Cholestasis, Progressive Familial Intrahepatic, 4

A number sign (#) is used with this entry because progressive familial intrahepatic cholestasis-4 (PFIC4) is caused by homozygous or compound heterozygous mutation in the TJP2 gene (607709) on chromosome 9q21.

For a phenotypic description and a discussion of genetic heterogeneity of progressive familial intrahepatic cholestasis, see PFIC1 (211600).

Clinical Features

Sambrotta et al. (2014) reported 12 patients from 8 families with early childhood onset of severe progressive liver disease. One child died at age 13 months, 9 patients required a liver transplant, and 2 had stable liver disease with mild portal hypertension at ages 4 and 7 years, respectively. Laboratory studies showed normal or mildly increased GGT levels. No additional clinical details were given. Most of the families were consanguineous.

Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma (HCC). The first was a 26-month-old Caucasian female who had had intermittent jaundice of neonatal onset and normal GGT. She presented in acute liver failure. CT scan showed innumerable well-defined hepatic masses. Serum alpha-fetoprotein (AFP; 104150) was 171,000 ng/mL, and liver biopsy found moderately differentiated HCC in a background of chronic cholestatic hepatitis with cirrhosis. The patient died 3 weeks after admission. An autopsy confirmed multifocal HCC. The second patient was a 6-month-old Caucasian male referred for persistent cholestasis with near-normal GGT after hepatoportoenterostomy for presumed biliary atresia. Icterus resolved by 19 months, but a growing lesion in the right liver lobe, with rising serum AFP, prompted liver transplantation at 2 years of age. The explanted liver was cirrhotic, with multiple cholestatic nodules and a single, well-encapsulated 2-cm tumor that diffusely expressed AFP and glypican-3 (300037); a central region of well-differentiated HCC was found. The patient was well post 2 years transplantation. Zhou et al. (2015) concluded that mutations in TJP2 resulting in progressive intrahepatic cholestasis may predispose to hepatocellular carcinoma in early childhood, warranting close monitoring and early liver transplantation.

Inheritance

The transmission pattern of PFIC4 in the families reported by Sambrotta et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 8 families with progressive familial intrahepatic cholestasis-4, Sambrotta et al. (2014) identified homozygous mutations in the TJP2 gene (see, e.g., 607709.0002-607709.0005). The mutations were identified by a combination of whole-exome sequencing and targeted sequencing of genes known to be associated with cholestasis. All mutations were predicted to abolish protein translation, consistent with a complete loss of function. Liver biopsy tissue available from several patients showed a lack of TJP2 protein expression. Patient liver tissue showed decreased localization of CLDN1 (603718) at tight junctions, although protein levels were normal; these findings suggested abnormal localization of CLDN1 in the absence of TJP2. Expression and localization of CLDN2 (300520) was normal. Transmission electron microscopy showed that the tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue were elongated and lacked the densest part of the zona occludens. Sambrotta et al. (2014) noted that homozygous loss of Zo2 in mice is embryonic lethal (Xu et al., 2008), indicating interspecies differences, and concluded that the lack of redundancy in humans must be restricted to the liver.

Zhou et al. (2015) reported 2 patients with PFIC4 who developed hepatocellular carcinoma. One was compound heterozygous for TJP2 mutations (see 615878.0006); the other was homozygous for a frameshift mutation (615878.0008).