Omphalocele, Exstrophy of Cloaca, Imperforate Anus, and Spinal Defects Complex: A Case Report.

 Omphalocele, exstrophy of cloaca, imperforate anus, and spinal defects complex is a rare malformation complex that includes omphalocele, cloacal exstrophy, imperforate anus and spinal defects with the incidence of 1 in 200,000 to 400,000 pregnancies and is even rarer in twin gestation. The etiology of this complex is still unclear. Most cases are sporadic. Prenatal screening must be done for diagnosis and appropriate multidisciplinary management of cases. In severe cases, termination of pregnancy is considered. We present a 4-day first twin child with underdeveloped ambiguous genitalia delivered via emergency lower section cesarean section at 32+3 weeks of gestation with giant liver containing omphalocele, cloacal exstrophy, imperforate anus and meningocele with severe pulmonary artery hypertension and non-visualization of right kidney and ureter, absence of uterus, fallopian tubes and right ovary. Separation and repair of the cecum and bladder were done. The ladd procedure was performed. Ileostomy was created and single-stage repair of the abdominal wall was done. Keywords: anorectal malformations; bladder exstrophy; case reports; neural tube defects; umbilicus.

Complexities of Müllerian Anatomy in 46XX Cloacal Exstrophy Patients.

STUDY OBJECTIVE: To characterize Müllerian anatomy in 46,XX cloacal exstrophy patients. DESIGN: Retrospective review of prospectively maintained, institutionally approved exstrophy-epispadias-cloacal exstrophy database. SETTING: Tertiary care, high-volume exstrophy center (Division of Pediatric Urology, The Johns Hopkins Hospital, Baltimore, Maryland). PARTICIPANTS: We included 31 patients who were genetically female with cloacal exstrophy for whom records included detailed evaluation of Müllerian anatomy. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Müllerian structures, method of evaluation, management, and sexual activity. RESULTS: Of our patients, 12.9% (3/31) had no identified abnormalities. Vaginal anatomy was described for 30 patients; 3/30 had vaginal agenesis, 14/30 had a single vagina, and 13/30 had vaginal duplication. Of 14 patients with 1 vagina, 5 had atresia/hypoplasia, and 1 had a lateral displacement. One patient with 2 vaginas also had distal atresia. Of the cervices evaluated, 9/14 were duplicated (2/9 with a solitary vagina), and 19/27 of the uteri were duplicated (6/22 with 1 vagina, 1/22 with no vagina). Five patients required imaging to fully characterize their anatomy, and 7 patients had studies that failed to identify Müllerian structures seen in the operating room or on physical examination. Common reconstructive surgeries included vaginoplasties, incisions of vaginal septa, colporrhaphies, and hysterectomies. Sexual activity was confirmed for 3 patients, 2 of whom had conceived. CONCLUSION: Most female cloacal exstrophy patients exhibit abnormalities of the Müllerian system. Axial imaging and ultrasound are helpful diagnostic adjuncts but do not replace careful physical examination and assessment in the operating room. Further studies of sexual activity and fertility are warranted.

A newborn with trisomy 13 presenting with cloacal exstrophy.

Trisomy 13 syndrome is a rare disorder that carries a high mortality rate due to abnormal prenatal development resulting in serious birth defects. Although genitourinary malformations are commonly seen in trisomy 13 syndrome, to our knowledge, the association of cloacal exstrophy with trisomy 13 has been extremely rarely reported. Herein, a newborn with trisomy 13 syndrome having multiple congenital anomalies, including cloacal exstrophy, is presented, and the importance of structural anomalies of the neutrophilic leukocytes on a blood smear in supporting diagnosis of trisomy 13 is discussed.

Bladder exstrophy-epispadias complex and triple-X syndrome: incidental finding or causality?

BACKGROUND: Bladder exstrophy is a rare malformation. Prenatal diagnosis is usually an incidental finding on routine ultrasound examination. Triple-X syndrome (karyotype 47,XXX) is the most frequent sex chromosome aneuploidy in live-born females (approximately 1 in 1000). The diagnosis is often not made because women with 47,XXX karyotype have no or hardly any clinical symptoms during life. METHODS: Prenatal diagnosis of triple X karyotype is usually an incidental finding when an invasive prenatal diagnosis is performed for other reasons. RESULTS: Here, we report on two cases with bladder exstrophy and triple-X syndrome, one in a fetus and one in an adult. In view of two previous reports of this association in literature, causality of these two conditions should be considered. CONCLUSION: A gene dosage effect as possible underlying mechanisms will be discussed.

New insights into the pathogenesis of bladder exstrophy-epispadias complex.

Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ΔNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.

Assisted reproductive techniques and risk of exstrophy-epispadias complex: a German case-control study.

PURPOSE: We assessed the risk of exstrophy-epispadias complex in children conceived by in vitro fertilization or intracytoplasmic sperm injection. MATERIALS AND METHODS: Data from the German Network for Congenital Uro-REctal malformations were compared to nationwide data from the German In Vitro Fertilization Register and the German Federal Statistical Office. Odds ratios (95% CI) were determined to quantify associations using logistic regression. RESULTS: A total of 123 patients with exstrophy-epispadias complex born in Germany between 1997 and 2011 were recruited through participating departments of pediatric urology and pediatric surgery throughout the country as well as the German self-help organizations Blasenekstrophie/Epispadie e.V. and Kloakenekstrophie. All German live births (10,069,986) between 1997 and 2010 comprised the controls. Overall, 12 subjects (10%) and 129,982 controls (1%) were conceived by in vitro fertilization or intracytoplasmic sperm injection. Conception by assisted reproductive technique was associated with a more than eightfold increased risk of exstrophy-epispadias complex compared to spontaneous conception (OR 8.3, 95% CI 4.6-15.0, p <0.001). Separate analyses showed a significantly increased risk of exstrophy-epispadias complex in children conceived by in vitro fertilization (OR 14.0, 95% CI 6.5-30.0, p <0.0001) or intracytoplasmic sperm injection (OR 5.3, 95% CI 2.2-12.9, p <0.0001). CONCLUSIONS: This study provides evidence that assisted reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are associated with a markedly increased risk of having a child born with exstrophy-epispadias complex. However, it remains unclear whether this finding may be due to assisted reproduction per se and/or underlying infertility/subfertility etiology or parent characteristics.

Female bladder exstrophy: report of 2 unique cases and review of the literature.

Bladder exstrophy is a rare lower urinary tract malformation that occurs less frequently in women than in men. We report 2 cases of bladder exstrophy occurring in women. One patient was an adult with congenital bladder exstrophy; the patient's bladder wall flap was used to reconstruct the neourethra after the bladder was closed using a conventional procedure. The other patient experienced lower abdominal trauma that led to widespread loss of skin and subcutaneous tissue, exposing the bladder in the lower abdominal wall. In this patient, a pedicled gracilis muscle flap was used to close the abdominal wall after the closure of the bladder. To our knowledge, the first is the fifth reported case of bladder exstrophy in an adult woman and the latter is the first reported case of bladder exstrophy caused by trauma. Both patients showed good outcomes after undergoing surgical treatment.

Bladder augmentation in a young adult female exstrophy patient with associated omphalocele: an extremely unusual case.

We present the case of a 20-year-old woman with uncorrected bladder exstrophy and omphalocele treated with ileocystoplasty and continent urinary stoma. To our knowledge this is the first reported case of a young adult patient presenting with both congenital anomalies. The treatment result suggests that bladder preservation is a safe and feasible therapeutic option in bladder exstrophy.

Epidemiological survey of 214 families with bladder exstrophy-epispadias complex.

PURPOSE: We sought to identify causative nongenetic and genetic risk factors for the bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 237 families with the bladder exstrophy-epispadias complex were invited to participate in the study, and information was obtained from 214 families, mainly from European countries. RESULTS: Two families showed familial occurrence. Male predominance was found among all subgroups comprising epispadias, classic bladder exstrophy and cloacal exstrophy, with male-to-female ratios of 1.4:1, 2.8:1 and 2.0:1, respectively (p = 0.001). No association with parental age, maternal reproductive history or periconceptional maternal exposure to alcohol, drugs, chemical noxae, radiation or infections was found. However, periconceptional maternal exposure to smoking was significantly more common in patients with cloacal exstrophy than in the combined group of patients with epispadias/classic bladder exstrophy (p = 0.009). Only 16.8% of mothers followed the current recommendations of periconceptional folic acid supplementation, and 17.6% had started supplementation before 10 weeks of gestation. Interestingly, in the latter group mothers of patients with cloacal exstrophy were more compliant with folic acid supplementation than were mothers of the combined group of patients with epispadias/classic bladder exstrophy (p = 0.037). Furthermore, mothers of children with cloacal exstrophy knew significantly more often prenatally that their child would have a congenital malformation than did mothers of children with epispadias/classic bladder exstrophy (p <0.0001). CONCLUSIONS: Our study corroborates the hypothesis that epispadias, classic bladder exstrophy and cloacal exstrophy are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full bladders with a focus on neural tube defects.

Common ("classical") and covered cloacal exstrophy: a histopathological study and a reconstruction of the pathogenesis.

Current opinion about structure and pathogenesis of cloacal exstrophy was challenged by histopathological findings and new insights into the normal development. Autopsy specimens of common (n = 3) and covered cloacal exstrophy (n = 4) with single intraexstrophic and -perineal phallic structures and perineo-exstrophic canals have been analyzed histopathologically. The findings were correlated to normal development to reconstruct the pathogenesis. By identifying a specific cloaca-derived urethra field as distinct from allantois-derived bladder fields, the exstrophic area is found to reflect the original hindgut configuration in embryos of approximately 26-29 postovulatory days gestational age (2-4 mm). Correlation to normal development suggests malfunctioning of the primitive streak/caudal eminence as a primary fault that leads to a defective cloacal region in the hindgut disturbing cloacal-intestinal-allantoic dissociation and also causes lengthening of the intestinal region into a blind-ending colon, teratoma-like lesions, and vertebral and muscular anomalies. The current idea that membranes in "covered cloacal exstrophy" represent persisting cloacal membranes is dismissed by finding an amnion-like structure, which suggests dysfunction of an umbilical ring placode as a simultaneous 2nd fault. This malfunctioning may cause omphalocele by defective demarcation of the umbilical cord and may replace midline stroma of the infraumbilical abdominal wall by extraembryonic tissue that stretches into a weak temporary membrane, may leave a perineo-extrophic canal, and may allow the formation of a single perineal or intraexstrophic phallus. Malfunctioning without replacement may result in a purely epithelial "allantoic" membrane, which by disintegrating in combination with the cloacal membrane will expose common cloacal exstrophy.

Epidemiology of bladder and cloacal exstrophies in New York State, 1983-1999.

BACKGROUND: Bladder exstrophy (BE) and cloacal exstrophy (CE) are rare birth defects that have been reported to occur in 1:30,000-50,000 and 1:200,000-400,000 live births. Disagreement exists as to whether they comprise two distinct disorders or are part of a spectrum. We examined epidemiologic trends and risk factors for BE and CE in a large population-based dataset. METHODS: Potential cases were identified in the New York State (NYS) Congenital Malformations Registry. When nonspecific codes for CE were reported, narrative descriptions were reviewed for classification. Birth certificate data were analyzed with descriptive statistics and Poisson regression was used to calculate crude (PR) and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). RESULTS: In NYS from 1983 through 1999, 95 BE cases and 29 CE cases were identified for a live-birth prevalence of 2.1 and 0.6 per 100,000 live births. BE showed a statistically significant downward linear trend by year. Factors associated with BE included summer conception (vs. winter, aPR 2.46, CI 1.19-5.10), white, non-Hispanic maternal race/ethnicity (vs. black non-Hispanic, aPR 3.20, CI 1.20-8.52), and male sex (female vs. male, aPR 0.53, CI 0.33-0.87). Factors associated with CE included preterm low birth weight birth (aPR 14.55, CI 5.28-40.07), multiple birth (aPR 6.68, CI 1.19-23.27), non-New York City residence (aPR 3.27, CI 1.04-10.22), and female sex (aPR 2.57, CI 1.00-6.64). Infant mortality was greater in the CE group. CONCLUSIONS: The epidemiology suggests different risk factor patterns for BE and CE. Classification of BE and CE is difficult due to the nonspecific coding.

On the spectrum of limb-body wall complex, exstrophy of the cloaca, and urorectal septum malformation sequence.

The limb-body wall complex (LBWC) is characterized by abdominal wall and limb defects, exstrophy of the cloaca (EC) by lack of closure of the lower abdominal wall and lack of cloacal septation, and the urorectal septum malformation sequence (URSMS) by absent perineal and anal openings, ambiguous genitalia, colonic, and renal anomalies. We report here on three fetuses whom have overlapping features of these disorders. Also we have reviewed the literature for cases with overlapping features of two or three of the above conditions. From the description of the cases reported on here and those in the literature, we propose that the overlap of features found among LBWC, EC, and URSMS represent a continuous spectrum of abnormalities, rather than three separate conditions. As such, we suggest that all three conditions may share a common etiology or pathogenetic mechanism.

Maternal phenylketonuria syndrome and case management implications.

Well-established dietary protocols have prevented mental retardation for infants born with phenylketonuria (PKU). Dietary protocols for managing females with PKU in their reproductive years exist but are not followed by most of them. Infants who are born to mothers with PKU who are not on dietary treatment usually have serious medical problems, such as mental retardation, heart defects, and other serious congenital anomalies (e.g., orofacial clefting and bladder exstrophy)--a condition known as maternal PKU syndrome. The focus of this article is to review the pathophysiology, associated developmental issues, and existing management protocols used to manage these two separate but highly connected disorders.

Anxiety disorders in children with epispadias-exstrophy.

OBJECTIVES: To evaluate the hypothesis that anxiety disorders are common comorbid conditions in children with the epispadias-exstrophy complex. METHODS: Twenty consecutive outpatient exstrophy subjects ranging in age from 5 to 22 years were assessed using a formalized semistructured psychiatric evaluation and were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, version IV, criteria. Disorders were identified if subjects endured moderate to severe impairment in their home, academic, and social environments. RESULTS: All 20 subjects met the criteria for at least one anxiety disorder; 19 met criteria for more than one anxiety disorder. The adolescent subjects described a gradual waning of some specific symptoms some time after surgical correction of the physical conditions (eg, incontinence) but intensifying sexual anxiety with age. CONCLUSIONS: The epispadias-exstrophy complex appears to be associated with clinically significant vulnerabilities for anxiety disorders in children.

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) in triplet pregnancy after IVF and CVS.

BACKGROUND: Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a rare sporadic condition. CASE: We identified an infant with major malformations resembling OEIS. He was the product of a 30-week triplet pregnancy conceived by in vitro fertilization (IVF) and evaluated by chorionic villi sampling (CVS). In this article, we review the possible pathogenetic mechanisms in this case, including IVF, multiple gestation, trauma to the uterus or uterine vessels following CVS, and placenta accreta. CONCLUSIONS: We conclude that the cumulative effects of all or some of these factors may have resulted in uteroplacental insufficiency adequate to produce this phenotype. This case provides additional evidence for the uterine vascular pathogenesis of OEIS complex in humans.