Published online Feb 7, 2020. doi: 10.3748/wjg.v26.i5.550
Peer-review started: November 18, 2019
First decision: December 23, 2019
Revised: January 12, 2020
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: February 7, 2020
Progressive familial intrahepatic cholestasis (PFIC) encompasses a group of autosomal recessive disorders with high morbidity and mortality. Variants in the gene encoding tight junction protein-2 (TJP2) have been linked to PFIC type 4 (PFIC4), which predominantly presents in childhood. However, there are only limited data from adults with TJP2-related PFIC4. We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.
The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers. In 2018, he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019. Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4 (TJP2([NM_004817.3]:c.[3334C>T]; [3334C>T])). The consanguineous family consists of the father and mother (both heterozygous) and their 12 children, of which five carry the variant in a homozygous state; however, these five siblings have highly variable expression of PFIC4. Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36. Two other homozygous brothers, age 23 and 19, and the homozygous sister, age 21, have elevated liver enzymes but presently no cirrhosis, which may suggest an age-dependent penetrance. In addition, five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state, respectively.
This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
Core tip: We report a family with progressive familiar intrahepatic cholestasis type-4 (PFIC4) with a novel variant in the tight junction protein-2 gene. The five homozygous children have highly variable expression of PFIC4. Two brothers presented with cirrhosis, portal hypertension and hepatocellular carcinoma at ages 19 and 36. Two other homozygous brothers and a sister (age 19-23) have elevated liver enzymes without cirrhosis. Furthermore, five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the tight junction protein-2 variant in homozygous and heterozygous states, respectively. Close monitoring for cirrhosis and hepatocellular carcinoma development is warranted in PFIC4 syndrome.