testing has been performed to identify the causes of many diseases that lead to fetal hydrops. The genetic causes include various chromosomal and monogenic disorders. Several studies have reported 131 genes highly associated with NIHF, and 46 genes with potential relevance. Among these, TTN has been identified in NIHF cases in infants with multiple congenital anomalies, including arthrogryposis [9]. Unlike previously reported cases, our preterm infants did not exhibit any joint contractures. Urinalysis and serum sodium, potassium, and creatinine levels were normal, as were liver enzyme, bilirubin, and γ-glutamyl transpeptidase levels. There were no abnormalities in his facial features, and he exhibited no signs of cryptorchidism.

Cardiomyopathy genetic testing by NGS was performed on the patient, revealing a heterozygous mutation in the TTN gene. Two heterozygous mutations in the TTN gene (c.13898A>T and c.27856G>T) were identified. TTN encodes titin, a protein that plays crucial structural, developmental, and mechanical regulatory roles in the cardiac and skeletal muscles. According to previous studies, over 127 mutations related to the TTN gene have been reported. These mutations can lead to cardiac muscle diseases, skeletal muscle diseases, or a combination of the two. Heterozygous TTN mutations have been associated with various cardiomyopathies [5,7,13,14]. Passive tension in the human heart is influenced by the expression patterns of titin isoforms. TTN gene mutations are thought to contribute to cardiomyopathies by disrupting sarcomere assembly or contractility, or by triggering aberrant splicing [5,7].

TTN mutations diagnosed by NGS are still rare. Several studies have reported cardiac-associated TTN mutations, and the association between TTN and cardiomyopathy has been studied in inherited dilated cardiomyopathy [15,16]. Our infant was diagnosed with a TTN gene mutation, and genetic testing was performed on both parents. The father had no gene variant or cardiomyopathy symptoms, whereas the mother was found to have a heterozygous variant (c.13898A) in the TTN gene; however, she had no cardiomyopathy symptoms or normal echocardiogram results. Of the two variants identified, c.27856G>T was the most likely cause of cardiomyopathy leading to NIHF. Among the various TTN mutations, none of the TTN gene variants (c.27856G>T) matched those of the patient in this case. Similarly, several reported studies revealed that none of the TTN mutations were identical to those found in our patient. Therefore, we were unable to compare the type, severity, and prognosis of the disease. If the TTN gene has a homozygous mutation, it would be possible to conclude that the patient's NIHF was due to a mutation in the TTN gene. However, considering that the patient had cardiomyopathy along with a heterozygous TTN mutation and normal results in various tests that could cause NIHF, there is a possibility that the TTN gene mutation was the cause of NIHF.

Relatively few patients have been tested for TTN mutations, and the number of patients with these mutations is also very small; therefore, the correlation between TTN mutations and clinical presentation remains limited. However, this case suggests that TTN mutations should be considered in cases of unexplained NIHF to guide future genetic screening strategies.

The causes of hydrops fetalis are diverse, and some cases of NIHF remain unknown. A premature infant with no specific findings during prenatal examination was diagnosed with cardiac tamponade and hydrops fetalis at birth, prompting emergency pericardiocentesis. Owing to the lack of specific findings in various tests for NIHF, additional genetic testing for cardiomyopathy was conducted. We report the case of a premature infant with hydrops fetalis in which a TTN gene mutation was identified using a cardiomyopathy NGS panel.