Phenotype severity in the bladder exstrophy-epispadias complex: Analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe

The bladder exstrophy-epispadias-complex (BEEC) occurs on a spectrum of severity. This includes the mildest form, epispadias (E), the intermediate form classic bladder exstrophy (CBE), and the most severe form, exstrophy of the cloaca (CE). The latter is also termed the OEIS (omphalocele, exstrophy, imperforate anus, and spinal defects) complex.1 The overall birth prevalence for the complete BEEC spectrum in children of European descent has been estimated to be 1 in 10,000.2 Birth prevalences (including terminated pregnancies) for the specific subtypes have been estimated to be 1 in 117,000 in males and 1 in 484,000 in females for E,3 1 in 37,000 for CBE,4 and 1 in 200,000 to 1 in 400,000 for CE.5 Although BEEC can occur as part of a complex malformation syndrome, the majority (~ 98.5 %) of cases are classified as isolated.6–8 Isolated BEEC is assumed to be multifactorial, involveing both genetic and environmental factors.6–8 Although progress has been made in the analysis of genetic risk factors,9,10 the identification of environmental factors is problematic. Due to the rarity of the phenotype, prospective population-based studies have little power to identify possible environmental factors. Birth registries provide access to larger samples of patients and controls, but information on phenotype expression and environmental risk factors is limited.6,11–13 The recruitment of BEEC cohorts at major treatment centers enables the collection of detailed clinical information and data on risk factors. However, a carefully matched control group is usually unavailable. An alternative approach is to identify genetic- and non-genetic factors in patient-subgroups formed according to phenotype severity. These risk factors also represent promising candidates for the risk of developing the disease per se. In a previous study, we used the latter approach to investigate a sample of 214 unrelated patients from Europe. Periconceptional maternal exposure to smoking was identified as a risk factor for severe BEEC (CE).8 For the purposes of the present study, this sample was enlarged by adding 60 new patients and combining it with a sample of 167 patients from North America. The aims of the present study were to corroborate our previous findings with improved statistical power, and to identify additional risk factors by comparing potential demographic and other risk factors between BEEC subgroups with mild, intermediate, and severe phenotypes.