GENETICS OF ANORECTAL MALFORMATIONS

Abstract

Purpose: Anorectal malformations (ARM), present in 2-5 per 10,000 live births in the general population, represent a diverse spectrum of abnormalities, and their etiology is unclear. Human and animal studies have pointed to genetic causes, so we studied patterns of heritability in a large case series. Methods: We searched our ARM database for all patients having family members with ARM or other congenital anomalies and analyzed the clinical characteristics of the proband and affected family member(s). Results: Out of 1606 patients with ARM, 24 patients (1.4%) had one or more family members with an ARM. Familial ARMs were 2.4-fold more common in girls. Certain types of ARM were more likely to be associated with a positive family history. Thus, girls with a positive family history were 2.0 (95% confidence interval, 1.5-2.7) times more likely to have vestibular or perineal fistula than those with a negative family history. Boys with a positive family history had a relative risk of 3.5 (95% confidence interval, 1.8-6.8) of having a perineal fistula. A total of 39 (2.4%) had a family member with any congenital anomaly. The male to female distribution was 1:1.3, similar to the 1:1.1 ratio for the entire series. The associated anomalies included a variety of caudal and genitourinary malformations, including sacral masses (four), gynecologic anomalies (three), and sacral anomalies (two), as well as hematologic anomalies (two), esophageal atresia, duodenal atresia, single kidney, meningocele and trisomy 21 (one each). Conclusions: Our results support a strong genetic component to ARM, with an incidence in family members of patients with ARM that is 28-70 times greater than the general population. The risk of having an affected family member is significantly increased in the presence of a vestibular or perineal fistula (females) and perineal fistula (males). Family members of patients with ARM also had a variety of caudal and genitourinary malformations. These new data allow for more informed counseling of families with an ARM and support the need for further genetic studies.