congenital bile acid synthesis defect 3

Congenital bile acid synthesis defect 3 is a severe liver disorder that presents in the neonatal period with cholestatic liver disease, marked by jaundice, acholic stools, and failure to thrive. It is caused by pathogenic variants in the CYP7B1 gene, which disrupt a critical step in bile acid synthesis. The condition follows an autosomal recessive inheritance pattern, meaning that affected individuals inherit two copies of the altered gene, one from each parent. It is very rare, affecting fewer than 1 in a million people.

The clinical presentation is dominated by severe liver-related findings. Affected newborns typically exhibit neonatal cholestasis with persistent jaundice, acholic stools, and failure to thrive. Additional consistent features include hepatomegaly, splenomegaly, and laboratory abnormalities such as elevated alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels, as well as prolonged prothrombin time and hyperbilirubinemia. Histologic features seen on liver evaluation include cirrhosis, hepatic bridging fibrosis, bile duct proliferation, and ductal bile plugs, with hematochezia also reported. Not all individuals experience every feature, and severity varies considerably.

This condition is caused by pathogenic variants in the CYP7B1 gene, which encodes an enzyme essential for the synthesis of bile acids. Disruption of this enzyme impairs normal bile acid production, leading to toxic accumulation of intermediates and resulting in severe liver injury. It is inherited in an autosomal recessive pattern, which means that both parents must carry one copy of the variant for an affected child to result. This condition is more common when parents share a common ancestor, as the chance that both carry the same rare genetic variant is increased. Genetic counseling is recommended for families to understand recurrence risks and discuss testing options. Associated genes include CYP7B1.