Role of HOXA13 Gene Polymorphisms in Children with Anorectal Malformations: A State-of-the-art Review

Anorectal malformations (ARMs) are congenital anomalies of the distal hindgut with an incidence of approximately 1 in 1500–5000 live births and frequently coexist with multisystem developmental defects. Although surgical advances have improved survival, long-term functional outcomes remain variable, highlighting the importance of understanding the genetic determinants of hindgut development. The HOXA13 gene, a member of the homeobox transcription factor family, plays a central role in caudal embryogenesis, including cloacal partitioning and genitourinary patterning. While pathogenic HOXA13 mutations are known to cause Hand-Foot-Genital Syndrome, emerging studies suggest that subtle variants and regulatory polymorphisms may influence susceptibility to both isolated and syndromic ARMs. This review synthesizes available clinical genetic studies, developmental biology research, and experimental models to evaluate the current evidence linking HOXA13 to anorectal development. The analysis emphasizes biological plausibility while acknowledging the limited size and heterogeneity of existing cohorts. Potential diagnostic implications, avenues for functional research, and future genomic approaches are discussed, with emphasis on the need for larger multicentered studies and mechanistic validation before translation into routine clinical practice. Improved understanding of HOXA13-related developmental pathways may ultimately contribute to refined risk assessment and targeted investigation in pediatric colorectal anomalies.