Zhang Jianhui, Chen Rongrong, Chen Xiang, Chen Ying, Chen Qilin, Lu Shiyun, Luo Jiewei, Zheng Xiaoling, Chen Mengshi
Department of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, China.
Department of Digestive Endoscopy, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001, China.
Front Med. 2025 Jul 5. doi: 10.1007/s11684-025-1142-6.
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)TAA (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)TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)TAA 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.
克里格勒 - 纳贾尔综合征（CNS）和吉尔伯特综合征（GS；OMIM：143500）是罕见的常染色体隐性疾病，由于尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）酶活性降低导致非结合性高胆红素血症。2型克里格勒 - 纳贾尔综合征（CNS2；OMIM：606785）会增加胆结石形成和胆囊炎的风险，而GS很少引发健康问题。我们发现一名28岁男性患者，反复出现右上腹疼痛，自出生起就持续黄疸。基因检测显示UGT1A1基因存在罕见的双纯合突变A(TA)TAA（rs3064744）和P229Q（rs35350960），诊断为伴有胆结石和胆囊炎的CNS2。经过家系调查，我们发现患者父母的胆红素略有升高，存在复合杂合突变A(TA)TAA和P229Q，这是GS。生物信息学分析表明，A(TA)TAA位于UGT1A1基因启动子的TATA框区域，影响基因转录起始，而P229Q改变蛋白质三维结构，可能具有危害性。在这个家系中，双纯合突变的表型比复合杂合突变更严重。排除胆道梗阻后，应怀疑高胆红素血症的遗传病因，早期降低胆红素（<103 µmol/L（6 mg/dL））可能会降低CNS2患者胆囊炎等并发症的风险，不过需要进一步的长期随访研究来证实这一观察结果。
