The morphogenesis of the exstrophy-epispadias complex: a new concept based on observations made in early embryonic cases of cloacal exstrophy.

BACKGROUND: The term exstrophy-epispadias complex (EEC) has been coined for a group of congenital malformations that includes epispadias, bladder exstrophy and cloacal exstrophy. It is usually thought that these malformations develop against a similar embryological background. This background, however, is still obscure. This is mainly due to the lack of availability of abnormal human or non-human embryos showing the crucial developmental steps in the morphogenesis of EEC malformations. In this paper, we present chick embryos that show cloacal exstrophy at early developmental stages. To the best of our knowledge, this is the first documentation of this rare malformation in young embryos. MATERIALS AND METHODS: Embryos with cloacal exstrophy (n=4) were found among embryos from two experimental series (n=50) that were primarily performed to document the early morphogenesis of facial and cardiovascular malformations. The malformations were induced by the administration of suramin according to established protocols. Suramin can induce a spectrum of malformations including facial clefts, heart defects, and cloacal exstrophy. RESULTS AND CONCLUSIONS: Besides the presence of an abnormal opening into the cloaca, all embryos were characterised by an abnormal broadening of the caudal trunk at the level of the leg buds, which, in the youngest embryos, was associated with the abnormal presence of large aneurysmatic swellings of the dorsal aortae at this side. We postulate that these aneurysmatic swellings might be the primary defects leading to the development of EEC malformations. These space-occupying anomalies seem to cause abnormal distensions of the developing pelvis and of the infra-umbilical portion of the developing body wall. In consequence, the mid-portion of the developing ventral body wall between the origin of the umbilical cord and the cloacal plate becomes stretched and thinned out. Tension and thinning of the ventral body wall might ultimately lead to its rupture with exposure of the lumen of the embryonic cloaca and allantois. This new concept on the morphogenesis of the EEC is the first not to be inferred from the conditions seen in fetal or postnatal human cases but is based entirely on data from malformed embryos.

Omphalocele-exstrophy-imperforate-anus-spina bifida (OEIS) complex in a male prenatally exposed to diazepam.

A male clinically affected by the OEIS complex was studied. His mother, aged 30 years, has an affective disorder and ingested 30 mg of Diazepam daily, from 3 months previous to the gestation and during the entire pregnancy. At birth, a closure during the entire pregnancy. At birth, a closure defect of the anterior abdominal wall, exstrophy of hemibladders, exposure of intestinal epithelium, abnormal pelvis, imperforate anus, and bifid penis were noted. Birth weight was 3600 g and other measurements were not recorded. Colostomy was performed in the postnatal period followed by partial closure of the abdominal wall defect, and iliac osteotomies. At six years, 6 months of age, physical examination showed somatometric measurements around the third percentile (height 109 cm, weight 17 kg, cephalic circumference 48.5 cm). Clinically he presented mild mental retardation, functional colostomy, incomplete closure of the vesical exstrophy, imperforate anus, bifid penis and scrotum, descended testes, diastasis of pubis, lumbosacral scoliosis and shortening of the left leg (clinical photograph of the external features is not included as we were not able to obtain authorization to do so). Radiological studies (Figure 1) revealed wide separation of the ischiopubic bones; lumbosacral region with rotoscoliosis, platyspondyly and dysraphism; left coxa valga, and right coxa vara. The abdominal ultrasonographic studies showed unilateral renal agenesis (left). Chromosomal analysis (GTG bands) in peripheral blood lymphocyte cultures demonstrated a normal 46,XY constitution. Exposure to other substances, particularly alcohol, were excluded with the study of the mother's medical history and through information obtained from relatives.(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital bladder exstrophy associated with Duogynon hormonal pregnancy tests-signal for teratogenicity or consumer report bias?

A combination of ethinylestradiol and 10mg norethisterone under the brand names of Duogynon (Germany) or Primodos (UK) was used as a pregnancy test until the 1970s. Until very recently there was continuing public concern about the safety of these drugs and legal proceedings were instituted against the medicinal authorization holder. Given the lack of epidemiological studies focusing on Duogynon/Primodos, the present study evaluates 296 consumer reports of the German Duogynon database and compares the reported birth defects with data from a population based birth registry. The most striking result is an increase of bladder exstrophy (OR=37.27; 95%-CI 14.56-95.28). Neural tube defects (OR=2.99; 95%-CI 1.85-4.84) and renal agenesis (OR=2.53; 95%-CI 1.17-5.45) were also significantly increased. Bladder exstrophy may be a yet undetected teratogenic effect of Duogynon, but may also represent a reporting bias. The present study highlights the difficulties of evaluating consumer reports which may be influenced by public media.

A chicken model to study the embryology of cloacal exstrophy.

BACKGROUND/PURPOSE: The embryology of bladder and cloacal exstrophy is a mystery. Reasons for this are the lack of human embryos showing these malformations as well as the scarcity of appropriate animal models. Here, the authors present cases of cloacal exstrophies found in chick embryos subsequent to the application of suramin and trypan blue. This animal model might facilitate insight into the embryology of cloacal exstrophy. METHODS: Fertilized chicken eggs were incubated at 38 degrees C and 75% humidity. Embryos were treated in ovo on incubation day 3. The egg shell was windowed, and solutions of suramin (stage 13, 2 x 40 microL/0.2%) or trypan blue (stage 14, 2 x 80 microL/0.03%) were injected into the coelomic cavity. The window was closed, and the embryos were reincubated until examination on incubation day 8. Fifty embryos were treated in each group. RESULTS: Among the surviving embryos, cloacal exstrophy was found in 2 cases in the suramin-treated group (2 of 29, 6.9%) and in 4 cases in the trypan blue-treated group (4 of 20, 20%). CONCLUSIONS: Suramin and trypan blue can induce cloacal exstrophy in chick embryos. The authors now are modifying their experimental protocols to increase the incidence of this malformation. This model might facilitate studies on the morphogenesis of cloacal exstrophy.