Study clarifies how biliary atresia overlaps with multiple congenital syndromes

Biliary atresia (BA) represents one of the leading causes of pediatric liver failure, often requiring surgical intervention or transplantation in early infancy. Although traditionally viewed as an isolated disease, emerging evidence suggests shared genetic and embryological origins with other congenital anomalies. The most recognized example is BA splenic malformation syndrome (BASM), where BA co-occurs with spleen and laterality defects. Despite decades of investigation, the molecular links between BA and its syndromic forms remain elusive, highlighting the need for deeper genomic exploration across populations.

A new review published (DOI: 10.1136/wjps-2025-001040) in World Journal of Pediatric Surgery on June 8, 2025, by Prof. Mark Davenport from King's College Hospital, London, systematically analyzes the syndromic variants of BA. Drawing on global case studies and molecular evidence, the study integrates clinical observations with recent genomic insights to clarify how BA overlaps with multiple congenital syndromes, including BASM, Cat-Eye, Kabuki, and Hardikar syndromes. The work provides one of the most extensive summaries to date of how developmental gene mutations and maternal factors may converge to shape these rare but clinically significant BA subtypes.

The study identifies BASM as the most prevalent syndromic form of BA, accounting for about 10% of European and North American cases but less than 3% in Asia. Hallmark features include polysplenia, situs inversus, and vascular anomalies such as a preduodenal portal vein. Genetic analyses highlight PKD1L1 as a key regulator of left-right asymmetry during embryogenesis, with additional contributions from CFC1 and ZIC3 involved in nodal signaling and cardiac development. Environmental influences, such as maternal diabetes, further appear to increase the risk of BASM and related anomalies.

Additional syndromic associations include Cat-Eye syndrome, linked to an extra chromosome 22 fragment, and Kabuki syndrome, associated with KMT2D and KDM6A mutations affecting chromatin remodeling. Hardikar and Zimmermann-Laband syndromes, though rarer, demonstrate similar developmental intersections between biliary, cardiac, and skeletal systems. Davenport emphasizes that while surgical outcomes for syndromic BA can parallel isolated forms when cardiac defects are managed, genetic and anatomical variability complicates treatment. The review concludes that BA represents not a single disease but a final common pathway resulting from diverse genetic disruptions in biliary development.

BA is not a single disease but a convergence of developmental errors leading to similar clinical presentations. Recognizing their syndromic forms and genetic signatures can refine diagnostic precision and anticipate related anomalies, guide early interventions, and reshape our understanding of this complex condition."

Prof. Mark Davenport, King's College Hospital, London

The comprehensive mapping of syndromic variants provides a new framework for both clinicians and geneticists. Identifying mutations such as PKD1L1 and CFC1 could enable early genetic screening for high-risk neonates and guide prenatal counseling for families with congenital laterality disorders. Understanding these pathways may also inform regenerative or gene-based therapeutic approaches for biliary reconstruction. Moreover, recognizing the developmental and environmental interplay—particularly maternal diabetes—offers opportunities for preventive strategies. Ultimately, the study paves the way for precision medicine approaches in pediatric hepatology, transforming BA from a purely surgical challenge into a genetically informed, multidisciplinary field.