Case Report
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2020; 26(5): 550-561
Published online Feb 7, 2020. doi: 10.3748/wjg.v26.i5.550
New tight junction protein 2 variant causing progressive familial intrahepatic cholestasis type 4 in adults: A case report
Chun-Shan Wei, Naja Becher, Jenny Blechingberg, Peter Ott, Ida Vogel, Henning Grønbæk
Chun-Shan Wei, Peter Ott, Henning Grønbæk, Department of Clinical Medicine - Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
Chun-Shan Wei, Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
Naja Becher, Jenny Blechingberg, Ida Vogel, Department of Clinical Genetics, Aarhus University Hospital, Aarhus N DK-8200, Denmark
Author contributions: Wei CS, Vogel I, and Grønbæk H designed the study and collected data; Becher N, Vogel I and Blechingberg J performed genetic testing and consultation; Ott P supervised manuscript writing and the histological evaluations; Wei CS, Becher N and Grønbæk H analyzed the patients’ data; Wei CS wrote the manuscript; all authors critically revised the manuscript; all authors reviewed the manuscript and approved the final version.
Supported by Sanming Project of Medicine in Shenzhen of China, No. SZSM201612074.
Informed consent statement: Written informed consent was obtained from the index patient and all individuals of the family in Denmark for the genetic study and publication of this case report.
Conflict-of-interest statement: All other authors declare that they have no conflicts of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Henning Grønbæk, MD, PhD, Professor, Department of Clinical Medicine - Department of Hepatology and Gastroenterology, Aarhus University Hospital, 99 Palle Juul-Jensens Boulevard, Entrance C, Level 1, C116, Aarhus N DK-8200, Denmark.
Received: November 18, 2019
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
Processing time: 81 Days and 3.1 Hours

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.

Keywords: Progressive familial intrahepatic cholestasis, Tight junction protein 2, Genetic variants, Liver cirrhosis, Liver cancer, Case report

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.