Exstrophy Of Bladder

Description

Bladder exstrophy and epispadias complex (BEEC) is an anterior midline defect with variable expression involving the infraumbilical abdominal wall including the pelvis, urinary tract, and external genitalia (Gearhart and Jeffs, 1998). BEEC is one of the most severe urologic birth defects because of its profound impact on continence, sexual function, and morbidity due to the effect of chronic and recurrent infections on renal function. The term 'exstrophy,' derived from the Greek work ekstriphein, which literally means 'turn inside out,' was first used by Chaussier in 1780.

Martinez-Frias et al. (2001) emphasized that exstrophy of the cloaca and exstrophy of the bladder are 2 different expressions of a primary developmental field defect. Cloacal exstrophy is a feature of the OEIS (omphalocele-exstrophy-imperforate anus-spinal defects) complex (258040). Exstrophy of the cloaca includes the persistence and exstrophy of a common cloaca that receives ureters, ileum, and a rudimentary hindgut and is associated with failure of fusion of the genital tubercles and pubic rami, incomplete development of the lumbosacral vertebrae with spinal dysraphism, imperforate anus, cryptorchidism and epispadias in males and anomalies of the mullerian duct derivatives in females, and a wide range of urinary tract anomalies. Omphalocele is common, and most patients have a single umbilical artery.

Clinical Features

Utsch et al. (2006) reported a newborn girl with classic exstrophy of the bladder. Prenatal ultrasound studies showed protrusion of the abdominal wall and a single umbilical artery. After birth, she was noted to have diastasis of the symphysis, epispadic open urethral groove, bifid clitoris and labia minora, an open laying bladder plate, and duplication of the vagina. In addition, she had macrothrombocytopenia consistent with Epstein syndrome (155100) and a heterozygous mutation in the MYH9 gene (160775.0012). Utsch et al. (2006) noted that although MYH9 mutations had not previously been associated with urogenital malformations, the mutation may have played a role in the bladder exstrophy in this patient.

Inheritance

Messelink et al. (1994) found reports of 18 familial cases. These included 16 patients from 6 reported series comprising a total of 682 patients and 2 cases separately described by Glaser and Rossiter Lewis (1961). Messelink et al. (1994) described 2 affected cousins and affected parent and child.

In a review of the literature, Reutter et al. (2003) found that although most cases occurred sporadically, 11 families had been reported in which BEEC was present in at least 2 members. According to their analysis of reported cases, 5 of 11 monozygotic twin pairs were concordant, all 5 of the dizygotic twin pairs were discordant, and 2 twin pairs with undetermined zygosity were concordant.

Shapiro et al. (1984) identified 3 children with isolated bladder exstrophy from a series of 215 offspring produced by parents with BEEC. Thus the recurrence risk of exstrophy in these offspring was 1 in 70 live births, which was thought to be 400-fold greater than in the general population.

Reutter et al. (2003) stated that 29 families with BEEC in multiple members had been reported. They located new families through 2 bladder exstrophy support groups and reported 6 new families with 2 occurrences of BEEC, including 1 family where the proband was a product of a consanguineous union; they also found 4 discordant twin pairs.

Reutter et al. (2007) analyzed 48 previously reported and 8 new twin pairs with BEEC and found significantly different pairwise concordance rates between monozygotic (MZ) and dizygotic (DZ) twins (45% vs 6%, respectively; p = 0.009); probandwise concordance rates were also significantly different (62% vs 11%, respectively; p = 0.0003), strongly suggesting that genetic factors play an important role in the development of BEEC. Reutter et al. (2007) noted that the 5.6:1 MZ/DZ probandwise concordance ratio, meaning that MZ twins are 5.6 times more likely to be affected if their twin is affected than DZ twins, indicates that genetic influences from multiple loci may be multiplicative rather than additive.

Population Genetics

The prevalence of BEEC among individuals of European descent has been estimated to be 1 in 30,000 to 40,000 live births with a male-to-female ratio of 2.3:1 (Shapiro et al., 1984; Utsch et al., 2006).

To describe the epidemiology of bladder exstrophy, Siffel et al. (2011) used data from 22 participating member programs of the International Clearinghouse for Birth Defects Surveillance and Research. All cases were reviewed and classified as isolated, syndromic, or occurring with multiple congenital anomalies. Siffel et al. (2011) estimated a total prevalence of bladder exstrophy and a calculated frequency and odds ratios for various maternal and case characteristics. A total of 546 cases were identified among 26,355,094 births. The total prevalence of bladder exstrophy was 2.07 per 100,000 births (95% confidence interval 1.90-2.25) and varied between 0.52 and 4.63 among surveillance programs participating in the study. Bladder exstrophy was nearly twice as common among male as among female cases. The proportion of isolated cases was 71%. Prevalence appeared to increase with increasing categories of maternal age, particularly among isolated cases. The total prevalence of bladder exstrophy showed some variations by geographic region, which was most likely attributable to differences in registration of cases. Siffel et al. (2011) suggested the higher total prevalence among male cases and older mothers, especially among isolated cases, warranted further attention.

Animal Model

Slaughenhoupt et al. (1996) reported a reproducible model of bladder exstrophy in the fetal lamb induced by surgical manipulation in utero.

Stec et al. (2002) found similar physical appearance and anatomic dimensions between naturally occurring bladder exstrophy in a rhesus monkey and a human newborn.