A novel UGT1A1 gene mutation causing severe unconjugated hyperbilirubinemia: a case report

BMC Pediatr. 2019 May 29;19(1):173. doi: 10.1186/s12887-019-1555-y.

Abstract

Background: Crigler-Najjar syndrome (CNs) presents as unconjugated hyperbilirubinemia, as a result of UGT1A1 deficiency, and can be categorized in a severe (type I) and mild (type II) phenotype. CNs type II patients usually benefit from phenobarbital treatment that induces residual UGT1A1 activity.

Case presentation: Here we present a CNs type II patient that is not responsive to phenobarbital treatment, which can be explained by two heterozygous mutations in the UGT1A1 gene. A 3 nucleotide insertion in the HNF-1α binding site in the proximal promoter previously reported in a Crigler-Najjar patient on one allele and a novel two nucleotide deletion in exon 1, resulting in a frameshift and a premature stop codon.

Conclusion: In newly diagnosed CNs patients with unconjugated bilirubin levels consistent with CNs type II but that are unresponsive to phenobarbital treatment, disruption of the HNF-1α binding site in the proximal promoter should be considered as a probable cause. Upon confirming a mutation in the HNF-1α site, phenobarbital treatment should be stopped or at least be reconsidered because of its sedative effects and its teratogenic properties.

Keywords: Crigler-Najjar syndrome; Genetic analysis; HNF-1α; UGT1A1.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Bilirubin / blood
  • Codon, Terminator / genetics
  • Crigler-Najjar Syndrome / blood
  • Crigler-Najjar Syndrome / drug therapy
  • Crigler-Najjar Syndrome / genetics*
  • DNA Mutational Analysis
  • Exons / genetics*
  • Female
  • Frameshift Mutation*
  • Glucuronosyltransferase / genetics*
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Humans
  • Mutagenesis, Insertional*
  • Phenobarbital / therapeutic use
  • Promoter Regions, Genetic

Substances

  • Codon, Terminator
  • Hepatocyte Nuclear Factor 1-alpha
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin
  • Phenobarbital

Supplementary concepts

  • Crigler Najjar syndrome, type 2