Congenital anorectal malformations (ARM) are rare disorders, occurring in approximately 1 in 5,000 to 1 in 1,500 live births worldwide [1
]. These disorders usually require surgical interventions in the neonatal period and postoperative follow-up and treatment to obtain and maintain fecal and urinary continence. Sequelae of ARM continue into adulthood and may include fecal incontinence and sexual dysfunction. All these issues cause major concerns for parents and children at school age and in later life, and pose a large social problem connected with acceptance of the population suffering from these problems. Clinical outcomes of ARM, such as functional stooling problems, are found to be directly associated with poor quality of life in ARM patients [2
]. These outcomes often deteriorate with age, which emphasizes the need for long-term follow-up and psychosocial treatment [2
]. As experience concerning ARM is scattered in many different hospitals in most European countries [4
], regional differences in clinical outcome and quality of life have been reported. Moreover, case comparison is difficult, as a detailed diagnosis according to Krickenbeck [5
] is often not stated in discharge letters.
Despite the great physical and social burden on ARM patients and their parents, the etiology is largely unknown. In rare cases, ARM can be explained by chromosomal abnormalities or is part of a well-known syndrome. Townes–Brocks syndrome, comprising ear, limb, anal, renal, and heart anomalies, is caused by mutations in the SALL1
], whereas mutations in the homeobox gene HLXB9
lead to Currarino syndrome, a combination of sacral agenesis, presacral mass, and ARM [8
]. However, clinical manifestations of syndromic forms of ARM may vary and genetics and underlying mechanisms remain elusive. The majority of ARM cases are not part of a syndrome and their etiology is assumed to be multifactorial with a causal interplay of genetic and environmental factors. Evidence for genetic factors involved in the anorectal development is mainly derived from syndromic ARM and animal studies rather than from studies on nonsyndromic ARM. In addition to genetic factors, an essential role is expected for environmental factors as ARM rarely aggregates in families [11
]. Some researchers studied environmental hazards and found associations between ARM and maternal alcohol intake [12
], tobacco smoke, and caffeine [13
], the benzodiazepine lorazepam [14
], paternal exposure to occupational hazards [15
], and folic acid supplementation [17
]. In addition to these factors, increased risks were found after in vitro fertilization [18
]. However, strong evidence is still scarce as most potential risk factors were found in only one study and the majority of the studies had low power.
To summarize, large scale studies on genetic and environmental risk factors with human ARM cases have not yet been performed, but could provide substantial clues on the pathogenesis of ARM. ARM would benefit from prevention, accurate diagnosis, and outlined clinical treatment. Clinical research on regional differences in clinical outcome and quality of life may contribute to improvements in patient care. Recently, the International Consortium on Anorectal Malformations, consisting of the Dutch AGORA project (Aetiologic research into Genetic, Occupational and environmental Risk factors for Anomalies in children), the German CURE-Net (German Network for Congenital Uro-REctal Malformations), the Italian MUGAR-Net (Network for Uro-Genito-Ano-Rectal malformations in Italy), and the French MAREP (National Center for AnoRectal Malformations and rare Pelvic Anomalies), has been established for etiologic and clinical research. Our multidisciplinary consortium of geneticists, epidemiologists, and clinician-scientists strongly believes that a fundamental prerequisite for progress in the field of rare developmental disorders, such as ARM, will be to strengthen the ties between clinical and basic research activities. In this report, our mission and specific research goals regarding the pathobiology of ARM will be addressed. In addition, the first results on environmental risk factors from the Dutch and German ARM cohort will be presented.