[Clinical features and genetic analysis of a child with Progressive familial intrahepatic cholestasis type 5 due to variant of NR1H4 gene].

OBJECTIVE

To explore the clinical, genetic, treatment and prognostic characteristics of progressive familial intrahepatic cholestasis type 5 (PFIC5).

METHODS

A retrospective analysis was carried out on the clinical data of a child diagnosed with PFIC5 at the Children's Hospital Affiliated to Zhengzhou University in June 2022. Peripheral blood samples from the child and his parents were collected, and trio-whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing and subjected to pathogenicity analysis. A literature search was conducted on various databases to identify previous reports on PFIC5-related cases due to variants of NR1H4 gene. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2023-H-H02).

RESULTS

The child, a 3-month-and-4-day-old boy, presented with persistent jaundice onset from the neonatal period, elevated transaminases and bile acids, while his gamma-glutamyl transferase (GGT) remained normal. Genetic testing revealed that he has harbored c.925C>G (p.L309V) and c.1012G>A (p.E338K) compound heterozygous variants of the NR1H4 gene. Neither of the variants were reported previously. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PM2_Supporting+PP1+PP2+PP3+PP4; PM2_Supporting+PP1+PM5+PP4). Literature search has identified 1 Chinese and 7 English reports on NR1H4 variant-induced PFIC5, totaling 15 cases including the present one, including 7 cases from China. The age of onset has ranged from 1 day to 16 months, with a median age of 1 week. Typical clinical manifestations have included onset of progressive cholestasis from the neonatal period, elevated transaminases and alpha-fetoprotein, normal GGT, accompanied by hepatosplenomegaly and coagulopathy, which could rapidly progress to end-stage liver disease. Genetic testing is the main diagnostic method. Seven children (46.67%) had undergone liver transplantation. During a follow-up of 1 to 8 years, 6 cases had achieved symptom resolution, while 1 case had deceased 1 year after the transplantation. Of the 8 non-transplanted patients (53.33%, 8/15), 1 had an unknown prognosis and 7 had deceased. Survival rates had differed significantly between the transplantation group and non-transplantation group (Fisher's exact test, P = 0.005).

CONCLUSION

The c.925C>G (p.L309V) and c.1012G>A (p.E338K) compound heterozygous variants of the NR1H4 gene probably underlay the pathogenesis of PFIC5 in this child. For children with early-onset, refractory cholestasis and normal GGT, PFIC5 should be suspected, and genetic testing should be performed to facilitate early diagnosis and treatment.