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

Crigler-Najjar syndrome (CNs) is a rare inherited liver disorder with a severely impaired metabolism of bilirubin, resulting in the accumulation of neurotoxic unconjugated bilirubin.

This deficiency of bilirubin glucuronidation is caused by mutations in the UGT1A1 gene encoding uridine diphosphate glucuronosyl transferase, resulting in impaired enzyme activity [1]. Clinically two types of CNs are recognized. In the most severe form, CNs type I, bilirubin glucuronidation is completely lacking, while in type II, some residual activity is present. The response to phenobarbital, that induces the expression of UGT1A1 by the mediating the binding of the constitutive androstane receptor (CAR; NR1|3) to the pBREM promoter region, is used in the clinic to distinguish both forms. In this report, we describe a second patient with a serum bilirubin level normally seen in Type II that is unresponsive to phenobarbital.

A 14-year old female patient from Bangladesh presented with serum total bilirubin levels around 250 μmol/L and conjugated bilirubin (measured as direct bilirubin using the Diazo method) of around 10 μmol/L, indicating a predominantly unconjugated hyperbilirubinemia. According to her parents’ description, her weight at birth was around 2000 g and 4 days after birth, her skin turned yellow. Clinical assessment revealed an unconjugated hyperbilirubinemia of 220 μmol/L without signs of erythrocyte hemolysis (major cause: ABO or Rh incompatibility). After undergoing phototherapy for 4 h a day for 4 consecutive days the serum total bilirubin levels were reduced to 153 μmol/L. The parents were advised to keep their daughter in the sunlight, but after a few months her serum total bilirubin increased again to over 300 μmol/L. From this point onward, the patient did not receive treatment and no clinical data is available because the family lives in the country side and has limited access to medical care. Between the age of 14 and 17 years her serum total bilirubin levels have been monitored and where stable around 200–250 μmol/L. Liver damage markers in serum were low (ALT) and a hemolytic cause of the hyperbilirubinemia was excluded with normal hemoglobin and reticulocyte levels (Table 1). These serum bilirubin levels without any treatment are in line with those seen in Crigler-Najjar syndrome (CNs) type II, indicating a partial deficiency of UGT1A1. However, inducing the residual UGT1A1 activity by administrating phenobarbital (30 mg/day) did not result in a significant change in total bilirubin (Table 1). The coding region and intron-exon boundaries of the UGT1A1 gene of the patient and parents was sequenced to determine what caused UGT1A1 deficiency and the absence of a response to phenobarbital.

Here we present a patient with an unconjugated serum bilirubin level reported for patients with CNs type II [4], that does not respond to phenobarbital treatment. The patient appeared to be heterozygous for two different UGT1A1 mutations.

We report a second patient with a CNs type II phenotype that is unresponsive to phenobarbital treatment due to a mutated HNF-1α binding site, in combination with a novel nonsense mutation. In newly diagnosed CNs patients with a similar phenotype, looking for mutations in the HNF1a binding site seems a good strategy. Upon confirming presence of a mutated HNF-1a binding site the use of phenobarbital should be reconsidered in view of its sedative effect and specifically in women, because of its reported teratogenic properties [5].