Variants in AKR1D1 and Infant Mortality: Should Bile Acid Screening be a Routine Part of Newborn Screening?

Biallelic pathogenic variants in AKR1D1 cause Δ4-3-oxosteroid 5β-reductase deficiency, disrupt bile acid synthesis, and result in Congenital Bile Acid Synthesis defect type 2 (CBAS2). CBAS2 presents in infancy with cholestasis, coagulopathy, and failure to thrive. We report an infant who unexpectedly died at age 8 weeks with hepatic dysfunction and intracerebral hemorrhage. Characteristic of CBAS2, postmortem biochemical findings showed near-absent primary bile acids and accumulation of atypical bile acid intermediates. Subsequent genetic testing found compound heterozygous AKR1D1 variants: NM_005989.3:c.[593C>T];[782G>A], p.(Pro198Leu);(Arg261His). This highlights the diagnostic challenge posed by bile acid synthesis disorders, the need for early diagnosis, and the potential for fatal outcomes without early intervention. Given the treatable nature of CBAS2, we advocate for expanded newborn screening or for rapid targeted bile acid or genetic screening in infants presenting with cholestasis, prolonged jaundice, or hyperbilirubinemia.