Genetic Aspects of Congenital Urologic Anomalies

Congenital malformations can be regarded as the result of abnormal foetal development. From a genetic point of view, most congenital malformations are complex genetic disorders. Both genes and environmental factors are important, but their relative impact differs in different malformations as well as individually. Malformations can thus arise through faults in different pathways, resulting in subgroups with different needs for treatment and follow-up.Most malformations are sporadic and isolated, but if families or relatives are affected, a genetic background is likely. The estimation of the genetic background is based on whether there are affected relatives or families with a Mendelian inheritance, concordance among twins, and association with other malformations or chromosomal aberrations.In paediatric urology, the genetic influence is especially high in vesicoureteral reflux and hypospadias, with a relative risk of 50 and 20, respectively, among siblings. Genes encoding for these malformations have been identified, especially for hypospadias. Bladder exstrophy is a rare malformation (1:35 000), but the risk for siblings is around 1%, resulting in a comparatively high relative risk. In cryptorchidism, there is an increased incidence among first-degree male relatives. In a small number of cases, there is a monogenetic explanation with mutations in the insulin-like 3 (Leydig cell; INSL3) gene and the corresponding receptor. In posterior urethral valves and congenital hydronephrosis, only a few familial cases have been described, indicating a low genetic influence. Improved knowledge of the molecular background of malformations allows for better information and counselling of affected patients and families.