Symposium on Medical Genetics

Craniofacial Malformations Clinical and Genetic Considerations

Ray E. Stewart, D.M.D., M.S.*

Malfonnations of the face and cranium constitute a special category of birth defects with significant connotations for the individual's potential for psychological, physiological, and social adaptation to his environment. Pruzansky l7 observed that, "The face of man is his window to the world. It contains the organs of sight, vision, and speech with which he communicates with his environment, receiving information and responding to it. The face reflects his state of health, emotion, and character. It is the facade by which others perceive and judge the individual. That which affects the face of man and its organs strikes at the most visible part of his body and his most human functions, such as speech." The psychological impact of a malformation of the craniofacial complex has only recently been the subject of extensive scientific inquiry. Clifford 1 reviewed the literature on the subject and found evidence for some significant correlates between facial deformity and psychosocial behavior. He, too, observed that the face is the primary focus of attention in interpersonal relationships and in the form of facial expression, serves as a basic form of communication. We look to the face for expressions of emotions as well as for social reactions. Facial appearance and expression are frequently used parameters in assessing the intellectual status or personality of the person, as in Down syndrome, where impressions of intellectual functioning are strongly implied. Clifford concludes that facial disfigurement leads to undesirable stigmatization. We may, for example, refer to individuals so affected as handicapped, or disabled. Such a person is "different" because he deviates from a culturally approved norm for facial appearance. The person who is disfigured is marked, not because he fails to achieve the ideal state of "being beautiful," but because he has failed to achieve an unstated minimal standard of acceptability. The behavioral patterns in patients with craniofacial anomalies has been investigated by Macgregor,12. 13 who was able to discriminate three distinct behavior patterns in the facially disfigured patients: withdrawal, hostility, and successful coping. Withdrawal patterns ranged from with*Associate Professor, Division of Medical GenetiCS, UCLA School of Medicine, Harbor General

Hospital, Torrance, California

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drawal from social activities to psychotic types of behavior, while hostility was manifested in interpersonal conflicts and antisocial behaviors. Coping behavior was manifested by developing excessive charm and friendliness, by making facetious remarks. The economic and social impact which birth defects have on society and upon the health science professions is significant. Conversely, however, the impact that society and the health sciences have had on the incidence and effects of birth defects is equivocal. The incidence of diseases with infectious or environmental causes, which earlier accounted for the majority of major medical problems, has steadily declined with the introduction and widespread use of antibiotics, vaccinations, and other drugs. The relative increase in the proportion of genetically determined diseases and malformations render them a major cause ofinfant mortality and morbidity, making it essential forpractitioners to become familiar with the role of heredity in the cause of orpredisposition to disease in man. Although incidence figures for specific orofacial anomalies and malformation syndromes are, with few exceptions, not readily available, the number of congenital malformations and genetic diseases which involve orofacial structures is indeed significant. Gorlin, Pindborg, and Cohen8 list more than 150 syndromes, many of which are genetically determined, and all ha ving clinical manifestations in the head and neck region. Smith and Bostian 19 reported that considered collectively, 71 per cent of minor anomalies observed at birth are located in the head and neck region. Cleft lip and palate is the most common craniofacial anomaly, and has an incidence of about 1 in 800 live births. Other craniofacial anomalies are considerably less frequent. One estimate of the incidence of Apert's syndrome places the prevalence in the living population as one in two million. 26 A few studies have surveyed limited populations, providing rough estimates of incidence. Lindsayll examined 2223 cases admitted to the Hospital for Sick Children in Toronto over a 5 year period, and found 25 cases of Crouzon syndrome and 4 cases of Apert syndrome. A recent public health survey23 found that 482,000 children received physicians' services under the Crippled Children's Program, and 20 per centofthese were classified as having congenital malformations. Of those with congenital anomalies, approximately 22,000 had clefts of the lip or palate, or both; 666 had congenital ptosis of the eyelids; and 1605 had congenital malformations of the ear. No other orofacial anomalies are listed. The fact that some orofacial anomalies have relatively low incidence rates should not reduce their importance as vital areas for study and research. These figures are probably underestimates because inadequate recognition and poor reporting, or by virtue of the fact that certain types of anomalies may not be apparent at birth and do not emerge until the child is older. A more pragmatic view would be that a knowledge of and awareness for specific abnormalities of the craniofacial complex can provide the pediatrician with an "early warning system" of underlying malformations of the brain and central nervous system. DeMeyer et al. 6 recognized this

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correlation and proffered that "the face predicts the brain" in the case of holoprosencephaly. Similarly, structural defects within the head of the newborn infant can be life-threatening if vital functions are impaired. Arrest of growth of the neurocranium, ifundetected and untreated during the period of rapid brain growth, can cause serious damage to the central nervous system. An oft-noted phenomenon is that patients who have the same syndrome resemble one another more closely than their own sibling, regardless of ethnic origin, and has lead to the cliche of "if you have seen one, you have seen them all." Clearly, well informed clinicians are able to identify disease entities and syndromes by recognizable related elements of the face that correspond with previously learned experience.

PRENATAL CRANIOFACIAL DEVELOPMENT

I·

In order to appreciate the origin and natural history of abnormalities of craniofacial development, a brief review of normal embryology and development of this region is appropriate. Development of the embryo commences at fertilization and proceeds sequentially through stages of cleavage, blastocyst formation, formation of the extraembryonic membranes, and the development of the presomite embryo. The first few days after fertilization are occupied with Inigration down the fallopian tube and cleavage to form the morula. At 7 or 8 days after fertilization, implantation of the early blastocyst takes place. By 14 days, the early presomite embryo has formed a circular bilaminar disc with prechordal plate, primitive streak, Hensen's node, notochordal process, and cloacal membrane (Fig. 1). Certain specific developmental processes occur in the region of Hensen's node that eventually give rise to many of the primordia of the craniofacial complex. During the fourteenth day at the anterior pole of the primitive streak, the prechordal plate makes its appearance and signals the earliest stages of development of the orofacial region, and gives rise to the oral pharyngeal membrane. The third primary germ layer, the mesoderm, appears during the third week of development and converts the bilaminar germ disc into a trilaminar structure. The midline axis is defined by the formation of the notochord, an anterior proliferation of the primitive streak. The notochord ends at the prechordal plate and marks the site of the future pituitary gland development. The three primary germ layers serve as a basis for the differentiating tissues and organ systems. From the ectoderm develop the cutaneous and neural elements of the embryo; from the mesoderm arises cardiovascular structures, such as heart and blood vessels, bones, muscles, and connective tissue; and from the endoderm develops the lining epithelium of the gut between the pharynx and the anus, as well as the secretory cells of the liver and pancreas and the lining epithelium of the respiratory system. Development of the ectoderm into its cutaneous and neural portions occurs by a proliferation of ectodermal cells that make up the neural plate. The neural plate overlies the notochord along the midline axis, which,

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BUCCOPHARYiEAL MEMBRANFCEPHALIC LOBE OF NEURAL PLATE

CLOACAL MEMBRANE

Figure 1. The dorsal view of the embryonic disc at approximately three weeks' development. Development of the trilaminar disc at this point occurs mainly in the cranial region. Elongation of the disc and development of the neural crests are a direct result of migration of mesenchymal cells away from the primitive streak. (After Hamilton.)

through differential proliferation, gives rise to the neural tube. This is the site of the development of a very important group of ectodermally derived cells between the cutaneous ectoderm of the neural crest and the endoderm. These cells are commonly referred to as "neural crest cells," and will be discussed in detail later. The early embryonic stage, which involves the differentiation ofvarious cell types and the development of primordia of certain structures and organs in the craniofacial complex, is controlled primarily by intrinsic genetic factors. These intrinsic genetic factors are also the primary sources of control for the metabolic processes of the cells through intracellular regulatory mechanisms and, furthermore, have direct control over the critical process of neural crest cell migration, which involves the movement of cells to predestined locations in the developing embryo, beginning during the gastrula stage. Similarly, intrinsic genetic factors are probably the primary controlling factors in the early interaction or induction that occurs between adjacent cell groups and tissue types. Induction is an essential determinant of later stages of embryonic development, and is a process by which certain cell groups mediate and direct the differentiation of adjacent groups. An example of this phenomenon exists in the early development of the neural tube and vertebral column. Induction occurs between a condensation of cells along the

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primitive streak of the gastrula (the notochord) and adjacent tissues to form somites, which are the structures from which a greater part of the axial skeleton and musculature will develop. Late in the gastrula stage (21 days), the periaxial mesoderm lateral to the notochord divides into a series of segments or somites. The 42 to 44 paired somites appear sequentially in a cranial to caudal direction, and are identified as occipital, cervical, thoracic, lumbar, sacral, and coxal somite regions. In the early somite stage (21 to 31 days), the cranial portion of the embryo develops the first of several ectodermally bound mesenchymal elevations. These elevations form the facial processes and pharyngeal arches. The facial processes surround the oral pharyngeal membrane which lies in a central depression, the stomodeum (Fig. 2). With the differential growth and proliferation of these mesodermal masses, the ectodermal grooves demarcating the facial processes soon become obliterated. Smooth contours develop, a characteristic feature of the later stages of embryogenesis. Itis along these depressions, or grooves, separating the facial processes during early development that facial clefts commonly develop. The oropharyngeal membrane forms the floor of the stomodeum, and is bounded cranially by the anterior projecting edge of the neural plate (later the bulge of the forebrain) and caudally by the bulge of the pericardium. Laterally, the stomodeum is bounded by swellings that have appeared in the angle between the neural plate and the pericardium, known as the mandibular process of the first branchial arch. These swellings, or facial processes, are the first signs of development of the face and viscerocranium. As successive arches appear, the pericardium is progressively removed from the caudal margin of the stomodeum.

I

i1 Figure 2. Development of the human face between the fourth and eighth weeks of development:A, 4 weeks; B, 4 lf2 weeks; C, 5 weeks; D, 5 If2 weeks; E, 6 weeks; F, 8 weeks. (After Patten.)

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Figure 3. Human embryo showing paired somites along neural tube axis (small arrows) and anterior neuropore (large arrow).

At approximately 24 to 26 days, the branchial arches appear. The otic vesicles invaginate into head mesenchyme and are no longer visible through the ectoderm. During this time, an evagination of the forebrain, the optic vesicle, which is the precursor of the eye, makes its appearance beneath the head ectoderm. Caudal to the first pharyngeal arch that borders the stomodeum is a wide first branchial cleft which separates the mandibular and maxillary processes. Caudal to the maxillary process is the prominent second (hyoid) arch and the narrower second branchial cleft (Fig. 2B). The otic placode is an ectodermal thickening that lies dorsal to the second branchial arch. This structure is the precursor of the membranous middle ear derivatives. The process of neural tube closure is critical to craniofacial morphogenesis. At the ten-somite stage, the three primary cerebral dilatations are obvious. Closure of the neural tube has progressed caudally beyond the region offormed somites and cranially to the midbrain region, resulting in the anterior and posterior neuropores (Fig. 3). This marks a critical stage in craniofacial embryogenesis beginning with the commencement of neural crest cell migration. The role of neural crest cells in the development of skeletal and connective tissue derivatives of the craniofacial complex has been well documented. They emanate from a condensation of ectodermal cells at the junction between the neural plate and surface ectoderm, and are labeled by their relationship to the developing otic capsule as preotic (cephalic location) and postotic (caudal location). Experimental evidence indicates that the postotic cells migrate lateroventrally into the facial region (Fig.

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4). There they interact with local cells and environment to form a variety of tissues, including bone, connective tissue and cartilaginous derivatives. Available information indicates that the preotic neural crest cells migrate anteriorly into the midface region. The source of the inductive influence that acts to produce and control differentiation leading to the development of specific craniofacial structures is not well understood. It seems certain, however, that cell interaction and localization probably are determined by various cell surface antigens or markers. Development of the viscerocranium during this period is marked by a breakdown of the oropharyngeal membrane establishing continuity between the stomodeum and the primitive pharynx. The maxillary process grows toward the stomodeum from the dorsal end of the first arch. The stomodeum is bounded cranially by the frontal bulge of the forebrain, laterally by the maxillary process, and caudally by the mandibular processes which approach each other and fuse at the midline to form the primitive lower jaw and lip (Fig. 2C). Bilateral ectodermal thickenings, the olfactory placodes, appear above the lateral angles of the stomodeum. Proliferation of the mesenchyme near each placode causes the elevation of a horseshoe-shaped area of surrounding ectoderm. The margins of the placode are called the medial and lateral nasal folds. The nasal folds, together with the intervening convex frontal area, constitute the frontonasal process (Fig. 2, B, C, and D).

The control factors that operate during differentiation of the chondrocranium during the embryonic period continue to be strongly genet-

Figure 4. Schematic representation of the origins and migration path s of preotic and postotic neural crest cells into the face and pharyngeal arches.

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ically determined, and are subject to minimal environmental influence. After initial differentiation of specific cell types, the growth of the desmocranium and viscerocranium appear to be su bj ect to diminishing intrinsic genetiC determinants, whereas the influence of epigenetic and local environmental factors become stronger. Both the findings in spontaneous malformations, as well as the results of experiments carried ou t in normal embryos, emphasize a close relationship between the development of the skull and the presence and the condition of the primordia of the other head structures (epigenetic factors). Van Limborgh 24 points out that good examples of these relationships are those existing between eye and orbit. If there is no eye primordium, there will be no orbit. If there is only a single eye primordium, a single orbit will develop. If two eye primordia lie close together, as in holoprosencephaly anomalad, two contiguous orbits will develop. If there is abnormal width between these primordia, the orbits also will develop with abnormal space between, as in hypertelorism. An abnormally large eye will result in large orbits, while small eye primordia result in small orbits. These observations provide evidence that the development of bony orbits with respect to their number, position, and size depend entirely on the presence, number, position, and size of the globe itself. A similar interactive developmental relationship exists for many other parts of the mesenchymal embryonic skull primordium, and has also been established where adjacent structures of the head determine the presence, position, and form of skull parts. It is, therefore, logical to assume that these adjacent structures exert powerful morphogenetic influences on one another; and since the development of the skull normally proceeds in a genetically determined, species-specific pattern, we may class these influences in the category of "local epigenetic factors." At approximately 45 days, the occipital sclerotomal mesenchyme (occipital somites) concentrates around the notochord underlying the developing hindbrain. From this region, the mesenchymal concentration extends cephalad, forming the posterior portion of a floor for the developing brain. Conversion ofthis undifferentiated mesenchyme into cartilage constitutes the beginning of the chondrocranium or cranial base (Fig. 5). The initially separate cartilaginous centers of cranial base fuse into a single, irregular cranial base. The early establishment of the blood vessels, cranial nerves, and spinal cord between the developing brain and its extracranial contacts before chondrification determines the presence of the numerous perforations (foramina) in the cartilaginous cranial base and in the subsequent osseous cranial floor. Almost simultaneously with the formation of the chondrocranium begins the differentiation of the desmocranium. The mesenchyme, which gives rise to the cranial vault, is first arranged as a capsular membrane around the developing brain. The membrane later subdivides into two layers, an inner endomeninges and an outer ectomeninges. Several primary and secondary ossification centers develop in the outer layer of the ectomeninges to form the individual calvarial bones. These centers, rather small in number, increase rapidly and soon take the shape of the bones to be formed in these areas, that is, the frontal bones, parietal bones, the interparietal (squamous) portion of the occipital, and

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Otic

Capsule

Parachordal

Cortilage

------t~-.sg2463~·.~~

Neurohypophysi

Rathke's

Pouch

Trabecular

Cartilage

•

Endochondral

Bone

CHONDOCRANIUM

(7th week)

Figure 5. Early development of the cartilaginous portions of the skull (chondrocranium) from condensed mesenchyme approximating the notochord. These structures will eventually coalesce to form the cranial base.

the squamous portions of the temporals. As the ossification centers grow, the quantity of interposed condensed mesenchyme decreases. The narrow strips of connective tissue remaining between the bones become the sutures; the membranous layer of mesenchyme covering the bones forms the periosteum. Until this time, genetic factors determining cell differentiation have played the predominant role in craniofacial development. During the late embryonic period, development of the face and viscerocranium is characterized mainly by changes in proportion and relative position of individual structures (Fig. 2F). Intrinsic genetic factors become less and less important while epigenetic factors increase in influence. The forebrain continues to expand, and the eyes, initially directed laterally, gradually become directed anteriorly. The nasal fossae are at first widely separated, but they come together as the intervening tissue. The primitive nasal septum becomes thinned, and the medial nasal folds fuse. At the same time, a transverse groove appears, defining the upper limit of the external nose and separating it from the frontal prominence. The primitive external ear, which develops around the margins of the first ectodermal groove, is at first caudal to the developing face, but gradually assumes a more cephalic orientation, and eventually passes the level of the mouth. At approximately 60 days' gestation, the embryo has acquired allofits basic morphologic characteristics and enters the fetal period. For the remainder ofits intrauterine existence, it will undergo a process of growth and maturation of these primordia, reorganize the spatial relationships between various structures, and begin to make functional use of some of its organ systems. Rapid and extensive growth characterizes the ensuing

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Figure 6. Sagittal section through human fetal cranial base illustrating progressive ossification of sphenoid and occipital bones, and continued existence of endochondral growth centers at sphenoccipital and spheno-ethmoidal synchondroses (dark arrows). Pituitary fossa is designated by open arrow.

7 months offetallife with an increase from 30 to 330 mm, accompanied by an approximately tenfold increase in volume. The expansion of the cranium that occurs from the fetal period onward takes place as a result of a combination of growth processes which includes interstitial, endochondral, and sutural or translational growth. The cartilage remnants of the chondrocranium that persist between the bones are known as synchondroses (Fig. 6). These cartilages contribute variably to cranial elongation and lateral expansion. In addition to growth changes which occur at the basilar synchondroses, the cranial base undergoes selective appositional remodeling by resorption and deposition. This process is mediated by activity on the part of the bone-forming cells, the osteoblasts, as well as bone-destroying cells, the osteoclasts, as described by Enlow. 7 Remodeling of bone allows preexisting spaces in the skull, such as the brain cavity and the orbits, to grow with the other structures, and enables new cavities, such as the paranasal sinuses, to be formed. Marked resorption also occurs in the floors of the cranial fossae, deepening these endocranial compartments. This deepening process is aided by the bodily displacement of the floors of the fossae as a result of sutural expansion of the lateral walls of the neurocranium. During the early stages of the fetal period, the initial centers of os- . sification in the facial region also begin to develop and enlarge intramembranously within the condensed mesenchyme of the embryonic facial processes.

POSTNATAL CRANIOFACIAL GROWTH A half century of controversy over the nature of the biological processes and the primary morphogenetic factors in postnatal craniofacial

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growth has been responsible for much interest in and investigation of the subject among clinicians and researchers alike. The problem goes beyond being one of simple academic or scholarly interest since an understanding of these growth processes is fundamental to a rational and successful approach to the diagnosis and treatment of individuals who present with acquired or congenital disturbances of growth in this region. There are four basic mechanisms that have been postulated by various workers to provide an explanation of the process of craniofacial growth with varying importance being attributed to the individual mechanisms, depending on the investigator. These four mechanisms include (1) interstitial expansive forces generated by sutural tissues, (2) interstitial expansive forces generated by endochondral bone formation, (3) deposition and resorption of bone tissue, and (4) the action of periosteal and capsular functional matrices (epigenetic factors). The most recent and widely accepted theory of growth and development of the craniofacial complex was conceived by van der Klaauw 25 and extended by Moss.14 They consider the growth of skeletal tissues to be secondary, compensatory, and mechanically obligatory responses to changes in the functional matrices. Moss states that, "The head is a composite structure, operationally consisting of a number of relatively independent functions: olfaction, respiration, vision, digestion, speech, audition, equilibration, and neural integration. Each function is carried out by a group of soft tissues which are supported and/or protected by related skeletal elements. Taken together, the soft tissues and skeletal elements associated with a single function are termed 'functional matrices.' " According to this hypothesis, the origin, growth, and maintenance of the skeletal unit depend almost exclusively on its related functional matrix; that is to say, functional matrices grow and skeletal tissues respond.

PATHOGENESIS OF CRANIOFACIAL MALFORMATIONS The processes involved in normal development of the craniofacial complex are never more evident than when an abnormality is produced, resulting in what is commonly referred to as "an experiment in nature." Numerous examples exist in which a single gene mutation results in significant structural alterations in the head and face. A detailed analysis of the precise nature ofthe gene mutation often reveals the mechanisms by which a particular structure or a group of structures affect overall craniofacial growth. For example, a number of aberrations in normal craniofacial growth ha ve been attributed to abnormalities or deficiencies in the initial formation, migration, and subsequent development of cranial neural crest cells. 9 These abnormalities can be divided into two broad pathogenetic categories, the first resulting from defects in neural crest cell formation, and the second in defects in neural crest cell migration. Deficiencies in the initial number of neural crest cells are frequently reflected in aberrant development in midfacial derivatives, and are usually accompanied by defects in the forebrain and ocular structures. Experiments that artificially reduce the number of neural crest cells in

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avian embryos through the extirpation of small portions of the neural folds before crest cell migration result in characteristic brain-eye-face malformations. The facial defects involving the frontonasal processes were most common, whereas defects or derivatives of the maxillary processes and visceral arches were rare. Similar defects have been produced in mice by irradiating specific areas of the neural plate, thereby producing cell death limited to that region. The number of migrating cells is thereby significantly reduced, resulting in facial clefts and other frontonasal deficiency defects. The mass of the remaining neural plate is concomitantly reduced, and presumably accounts for the associated brain and eye defects. A group of human malformations similarly appear to be a result of variable deficiencies of the derivatives of neural crest cells. DeMeyer and associates have described a spectrum of brain-eye-face malformations in which the most consistent feature is a deficiency and variable degree of fusion of the cerebral hemispheres called holoprosencephaly. This group of malformation syndromes is discussed in detail under midface malformations. The second group of anomalies that results from an apparent hindrance ofnormal crest cell migration may be involved in the genesis of the midface cleft malformation, which is characterized by severe orbital hypertelorism, in which the two lateral facial primordia fail to fuse at the midline. This group of malformations, frequently referred to as fron" tonasal dysplasia, rarely have accompanying brain abnormalities or mental retardation. Treacher Collins syndrome (mandibulofacial dysostosis) is a malformation complex that involves coloboma of the eyelids, abnormal external ear development, micrognathia, and hypoplasia of the zygomaticomalar regions of the cranial skeleton. Treacher Collins syndrome has been produced in experimental animals by administering extremely high doses of vitamin A. Hypervitaminosis A results in an interruption in neural crest cell migration with the subsequent branchial arch anomalies. Some craniofacial malformations occur as indirect effects of gene mutation. For example, diseases which affect endochondral bone growth are generally reflected in the cranial base and produce what is described clinically as a "dished face" deformity and/or brachycephaly of the neurocranium. Conditions such as achondroplasia produce characteristic facial deformities by virtue oftheir effect on chondrocranial growth. Certain forms of prognathism have also been shown to be related to defects of the chondrocranium. The neurocranium is particularly susceptible to a number of genetic defects ranging from chromosomal to endocrine in etiology. The time of. closure of the sutures is altered in many diseases leading to variable distortions of skull shape. In conditions such as cretinism, trisomy 21, and cleidocranial dysplasia, there is a delayed midline ossification of the frontal (metopic) and sagittal sutures of the calvaria, resulting in an anterior fontanelle that may remain open into adult life. The resulting brachycephalic skull in these conditions is typified by a broad forehead and hypertelorism. Premature synostosis of various cranial sutures characterizes cases of acrocephalosyndactyly (Apert syndrome) and craniofacial dysostosis

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(Crouzon disease). The inability of the calvaria to grow normally in both of these conditions leads to skull distortion known as acrocephaly, oxycephaly, or turricephaly, all characterized by peaking of the vault of the skull. These skull anomalies invariably become worse during growth. Defects offacial bones may occur as part ofvarious genetic disorders. Among the more noteworthy anomalies are the scooped-out facial appearance due to maxillary hypoplasia and a depressed nasal bridge in achondroplasia, Down's syndrome (trisomy 21), and anhidrotic ectodermal dysplasia. In mandibulofacial dysostosis (Treacher Collins syndrome), the sunken appearance of the midface occurs secondary to severe hypoplasia, or absence of the zygomatic bones. The combination of this direct and indirect evidence of the importance of the neural cest cells in normal craniofacial development provides strong evidence for the importance of the classical genetic mechanisms that involve DNA translation, transcription, and protein synthesis as a basic mechanism in craniofacial growth. The normal development of the craniofacial complex is organized and guided by an orderly and sequential turning on and off of the specific genes at specific places and times. Certain parts of the genetic material are activated at particular stages of the development, while other portions of the genome remain quiescent at those times, only to become activated at some later stage in development. Normal development also depends on the inductive effect of one embryonic tissue on another. The phenotypic characteristics of a differentiated cell will depend both on its genotype and on the type and degree of gene repression and environmental influence that takes place in the course of differentiation. Disturbances in normal growth and development may result from defective genes or mutations, abnormal amounts of genetic material as in the case of aneuploidy or polyploidy, or disturbances of the inductive patterns of embryonic tissues. A large number of craniofacial malformation syndromes can be classified into subgroups based on pathogenesis, location of anatomic defect, and structures or organs involved: (1) otocraniofacial syndromes; (2) craniosynostosis syndromes; (3) midface syndromes: holoprosencephalic malformation complex, frontonasal dysplasia malformation complex; and (4) craniofacial clefts.

CLASSIFICATION OTOCRANIOFACIAL SYNDROMES

This heterogeneous group of malformation syndromes has been referred to by various terms, such as branchial arch syndromes, branchial arch dysplasias, first-arch syndromes, first and second branchial arch syndromes, and hemifacial microsomia. All of these terms are oversimplifications, and leave the erroneous impression that only branchial arch derivatives of the face are dysmorphically involved. In many cases, however, cardiac, renal, and extracranial skeletal anomalies occur, and must be considered as much a part ofthe syndrome as structures derived from branchial arch components.

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For convenience, this group of malformations will be considered under two primary subheadings. The first will include those entities that have bilateral, symmetric facial involvement, and the second will include those entities that have asymmetric facial involvement. In the second group, both sides of the face are often affected.

Syndromes with Bilateral, Symmetric Facial Involvement The most common of the bilateral symmetric otocraniofacial syndromes is Treacher Collins syndrome, or mandibulofacial dysostosis. The syndrome is inherited in an autosomal dominant manner with complete penetrance but variable expressivity. The gene does seem to have some lethal effects prenatally since fetal wastage is common in families carrying this gene (Fig. 7). The major features of this syndrome seen in virtually all cases include hypoplasia of the malar bones, antimongoloid slant of the palpebral fissures owing to a downward displacement of the lateral canthus secondary to a cleft in the lateral orbital rim. There are frequently colo born as in the outer third of the lower eyelid (75 per cent), and frequently a deficiency of the eyelashes medial to the coloboma (50 per cent). Approximately 25 per cent of affected individuals have an unusual tongueshaped process of hair that extends downward and forward from the temporal region onto the cheek. Eartags and blind end fistulas, or preauricular pits, occur between the tragus ofthe ear and the angle of the mouth in over half of the cases. The external ear is frequently deformed, being large and floppy in some cases, and crumpled or anteriorly displaced in others. Approximately 30 per cent of patients have absence of the external auditory meatus which is frequently accompanied by malformations of the middle ear ossic1es compounding the problems of conductive deafuess. Tomographic examination of the temporal bones is essential in all patients with Treacher Collins

Figure 7. Treacher Collins syndrome in a mother and daughter demonstrating characteristic facial features with variable expression.

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Table 1. Otocraniofacial Syndromes with Bilateral, Symmetric Involvement CLINICAL

SYNDROME

FEATURES

Treacher Collins syndrome

Mandtbulofacial dysostosis, occasionally other extracranial anomalies (heart)

Autosomal dominant

Nager acrofacial dysostosis

Mandibulofacial dysostosis, preaxial upper limb deficiency, other anomalies

Autosomal recessive

Wildervanck-Smith syndrome

Mandibulofacial dysostosis, preaxial and postaxial upper and lower limb deficiency, other anomalies

Unknown; sporadic to date

ETIOLOGY

Figure 8. Nager's acrofacial dysostosis closely resembles Treacher Collins syndrome; however, it is inherited as an autosomal recessive, and typically has associated limb malformations.

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syndrome suspected of a conductive hearing loss in order to fully evaluate the competency of the hearing mechanism. The mandible is frequently hypoplastic, and the chin severely retruded. Radiographs show a characteristic curvature in the lower border of the mandible, and oftentimes reveals hypoplasia of the coronoid and condylar process. The palate is cleft in approximately 30 per cent ofpatients, and a high frequency of dental malocclusion results from the discrepancy in size between jaw and tooth. Mental retardation has often been reported in the literature, but in many cases may have been attributable to hearing loss rather than actual intellectual deficiency. Other defects which have been described as being associated with Treacher Collins syndrome, but which occur less frequently, include ventricular septal defects and other cardiac malformations. There are two other syndromes which are bilaterally symmetrical and . share many clinical features with Treacher Collins syndrome (Fig. 8). These syndromes are presented in Table 1. Syndromes with Asymmetric Involvement This subgroup of otocraniofacial syndromes is characterized by asymmetric involvement of craniofacial structures, most of which are branchial arch derivatives. Affected individuals commonly have asymmetric microtia, macrostomia, and hypoplasia of the mandibular ramus and condyle. Gorlin and associates 8 have postulated that this group of disorders has been the subject of improper nosological classification. It certainly is one which contains considerable variability as observed in the majority of cases, which appear to be sporadic. In those families with multiple occurrences, reports concerning the mode of inheritance are conflicting. Several reports of successive generations have been published, as well as affected siblings of normal parents. It appears that autosomal dominant, autosomal recessive, and multifactorial modes of inheritance are all possible. Overall, this group of malformations appears to occur with quite a high frequency. It has been estimated that 1 in 3500 live born infants are affected. Of the variants which have been described among these disorders, two make up the vast majority of reported cases. Although there are many transitional forms between these two entities which, in fact, may represent a spectrum of the same syndrome, it is convenient to discuss them separately as Goldenhar syndrome (oculoauriculovertebral dysplasia) and hemifacial microsomia. The Goldenhar variant is distinguished from hemifacial microsomia primarily upon the presence of epibulbardermoid cysts which occur at the limbus or corneal margin of the lower outer quadrant. These lesions are usually milky-white to yellow in color, and have a solid, smooth surface. These lesions can oftentimes be difficult to ascertain, and may appear only as small, white streaks. The ocular defects generally occur bilaterally; however, approximately 30 per cent of patients have unilateral lesions (Figs. 9 and 10).

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J Figure 9. 9. Goldenhar syndrome demonstrating asymmetrical involvement offacial strucFigure Goldenhar syndrome demonstrating asymmetrical involvement offacial structures, typical features ofof macrostomia, malformations, epibulbar dermoid cysts. tures,and and typical features macrostomia,ear ear malformations,and and epibulbar dermoid cysts.

Figure 10.10.Hemifacial microsomia demonstrating marked asymmetry. Figure Hemifacial microsomia demonstrating marked asymmetry.

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The Goldenhar variant of this complex is marked by striking facial dysmorphogenesis resulting largely from the hypoplasia and displacement of the external ear structures, maxillary, temporal, and malar bone hypoplasia, and facial flattening resulting from hypoplasia of the mandibular ramus and condyle. Approximately 10 per cent of patients have bilateral involvement; however, one side is nearly always more severe than the other. Interestingly, the right side is involved most severely in approximately 62 per cent of cases. Malformation of the external ear varies widely from complete aplasia to large, hypoplastic pinnae which may be displaced anteriorly and inferiorly. Ear involvement may occur bilaterally. Supernumerary eartags occur frequently on the cheek between the tragus of the ear and the angle of the mouth. These structures are most commonly seen in patients who have concomitant macrostomia. Preauricular pits are often found in the same areas. Conductive hearing loss due to middle ear abnormalities and/or the absence of an external auditory meatus is noted in approximately 50 per cent of cases. An important clinical consideration is the significant correlation between external ear abnormalities and hearing loss caused by hypoplasia of the ossicles. Eyelid colobomas are also a common finding, with defects in the upper lid occurring in 50 to 60 per cent of patients who have epibulbar dermoids. The defect most generally occurs in the medial one third of the upper lid. Microphthalmia may also be present in severely involved cases and, when present, is usually accompanied by mental retardation. There is a wide range of dysplastic involvement of the condyle and ramus of the mandible on the affected side. Microtia occurs in over 70 per cent of patients with severe ramal hypoplasia, and at least 30 per cent of patients with agenesis of the ramus have associated macrostomia on the affected side. There is frequent failure of development of the parotid gland, as well as hypoplasia of various muscles in the affected area which include the masseter, temporalis, pterygoids, and muscles of facial expression. The severity of malocclusion which characterizes this syndrome is proportional to the degree of dysmorphia of the maxilla and mandible. Close assessment of these features is essential, particularly when planning a coordinated surgical-orthodontic reconstruction for affected individuals. It is also noteworthy that in severe cases, the facial asymmetry tends to increase with increasing age. This phenomenon is probably due to an imbalance in growth rates between the normal and affected sides ofthe face which tends to accentuate the asymmetry. Extracranial abnormalities have been observed in many patients. Anomalies of the axial skeleton, particularly in the cervical region, is seen in approximately 50 per cent of patients. The most common findings include occipitalization of the atlas, cuneiform vertebrae, and complete or partial cervical fusion. Also observed are supernumerary vertebrae, hemivertebrae, spinabifida occult a, and anomalous ribs. Clubfoot has been observed in approximately 20 per cent of cases. Approximately 50 per cent of patients have varying forms of congenital heart disease, ranging from ventricular septal defects and patent ductus arteriosus to tetralogy of Fallot. Pulmonary agenesis or hypo-

1 I

I

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plasia has been noted in several cases, the lung missing on the same side as the facial abnormalities. The etiology and pathogenesis of these unilateral asymmetric anomalies have recently been duplicated experimentally in laboratory animals 15 by interfering with differentiating tissues in the region of the ear and jaw. This disruption is caused by an expanding hematoma produced during a critical period in stapedial artery complex development. The severity of the facial malformations is directly related to the degree oflocal destruction and disruption caused by the hematoma. With respect to confirmation of a diagnosis and subsequent genetic counseling in cases of otocraniofacial syndromes, it is fair to say that one should evaluate each patient and his family individually, bearing in mind the extreme variability of expression which is characteristic of this group of malformations. Although familial occurrence of Goldenhar syndrome has been encountered, the mode of inheritance and, therefore, recurrence risks are not entirely clear because of the small number of families with multiple cases. The importance of recognizing minimal manifestations in family members of affected individuals cannot be overemphasized, andis extremely important for accurate genetic counseling. For the purposes of genetic counseling, a thorough evaluation of the skeletal, cardiac, and other extracranial systems should also be carried out on all patients and their first-degree relatives whenever possible. The presence of single, minor anomalies, such as preauricular tags, pits, or a hypoplastic ear, or isolated skeletal cardiac or renal anomalies in relatives, has genetic significance and should be considered when an attempt is made to establish risk of recurrence.

CRANIOSYNOSTOSIS SYNDROMES

Craniosynostosis, or the premature fusion of cranial sutures, is a nonspecific abnormality which may occur as an isolated finding or in conjunction with other abnormalities, producing various syndromes. Whether isolated or as a part of a syndrome, craniosynostosis occurs when there is an arrest of growth in one or more of the cranial sutures brought upon by a premature fusion of the cranial bones with subsequent limitation of expansive growth normally accommodated by that suture. Although the underlying cause is not known, it is clear that premature fusion can precipitate secondary changes in the underlying brain through the effects of increased intracranial pressure and subsequent deformation. As pointed out in the discussion of the mechanisms of normal craniofacial growth, the development of the neurocranium is, in a large part, influenced by the development of the underlying brain. At birth, the size of the cranium is approximately 65 per cent of its adult size, and by 5 years, it reaches approximately 90 per cent of adult size. The adult width of the cranium is attained approximately during the first or second year. In the newborn infant, several fontanelles, or "soft spots," are present between the bones ofthe cranium. These fontanelles close at various times, but under normal circumstances, all have been

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reduced to sutures by approximately the eighteenth month. The sutures themselves are relatively smooth with very little interlocking and interdigitation as observed in an adult suture. The metopic suture which separates the right and left halves of the frontal bone is the first to fuse, and does so at approximately 2 years of age. The other sutures close gradually over a period of time following completion of brain growth, and normally remain patent well into the second decade oflife. An important concept, and one which is frequently overlooked, is that the cranial sutures grow indirectly in response to the expanding brain which acts to separate the bones of the calvarium and displace them in an outward direction. This movement causes tension at the sutures which respond by depositing new bone at the sutural edges. An overall increase in cranial volume is accomplished by an outward drifting of the cranial bones, accompanied by remodeling on the inside and the outside of the cranial table. Premature fu sion of one or more of the cranial su tures of the neurocranium at this early time generally results in an arrest of growth in one dimension with compensatory growth occurring in a direction accommodated by sutures which remain patent. It is assumed that this compensatory growth occurs as a result of the increased intracranial pressure exerted by the growing brain, and leads to the alterations in the size, shape and contours of the skull. Figure 11 illustrates the effects of premature synostosis of selected sutures and the typical patterns of subsequent cranial distortion. On this basis alone, an astute clinician is frequently able NORMAL SKULL

~

Bilateral Coronal Synostosis

Sagittal Synostosis

o

Unilateral Coronal Synostosis

BRACHYCEPHALIC

~ SCAPHOCEPHALIC

PLAGIOCEPHALIC Figure 11. Effects of premature synostosis of selected sutures and the typical patterns of cranial distortion that result.

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to predict craniosynostosis and which of the cranial sutures have been prematurely fused. In addition to the direct effects on skull shape, a number of secondary effects occur as a result of the altered cranial growth through craniosynostosis. Specifically, the proptosis, or apparent exophthalmic condition, frequently observed in these patients results indirectly from the effects of the increased intracranial pressure of the growing brain on the restricted calvarial capacity. This pressure phenomenon leads to a displacement of the greater wings of the sphenoid which are projected anteriorlyfrom their normal position in the middle cranial fossa, and thereby impinge on and restrict normal growth of the bony orbit. The apparent exophthalmos results from the reduced size of the orbit. Similarly, it is the indirect effects of the increased intracranial pressure which cause a downward and forward displacement of the ethmoid plate which results in hypertelorism frequently observed in patients with craniosynostosis. The severe distortion of the cranial base which often results in cases of untreated craniosynostosis leads to restricted growth in the maxilla frequently reflected by a reduced size of the nasopharynx and restricted capacity for air exchange. An important feature exhibited by many of the craniosynostosis syndromes is a propensity toward increasing severity in the craniofacial disproportion and deformity with increasing age. The classification and nosology of the craniosynostosis syndromes has been the subject of considerable confusion and misconception. Cohen 2 noted that the craniosynostosis syndromes should never be classified on the basis of which sutures are prematurely fused, or on the degree of mental retardation which may accompany the syndrome. It is clear that different sutures may be affected in different patients with the same syndrome. The primary concern confronting the pediatrician and the surgeon, once it has been established that a suture is synostosed, is related to the risk of central nervous system damage created by the increased intracranial pressure frequently observed in these conditions. It is evident that the primary concern in the presence of synostosis of the midsagittal suture is cosmetic in nature. Rarely is there evidence of brain damage secondary to increased intracranial pressure when this suture alone is involved. The risk of damage to the central nervous system is significantly higher when the coronal and/or lambdoidal sutures are involved. For whatever the reason, once craniosynostosis is diagnosed, immediate craniectomy procedures are indicated to relieve both the cosmetic and functional problems which may ensue. In the case of synostosis of an isolated sagittal suture the urgency of surgery is reduced, but surgery remains a definite consideration. A large number of syndromes with associated craniosynostosis have been described. Only the most common are detailed in Table 2, including Crouzon syndrome (Fig. 12), Apert syndrome (Fig. 13), Pfeiffer syndrome (Fig. 14), Saethre-Chotzon syndrome (Fig. 15), and Carpenter syndrome (Fig. 16).

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Table 2. Syndromes Associated with Craniosynostosis* FREQUENCY OF SYNDROME

Apert syndrome

Carpenter syndrome

Crouzon syndrome

Pfeiffer syndrome

Saethre-Chotzen syndrome

CLINICAL FEATURES

Craniosynostosis, proptosis, down slanting palpebral fissures, strabismus, orbital hypertelorism, midface deficiency, higharched palate, symmetric syndactyly of hands and feet involving second, third, and fourth digits Craniosynostosis, mental deficiency, preaxial polysyndactyly of feet, variable soft tissue syndactyly with brachymesophalangy of hands, displaced patellae, congenital heart defects, short stature, obesity Craniosynostosis, shallow orbits with proptosis, strabismus, midface deficiency Craniosynostosis, proptosis, strabismus, ocular hypertelorism, down slanting palpebral fissures, midface defiCiency, broad thumbs and great toes, mild and variable cutaneo'us syndactyly of fingers and toes Craniosynostosis, facial asymmetry, low-set frontal hairline, ptosis, deviated septum, variable brachydactyly and cutaneous syndactyly especially of second and third fingers, normal thumbs and toes

CRANIOSYNOSTOSIS

INHERITANCE

Almost all cases

Autosomal dominant

All reported cases

Autosomal recessive

Almost all cases

Autosomal dominant

All known cases

Autosomal dominant

All known cases

Autosomal dominant

*Modified from Cohen, M. M.: Dysmorphic syndromes with craniofacial manifestations. In Stewart, R. E., and Prescott, G. R.: Oral Facial Genetics. St. Louis, C. V. Mosby Co., 1976.

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Figure 12

Figure 13

Figure 12. Crouzon syndrome. Figure 13. Apert's syndrome demonstrating typical facial features and marked syndactyly of hands and feet . Figure 14. Pfeiffer syndrome. (Courtesy of Dr. Judith Hall, Seattle, Washington.)

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Figure15.15. Saethre-Chotzen Saethre-Chotzensyndrome. syndrome. Figure

Figure 16. Carpenter syndrome. (Courtesy of Dr. Judith Hall, Seattle, Washington.)

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MIDFACE ABNORMALITIES

Holoprosencephalic Malformation Complex Malformation syndromes affecting primarily the midline structures of the face and cranium may be divided into two major categories. The first category is marked by malformations which result from a deficient volume of tissue resulting in an absence, or reduction, in the various parts. This group of malformations is referred to as the holoprosencephaly malformation complex, denoting the fact that the developing prosencephalon develops abnormally, or holistically, when proper cleavage does not appear. Normally, the prosencephalon divides sagittally to produce the cerebral hemispheres, horizontally into the olfactory and optic bulbs, and transversely into the telencephalon and diencephalon. DeMeyer et at. 6 were the first to point out the intimate relationship between the prosencephalon and various midfacial structures. They observed that the severity of anomalous facial development reflects and is accompanied by equally significant abnormalities in the brain. Cohen and associates 4 have postulated that the basic pathogenetic mechanism of the holoprosencephalic malformation complex lies in the faulty interaction between the notochord plate, the neuroectoderm of the developing brain, and the oral plate. Normally, the notochord arises just caudal to the optic plates. If the notochord is abnormally short and assumes a caudally displaced position, abnormalities result in the development of the neuroectoderm at the cephalic extension, including the entire frontonasal process of the developing embryo. The net result is a failure of the optic placodes to move laterally, giving rise to the hypoteloric deformities which characterize this malformation complex. Several facial anomalies are associated with holoprosencephaly, and have been classified into five subtypes according to the faciocerebral relationships. In effect, this classification represents a transition through varying degrees of severity of the holoprosencephaly malformation complex (Fig. 17, A to D). CYCLOPIA (FIG. 17A). A single or partially divided eye in a single orbit. Absence of the nose, or presence of proboscis. Severe microcephaly with no division between the anterior lobes of the brain (a lobar holoprosencephaly). ETHMOCEPHALY (FIG. 17B). Severe hypotelorism with separate and distinct orbits. May have absence of the nose, or a proboscis. Severe microcephaly and accompanying a lobar holoprosencephaly. CEBOCEPHALY (FIG. 17C). Severe hypertelorism with separate orbits. Proboscis-like nose. Severe microcephaly most commonly with a lobar holoprosencephaly. MEDIAN CLEFT LIP (FIG. 17D). Orbital hypertelorism with separate orbits. Hypoplastic nose. Premaxillary agenesis and absence of the median portion of the upper lip. Usually a lobar holoproscencephaly. MEDIAN CLEFT LIP WITH PREMAXILLARY ANLAGE. Orbital hypotelorism with separate orbits. A median cleft of the upper lip with hypoplastic premaxilla. Hypoplastic and flattened nose. Microcephaly with partial formation of interhemispheric fissure (semi-lobar holoprosencephaly).

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Figure 17. 17. Facial Facial anomalies anomalies that that Figure represent the the holoprosencephalic holoprosencephalic malmalrepresent formationcomplex complexinclude: include:AA, cyclopia; formation , cyclopia; ethmocephaly;C,C,cebocephaly; cebocephaly;andD, andD, BB, , ethmocephaly; mediancleft cleftlip lipwith withpremaxillary premaxillaryagenea genemedian sis. sis.

The role of heredity in the holoprosencephalic malformation complex is not entirely clear, the majority of cases being sporadic with no positive family history. This anomaly has been a frequent feature of the trisomy-13 syndrome, and an occasional feature in the short-arm 18 deletion syndrome. An autosomal recessive mode of inheritance appears to be the determining etiology in certain families where the malformation occurs in siblings born to normal parents. The prognosis for central nervous system function in individuals manifesting these types of facial defects is very poor. Patients with the more severe form of this complex usually do not survive beyond hours or days. The less severe forms may have extended life expectancies, however, uniformly have severe developmental and intellectual anomalies.

Frontonasal Dysplasia Malformation Complex The frontonasal dysplasia malformation complex is characterized by the presence of ocular hypertelorism, broad nasal root, widow's peak

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Figure 18. Frontonasal dysplasia demonstrating orbital hypertelorism, broad nose, and partial cleft of the midline of the upper lip.

hairline at the median portion ofthe forehead, median clefting of the nose and/or lip, cranium bifidum occultum, and varying degrees of cleft lip with or withou t cleft palate. This malformation complex has been referred to by various terms which include median cleft face syndrome. 5 The term frontonasal dysplasia was applied to this condition by Sedano and associates, 18 who provided one of the most complete and thorough reviews of the condition. Embryologically, this malformation complex differs from the holoprosencephalic complex in that the amount of tissue in the structures of the midface are very nearly normal in amounts and occasionally exist in excess. The defects which occur in this condition are thought to be a result of a failure of the nasal capsule to develop properly, thereby allowing the primitive brain vesicles to be dislocated inferiorly and occupy the space normally assumed by the nasal capsule. This inferior displacement of the brain produces anterior cranium bifidum occultum, and also causes an arrest in the normal development of various facial structures. For example, preventing the eyes from developing in a normal relationship, lack of formation of the nasal tip with occasional clefting of the nose, and occasionally the upper lip (Fig. 18). The widow's peak hair pattern results from this same process, and is directly related to the orbital hypertelorism which occurs since the two periocular fields of hair growth suppression are more laterally displaced than usual. 20 Mental retardation is occasionally present, but is much less common than in holoprosencephaly. DeMeyer has observed that when the orbital hypertelorism is severe, and when the craniofacial malformations are accompanied by extracephalic anomalies, the probability of mental deficiency is increased. 5 In less severe forms of hypertelorism, and in the absence of extracephalic anomalies, the probability of mental deficiency is greatly reduced.

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Radiographic examination frequently reveals anterior cranium bifidum, and obliteration of the frontal sinuses. There is frequently an accompanying anterior encephalocele, and less frequently, lipomas or teratomas may be associated with the condition. Almost all reported cases offrontonasal dysplasia have been sporadic; however, the condition has been observed in multiple individuals in some kindreds, suggesting the possibility of dominant inheritance with the majority of cases representing fresh mutations. Polygenic inheritance is also a possibility. The condition is most likely etiologically heterogeneous since the occasional findings of anterior encephaloceles, frontal lipomas, and frontal median teratomas are known to give rise to the same facial anomalies characterizing this malformation complex.

CRANIOFACIAL CLEFTS

Of all the craniofacial anomalies, none is more apparent than the occurrence of clefts, which result from a failure in normal development characterized by a dehiscence of facial structures which are normally contiguous. The morphogenesis of craniofacial clefts is thought to be largely due to a combination of events leading to a lack of fusion between normally joined parts, or by alack of nor mal development and penetration of mesodermal tissue in the cleft areas. The most common and widely recognized of the craniofacial clefts are the common clefts of the lip and primary and secondary palates. These and other more rare forms of clefting coincide with the appositional planes of the primordial facial processes. Although several systems for classifying craniofacial clefts have been proposed, that most recently delineated by Tessier22 and described by Kawamoto 10 is the most comprehensive and uniform. The Tessier system will be used herein to discuss this interesting group of anomalies. Prior to this proposed system of classification, craniofacial clefts were referred to as cleft lip, cleft palate, naso-ocular clefts, oro-ocular clefts, oro-aural clefts, and mandibular clefts. It is immediately obvious that this system is inadequate and fails to include many major cleft types, such as midline or midface clefts, and those clefts observed in the Treacher Collins syndrome. The Tessier classification is unique in that it is based on personal experience and his own observations, rather than on a collection of examples from reviews of the literature and hospital records. Tessier's pioneer work and success in the field of craniofacial surgery has provided him with an unrivaled opportunity to observe and to study a vast number and variety ofrare craniofacial clefts. His classification incorporates not only the surface description of the clefts, but also the direct observations made of the underlying bony structures at the time of reconstructive plastic surgery. This correlation of the clinical appearance with surgical anatomy makes the system informative, practical, and most meaningful, especially for the plastic surgeon.

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Figure 19. Tessier classification of craniofacial clefts showing coarse and involved structures of various clefts: soft tissues (left); skeletal tissues (right).

The clefts are numbered from 0 to 14 and extend along continuous axes through the eyebrows or eyelids, the maxilla, the nostrils, and the lip (Fig. 19). The orbit is regarded as an important landmark since it is considered to be part of both the cranium and the face. The clefts that are directed cephalad or "northbound," extend through the upper eyelid, and are considered mainly "cranial" in nature. The caudally directed, or "southbound," clefts pass through the lower eyelid to become "facial." The combination of northbound and southbound clefts may be combined to form "craniofacial" clefts. When this occurs, the clefts consistently follow a well defined course. Thus, the following combinations can be seen clinically: 1-14, 1-13, 2-12, 3-11, and 4-10. Keeping this cleft extension concept in mind forces the clinician to look up and down the entire axis for malformations. An examination conducted in this manner will often reveal unexpected findings of soft and bony tissue malformations. For example, the common cleft lip is a part of clefts 1, 2, and 3. This should alert the clinician to carefully inspect the more cephalic structures with care to rule out involvement of cranial and facial structures. An example is the combination of a common bilateral cleft lip with a porcine-type nose. The porcine nose is usually associated with a short frontal process of the maxilla. These two features are also part of the No.3 cleft. On close examination, a slight medial canthal dystopia and excessive tearing, indicative of a blocked lacrimal apparatus, !night be observed. A forme fruste of an oronasoocular cleft would be highly probable. The extent of involvement of the soft and bony tissue is variable. Seldom are they affected with equal severity. As a general rule, facial clefts located between the !nidline and the infraorbital foramen have proportionally less bony deformation when compared to those found . lateral to the foramen.

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CONCLUSIONS A great deal of progress has been made in the last decade toward the understanding of the pathogenesis of craniofacial malformations. Similarly, rapid progress has been made in the areas of nosological delineation of the various malformations based on the location of affected structures, the embryological mechanisms which give rise to the anomalies, and the general location of the deformities within the craniofacial complex. Although most of these deformities are considered rare, it is certain that many of the mild forms of these syndromes go undetected or unrecognized. It is hoped that this brief review will stimulate the pediatrician who is in the best position to observe for these abnormalities early in life to evaluate more closely the craniofacial complex, and to be alert for morphologic changes which may herald additional, and sometimes, more severe underlying defects. The recognition of the various midfacial abnormalities is of particular importance when one considers the association of central nervous defects and severe retardation and the very poor prognosis that accompanies these malformations. It should be emphasized that despite the severity ofmany of the malformations discussed in this review, many ofthe individuals do not show mental retardation. The past few years have seen the development of specialized treatment centers for the care and treatment of individuals with these malformations springing up across the country. This movement has been prompted by the significant advances which have occurred and the development of highly sophisticated surgical techniques for treating craniofacial malformations. These major centers employ an interdisciplinary team approach to the treatment of affected individuals with the primary goal of making it easier for those unfortunate persons affected with craniofacial malformations to benefit from cosmetic correction of their deformities, thereby allowing them to assume a productive role in society.

REFERENCES 1. Clifford, E.: Psychosocial aspects of orofacial anomalies: Speculations in search of data. In ASHA Reports #8. Orofacial Anomalies: Clinical and Research Implications, 1973. 2. Cohen, M. M., Jr.: An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects, 11: 137-189, 1975. 3. Cohen, M. M.: Dysmorphic syndromes with craniofacial manifestations. In Stewart, R. E., and Prescott, G. H.: Oral Facial Genetics. St. Louis, C. v. Mosby, 1976. 4. Cohen, M. M., Jr., Sedano, H. 0., Gortin, R. J., et al.: Frontonasaldysplasia (median cleft face syndrome): Comments on etiology and pathogenesis. Birth Defects, 7:117,1971. 5. DeMeyer, W.: The median cleft face syndrome. Differential diagnosis of cranial bifidum occultum, hypertelorism, and median cleft nose, lip and palate. Neurology, 17:961, 1967. 6. DeMeyer, W., Zeman, W., and Palmer, C. A.: The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arrhinencephaly). Pediatrics, 34:256, 1964. 7. Enlow, D. E.: The Human Face: An Account of the Postnatal Growth and Development of the Craniofacial Skeleton. New York, Harper & Row, 1968. 8. Gorlin, R. J., Pindborg, J. J., and Cohen, M. M., Jr.: Syndromes of the Head and Neck. Edition 2. New York, McGraw-Hill Book Co., 1976. 9. Johnston, M. C.: Morphogenesis and malformation offace and brain. Birth Defects, 11 : 1, 1975.

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10. Kawamoto, H. K.: The kaleidoscopic world of craniofacial clefts: Order out of chaos (Tessier Classification). Clin. Plast. Surg., 3:529-572, 1976. 11. Lindsay, W. K.: The epidemiology of usual facial clefts in Ontario, Canada. In Longacre, J. J. (ed.): Craniofacial Anomalies: Pathogenesis and Repair. Philadelphia, Lippincott Co., 1968. 12. Macgregor, F. C.: Social and psychological implications of dentofacial disfigurement. Angle Orthodont., 40:231-233, 1970. 13. Macgregor, F. C., Abel, T. M., Bryt, A., et al.: Facial deformities and plastiC surgery: A psychosocial study. Springfield, Illinois, Charles C Thomas, 1953. 14. Moss, M. L., and Salentijn, L.: The primary role of functional matrices in facial growth. Amer. J. Orthodont., 55:566-577,1969. 15. Poswillo, D.: The pathogenesis of the first and second branchial arch syndrome. Oral Surg., 35:302, 1973. 16. Poswillo, D.: The pathogenesis of the Treacher-Collins syndrome (mandibulofacial dysostosis). Brit. J. Oral Surg., 13:1, 1975. 17. Pruzansky, S.: Clinical investigation of the experiments in nature. In ASHA Reports #8. Orofacial Anomalies: Clinical and Research Implications, 1973. 18. Sedano, H. 0., Cohen, M. M., Jr., Jirasek, J., et al.: Frontonasal dysplasia. J. Pediat., 76:906, 1970. 19. Smith, D. W., and Bostian, K. E.: Congenital anomalies associated with idiopathic mental retardation. J. Pediat., 65:189-196,1964. 20. Smith, D. W.: Recognizable Patterns of Human Malformation. Edition 2. Philadelphia, W. B. Saunders Co., 1976. 21. Stewart, R. E.: Genetic factors in craniofacial morphogenesis. In Oral Facial Genetics. St. Louis, C, V. Mosby Co., 1976. 22. Tessier, P.: The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis, Crouzon's and Apert's diseases. Plast. Reconstr. Surg., 48:419442,1971. 23. U.S. Public Health Service: Children Who Received Physician's Services under the Crippled Children's Program: Fiscal Year 1969. Washington, D.C., Health, Education, and Welfare, 1971. 24. van Lirnborgh, J.: A new view on the control of the morphogenesis of the skul!. Acta Morpho!. Neerl. Scand., 8:143-160, 1970. 25. van der Klaauw, C. J.: Size and position of the functional components of the skull: a contribution to the knowledge of the architecture of the skull, based on data in the literature (conclusion). Arch. Neerl. Zoo!., 9:369-560, 1952. 26. Warkany, J.: Congenital Malformations. Chicago, Year Book Medical Publishers, 1971. Harbor General Hospital 1000 West Carson Street Torrance, California 90509