Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS; OMIM: 143500) are rare autosomal recessive diseases that cause unconjugated hyperbilirubinemia due to decreased UGT1A1 enzyme activity. Crigler-Najjar syndrome type 2 (CNS2; OMIM: 606785) increases the risk of gallbladder stone formation and cholecystitis, while GS seldom causes health issues. We found a 28-year-old male patient with recurring right upper abdomen pain who experienced persistent jaundice from birth. CNS2 with gallbladder stones and cholecystitis was diagnosed after genetic testing revealed rare double homozygous mutations A(TA)₇TAA (rs3064744) and P229Q (rs35350960) in the UGT1A1 gene. After pedigree investigation, we found that the patient's parents with modestly increased bilirubin had compound heterozygous mutations A(TA)₇TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)₇TAA is in the TATA-box region of the gene UGT1A1 promoter, affecting gene transcriptional initiation, whereas P229Q modifies protein three-dimensional structure and may be harmful. In this pedigree, double homozygous mutations have a more severe phenotype than compound heterozygous mutations. Inherited causes of hyperbilirubinemia should be suspected after ruling out biliary obstruction, and early bilirubin reduction (< 103 µmol/L (6 mg/dL)) may reduce the risk of complications like cholecystitis in CNS2 patients, though further studies with longer follow-up are needed to confirm this observation.
Humans ; Male ; Glucuronosyltransferase/genetics* ; Adult ; Crigler-Najjar Syndrome/complications* ; Cholecystitis/etiology* ; Homozygote ; Mutation ; Pedigree

Patients with co-existing hereditary spherocytosis (HS) and UDP-glucuronosyltransferase 1A1 (UGT1A1) deficiency as Gilbert's syndrome (GS) have been reported, and previous studies have demonstrated an increased risk for developing gallstones in patients with co-inheritance of GS and HS. We experienced an interesting case of HS showing persistent jaundice after splenectomy, and upon further evaluation, the 25-year-old female patient was found to have HS combined with UGT1A1 deficiency. Sequence analysis of the UGT1A1 gene revealed that she was a compound heterozygote with p.[G71R; Y486D] + [Y486D] mutations, which suggests Crigler-Najjar syndrome type II rather than GS. Careful evaluation of inappropriately elevated bilirubin level compared with the degree of hemolysis is important, reflecting the therapeutic implication of splenectomy and cholecystectomy.
Adult ; Crigler-Najjar Syndrome/genetics ; Female ; Glucuronosyltransferase/*deficiency/genetics ; Heterozygote ; Homozygote ; Humans ; Jaundice/etiology/genetics ; Mutation, Missense/genetics ; Point Mutation/genetics ; Spherocytosis, Hereditary/complications/*genetics ; Splenectomy/adverse effects

Crigler-Najjar Syndrome ; complications ; diagnosis ; Female ; Humans ; Infant ; Jaundice ; etiology