The recent advances in recombinant DNA technology are now being applied to map and clone the genes for dysmorphic syndromes. The genes for almost 40% of the malformation and dysplasia syndromes listed in Smith's Recognizable Patterns of Human Malformation [Jones, 1988] have now been mapped and/or identified. This strategy has dramatically changed the way in which clinical geneticists look at the basic mechanisms of genetic disorders. The primary purpose of applying positional cloning to human disease, including malformation syndromes, is to use the cloned gene to understand the basic pathogenesis of the disorder at hand. The importance of the application of knowledge of mouse models, to human molecular biology and the significance of the role of the clinician in documenting astute observations that assist in mapping cannot be overemphasized. Many of the successful outcomes in gene cloning in dysmorphic syndromes that have occurred thus far were clearly helped by the recognition of patients with chromosomal rearrangements. Collaboration of molecular biologists and clinical geneticists will clearly lead to the continued elucidation of the map location and cloned gene of many other disorders.
Coming-on-land by vertebrates during the Devonian was preceded by a 100 million year history of evolution of fins from an early agnathan to a sarcopterygian state with proximal single stylopod bone and probable paired zeugopod bones. There is little disagreement about the homology [Owen, 1837: See Desmond, 1982; Owen, 1849 for a general discussion see Roth, 1988] of these three bones to the corresponding ones of present land vertebrates including those of birds and mammals; or, that the concept of homology in this context may safely be interpreted as meaning structural "identity" by virtue of descent from a common ancestor with a prototypic developmental plan irregardless of the corresponding innervating vertebral segments [qv Roth, 1988]. This extraordinarily conserved body plan in all four classes of tetrapods, including some 4500 living species of mammals, suggests early successful selection, adaptation, and emergence of developmental constraints assuring "proper" succession of proximo-distal epimorphic events and the structural and functional integrity of the autopod. The autopod is the most variable part of the tetrapod limb with humans, in contract to most other primates, retaining its most general form with little modification except for use of the thumb [Ankel-Simons, 1983]. There is also no question about the fact that during the later stages of blastogenesis the limb arises as a prepatterned single morphogenetic field from lateral plate (and somite) mesoderm and overlying ectoderm organizing in concert a single, orthotopic developmentally reactive system of ectoderm-covered mesodermal core with distal apical ectodermal ridge and posterior zone of polarizing activity. This assertion is based on two lines of evidence. First, experimental results [beginning with Harrison and Detweiler in 1918] recognized almost immediately as demonstrating not symmetrical, but "equipotential" fields with identical morphogenetic reaction potential in all vertebrates studied so far. One is tempted to say that these morphological results and interpretations have been, "triumphantly" confirmed by recent molecular work. Second, clinical insights beginning with thalidomide, and then drawing on the acrofacial dysostoses, the associations (VATER), and the discovery of the acrorenal polytopic field defect in humans, which found its explanation in the work of Lash and of Geduspan and Solursh (possibly involving a single molecule, namely, the insulin-like growth factor-I). It is evident that the gross morphological pattern set up in subsequent normal limb development is proximo-distally hierarchical (or at least sequential), and that the complex group of secondary (epimorphic) fields (perhaps as many as 33 as identified by analysis of mendelian mutations) is determined before cellular differentiation of the individual tissue components of the limb. The Anikin [1929] patterns of precartilage condensations, segmentations, and branchings in limb rudiments, while involving a specific type of cell (precartilage mesenchyme) in complex interaction with the extracellular matrix, must be looked at primarily as gross morphogenetic field events rather than as "fine" tissue differentiation sensu stricto. In view of the clinical evidence, the Shubin-Alberch-Oster model of (pre) cartilage events (condensation, segmentation, and branching), while universally valid as such, had best be regarded as events with morphogenetic potential rather than as invariable predictors of final structure.
We present evidence for multisite NT closure in humans with representative examples of types of NTDs that would be expected if NT closure in humans is similar to experimental mice models. We determine that the majority of NTDs can be classified by the multisite closure model. Further evidence for multisite closure of the NT is apparent in previous epidemiological studies, recognized monogenic disorders, and environmental and teratogenic exposures. Previous reliance on the single-site closure model has resulted in grouping of anomalies, obscuring evidence for multisite NT closure, etiological heterogeneity, varying recurrence risks, and site-specific effects of environmental factors. The NTDs have been previously referred to as being multifactorial, due to multiple genes and environmental factors. Etiological heterogeneity has been demonstrated previously as well. Classification of NTDs by closure site will be beneficial in better defining etiologies and environmental susceptibilities. Similarly, it is apparent to us that genetic variations in closure sequence, rate, and location are most likely monogenic and result in affected embryos being more susceptible to specific environmental factors, such as the effect of folic acid deficiency. Individual closure sites are most likely under the control of specific embryonically expressed genes, whose monogenic nature may not be apparent postnatally. For the disorders such as Meckel-Gruber syndrome and Walker-Warburg syndrome, the monogenic etiology for NTDs in affected individuals is apparent because of associated malformations. There are three important implications of this study: The first is that monogenic mouse models will be helpful in investigating the pathogenesis of NTDs in humans. The homologies between the mouse and human genome may allow linkage studies to be done in some families who have recurrence of NTDs. Second, in order to have useful results from studies of NTDs, NT anomalies need to be accurately described, either by the classical nomenclature (eg, meroacranium) or by referring to the corresponding closure site involvement (eg, closure 2 defect). Special attention needs to be addressed to those NTDs that do not appear to fit into a discrete closure site (eg, midthoracic spina bifida cystica) or laterally displaced NTDs, since they may be due to other etiologies. With improved nutrition, particularly folic acid treatment, specific etiologies for the remaining NTDs may become more apparent. Finally, recurrence risks for NTDs may vary between families based on the closure site affected, and whether or not associated anomalies are present.
