Simultaneous TFAM and TJP2 Variants in a Child With Cirrhosis and Hepatocellular Carcinoma.

Abstract

Pediatric hepatocellular carcinoma (HCC), a rare and life-threatening malignancy that typically arises de novo, is strongly associated with underlying metabolic or genetic disorders. Its molecular pathogenesis remains poorly understood due to the limited number of well-documented cases. Herein, we present the case of an 11-year, 5-month-old boy who presented with incidentally detected cirrhosis, growth retardation, and severe pruritus. Whole-exome sequencing revealed a novel homozygous variant in the mitochondrial transcription factor A (TFAM) gene (c.197C>A; p.Pro66His) and compound heterozygous variants in the tight junction protein 2 (TJP2) gene (c.142G>C; p.Val48Leu and c.877C>T; p.Arg293Trp), all classified as variants of uncertain significance (VUS). Immunohistochemistry confirmed reduced expression of TFAM and TJP2, while electron microscopy demonstrated abnormal mitochondrial ultrastructure and compromised biliary epithelial integrity, supporting a diagnosis of combined TFAM and TJP2 deficiency. The disease rapidly progressed from moderately to well-differentiated HCC within 15 months. Following laparoscopic tumor resection, the patient successfully underwent orthotopic liver transplantation at 13 years of age, with normal graft function maintained at the 8-month follow-up. This case provides insights for the diagnosis and management of pediatric liver disease involving multiple VUS, suggests a potential novel pathogenic mechanism of HCC, and highlights the possible synergistic effects of multigene variants. Whether combined TFAM and TJP2 deficiencies directly and synergistically accelerate liver disease progression and hepatocarcinogenesis warrants further validation through additional clinical cases and functional studies.