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.

Hypospadias and associated penile anomalies: a histopathological study and a reconstruction of the pathogenesis.

Hypospadias is considered to be the result of inadequate fusion of urethral folds and, possibly, of canalization of a glandar epithelial cord during the formation of the spongy urethra. This theory had to be reconsidered because a recent study in normal human embryos has exposed such fusion and invagination as misconceptions. Autopsy specimens of five penises with hypospadias from foetuses and neonates were studied histologically. The findings complemented with data from the literature were correlated to the normal developmental process to reconstruct the pathogenesis of the disorder. Histopathological analysis revealed that the hypospadic orifice was the proximal part of a mucosal delta which revealed the structure of the roof and meatus of a flattened distal urethra. Branches of the raphe bordering the delta and terminating in prominent 'dog ears' had the characteristics of the transient urethral labia (folds). Associated curvature and torsion could be related to structural abnormalities of vascular structures, notably the distal corpus spongiosum, and fasciae predominantly proximal to the hypospadic orifice. Correlation with normal development indicated that hypospadias and associated anomalies are not caused by disturbed fusion or glandar invagination but by maldevelopment of a complex of primordial fascial and vascular tissue proximal to the urethral orifice which normally form the venter side of the penis by disproportionately strong proliferation and make the urethral orifice shift distalward. Insufficient growth may disturb that shift with the degree of deficiency determining the precise position of the urethral orifice, size of the urethral delta and defect of the prepuce. Shortage and/or poor organisation of these tissues explain curvature and, if asymmetrical, torsion, both of which can occur also with minimal urethral deformity or as congenital ventral curvature and torsion without hypospadias.

Anal and ano-urogenital malformations: a histopathological study of "imperforate anus" with a reconstruction of the pathogenesis.

Histopathological information about "anorectal malformations" is scarce and the pathogenesis still controversial. Autopsy specimens of 20 human fetuses and newborns with "main" types of the disorder were studied histologically. Supplemented with surgical-anatomical data from the literature and with information from our own and earlier embryological research in animal models as well as from recent observations on the normal development of the human perineum, the study allowed for a new reconstruction of the pathogenesis of the disorder. The histological analysis of the malformations in human fetuses and newborns showed a ventralward deviation of the anal canal as the principal deformity. Ano-urogenital communications and differently structured ectopic anocutaneous canals issued from anywhere between the bladder and the vestibular/urethral orifice (female urethra excluded) and between the orifice and the usual site of the anus, respectively, or they ended blindly, but with a suggestion of lost communication. They occurred isolated or in association with other primary or secondary regional anomalies. Patho-embryological data from animal models revealed that the deviation was caused by defective development of the dorsal cloaca and not by disturbances in a series of fusion processes inside and outside the cloaca, as is currently believed. This mechanism fits well into recent adjustments of ideas about the normal development of the perineum. The cause of the defect is still obscure, but a malfunctioning of cells ingressing from an end-stage primitive streak that affects the dorsal side of the prospective cloaca appears most likely. The data collected permit a new reconstruction of the pathogenesis of anal and ano-urogenital malformations.