Between Crigler-Najjar Syndrome Type II and Gilbert Syndrome: Expanding the Spectrum of Uridine Diphosphate Glucuronosyltransferase 1A1 (UGT1A1)-Related Hyperbilirubinemia

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS) are inherited non-hemolytic unconjugated hyperbilirubinemias caused by mutations in the uridine diphosphate glucuronosyltransferase 1A1 (<i>UGT1A1</i>) gene, resulting in reduced or absent bilirubin conjugation. These disorders form a phenotypic spectrum, with CNS type I (CNSI) representing the most severe form, CNS type II (CNSII) an intermediate phenotype, and GS the mildest. Differentiation between CNSII and GS can be challenging due to overlapping bilirubin levels and genetic variants. We report the case of a female newborn of Nepali descent who developed jaundice within the first 24 hours of life, requiring multiple courses of phototherapy. Persistent unconjugated hyperbilirubinemia was documented beyond the neonatal period, in the absence of hemolysis or hepatic dysfunction. Genetic testing identified compound heterozygosity for <i>UGT1A1</i> variants: <i>c.1456T>G (p.Tyr486Asp)</i>, associated with CNSII when homozygous, and the promoter polymorphism <i>UGT1A1</i> <i>*</i> <i>28</i>, characteristic of GS. Over time, bilirubin concentrations progressively declined, reaching normal values by 11 months of age, and the patient remained clinically well with normal growth and neurodevelopment. This case highlights the diagnostic overlap between CNSII and GS, emphasizing the importance of correlating biochemical, genetic, and longitudinal clinical data. The coexistence of pathogenic and polymorphic <i>UGT1A1</i> variants likely resulted in an intermediate phenotype, with early CNSII-like bilirubin levels followed by normalization consistent with GS. These findings broaden the understanding of the <i>UGT1A1</i>-related hyperbilirubinemia spectrum and reinforce the view that CNS and GS represent a clinical continuum rather than distinct entities. Comprehensive genetic testing and long-term follow-up are essential for accurate diagnosis, prognosis, and family counseling.