An association of caudal malformations arising from a defect in the “axial mesoderm” developmental field

Abstract

We have studied two newborn infants with a remarkable genital malformation, failure of urethral development with enormous bladder distension, atresia of the distal hindgut, vertebral abnormalities, and compression deformities. This is a pattern of anomalies similar to, and probably an extension of, the association of female pseudohermaphroditism and other anomalies (FPA) described by Lubinsky [Am J Med Genet 6:123-136, 19801. We propose that its pathogenesis involves a defect expressed in mesoderm, especially caudal mesoderm. We offer some speculation on what might be its nature, with particular reference to the theory of cell surface molecules having a role in morphogenesis. We apply the concept of the developmental field to provide a clarifying perspective.Key words: developmental field, axial mesodermal defect, caudal "regression," female pseudohermaphroditism, genital hypertrophy INTRODUCTIONA large number of disorders involve characteristic patterns of malformation of the caudal region, with various types and combinations of defects of urogenital tract, distal gut, caudal vertebral column, and lower limbs. To bring some order to the complexity of this clinical heterogeneity, commonalities may be sought at the phenotypic level [Kallkn and Winberg, 1974;Pinsky, 1978;Evans, 1982; Khoury et al, 19831, or in terms of an underlying process. A propos of the latter, a concept gaining currency is that of the developmental field [Opitz, 1979; Lubinsky, 1980 al, 1983; Optiz, 19851. After Lubinsky [1980], we may imagine a caudal developmental field, in which districts give rise to external genitalia, urogenital tract, distal gut, and other structures. What comprises the physical basis of this field may be an embryonic primordium destined to give rise to specific tissues, and through which may be bestowed vulnerability upon the processes of morphogenesis, leading to primary malformation. Further substance to this concept is afforded by reference to theories of the morphogenetic role of axial mesoderm [Russell et al, 1981; Jones et al, 19821; we may consider the identity of the embryonic primordium in question to be, in fact, mesoderm of axial origin and caudal destination.We apply these principles to a study of two infants with caudal malformations characterised in particular by excessive and distorted growth of the external genitalia. CLINICAL REPORTS Patient 1This baby boy was the 3rd child of nonconsanguineous parents of Anglo-Saxon origin, with two normal elder brothers. The father was 32 and the mother 31 years old at the birth of the infant. There is no known family history of a similar disorder or of diabetes. An attempted external version at 38 wk gestation was unsuccessful, presumably reflecting the oligohydramnios noted at birth. He was delivered at term from a breech position, weighing 3,610 gm. Major abnormalities were obvious (Fig. 1). The positioning of the limbs, especially the lower limbs, was distorted, with hip dislocation and external rotation on the left, and incurving on the right. The abdomen wa...

The Embryogenesis of Complex Dysraphic Malformations: A Disorder of Gastrulation?

“…138] have proposed that midline anomalies such as dysraphie malformations may be attributable to a disorder of a midline 'developmental field". As previously discussed, a similar axial mesodermal 'developmental field' has been proposed lor the myriad-associated meso dermal anomalies of the caudal agenesis sequence [56]. Although attractive, neither the cellular origin nor the mechanism of action of these 'developmental fields' are known.…”

“…Gardner and Nelson [56] invoked a disorder of an axial 238 Dias/Walker The Embryogenesis of Complex Dysràphic Malformations mesodermal 'developmental field" which is responsible for orchestrating migration and determination of prospective caudal mesodermal cells during gastrulation. According to this theory, malformations arise w'hcn epiblast cells mi grating through the primitive streak '...fail to make, at the proper time, the proper transition whereby they come to acquire mesodermal characteristics'.…”

Prenatal Diagnosis of Cloacal Dysgenesis Sequence: Differential Diagnosis from Other Forms of Fetal Obstructive Uropathy

“…More recently, there has been recognition that cloacal dysgenesis can also occur in male fetuses [1,10]; indeed, 6 of the 8 fetuses in the present series were male. Because the patterns vary depending on the gender of the fetus and the organs which are malformed, the term 'cloacal dysgenesis sequence' might be more appropriate for this group of disorders, because it tends to include a wide spectrum of anomalies which have in common maldevelopment of the cloaca [17].…”

“…Gardner and Nelson [17] described 2 infants and reviewed the literature for similar cases; based on their comparative analysis, they proposed a spectrum of 'cloacal dysgenesis' with various associated and consequential defects in which external genital growth may be absent, diminished, or excessive. Robinson and Tross [1] ascribed the abnormalities to agenesis of the cloacal membrane and separated the morphologic findings into primary malformations and secondary deformations, with the primary malformations involving structures derived from the anogenital folds, genital tubercle, labioscrotal folds, and urogenital sinus and the secondary deformations resulting from oligohydramnios and distension of the urinary tract secondary to urethral atresia.…”

“…Some investigators [1,2] have divided the different malformations into separate syndromes based on maldevelopment of structures involved and the resulting anomalies, while others [17] have presented a more unified con-cept. Gardner and Nelson [17] described 2 infants and reviewed the literature for similar cases; based on their comparative analysis, they proposed a spectrum of 'cloacal dysgenesis' with various associated and consequential defects in which external genital growth may be absent, diminished, or excessive.…”