Cerebro-Craniofacial and Craniofacial Malformations: an Embryological Analysis

Cerebro-Craniofacial and Craniofacial Malformations: An Embryological Analysis CHRISTL VERMEIJ-KEERS, M.D. R. F. MAZZOLA, M.D. J. C. VAN DER MEULEN, M.D. M. STRICKLER, M.D. Leiden, The Netherlands A macro- and/or microscopical study on the normal and abnormal development of the forebrain with the eyes, nose, and cranium, was performed in 139 mouse embryos, 120 normal and 19 abnormal human embryos and fetuses, and in about 2,300 human skulls. The results suggest that from the embryological point of view, a distinction should be made between facial defects involving the brain and/or the neural elements of the eyes, i.e., the cerebro-craniofacial dysplasias, and malformations of the face and cranium only, called the craniofacial dysplasias. Both groups can be subdivided into early or primary defects (in embryos <17 mm C-RL) and late or secondary defects (in embryos >17 mm C-RL). Almost all of the primary defects can be considered to originate from disorders occurring during the transformation of the brain and face. The secondary defects concern defective differentiation of neurectoderm and of the mesenchyme into bone centers, cartilage, and muscles. All of the defects in question can be explained by insufficient cell proliferation, degeneration, and/or differentiation. New terminology is proposed. Introduction the literature some of the malformations have been given an embryological explanation in Knowledge of the normal embryonic and terms of the fusion (His, 1892) and merging fetal growth processes in the human brain, (Patten, 1961) theories of the facial processes, face, and cranium, is of practical value to whereas others-the rare craniofacial clefts- those who wish to understand the deviations do not fit into these schemes (Kawamoto, that occur during pathologic development. In - 1976). The neural crest cell migration theory, how- Dr. Chr. Vermey-Keers is in the Department of Anat- - ever, supported by Weston (1963) and John- omy and Embryology, University of Leiden, Wassenaar- ston (1966), leads to a possible explanation of seweg 62, 2333 AL Leiden The Netherlands, Tel.nr.: 071 - 148333 tst. 2993. Dr. R. F. Mazzola is affiliated with the some of these rare abnormalities seen in man Cattedra di Chirurgia Plastica Recostruttiva (Johnston, 1975). According to this hypothe- nell: Universita di Milano, I - 20122 Milan, Italy. Prof.Dr. sis, the neural crest cells, which are responsible J. C. van der Meulen is with the Department Plastic and for the origin of the skeletal and connective Reconstructive Surgery, University Hospital, Rotterdam, The Netherlands, and Prof.Dr. M. Stricker is affiliated tissues of the face, migrate subepidermally with the Service de Chirurgie Plastique de la face et from the ectoderm of the neural fold to their Stomatologie, Centre Hospitalier de Nancy, F - Nancy, destination, and form most of the mesen- France. Address correspondence to Dr. Chr. Vermeij- chyme of the facial processes. If they do not Keers migrate completely, are deficient in number Presented at the 4th International Symposium on Orbital Disorders on August 31, 1981 in Amsterdam, The due to defective formation or proliferation, or Netherlands. undergo abnormal differentiation, a malfor- 128 Vermeij-Keers ef al., CRANIOFACIAL MALFORMATIONS 129 mation will ensue, the severity depending on normal outgrowth of, for example, the facial the stage in which the deviation occurs. On swellings in human and mouse embryos (Ver- this basis it seemed possible to explain the mei-Keers, 1972 b, 1975 a; Gaare, 1976; Poel- pathogenesis of anomalies such as some cases mann and Verme-Keers, 1976; Gaare and - of cyclopia, severe hypotelorism, midline fa- Langman, 1980) and of the neural tube cial clefts, and the Treacher Collins syndrome. (Schluter, 1973; Geelen and Langman, 1977). However, recent microscopical studies Verme-Keers and Poelmann (1980) sug- (Vermeij-Keers and Poelmann, 1980) on the gested that a relatively high frequency of neural crest in mouse embryos showed that it physiological cell degeneration locally in the is improbable that crest cells migrate. In that neural crest is related to disorganization of study only one aspect of cell migration is the epithelium and breakdown of the basal considered, i.e., the active movements of cells lamina, as a result of which the neural crest or sheet of cells relative to the surrounding cells lost their epithelial arrangement. tissues. Movements of cells within an epithe- Johnston (1966, 1975), Noden (1975), Le lium or displacement caused by proliferation Lievre and Le Douarin (1975), and Le are not taken into account. The following can Douarin (1975) describe migration of neural be stated in this respect. The neural crest loses crest cells in the head-neck area on the basis its epithelial arrangement locally before the of transplantation experiments. This type of stage of neural fold elevation, even before the experiment has, however, several drawbacks. stage of neural plate formation, i.e., in pre- In the first place, the basal lamina of the somite stages. Thus, this event starts much neural crest becomes disrupted to a far greater earlier than is generally accepted. extent than occurs under physiological con- Cells that have been separated from the ditions. Secondly, cell-free zones into which neural crest join the mesoderm and do not cells might migrate can be introduced artifi- migrate to large cell-free zones between the cally. Thirdly, during the operations a num- mesoderm and the surface ectoderm, as stated ber of cells are undoubtedly damaged, and by some authors (Johnston, 1975). It should this artificial cell degeneration could play an be kept in mind here that cell-free spaces additional role in the disruption of the epithe- occurring in sections of intact mouse embryos lium. Thus, the transplantation procedures should be considered fixation artifacts, as in- might even induce the process of cell migra- dicated by van Oostrom, (1972) and tion. Finally, none of these experiments has Keers and Poelmann (1980). shown conclusively that an individual crest Vermeij-Keers and Poelmann (1980) have cell migrates from the neural fold to, for shown that due to outgrowth of the neurec- example, one of the facial processes, without toderm to the neural plate, of the plate to the proliferation. neural groove, and of the groove to the neural Identification of the contribution of the tube, the neural crest is shifted first laterally neural crest cells to the mesenchyme requires and then dorsally and medially relative to the a marker system developed specifically for the notochordal plate (Figure 1). During this crest cells. Use can be made of, for instance, transformation the neural crest "drops" cells immunological techniques. From present which retain their position and divide imme- knowledge it may be concluded, without in- diately. High local proliferative activity of voking the theory of neural crest cell migra- these cells can explain the development and tion, that the basic developmental processes outgrowth of the facial processes (Vermey- occurring in the cephalic region (cell prolif- Keers and Poelmann, 1980). A similar process eration, degeneration, and differentiation) is described by Gasser (1979) for the growth- can lead to normal craniofacial morphogene- associated movements of the somites and by sis (Vermeij-Keers and Poelmann, 1980). As Poelmann (1981) concerning the formation of we shall see, interference with these processes the embryonic mesoderm. may give rise to the various malformations Apart from the migration theory, Johnston observed in man. (1975) suggested that in man massive cell death could be involved in the pathogenesis Materials and Methods of brain-eye-face malformations. However, The embryonic development of the face the local occurrence of massive cell degener- and brain in man is not only extremely com- ation is a phenomenon associated with the plex but also difficult to study. When avail- 130 _ Cleft Palate Journal, April 1983, Vol. 20 No. 2 able, very young human embryos are usually fusion of the prosencephalon was studied in a in a bad cellular condition. The components 9.5 mm C-RL human embryo cut transversely of the craniofacial region are initially visible into 10 um sections. Abnormal development on the surface of the embryo but submerge as of the nose with a bilateral persistent bucco- the outgrowth of the neural folds and facial nasal membrane and a bilaterally cleft lip was processes proceeds, and become almost invis- investigated in 10 um thick transverse sections ible. Therefore, one must section the embryo, of a 20 mm C-RL human embryo. but in doing so one loses the three-dimen- Macroscoricar OmsERvATIONS In Human sional picture. Recourse must be had to vol- SKULLs. The variations found in the localiza- ume reconstructions, le. transparent (Ver- tion and direction of different facial clefts led meij-Keers, 1967; 1972 a) and graphic recon- us to examine normal human skulls to obtain structions (Tinkelenberg, 1979). The above- a basis for the explanation of certain abnor- mentioned limitations and the availability of malities. About 2,300 human skulls, repre- scanning electron microscopy explain the re- senting an unselected collection with respect searcher's unrelenting desire to study other to craniofacial defects, were used to assess the species in the hope of filling the gaps in the occurrence of agenesis of bones, the absence information on man. Animal models have of sutures, and the presence of persistent and indeed partially solved the problem, particu- extra sutures. larly because in the early stages of embryonic development the morphological differences Results between the human and non-human facial Earcty DEVELOPMENT OF THE FOREBRAIN and brain structures are small, but our present Anp Exes in ReratIONs To THE NaAsaL FIELDS knowledge still does not cover all of the stages (Pracopes). Scanning-electron- and light-mi- of cerbrofacial morphogenesis. croscopical observations in mouse embryos: Normar DEvEropmENT: Human anp Mu- day 6.6 First indication of the prospective rInE MaTERIAL.

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