Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS) are rare autosomal recessive disorders causing unconjugated hyperbilirubinemia due to reduced UGT1A1 enzyme activity, with CNS type 2 (CNS2) carrying a higher risk of gallbladder stones and cholecystitis than the typically benign GS. This case report details a 28-year-old male patient with recurrent right upper abdominal pain and lifelong persistent jaundice, diagnosed with CNS2 complicated by gallbladder stones and cholecystitis after genetic testing revealed rare double homozygous mutations—A(TA)₇TAA (rs3064744) and P229Q (rs35350960)—in the UGT1A1 gene. Pedigree analysis showed the patient’s parents, who had mildly elevated bilirubin levels, carried compound heterozygous mutations of the same two variants and were diagnosed with GS. Bioinformatics analysis indicated A(TA)₇TAA, located in the UGT1A1 promoter’s TATA-box region, impairs gene transcriptional initiation, while P229Q alters the protein’s three-dimensional structure and is likely pathogenic. The double homozygous mutations in the patient resulted in a more severe phenotype than the compound heterozygous mutations in his parents. The case highlights the need to suspect inherited hyperbilirubinemia causes after ruling out biliary obstruction, and suggests early bilirubin reduction (to < 103 μmol/L (6 mg/dL)) may lower CNS2 patients’ risk of complications like cholecystitis, though longer follow-up studies are required to confirm this.
The patient’s clinical presentation began with paroxysmal right upper abdominal pain radiating to the waist and back, accompanied by nausea, vomiting, yellow sclera, and dark urine—symptoms that initially led to a local hospital diagnosis of gallbladder stones and cholecystitis, with temporary improvement after spasmolysis and pain relief. A recurrence three days later prompted further evaluation, during which physical examination revealed marked skin and scleral jaundice, right upper abdominal tenderness, and a positive Murphy’s sign. Laboratory tests showed significantly elevated total bilirubin (358 μmol/L, normal ≤ 23.0 μmol/L), with both conjugated (169 μmol/L, normal ≤ 8.0 μmol/L) and unconjugated (189 μmol/L, normal 0–17.1 μmol/L) fractions increased, alongside elevated liver enzymes (ALT 267 U/L, AST 151 U/L) and inflammatory markers (CRP 6.35 mg/L, normal 0–3 mg/L). Imaging studies—abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP)—confirmed gallbladder stones, thickened gallbladder walls, and cholecystitis, while liver parenchyma appeared normal. Liver biopsy revealed mild lobular inflammation, hepatocellular and capillary biliary sludge, and small bile duct atrophy without significant fibrosis, ruling out severe liver damage.
Genetic testing was critical to confirming the underlying cause of the patient’s lifelong jaundice. Second-generation sequencing (NGS) identified two homozygous mutations in the UGT1A1 gene: c.-41_-40dupTA (rs3064744), which inserts two TA bases into the promoter’s TATA-box region (converting A(TA)₆TAA to A(TA)₇TAA), and c.686C>A (rs35350960) in exon 1, which substitutes proline with glutamine at position 229 (P229Q). Sanger sequencing validated these mutations, and ACMG guidelines classified A(TA)₇TAA as likely pathogenic and P229Q as pathogenic. Bioinformatics modeling showed the P229Q mutation disrupts the protein’s three-dimensional structure, potentially altering hydrogen bonding with leucine at position 233 and impairing enzyme function. Pedigree analysis confirmed the patient’s parents were compound heterozygotes for these two mutations, with only mild bilirubin elevation and no gallbladder complications—consistent with a GS diagnosis. This contrast underscores the genotype-phenotype correlation: double homozygosity leads to more severe UGT1A1 enzyme deficiency (CNS2) than compound heterozygosity (GS).
Treatment focused on managing both cholecystitis and hyperbilirubinemia. Initial therapy with cefoperazone sodium-sulbactam for infection and bicyclol for liver protection improved inflammatory symptoms and liver enzyme levels but did not reduce bilirubin. After the patient declined elective gallbladder surgery, phenobarbital—first-line treatment for CNS2, which induces UGT1A1 activity—was added. Three months later, total bilirubin decreased to 78.1 μmol/L, liver enzymes normalized, and no acute cholecystitis recurrences were reported. This response supports the potential of early bilirubin reduction to mitigate CNS2-related complications, as excess unconjugated bilirubin in bile can form calcium bilirubin precipitates, leading to gallstone formation and cholecystitis.
This case contributes valuable insights to the understanding of UGT1A1-related disorders in Chinese populations. Double homozygous mutations in UGT1A1 are rarely reported, and this instance highlights how their combined effect exacerbates enzyme deficiency, leading to a more severe phenotype than single mutations or compound heterozygosity. It also emphasizes the importance of genetic testing in patients with unexplained lifelong jaundice, even when complicated by biliary conditions like cholecystitis, to avoid misdiagnosis and guide targeted treatment. While the patient’s response to phenobarbital is promising, longer follow-up is needed to confirm whether sustained bilirubin control can prevent long-term complications, offering a foundation for improved clinical management of CNS2.
ＤＯＩ：10.1007/s11684-025-1142-6