American Journal of Medical Genetics 76:291–296 (1998) Errors of Morphogenesis and Developmental Field Theory Maria-Luisa Martı´nez-Frı´as,1* Jaime L. Frı´as,2 and John M. Opitz3 1ECEMC and Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain 2Department of Pediatrics, University of South Florida, Tampa, Florida 3Division of Medical Genetics, Departments of Pediatrics and Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah Field theory provides a rational basis for malformation sequence (e.g., spina bifida) birth defects terminology. During blasto- are genetically normal. Polytopic field genesis in higher metazoa, pattern forma- anomalies, per se, must be distinguished tion in the primary field leads to the estab- from pleiotropy, although such anomalies lishment of upstream expression domains of may constitute a part of pleiotropy (e.g., in growth and transcription factors, which, in trisomy 18). Because they are downstream various permutations and at specific sites from pattern-forming events in the primary and times, lay down the pattern of progeni- field, multiple anomalies of organogenesis tor fields. Further spatially coordinated, more likely represent syndromal pleiotropy. temporally synchronized, and epimorphi- Am. J. Med. Genet. 76:291–296, 1998. cally hierarchical morphogenetic events, © 1998 Wiley-Liss, Inc. mostly during organogenesis, lead to the at- tainment of final form in the secondary, epi- KEY WORDS: developmental field defects; morphic fields. Because of shared molecular sequences; associations; syn- determinants, spatial contiguity, and close dromes; blastogenesis; organo- timing of morphogenetic events during genesis; pleiotropy; epidemiol- blastogenesis, most malformations arising ogy; polytopic anomalies; during blastogenesis are polytopic, i.e., in- monotopic anomalies; pri- volving two or more progenitor fields, e.g., mary field; progenitor field; acrorenal, cardiomelic, gastromelic, or sple- secondary epimorphic field nomelic anomalies. Defects of organogen- esis tend to be monotopic malformations, e.g., cleft palate or postaxial polydactyly. We suggest that what were called ‘‘asso- INTRODUCTION ciations’’ (e.g., VATER, schisis) be desig- nated primary polytopic developmental In 1982, an International Working Group (IWG) field defects, or simply polytopic field de- [Spranger et al., 1982], proposed a new terminology of fects, and that the term ‘‘association’’ be re- errors of morphogenesis based on their pathogenesis. served for the original definition of a statis- The group embraced the developmental field concept tical combination of anomalies (mostly of and concluded that ‘‘...most, if not all malformations organogenesis) [Spranger et al. (1982): J Pe- are field defects.’’ At the International Congress of Hu- diatr 100:160–165]. If genetically caused or man Genetics in Berlin, the IWG terminology was predisposed, all structures involved in a clarified and amended [Opitz et al., 1987], particularly polytopic or monotopic malformation are with respect to the concepts of syndrome and associa- genetically abnormal, whereas the parts tion [Lubinsky, 1986]. The latter term, without ques- secondarily affected as a consequence of a tion the most difficult one considered by the IWG and the Berlin nomenclature group [Opitz et al., 1987], was subsequently defined as multiple idiopathic anomalies Contract grant sponsor: Fundacio´n 1000 of Spain; Contract of blastogenesis [Opitz, 1993, 1994]. The concept of grant sponsor: Ministerio de Sanidad y Consumo of Spain. blastogenesis occurring in a primary field [Opitz and *Correspondence to: Dr. Maria-Luisa Martı´nez-Frı´as, ECEMC, Gilbert, 1982] has lent itself to several fruitful epide- Facultad de Medicina, Universidad Complutense, 28040 Madrid, miological analyses [Khoury et al., 1989; Martı´nez- Spain. Frı´as, 1994, 1995; Martı´nez-Frı´as et al., 1995]. How- Received 19 May 1997; Accepted 2 July 1997 ever, the emphasis on the midline [Opitz and Gilbert, © 1998 Wiley-Liss, Inc. 292 Martı´nez-Frı´asetal. 1993], while not incorrect, evidently did not reflect the determined in its developmental fate on the basis of its entire story, and the transition from primary field to unique location and permutation of growth/tran- final structure under normal or abnormal circum- scription factors. Cascades of further upstream and stances was difficult to grasp for clinicians without a downstream gene regulatory systems are then respon- background in developmental biology or developmental sible for the epimorphically hierarchical subdivision of genetics. This has led to inappropriate use of terms, the progenitor fields into the secondary (epimorphic or engendering and perpetuating misunderstanding, subsidiary) fields which give rise to final structure dur- which calls for further clarification of the terminology. ing organogenesis. Downstream specification of cell lin- Advances in evolutionary developmental biology [Dav- eages does not occur during pattern formation but is a idson, 1991; Davidson et al., 1995] have now provided later event during development. Thus, histogenesis is the necessary theoretical framework for a logical ter- not required for the initial stages of morphogenesis; minology uniting theoretical and clinical perspectives. most malformed organs are histologically normal and The comments that follow represent an effort to rarely give rise to cancers. If histogenesis after mor- clarify and delineate some of these concepts, based pri- phogenesis is abnormal (as in Denys-Drash syndrome marily on new information in the areas of developmen- due to WT1 mutation [Machin, 1996]), then cancers tal biology, clinical and molecular genetics, and epide- may occur (in this case, Wilms tumors and gonadoblas- miology. tomas [Machin, 1996]). In higher land metazoa, pat- tern formation is a highly conserved and buffered an- PROGENITOR FIELDS cient process which, in part, represents developmental integration and coordination of formerly simpler meta- All land metazoa, including vertebrates, undergo merically repeated structures into more complex non- type II or direct development [Davidson et al., 1995], metameric structures. Recent advances in comparative which enables the construction of large animals by un- molecular genetics have shown that all metazoa use coupling the initial events of morphogenesis (i.e., of permutations of the same transcription factor systems, blastogenesis) from the specifications of cell lineages and that the development of several progenitor fields in typical of animals with type I development, and cou- the same organism may involve in part the same up- pling later embryonic/fetal development with growth. stream gene systems. Contrary to those with type I development, the initial Because of the simultaneity, close spatial contiguity, events of cleavage, morula, and early blastula forma- and shared molecular mechanisms of pattern forma- tion in type II animals create a primary field, i.e., a tion events in the primary field, a single ‘‘hit’’ (genetic pluripotent mass of cells which are individually ca- and/or environmental) in blastogenesis during the es- pable of beginning development anew toward a com- tablishment of the progenitor fields may result in de- plete organism of normal size. Even at the first cleav- fects of two or more primordia, i.e., primary polytopic age division, those with type I development undergo field defects. However, because of the known redun- immediate specification of cell lineages through the ex- dancy of molecular mechanisms involved in the mor- pression of batteries of cell-specific gene products, each phogenesis of complex metazoan structure, it is pos- of the cells of the morula leading to a specific clone that sible that a second ‘‘hit’’ may be required for there to be will result in a predetermined part of the larva; such polytopic field defect. The first may be a transmitted animals do not go through the stage of a primary field. constitutional genetic defect, but because of the low However, in these larvae groups of mesodermal set- probability of a second hit may represent only a low aside cells are organized into imaginal disc-like struc- recurrence risk to subsequent fetuses. tures which, during metamorphosis, give rise to the In this context, a malformation could be considered a definitive parts of the adult organism while it is under- primary field defect when it is produced during early going the complete destruction of all other larval struc- blastogenesis, i.e., during the formation of progenitor tures. fields, or a secondary (epimorphic) field defect when it Davidson et al. [1995] postulated that the type I pat- is produced during organogenesis after the formation of tern of development was the foundation on which all progenitor fields, in which the timing, duration, and forms of type II development evolved. In organisms intensity of the insult were different, and perhaps that undergo metamorphosis (insects), the larvae are milder. reshaped into their adult form from imaginal discs without being destroyed, a process clearly distin- DEVELOPMENTAL FIELD DEFECTS guished from the epigenesis of vertebrates by William Harvey [1651]. As defined by the IWG, ‘‘a morphogenetic (or devel- All animals undergoing type II development go opmental) field is a region or a part of the embryo through the stage of a primary field, which comprises which responds as a coordinated unit to embryonic in- the whole embryo during blastogenesis. The