ACRT Journal

Introduction

Ebstein anomaly is a rare congenital heart condition that affects only about 0.005% of live births and is responsible for between 0.3 to 0.6% of all congenital heart disease [1]. The defect is characterized by malformation and downward displacement of the tricuspid valve [2]. This malformation results in the right ventricle being smaller than normal while the right atrium is larger than normal [2]. Tricuspid regurgitation is detected in almost all cases of Ebstein’s anomaly, exposing patients to a high possibility of cardiac hypertrophy and heart failure [3]. Causes and risk factors of Ebstein’s anomaly are largely unknown, but genetics and environmental factors are believed to be involved [4]. For instance, maternal exposure to some medication and cigarette smoke are believed to increase the possibility of the condition. The clinical presentation can vary, with some cases being asymptomatic, in which case it is detected incidentally. In neonates, it often presents through cyanosis, in infants through heart failure, and in children though murmur [1].

On the other hand, the Dubin-Johnson Syndrome (DJS) is a rare autosomal recessive liver disorder characterized by prolonged or intermittent jaundice and liver pigmentation [5]. The prevalence of DJS is estimated to be less than 1 in 100,000 globally [6], but it tends to be more common in certain ethnic groups, such as among Sephardic Jews, where incidence rates of up to 1 in 3000 have been reported [7]. Many of the symptoms of DJS are shared with other diseases, which increases the likelihood of misdiagnosis. Pathogenic mutations in the adenosine triphosphatebinding cassette subfamily C member 2(ABCC2) gene were first observed and described in 1997 [8]. Since then, more than 50 different mutations of the ABCC2 that cause significant have been confirmed in different DJS patients [5]. The mutations lead to the formation of a dysfunctional MRP2 protein or accelerate mRNA degradation, which then results in diminished glycosylation and impaired sorting [9]. Although most cases of DJS present during adolescence, they also occur among new-borns.

The current study reports the case of a neonate patient who presented with persistent conjugated hyperbilirubinemia and was subsequently found to have mild Ebstein’s anomaly as well as DJS variants. Prior to this case, there was no any other known case of the two conditions coexisting in a single patient

Case Presentation

We present the case of a male neonate born to a 38-year-old gravida 4, para 3 mother who experienced premature prolonged rupture of membranes (PPROM) for 24 hours at 31 weeks’ gestation. The pregnancy had been otherwise uneventful, and the mother had no significant medical history. She had previously delivered three children vaginally without complications. Due to the presence of fetal distress and meconium-stained amniotic fluid (MSAF), an emergency cesarean section was performed.

At birth, the infant was non-vigorous, covered in thick MSAF, and had Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. Initial resuscitation included one cycle of positive pressure ventilation followed by endotracheal intubation. He weighed 1.56 kg, indicating intrauterine growth restriction (IUGR), and was clinically estimated to be 33-34 weeks gestational age. The neonate was transferred to the neonatal intensive care unit (NICU) for further management.

On initial physical examination, the baby appeared active, pink, and non-dysmorphic. He had no apparent major anomalies except for right-sided talipes. Cardiovascular examination was unremarkable, with normal heart sounds and no audible murmur. Respiratory examination showed equal air entry through the endotracheal tube. Neurological reflexes were intact, and the musculoskeletal and abdominal exams were within normal limits, with a patent anus and palpable testes.

The infant was managed in the NICU with a dose of intratracheal surfactant (Survanta), empiric antibiotics ampicillin and gentamicin, caffeine citrate, and supportive care. He was initially kept NPO and later transitioned to enteral feeding with expressed breast milk. Phototherapy was initiated for neonatal jaundice. He was extubated successfully within the first 24 hours of life, and respiratory status improved steadily with non-invasive ventilation.

In the second week of life, laboratory evaluation revealed persistently elevated bilirubin levels, with a total bilirubin peaking at 20.5 mg/dL and a direct conjugated component of 10.2 mg/dL. Liver function tests showed elevated Alanine Transaminase (130199 IU/L) and Aspartate aminotransferase (300-525 IU/L), while gamma-glutamyl transferase (GGT) remained within normal range (60 - 64 IU/L) as detailed in (Table 1), which presents a chronological summary of key laboratory parameters including bilirubin levels and liver enzymes, organized by postnatal day. Albumin and INR levels were stable, and synthetic liver function was preserved. The infant had pigmented stools, though they were occasionally lighter than expected. Abdominal ultrasound revealed a normal hepatobiliary anatomy with no signs of obstruction or biliary atresia. Cranial imaging was unremarkable.

Table 1: liver function test reports

Given the direct hyperbilirubinemia with normal GGT and preserved liver function, a differential diagnosis including progressive familial intrahepatic cholestasis (PFIC), Dubin-Johnson syndrome (DJS), bile acid synthesis defects, and neonatal metabolic or mitochondrial hepatopathies was considered. Comprehensive metabolic screening, including GALT, biotinidase, and carnitine levels, returned normal. Urinalysis was negative for reducing substances and tyrosinemia screening was also unremarkable.

During the course of evaluation, echocardiography revealed a mild form of Ebstein anomaly characterized by apical displacement of the tricuspid valve. Additionally, a small secundum atrial septal defect with left-to-right shunt and partial anomalous pulmonary venous drainage (PAPVD) of the left upper pulmonary vein to the innominate vein were identified. Computer Tomography chest angiography confirmed these findings, and left ventricular function was preserved. As Shown in (Figure 1), Electrocardiography showed bradycardia and a prolonged QT interval. No arrhythmias or signs of heart failure were observed.

Figure 1: Computer Tomography chest angiography showed bradycardia and a prolonged QT interval. No arrhythmias or signs of heart failure were observed.

Due to the unusual combination of clinical findings and persistent cholestasis, whole exome sequencing was (WES) performed and revealed two heterozygous variants of uncertain significance (VUS) as shown in (Table 2). These findings were interpreted as being consistent with Dubin-Johnson syndrome in the appropriate clinical context, as both variants have been previously reported in association with impaired MRP2 function.

Table 2: Whole Exome Sequences (WES) have identified two heterozygous variants in the ABCC2 gene.