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 initial duction and results in complex or multiple anatomic events of morphogenesis involve a process of pattern structures.’’ Since all development occurs in develop- formation that gradually subdivides the primary field mental fields, and evolutionary changes of form reflect into component progenitor fields which are the primor- permanent modifications of morphogenetic events, it dia of all final structure. Pattern formation (or induc- is evident that the developmental field is the funda- tion) proceeds by establishing upstream domains of mental unit of development and of evolution [Opitz, growth and/or transcription factor expression during 1982, 1986, 1993; Opitz and Gilbert, 1993; Gilbert et blastogenesis, each progenitor field being specified or al., 1996]. This inference is based on three essential Field Theory and Morphogenesis 293 attributes of the developmental field: heterogeneity, divided into progenitor fields. The parts that give rise homology, and phylogeneity. to final structures during organogenesis are the sec- ondary or epimorphic fields. Localized defects (affect- Heterogeneity ing one structure or one part of the body) of differen- If a given malformation (i.e., defect of blastogenesis tiation during organogenesis constitute monotopic field or organogenesis) can be demonstrated to be heteroge- defects; correlated defects of different parts of the body, neous, then it represents a dysmorphogenetic unit of arising earlier as inductive defects of blastogenesis are the embryo in the sense that in response to different polytopic field defects (affecting different structures in causes, evidently all parts of the abnormal organ or different parts of the body, such as acrorenal or cardio- structure became malformed together in the same melic field defects). manner. Therefore, it seems reasonable to postulate Regardless of how small, or how far advanced in or- that these parts also constitute a morphogenetic unit ganogenesis, a field is still a field as long as it is capable under normal circumstances. These morphogenetic of reacting dysmorphogenetically to mutations or te- units of the embryo were designated developmental ratogens (i.e., cleft of the distal phalanx of the thumb fields by Gurwitsch [1922], Spemann [1921, 1936, on one side, and duplication of thumb on the other). 1938], and Weiss [1926, 1936; see also Haraway, 1976] A final caveat pertains to the occurrence of apparent earlier in the century, and we would like to submit that anomalies of organogenesis such as cleft palate, hypo- they correspond to the developmental fields of the clini- spadias, or postaxial polydactyly. The apparently be- cal geneticists. They represent the ‘‘final common nign nature and late occurrence of such a malformation paths’’ of development and are the fundamental units may lull a clinician into a false sense of security and, of the construction of all metazoa. In these units, mor- thus, lead to a failure to search for other defects of phogenetic events are evidently spatially coordinated, development. Such anomalies may, as in the infant of a temporally synchronized, epimorphically hierarchical, diabetic mother, in fact, be defects of blastogenesis, but and self-organizing in response to an inductive (‘‘orga- which, because of the more or less strong buffering ca- nizing’’) stimulus. Spemann [1936] summarized suc- pacity of early development, were extensively redi- cinctly, ‘‘Induktion ist nichts anderes als Feld- rected toward a more normal pattern of morphogen- wirkung,’’ i.e., induction is nothing else but field effect. esis. Given the extraordinary diversity of fossil and living By considering the whole process of development as metazoa and the great number of genes that must par- one based in developmental units or fields, it is easier ticipate in development, it is remarkable how few of to understand different aspects of the clinical manifes- these units constitute the final anatomical makeup of tations of congenital defects. These include: (1) causal animals (and plants). It is one of the challenges of de- heterogeneity as one of the criteria defining field de- velopmental biology to discover all of these units and fects [Opitz, 1986, 1993]; the nontautological criterion their hierarchical relationship to each other under nor- of causal heterogeneity is of crucial importance to the mal and abnormal circumstances. The inference that a concept of the developmental field; and (2) the presence certain anomaly represents a field defect is greatly of different types of field defects among the pattern of strengthened if, in case of a bilaterally symmetrical congenital anomalies observed in infants with well- structure, there is concordant involvement of both defined syndromes (whether chromosomal or Mende- sides. lian), embryo(feto)pathies (teratogenic disruptions), some of the so-called nonrandom associations, and Homology MCA patterns of unknown cause, as was demonstrated in prior epidemiological analyses [Martı´nez-Frı´as, The inference is even stronger if the anomaly is not 1994]. only bilaterally symmetrical, but also affects concor- dantly, or in like manner, different parts of the body known to be (serially) homologous structures, i.e., re- SEQUENCES spectively, radius and tibia, ulna and fibula, etc. The IWG defined a sequence as ‘‘a pattern of multiple Phylogeneity anomalies derived from a single known or presumed prior anomaly or mechanical factor’’ and referred to a The inference is most convincing if these structures sequence as ‘‘a pathogenetic and not a causal concept.’’ are also known to be historically homologous, i.e., de- This definition implies that to identify an MCA pattern velopmentally equivalent in different species by virtue as a sequence, we must know its pathogenetic mecha- of descent (with or without modification) from a com- nism. Spranger et al. [1982] provided excellent ex- mon ancestor with a prototypic developmental pattern, amples to explain that although a sequence may be and to react in like dysmorphogenetic manner to mu- causally heterogeneous, its pathogenesis is the same. tation (or transgenic manipulation) of the same gene or The distinction between a sequence and a polytopic de- to the same teratogen. The oldest and best-known ex- velopmental field defect may impress one as difficult, ample of the phylogeneity of an anatomic structure is but in practice it rarely is. Thus, a sequence is charac- that group of primordia malformed together in (alobar) terized by effects evidently secondary to a primary holoprosencephaly in many vertebrate species, first anomaly as a cascade of consequences with known recognized as such by Geoffroy St-Hilaire [1837/1838]. pathogenetic mechanisms. Thus, if a malformation is During blastogenesis, the whole embryo constitutes just that, without a cascade of consequences, it will a developmental field, the primary field, which is sub- suffice to refer to it as such, e.g., polydactyly, Poland 294 Martı´nez-Frı´asetal. anomaly, bifid rib, unilateral renal agenesis, or acrore- ways severe enough to result in the pathogenetically nal anomaly. If there are evident secondary effects on rather uniform consequences of oligohydramnios. structure, function, form, or growth, the term sequence This differentiation is important since, in a se- or (anomaly sequence) is appropriate. Instructive ex- quence, there is only one anomaly in morphogenesis, amples are: which in turn alters other structures (consequences) which are genetically normal. In a developmental field Pierre Robin sequence with glossoptosis, stridor, ob- defect, all the anomalies (or at least most of them) are structive cor pulmonale, cerebral hypoxia, etc. malformations or disruptions, some of which could lead DiGeorge sequence with tetanic hypoparathyroidism, to a sequence. We cannot overemphasize the impor- immunodeficiency, (cyanotic) heart failure, etc. tance of these concepts for the study of the causes and Potter sequence due to bilateral renal agenesis or in pathogenesis of congenital anomalies. sirenomelia. Fetal hypokinesis sequence with arthrogryposis, popli- ASSOCIATIONS teal pterygia, Pierre Robin anomaly, etc. Disruption sequences, e.g., due to rubella, alcohol, tha- The IWG defined association as ‘‘a non-random oc- lidomide, or warfarin, may be referred to as a syn- currence in two or more individuals of multiple anoma- drome since cause is known, or as a sequence to des- lies not known to be polytopic field defect, sequence, or ignate the consequences of the action of the causal or syndrome.’’ Further, it stated that ‘‘it refers solely to teratogenic agent or event. Formerly such exogenous statistically, not pathogenetically or causally related defects of morphogenesis were referred to as ‘‘second- anomalies.’’ On the other hand, Opitz [1993, 1994] con- ary’’ malformations, ‘‘primary’’ ones representing sidered associations real biologic entities represent- constitutional defects due to Mendelian or chromo- ing the ‘‘idiopathic occurrence of multiple congenital some mutations. And because of the fact that in ap- anomalies of blastogenesis,’’ affecting overwhelmingly parent anomalies of organogenesis it is not always midline derivatives. Our epidemiologic data support possible to distinguish between a defect of the pri- Opitz’ postulate, as infants with known associations mary (progenitor) or a secondary field, it is probably have a higher incidence of blastogenetic defects than best, at this time in history, to avoid the terms ‘‘pri- other children with MCA patterns [Martı´nez-Frı´as, mary’’ and ‘‘secondary’’ malformation. In genetic 1994]. anomaly sequences, the secondarily involved organs, Our studies also confirm the assumptions (Opitz, and functional or growth processes, are genetically 1994] that anomalies of blastogenesis tend to be severe, normal, whereas in a polytopic field defect, all of the lethal, complex, and multisystemic, affect the midline, malformations present must be presumed to be ge- are frequently associated with twinning, and have a netically abnormal until proven otherwise. low recurrence risk [Martı´nez-Frı´as, 1995]. However, this low recurrence risk at birth may only be apparent However, the term ‘‘sequence’’ has been used indis- and may result from an effect due to their high lethal- criminately and some of the published ‘‘sequences’’ ap- ity. In fact, we have observed [Martı´nez-Frı´as and pear to be, in fact, uncomplicated field defects. This is Frı´as, 1997] that mothers of infants with blastogenetic the case of the so-called lower mesodermal defects defects have a greater number of spontaneous abor- sequence [Pauli, 1994], the axial mesodermal dysplasia tions than mothers of infants with nonblastogenetic de- sequence [Stewart et al., 1993; Martı´nez-Frı´as and fects and of nonmalformed infants. Gomar, 1994], and others, such as the laterality se- We think that those associations that represent the quences [Jones, 1988; Mathias et al., 1987; Mikkila¨et response to a ‘‘hit’’ early in blastogenesis or during the al., 1994], in which we do not know the exact patho- establishment of the progenitor fields should be differ- genesis. As stated previously, the fact that we can as- entiated from the statistical associations discussed by sume a group of defects is related, does not entitle us to the IWG, and which may represent mostly multiple consider them as a sequence if we do not know the defects of organogenetic origin. Thus, we propose that pathogenetic mechanisms. combinations of anomalies of blastogenetic origin (such Clinical variability is another difference between as VACTERL) be considered and called (primary) polytopic field defects and sequences. A field defect, polytopic (developmental) field defects, and that the particularly a polytopic one, could, by definition, have term ‘‘association,’’ as defined by the IWG [Spranger et different expression in different children, while a se- al., 1982], be restricted to the idiopathic statistical oc- quence usually presents a more uniform degree of clini- currence of multiple congenital anomalies apparently cal manifestation, i.e., spina bifida sequence usually of nonblastogenetic origin. has similar secondary manifestations. On the other Duncan and Shapiro [1993] detected a relationship hand, with respect to the acrorenal (polytopic) field de- between hemifacial microsomia, VATER, and sire- fect, variability ranges from renal agenesis ipsilateral nomelia. They postulated that ‘‘the primary pathoge- to the limb defect, to crossed/fused ectopia, to renal netic alteration interferes with the nutrition (endocy- hypoplasia, to contralateral renal defects, and, with re- tosis) of the embryo and placenta by subcellular dys- spect to limb involvement from 1, 2, 3, or 4 limbs, only genesis of the trophoblast and primitive endoderm of upper or lower, only left or right, with limb deficiencies the blastocyst about day 4–7.’’ An alternative explana- (radial agenesis) and/or duplications (bifid hallux or tion is that those three phenotypes represent different thumb). In the true Potter sequence, there is some vari- types of involvement of the primary field. Conse- ability of the primary renal defect; however, it is al- quently, they are primary field defects and it is not Field Theory and Morphogenesis 295 surprising that they overlap. Recently, Damian et al. Davidson EH (1991): Spatial mechanisms of gene regulation in metazoan [1996] reported on a family with mitochondrial cytopa- embryos. Development 113:1–26. thy due to A-G point mutation at nucleotide position Davidson EH, Peterson KJ, Cameron RA (1995): Origin of bilaterian body plans: Evolution of developmental regulatory mechanism. S. Science 3243 of mitochondrial DNA, commonly associated with 270:1319–1325. encephalopathy, lactic acidosis, and strokelike episodes Duncan PA, Shapiro LR (1993): Interrelationships of the hemifacial micro- (MELAS), and also recognized to cause diabetes melli- somia-VATER, VATER, and sirenomelia phenotypes. Am J Med Genet tus [Kadowaki et al., 1994]. One of the children in this 47:75–84. family had, in addition to the mutation, the VACTERL Geoffroy Saint-Hilaire I (1837/1838): ‘‘Histoire Ge´ne´rale et Particulie`re des ‘‘association.’’ This case illustrates that a single agent Anomalies de l’Organisation chez l’Homme et les Animaux, Ouvrage Comprenant des Recherches sur les Caracte`res, la Classification, (‘‘hit’’) acting during blastogenesis may produce a blas- l’Influence Physiologique et Pathologique, les Rapports Ge´ne´raux, les togenetic MCA pattern that is the single primary poly- Lois et les Causes des Monstruosite´s, des Varie´te´s et Vices de Confor- typic field defect known as VACTERL. Thus, what we mation, ou Traite´deTe´ratologie.’’ Bruxelles; Societe´ Belge de Libraire, etc., Hauman, Cattoir et Co. now regard as an association may in fact represent Gilbert SF, Opitz JM, Raff RA (1996): Resynthesizing evolutionary and nothing more than the presence of two or more polytop- developmental biology. 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