Cholestasis, Progressive Familial Intrahepatic, 5

A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-5 (PFIC5) is caused by homozygous or compound heterozygous mutation in the NR1H4 gene (603826) on chromosome 12q.

Description

Progressive familial intrahepatic cholestasis-5 (PFIC5) is an autosomal recessive severe liver disorder characterized by onset of intralobular cholestasis in the neonatal period. The disease is rapidly progressive, leading to liver failure and death if liver transplant is not performed. Other features include abnormal liver enzymes, low to normal gamma-glutamyl transferase (GGT) activity, increased alpha-fetoprotein, and a vitamin K-independent coagulopathy (summary by Gomez-Ospina et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600).

Clinical Features

Gomez-Ospina et al. (2016) reported 4 children from 2 unrelated families with onset of severe cholestasis in early infancy. Three patients presented with neonatal cholestasis, jaundice, and failure to thrive in the first weeks of life, and 1 presented with ascites, pleural effusions, and intraventricular hemorrhage at birth. Laboratory studies showed conjugated hyperbilirubinemia, elevated aminotransferases, low to normal GGT, and prolonged prothrombin time and INR. Coagulation factors V and VII were decreased in 2 patients, alpha-fetoprotein was increased in 3 patients, and serum bile acids were increased in 1. Three patients developed liver failure in the first 2 years of life, with worsening coagulopathy, hypoglycemia, and hyperammonemia. Two patients in 1 family underwent liver transplantation. In the second family, 1 patient died awaiting transplantation and the other patient died at age 5 weeks from complications of an aortic thrombus. Liver biopsies showed intralobular cholestasis, diffuse giant cell transformation, ballooning hepatocytes, and ductular reaction. Micronodular cirrhosis and fibrosis were evident at later stages. Immunohistochemical analysis showed no detectable BSEP (ABCB11; 603201), a target gene of NR1H4, in bile canaliculi in all patients; sequencing of this gene in 1 patient from the first family was normal.

Inheritance

The transmission pattern of PFIC5 in the families reported by Gomez-Ospina et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 infants from 2 unrelated families with PFIC5, Gomez-Ospina et al. (2016) identified homozygous or compound heterozygous loss of function mutations in the NR1H4 gene (603826.0001-603826.0003). The mutations, which were found by whole-exome sequencing and SNP array analysis, segregated with the disorder in the families. One of the mutations (R176X; 603826.0001) had previously been identified in the heterozygous state in a Chinese infant with infantile cholestasis and increased GGT (Chen et al., 2012), but the heterozygous parents in the first family reported by Gomez-Ospina et al. (2016) had normal liver biochemistry and the mother did not have symptoms of cholestasis during any of her 3 pregnancies, suggesting that heterozygosity for R176X is not sufficient to cause infantile cholestasis. Gomez-Ospina et al. (2016) suggested that the patient reported by Chen et al. (2012) may have had a deleterious mutation in another gene. In the second family reported by Gomez-Ospina et al. (2016), 1 patient (patient 4) also carried a heterozygous W66X variant in the SLC10A2 gene (601295) and a homozygous common variant (V444A) in the ABCB11 gene (603201). This patient's sib (patient 3) did not carry the SLC10A2 variant and was heterozygous for the ABCB11 V444A variant. Both the SLC10A2 and ABCB11 genes are involved in bile transport; functional studies of these variants were not performed, and Gomez-Ospina et al. (2016) concluded that these variants did not contribute to the phenotype. Overall, the findings demonstrated a pivotal role for NR1H4 in bile acid homeostasis and liver protection from bile acid-induced liver toxicity.