Anatomical abnormalities in mandibulofacial dysostosis.

American Journal of Medical Genetics 3:225-259 (1979)

Anatomical Abnormalities in Mandibulofacial Dysostosis Susan W. Herring, Ursula F. Rowlatt, and Samuel Pruzansky Department of Oral Anatomy, College o f Dentistry (S.W.H); Department of Pathology, Abraham Lincoln School o f Medicine (U.F. R.); and Department of Pediatrics and Center for Craniofacial Anomalies, Abraham Lincoln School of Medicine (S.P.), University o f Illinois at the Medical Center, Chicago

A detailed dissection of the head and neck of a 7-month-old boy with mandibulofacial dysostosis is described and compared with other reported cases. A general growth retardation was found in the bones of t h e basicranium and calvaria as well as the face. The base of the skull was kyphotic, and the elements derived from the branchial arches articulated with the basicranium more anteriorly than usual. Certain middle ear structures were found t o be extracranial. The facial muscles were generally normal except for t h e absence of elevators of the upper lip. The laryngeal cartilages were shortened anteroposteriorly , resulting in drastic reduction of the rima glottidis. The attachments of t h e masticatory muscles t o the mandible suggested that the area of the temporomandibular joint had not completed normal differentiation, and that that part of the mandible which functioned as a condyle was actually an ossification around Meckel’s cartilage. There was no infraorbital foramen, and the infraorbital neurovascular bundle was distributed instead t o the palate. Clinical and functional correlations of the various defects are considered. Theories of pathogenesis are discussed o n the basis of these findings. It is argued that these observations could be accounted for by an altered intercellular matrix with separate effects o n skeletal growth and neural crest cell migration. Key words: abnormalities, anatomy, birth defects, branchial arches, craniofacial anomalies, embryology, mandibulofacial dysostosis, otomandibular defects, Treacher Collins syndrome INTRODUCTION Mandibulofacial dysostosis (MFD) is a common, well-known malformation affecting the orbit, face, and ear bilaterally. Although there are hundreds of case reports in the literature, recently summarized by Behrents et al [1977], almost all are clinical accounts and deal only with surface or radiographic aspects. The subsurface anatomy of this condition is still partly unexplored, since there have been only two reported dissections of MFD individuals. Lockhart [ 19291 described portions of the skull and masticatory muscles in

Received for publication July 19, 1978; revision received November 7, 1978. Address reprint requests to Dr. Susan W . Herring, Departinent of Oral Anatomy, University of Illinois at the Medical Center, Chicago, IL 60612.

0148-7299/79/0303-0225$05.90 0 1979 Alan R. Liss, Inc.

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an adult of unknown background. McKenzie and Craig [1955] performed a full head and neck dissection on a 10-week-old male infant, but except for the description of the arterial branching pattern, practically no details are given in their account. In additiotl, Behrents et a1 [1977] provided a histologic study of the head of a 15-week fetus, and Dahl et a1 [1975] reported a dry adult skull. Several studies have dealt with histopathologic changes of the ear in MFD (see Lapayowker [ 19741, Sando et a1 [ 19681, and references cited). Thus, many important areas have not been described at all, including facial musculature, pharynx and larynx, and the extracranial course of trigeminal and facial nerves. Moreover, anatomic variation has not been assessed. A thorough knowledge of the anatomic changes in malformations such as MFD and their range of variation is necessary for two reasons. First, this information is useful for the construction of hypotheses of pathogenesis. The recent studies of 18-trisomy by Wisconsin researchers [Barash et al, 1970; Bersu and Ramirez-Castro, 19771 exemplify the utility of this approach. Second, this anatomic information will furnish a more rational basis for reconstructive surgery, prosthetic devices, and physical therapy than presently exists. The purpose of this paper is to provide a more complete description of MFD by reporting a detailed head and neck dissection of a new case and comparing results in this subject with those of previous reports. REPORT OF PATIENT

The subject was a 7-month-old white male born at term to a 20-year-old woman, whose only previous pregnancy had ended in miscarriage. The father was 2 2 . There was no familial history of MFD, and the parents have since had a normal child. MFD was diagnosed at birth. Difficulty with feeding and breathing required a gastrostomy and a tracheostomy at 6 weeks. The gastrostomy was closed shortly afterwards, but attempts at various times to remove the tracheostomy tube were unsuccessful. The infant’s condition was complicated by a series of infections, the last of which led to his death. The value of detailed anatomic studies was explained to the parents, who were well-educated. Permission was received to perform a full dissection, and the body was donated to the University of Illinois. Autopsy showed pneumonia and changes in the brain and other organs due to hypoxia and a preterminal stay of 11 days on the respirator. METHODS

After autopsy the body was embalmed by perfusion with 10% formalin and immersed in Kaiserling I11 solution. Most of the dissection was performed under a stereodissecting microscope with microdissection instruments. A clinically normal newborn infant was dissected at the same time. Where appropriate, small tissue samples were removed for histologic examination. A record of the dissection was kept with freehand and camera lucida drawings. At the completion of the dissection the skull was cleaned and photographed. FINDINGS External Aspects

Crown-heel length was 60 cm. No other anomalies were present except for mild cutaneous syndactyly of the toes. The head showed all the diagnostic features of mandibulofacial dysostosis (Fig. 1). Lacrimal puncta were found on the upper but not the lower lids. The up-

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Fig. 1. Frontal, right, and left lateralviews of the patient at 4 months.

per eyelashes were strikingly long but lower lashes were few and hypoplastic. The inner surface of the lower lid appeared t o contain many fine hairs covered by epithelium, but we were unable t o confirm this observation histologically. Sebaceous glands were present in the lid margins. There was a preauricular extension of the hairline. There were no external auditory canals and external ears were low-set and rudimentary, consisting of several small isolated cartilages set in striated muscle and covered by skin. The tongue was relatively large, and there was a slight macrostomia. The secondary palate had a V-shaped cleft posteriorly. The zygomatic arches appeared t o be absent. Skull

Neurocranium (Figs. 2-41. Skull shape was dolichocephalic. Fontanels were normal for age: The posterior and sphenoidals were closed, the mastoidals were small, and the anterior was large. The sutures were patent except for the metopic, which showed considerable synostosis, especially on its endocranial surface. There were several small sutural bones in the lambdoid suture and two large ones in the squamous suture. The more posterior of these was in the triple intersection between petrous, squamous, and parietal bones. The endocranial surfaces of the frontals, parietals, and occipital showed shallow digital impressions. The cranial base was unusual in several respects. 1) The synchondrosis between pre- and postsphenoid elements, which usually is obliterated before birth [Sperber, 19761 , was still present. 2)

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Pig. 2 . Photographs and drawings of lateral vicw of skull and mandible (A) and frontal view of skull (B). The arrows in A (photograph) point to the rudimentary zygomatic processes of frontal, maxillary, and squamous bones. Also note suture bones in squamosal suture and the abnormal angulation between viscerocranium and neurocranium. In B (photograph), note the partial synostosis of the metopic suture and the absence of the infraorbital foramen. The Iarge foramen medial to the orbit is the nasolacrimal duct. The orbit is partially closed laterally by one of the bars representing the greater wing of the sphenoid.

There was a well-developed middle clinoid process. 3 ) The sphenoethrnoidal angle measured about 140°, vs 149" in normal neonates or greater in older individuals [Moore and Lavelle, 19741.


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Fig. 3 . Closeup of Figure 7A, showing structures of the ear region. Hatching represents cartilage. The lower arrow points to thc facial nerve foramen, the upper to the foramen for the middle meningeal artery, which arc partially obscured in this view. h) Hamulus; m) mastoid process; s) greater wing of sphenoid closing orbit laterally; st) styloid process with stapes superstructure fused t o the lateral wall of the carotid canal; t) auditory tube; z) zygomatic process.

The squamous and petrous parts of the temporal bone were unfused, as is normal for this age. No tympanic part could be identified. On the left side the squamous extended anteriorly beyond its usual boundaries to replace the very hypoplastic greater wing of the sphenoid; it articulated directly with the frontal at the anterior end of the temporal fossa, and formed a section of the lateral orbital wall. It also provided the lateral roof of the infratemporal fossa, the medial roof being completed by membrane. On the right side the temporal surface of the greater wing of the sphenoid was separately ossified and the sutural pattern of the squamous was comparatively normal. The suture between the squamous and greater wing was very tight, and it seems likely that such a suture had been present on the left

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Fig. 4. Photograph and drawing of palatal view of skull. The membranous maxillary tuberosity has been removed, as has the bone around the greater palatine foranicn, between the palatine bone and hamulus. The two arrows o n the palate point t o the anterior and middle palatal foramina. c) Carotid canal; h) hamulus; m) maxillary bone; oc) occipital condylc; p) palatine bone; st) styloid process/ stapes; t) auditory tube; z) zygomatic processes. The roof of the infratemporal fossa, seen just latcral t o the auditory tube, mas mcmbranous.

side and had become obliterated. Inferolaterally on the squamous were several small exostoses, without any apparent hoinologs, somewhat more clearly developed on the left than on the right side (Fig. 3). These exostoses served anteriorly as the infratemporal crest, delimiting the temporal and infratemporal fossae. Portions of the lateral pterygoid muscle arose from their inferior surface, and a small muscle thought t o represent the stapedius inserted on the tip of the largest of these squamosal processes. Intracranial and basilar views of the petrous appeared normal (Fig. 4). The p r h o r d i u m of the mastoid process was present. The Eustachian tubes were in their usual position but reached the middle ear cavity only on the right. On the left it ended blindly. Dissection of the left middle and inner ears revealed no abnormalities in the osseous labyrinth, but the promontory was fused with the outer surface of the cranium. The facial canal had no genu, and after giving off the greater superficial petrosal branch, the facial nerve coursed directly later-


231

ally out of the skull anterior t o the promontory. Since the chorda tympani and facial trunk were still together at this point (see below), this foramen probably corresponds to the petrotympanic fissure. There was a small tympanic cavity posterior t o the promontory, probably equivalent to the mastoid antrum. A single window on the medial wall of this cavity led anteroinferiorly t o the carotid canal. Anterior to the promontory the tympanic cavity was absent. The petrous was most unusual in its lateral aspect, due to the absence of the external ear. The bone in this area was thin and its surface concave and perforated by vascular foramina; the largest of these was on the suture between squamous and petrous bones and transmitted the middle meningeal artery. The anteroinferior section showed exostoses similar t o those of the neighboring squamous, and one such provided the origin of the “stapedius” muscle. Just below these exostoses and the foramen for the facial nerve there was a “Y”. shaped cartilage, which appeared t o represent the fused stapes and styloid process. The anterior and posterior crura of this cartilage were fused t o the lateral wall of the carotid canal, where they were partially encased by thin sheets of bone. No other ossicles were present. The lesser wings of the sphenoid were normal. The greater wings and pterygoid processes were greatly affected. The following description pertains mainly t o the right side, since sutural boundaries were missing on the left. The temporal surface showed two unusual features: 1) There was a foramen for an endocranial branch of a deep temporal artery; 2 ) there was a large protuberance, vaguely resembling a zygomatic process, from which arose parts of the deep masseter. The infratemporal surface of the greater wing was almost completely unossified, so that there was no foramen ovale as such. The orbital surface of the greater wing consisted of two bars of bone. One was a compound of two thin, flat ossifications united by a fibrous suture. It extended from the temporal surface of the greater wing, near the frontal articulation, to the posterolateral edge of the maxillary tuberosity. This bone formed the lateral edge of the inferior orbital fissure but did little to complete the lateral wall of the orbit. The other portion of the orbital surface was a bar of bone, also attaching t o the remainder of the greater wing near the frontal junction, which coursed medially and slightly inferiorly to join the pterygoid process. This bar formed the posterior boundary of the inferior orbital fissure and the inferior boundary of the superior orbital fissure, and it was pierced near its medial end by the foramen rotundum. It was the major site of origin for the medial pterygoid muscle. The pterygoid process of the sphenoid was a simple strut of bone which represented the medial pterygoid plate and hamulus anteriorly and the medial edge of the foramen ovale posteriorly. It was closely associated with the Eustachian tube and provided partial origin for the tensor veli palatini. The pterygoid process articulated posteriorly with the petrous temporal, superiorly with the posterior orbital portion of the greater wing, and anteriorly with the maxillary/palatine. Just above the hamular process it was perforated by the pterygoid canal. N o structure resembling a lateral pterygoid plate was seen. Viscerocranium. The anterior inferior border of the mandible (Fig. 5 ) was strongly everted, and the concave anterior surface was penetrated by several foramina transmitting vessels. A single mental foramen was normally positioned. There was a small, very obtuse angular process and an anteroposteriorly broadened coronoid process which was directed more posteriorly than usual, relative to the alveolar ridge. There were two condylar structures inferior to the alveolar ridge. The more lateral of these was elongated anteroposteriorly and seemed to arise from the same plate of bone as the coronoid process. Although this lateral condyle did not form a joint with the skull, its soft tissue relations suggest it may be the homolog of the normal condylar process; we will refer to it as the “lateral condyle.” The medial condylar structure was also elongated anteroposteriorly and was associated with the plate of bone forming the angle. This “medial condyle” made fibrous contact

232


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'I c

c1

I

ia

mc

Fig. 5 . Photographs and drawings of mandible. A) Lateral, B) medial, C) posteroinferior views. The bone is from the right side, but the prints have bccn reversed to correspond with thc skull. a) angle; c) coronoid process; ia) inferior alveolar artery; lc) lateral condyle; mc) medial condyle; n) inferior alveolar nerve.

with the infratemporal region of the skull along its medial and posterior surfaces. The medial condyle may represent an ossification around the cranial portion of Meckel's cartilage, which forms the jaw joint in lower vertebrates and, temporarily during ontogenesis, in mammals. The mandibular foramen was on the superior surface of the mandible between the medial and lateral condyles. The body was filled with developing teeth in their crypts. The frontal and alveolar processes of the maxilla appeared t o be normal. The inferior rim of the orbit was poorly defined, and the infraorbital foramen absent. The fossa for the lacrimal sac was larger than usual and so poorly ossified that the inferior oblique muscle of


233

c Fig. 6 . Sagittal section of skull; mandible and nasal septum removed. The hatched areas are cartilage; note the synchondrosis between the two parts of the sphenoid. A) Superior concha; B , C) separated parts of middle concha; D) inferior concha. 1 , 2 , 3 ) Probes located respectively in the greater palatine, middlc palatal, and anterior palatal foramina; 4) incisive nerve.

the eye originated from membrane rather than bone. The nasolacrimal canal was short but otherwise normal. A tiny zygomatic process protruded laterally and served t o anchor a fascia which also attached to the zygomatic process of the frontal and was associated with the superficial masseter. The orbital surface of the maxilla sloped downward posteriorly. The palatine processes of the maxilla were approximated but did not meet, and thus the cleft of the secondary palate was complete submucosally. Each palatine process contained two foramina which opened into the infraorbital canal (Fig. 6). The incisive suture was in its usual position. The horizontal plates of the palatine bones diverged widely in the area of the cleft. The major palatine foramina were normal, and the pyramidal processes articulated firmly with the medial pterygoid plates. The vertical plates were short but well ossified. The sphenopalatine foramina were present but located more posteriorly than usual, near the posterior edges of the bones. The two laminae of the vomer were fused only at their inferior edge, where the bone sat in the midline cleft between the palatine processes of the maxilla and the horizontal plates of the palatines. The inferior nasal conchal, nasal, and lacrimal bones appeared to be normal. The crista galli and perpendicular plate of the ethmoid were cartilaginous, as expected at this age. The lamina papyracea, ethmoid air cells, and uncinate process were normal, but the superior and middle conchae were irregular and poorly separated from each other (Fig. 6). Hyoid. The body of the hyoid was ossified and strongly concave posteriorly. The lesser horns were very long and cartilaginous, and the joint between the lesser horn and the body was freely mobile. The greater horns were also cartilaginous, but the joint between the greater horn and the body was relatively immobile. Muscle attachments were normal.

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Fig. 7. Hyoid and larynx. Lateral and slightly inferior view of right side. Muscle attachments are stippled. ca) Posterior cricoarytenoideus, with the most lateral fibers inserting on the infcrior horn of the thyroid; ct) cricothyroideus; f) foramen for external laryngeal nerve; 1) median thyrohyoid ligament (the lateral ligament is very short); mc) middle constrictor. The muscle attachment above the foramen is for part of the inferior constrictor; that below the foraincn is for sternothyroidcus, thyrohyoideus, and infcrior constrictor.

Larynx. The larynx was elongated craniocaudally, shortened anteropostenorly, and widened laterally (Figs. 7,s). The dimensions of the laryngeal cartilages of the patient and the newborn infant are compared in Table I. Taking into account the expected differences in size and maturity, the major points include: 1) relatively large arytenoids, especially in vertical dimension; 2) a cricoid with proportions similar t o those of a newborn infant except for greater width; 3 ) a thyroid large in the craniocaudal and mediolateral dimensions, but small anteroposteriorly , with a concomitant drastic shortening of the vocal ligament. The anteroposterior shortening of the thyroid cartilage was also reflected in the linear arrangement of the horns, which contrasts with the usual posterior slope of the superior horns, and in the anterior position of the cricothyroid joints (Fig. 7 ) . In addition, there was an abnormal foramen in the thyroid lamina near the oblique line for the exit of the external laryngeal nerve. Near the site of the tracheostomy the tracheal cartilages were small and partially collapsed. Muscles Facial muscles. The facial muscles were generally thin and pale. However, most of the muscles were normal in their attachments (Fig. 9) except for zygomaticus major, which in the absence of the zygoma originated from the zygomatic process of the frontal, and levator labii superioris alaeque nasi, which could be traced to the wing of the nose but not the upper lip. Several muscles or muscle groups were present but abnormal: 1) Risorius was represented by a stout, fusiform belly, tendinous at both ends and completely differentiated from platysma. It originated from fascia over the superficial masseter muscle. 2) Levator

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235

A

Fig. 8. Sagittal sections of the patient (A) and a normal neonate (B). c) Cricoid cartilage; e) epiglottis; g) geniohyoid muscle; h) hyoid; t) thyroid cartilage. The vocal cords in the subject were extremely short.

anguli oris had an extremely medial origin close to the medial angle of the eye. 3 ) The anterior auricular muscle was small but normal, attaching to the upper surface of the “pinna.” The superior auricular muscle was represented by two thin bellies which fused at an intermediate tendon, became muscular again, and passed down into the fascia of the neck without contacting the “pinna.” No posterior auricular muscle was found. 4) Finally, there was complete absence of zygomaticus minor and levator labii superioris, which were replaced by dense connective tissue.

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TABLE I. Dimensions of Laryngeal Cartilages Patient (7 months)

Control (neonatal)

12.1 mm

12.7 mm

8.1 23.5

5.6 17.9

12.6

6.5

10.4 10.2 5.1

8.9 8.2 3.2

Arytenoid cartilage Vertical height Anteroposterior length

8.0 5.5

4.7 3.5

Vocal ligament Length

2.2

3.2

Thyroid cartilage Maximum anteroposterior length Height at incisure Distance between tips of superior and inferio1 horns Width of lamina in frontal projection Cricoid cartilage Antcropostcrior diameter Height of posterior plate Width: midline to cricothyroid joint

Suprahyoid musculature. The muscles of the oral floor were well developed but showed various abnormalities in structure (Fig. lo>,which may be due to the reduction of available space. The distance between the chin and hyoid bone was about 7 mm in the patient, ascompared to 25 mm in the newborn infant (Figs. 8, 10). Thus the mylohyoid muscle was very short anteroposteriorly but quite deep (up to 3 mm thick, in contrast to 1 mm in the control), as if the fibers were piled up. The posterior belly of the digastric was normal in form and attachment, but several fasciculi of the anterior belly originated from the body of the hyoid instead of the intermediate tendon. The stylohyoid muscle originated from the styloid process, and was joined by an accessory slip from the posterior digastric. The muscle became tendinous and then joined the intermediate digastric tendon. This common tendon, as well as giving rise t o the anterior digastric, was the origin of two sets of muscle fibers, one going deep to join hyoglossus, and one, evidently the rest of stylohyoid, attaching to the body and greater horn of the hyoid. It appeared that the digastric and stylohyoid had lost their separate identity. The other muscles of this region seemed normal, although the geniohyoid was greatly reduced (Fig. 8). The stylohyoid ligament was thin and lax. Trigeminal muscles. There was a distinct superficial masseter (Fig. 11A, B) arising from a broad fascia rooted at the zygomatic processes of the frontal, sphenoid, and maxilla. It inserted on the ventral and posterior edges of the mandibular angle. The superficial masseter was completely independent of any other muscle layer (unlike the normal situation in man but resembling that found in some other mammals-see Turnbull [ 19701>.Its posterior border was the insertion of a ligamentous fascia arising from the tissue covering the lateral condyle. Beneath the superficial masseter were separable layered fascicles of deep masseter, arising from the zygomatic process of the greater wing of the sphenoid and grad-

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Fig. 9. Facial muscles of the patient (A) and a normal neonate (B). a) Auricular muscles; at) auriculotemporal nerve; da) depressor anguli oris; dl) depressor labii inferioris; f) frontalis; g) parotid gland with duct; la) levator anguli oris; 11) levator labii superioris; In) levator labii superioris alaeque nasi; n) nasalis; oc) orbicukdris oculi; or) orbicularis oris; p) platysma; r) risorius; s) supraorbital nerve; v) superficial temporal vein; z) zygomaticus major.

ing into temporalis. Layer 1 arose by a round tendon and inserted on the edge and lateral surface of the mandibular angle just anterior to the superficial masseter. Layers 2 and 3 were both deep to a neurovascular bundle, consisting of branches from the maxillary artery and mandibular nerve, which traversed the area. Layer 2 arose tendinously and inserted just above layer 1. Layer 3, which had a fleshy origin and a tendinous insertion at the base of the external oblique crest, was intimately associated with the temporalis. Temporalis was broadly divided into three parts: superficial-insertion on the lateral side of the coronoid process, middle-insertion on edge of coronoid process, deep-origin from

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Fig. 10. Suprahyoid muscles of the patient (A) and a normal neonate (B), right lateral view. Note the interconnections of digastric, stylohyoideus, and tongue muscles in A . a) Anterior belly of digastric; b) hyoid bone; d) mandible; e) external carotid artery with branches; g) styloglossus; h) hyoglossus; m) mylohyoideus; p) posterior belly of digastric; s) stylohyoidcus; t) thyrohyoideus; x) fibers from digastric tendon to tongue.

infratemporal fossa and insertion on medial side of coronoid process, along the temporal crest [Sicher and Du Brul, 19751. Each part was then subdivided according to fascia1 separations. There were two separable parts of superficial temporalis. The anterior superficial temporalis, which is commonly found in well-developed normal subjects, was very thin and had a tendinous origin from the edge of the temporal fossa. The insertion was also tendinous and ran deep to the neurovascular bundle to insert on the anterior edge of the coronoid process. The posterior superficial temporalis arose as two bellies-one from the posterior edge of the temporal fossa, the other from an accessory portion of temporal


2 39

fossa separated from the main part by a slight bony elevation. The combined bellies became tendinous and inserted partly on the tissue covering the lateral condyle and partly on the lateral surface of the coronoid process. This tendon was superficial to the neurovascular bundle. The middle layer of temporalis (Fig. 1 lB, C) also had two parts; both arose from the temporal fossa and inserted on the superior part of the coronoid process. The more posterior portion inserted on the top edge of the coronoid process, while the more anterior portion inserted on the medial side of the coronoid process close to its superior edge. The two parts of deep temporalis (Fig. 1 lB, C) arose from the roof of the infratemporal fossa and were separated by the buccal nerve. The more posterior and superficial portion arose just deep to deep masseter and inserted along the temporal crest. The more anterior and deep portion inserted at the base of the temporal crest. The lateral pterygoid (Fig. 1l C , E) originated from the poorly ossified roof of the infratemporal fossa as three separate heads separated by branches of the buccal nerve. The posterior head was directed almost vertically, while the anterior two heads pulled somewhat anteriorly. All three converged to insert on the anterior and lateral surfaces of the medial condyle. This insertion is therefore on the “wrong” side of the condyle and suggests that the medial condyle represents the primary jaw joint, the lateral pterygoid having failed to transfer its attachment to the secondary (in this case lateral) condyle. The medial surface of the mandibular angle was devoid of attaching muscles, so the medial pterygoid muscle was at first thought to be missing. However, an anteroposteriorly oriented muscle otherwise had the correct relations and was presumably the medial pterygoid. This muscle (Fig. 1lD, F) originated from the lower orbital bar and pterygoid process of the sphenoid just behind the pterygomaxillary fissure. It was deep to all branches of the mandibular nerve but was penetrated near its insertion by the lingual nerve (Fig. 12). The muscle inserted on a line just above the mylohyoid line and onto the anterior and medial surfaces of the medial condyle, and the most posterior fibers attached to the skull adjacent to the articulation (Fig. 11F). Those fibers inserting on the medial condyle and skull were taken to represent an undifferentiated tensor tympani muscle, which is thought to be homologous to part of the reptilian pterygoideus muscle [Parrington and Westoll, 19401. Closely associated with the medial pterygoid was the large tensor veli palatini (Figs. 1l E , 13), which originated from the posterior end of the Eustachian tube and a longitudinal area close to the cranial attachment of the medial pterygoid. The fibers ran anteriorly and medially in the horizontal plane (rather than vertically, as usual) and became tendinous shortly before reaching the hamulus. A small portion of the tendon went laterally to attach to the maxillary tuberosity (Fig. 13), but most of it rounded the hamulus to insert on the medial border of the cleft secondary palate. There was no palatal raphe or aponeurosis. The mylohyoid originated from the mylohyoid line, which extended from Inidway along the body of the mandible to the medial condyle. Finally, there were several anomalous striated muscle slips (as determined histologically) helping to close the orbit laterally (Fig. 1lB, E). They attached superiorly to the zygomatic process of the frontal and inferiorly to the maxilla and the orbital part of the greater sphenoidal wing. The most superficial of the motor branches of the mandibular nerve (Fig. 11A) was traced into one of them. Thus they were presumably trigeminal derivatives, probably from temporalis. Other muscles. Posterosuperior to the jaw articulation was a small striated muscle belly which we have tentatively identified as stapedius (Fig. 1lF), for the following reasons: l) Although no motor nerve was seen, the muscle was completely isolated from the

240


\

1

I;

/------

Fig. 11. Masticatory musculature in progressively deeper dissections, right lateral view. A) Masseter and superficial temporalis; B) middle temporalis; C) lateral pterygoid. Although the cranium is still seen in lateral view, the m.andible has been twisted laterally so that it is seen from a superior view and the contents of the infratemporal fossa are stretched. D) Medial pterygoid muscle, mandibular and facial nerves. Orientation as in (C) but mandible twisted further laterally. E) Muscle attachmcnts of the infratemporal fossa. The mandible has bccn removed. F) Presumcd tensor tympani and stapedius homologs. adt) Anterior deep temporalis; amt) anterior middle temporalis; ast) anterior superficial temporalis; at) auriculotemporal nerve; b) buccal nerve; c) coronoid process; ct) chorda tympani nerve; d l , d2, d3) three layers of deep masseter; dt) deep temporalis; f) cervical fascia attaching to mandibular angle; fo) foramen ovale; h) hamulus; ia) inferior alveolar vessels (the artery arises in common with the sphenopalatine artery); j) joint surface; 1) ligament between lateral condyle and superficial masseter; lc) lateral condyle; lg) lingual nerve; Ip) lateral pterygoid muscle; mb) muscular branches of V,; mc) medial condyle; mm) middle meningeal artery; mp) medial pterygoid muscle; 0 ) orbital muscle ; pdt) posterior deep temporalis; pmt) posterior middle temporalis; pst) posterior superficial temporalis; s) styloid process; sm) superficial masseter; sp) sphenopalatine artery (inferior alveolar branch removed); ss) stapedius; st) stylohyoideus; tp) tensor velj palatini; tt) tensor tympani.

E

242

Herring, R o w l a t t , a n d P r u z a n s k y

mt ,,.

C

Fig. 12. Right mandible. A) Medial view with muscles in place (arrow points t o gap in medial pterygoid muscle for lingual nerve); B) medial view showing muscle attachments; C) inferior view. a) Mandibular angle; dt) deep temporalis; Ic) lateral condyle; Ip) lateral pterygoid; m) mylohyoid; mc) medial condyle; mp) medial pterygoid.

Fig. 13. Palatalview of skull and mandible, right side. e ) Eustachian tube; h) hamulus; 1) longus capitis; lc) lateral condyle; m) mylohyoid; mc) medial condyle; mp) medial pterygoid/tensor tympani, oc) occipital condyle; tp) tensor veti palatini.

nearby trigeminal muscles and was immediately adjacent to the facial nerve. 2) If our interpretation below is correct, other parts of the middle ear seem to be on the outer cranial surface in this subject, including the malleus (not differentiated from the mandible), tensor tympani (not differentiated from the medial pterygoid), and the incus and stapes (fused to


A

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B

Fig. 14. A) Pharyngeal muscles, left side. The tongue and velum have been removed. B) Palatal muscles, left side. Note the horizontal orientation of the muscles. The tongue has been pulled down o u t of the way, and the velum has been reflected forward t o demonstrate the muscles. The laryngeal airway is hatched. b) Hyoid bone; bu) buccinator; e) opening of the Eustachiaii tube; h) hamulus; 1) levator veli palatini; m) mylohyoid; p) palatopharyngeus (two parts); sc) superior constrictor; tp) tensor veli palatini; u) uvula.

the outside of the petrous). 3) The muscle originates from an exostosis on the petrous which resembles the pyramid. 4) We can think of no other possible homology except possibly tensor tympani, but the probable facial innervation and alternate identification of a tensor tympani speak against this suggestion. However, it should be noted that the muscle inserts tendinously on an exostosis of the squamous which is very unlikely to be derived from the second branchial arch. Moreover, the muscle was presumably functionless, since it both arose from and inserted on the skull. The superior constrictor and palatopharyngeus were separable only at their anterior attachments (Fig. 14A). Palatopharyngeus arose from the edge of the cleft soft palate, where it was in close association with levator veli palatini (Fig. 14B). Posteriorly and inferiorly, superior constrictor and palatopharyngeus became a continuous longitudinal sheet and inserted together on the posterior raphe. Levator veli palatini arose from the vicinity of the Eustachian tube and coursed anteriorly and slightly inferiorly to insert in the connective tissue of the cleft soft palate and the edge of the cleft hard palate. The insertion of the levator and the origin of the palatopharyngeus were continuous. There were also some longitudinal fibers running in the posterior wall of the pharynx, representing the posterior part of palatopharyngeus, which arose from the cleft edges of the hard palate and nearby connective tissues, and a tiny fasciculus originating from the skull medial to the jaw articulation and inserting with superior constrictor. Other pharyngeal muscles were normal. In summary, the major abnormalities of the velopharyngeal muscles were 1) the horizontal orientation of the palatal tensor and levator, related to the acute basicranial angle, and 2) the expected disruption of midline areas caused by the cleft palate. The soft tissues of the larynx were normal, with the following exceptions. The external laryngeal nerve emerged from a foramen just behind the oblique line of the thyroid lamina instead of branching from the superior laryngeal nerve before the latter penetrated

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A

Fig. 15. Maxillary artery, left side, of subject (A); and of normal neonate (B). b) Buccal artery; dt) deep temporal artery; e) endocranical branch; ec) external carotid; ia) inferior alveolar artery; 1) lingual artery; m) maxillary artery; mm) middle meningeal artery: psa) posterior superior alveolar artery; st) superficial temporal artery.

the thyrohyoid membrane. The oblique line was extended 1-2 mm laterally as a raphe for the common attachment of sternothyroid, thyrohyoid, and inferior constrictor. The transverse part of the arytenoideus was very large. The lowest, most horizontal fibers of the posterior cricoarytenoideus inserted abnormally on the inferior horn of the thyroid cartilage (Fig. S), bridging the entry of the inferior laryngeal nerve. Surprisingly, the same structure was found when the larynx of the presumably normal newborn control was dissected. Reference to this abnormality is very rare in standard anatomic texts, but according to Poirier and Charpy [ 19011 such a muscle, called “ceratocricoid” or “posterior cricothyroid,” is found in 20-2.576 of individuals. The position of this muscle also corresponds t o that of a ligament, usually called “lateral ceratocricoid,” and it seems possible that the muscle and ligament are homologous. Neck muscles innervated by cervical nerves were all normal.


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Vessels and Nerves Vessels. The common carotid and internal carotid arteries were completely normal, as were the external carotid and its branches until the retromandibular area was reached. After the superficial temporal was given off, the maxillary artery gave rise t o several large branches which entered the skull near the ear region (Fig. 11A, E). The largest of these entered about 4 mm superior to the facial nerve foramen and was clearly a meningeal artery. Beyond this point the branching pattern differed on the two sides. On the left (Fig. 15), from the same stem as these cranial branches, came a large muscular branch which extended anteriorly between various layers of temporalis and masseter. In distribution it corresponded to the posterior deep temporal plus masseteric arteries. The remainder of the maxillary artery gave off apparently normal inferior alveolar, buccal, and posterior superior alveolar arteries plus another endocranial branch, more anterior than the middle meningeal, before entering the pterygomaxillary fissure. The inferior alveolar gave off a lingual branch which joined the lingual nerve; this is a fairly common anomaly [Warwick and Williams, 19731. The right side was more abnormal (Fig. 11C,E). The vessel corresponding in position to the maxillary trunk on the left side gave rise only to inferior alveolar (plus lingual) and sphenopalatine arteries. These two branches arose together at the posterior border o f the lateral pterygoid muscle (Fig. 11C). The inferior alveolar artery passed superficial to the posterior two heads of lateral pterygoid but deep to the anterior head before entering the mandibular foramen. The sphenopalatine went deep to lateral pterygoid, over the superior border of medial pterygoid (Fig. 1 lD), and deep to that muscle until reaching a foramen at the inferior border of the pterygoid process, near the hamulus (Fig. 11E). On the right side the vessel resembling the left side’s posterior deep temporal turned out to have a deeper branch corresponding to the maxillary trunk. This artery (Fig. 11E) passed superficial to the lateral pterygoid muscle and entered the inferior orbital fissure by winding around the posterior orbital muscle. The right maxillary artery was smaller than its counterpart on the left. The further course of the maxillary artery was followed only on the left side, to minimize destruction of bone (Fig. 16). After leaving the infratemporal space, the left maxillary artery coursed medially to the lateral portion of the orbital apex, a position corresponding to the pterygopalatine fossa. It then divided into two equal branches. The more posterior division was the sphenopalatine artery. This vessel continued on a medial course across the membranous posterior floor of the orbit and passed through the sphenopalatine foramen to supply the nasal cavity in the usual fashion. Just before entering the foramen the sphenopalatine artery gave off a small palatine branch which was traced anteroinferiorly to the greater and lesser palatine foramina. A larger posterior nasal artery was given off within the nasal cavity. The more anterior division of the maxillary artery was comparable to the infraorbital artery and coursed anteromedially over the membranous posterior orbital floor. When the membranous floor was replaced anteriorly by the orbital part of the maxillary bone, the infraorbital artery entered a foramen in the bone. Its further course was intraosseous, thi-ough an infraorbital canal located more medial than usual. A large, abnormal palatine branch was given off in a posteroinferior direction near the front of the orbit. This vessel emerged from a palatal foramen about 9 mm anterior to the greater palatine foramen, and we will refer to it as “middle palatal artery” (Fig. 6). Several small lateral and anterior branches of the infraorbital artery were seen, supplying the maxillary bone and occasionally, especially anteriorly, emerging from tiny foramina to supply soft tissues such as buccal gingiva. There was no infraorbital foramen per se, and the infraorbital artery terminated as another large palatal vessel, also directed posteroinferiorly, which emerged from a

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Fig. 16. Termination of left maxillary nerve and artery. Superior view from top of orbit. cr) Cribriforin plate; e) ethmoid-maxillary suture; io) infraorbital nerve and artery; m) maxillary nervc; max) orbital part of maxilla; p) position of greater and lesscr palatine nerves and arteries; pt) position of pterygoid nerve and ganglion; sp) sphenopalatine artery; st) sella turcica.

foramen on the palate about 7 mm anterior to the “middle palatal artery” and 15 mm posterior to the anterior margin of the palate. This vessel will be referred to as the “anterior palatal artery.” Nerves. The left optic, oculomotor, trochlear, abducens, and ophthalmic nerves were dissected with the orbit, and no abnormalities were found. The maxillary division of trigeminal was dissected on the left side (Fig. 16). From the foramen rotunduin the nerve coursed inferiorly as well as anteriorly. The trunk appeared fused to the pterygopalatine ganglion. Distal to the ganglion the trunk continued anteroinferiorly, and the majority of fibers were given off as major and minor palatine nerves, in association with the arteries of the same name. The remaining portion of the maxillary nerve coursed superiorly and slightly laterally, and soon divided into two slender branches. One, the infraorbital, accompanied the infraorbital artery anteriorly, but it could not be determined whether anterior and middle palatal nerves were given off. The second terminal branch of the maxillary coursed laterally along the path of the sphenopalatine artery. Presumably this lateral branch provided zygomatic and posterior superior alveolar nerves, but, again, these could not be followed. No branches of the maxillary nerve were seen entering the nasal cavity through the sphenopalatine foramen or elsewhere. However, it is likely that small branches were missed during this difficult dissection. That the nasal cavity received normal maxillary innervation is suggested by the presence of a severed incisive nerve (a branch of nasopalatine) in the incisive canal. The mandibular division of trigeminal, dissected on the right side, emerged from the skull through a foramen ovale positioned just below the origin of lateral pterygoid, between its middle and posterior heads (Figs. 1l D , E). The auriculotemporal nerve had a direct connection with the facial nerve. In addition the auriculotemporal must have carried


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motor fibers because a branch turned anteriorly and ran superficially to temporalis and masseter (Fig. 11A). The inferior alveolar and lingual nerves passed as usual between lateral and medial pterygoid muscles, the lingual reaching its destination by piercing medial pterygoid. The mylohyoid nerve was given off as the inferior alveolar entered the mandibular foramen and reached the lower surface of mylohyoid by passing through a foramen formed by a bony notch and a covering ligament. The buccal nerve arose as two branches, one passing between the anterior and middle heads of lateral pterygoid, and the other, in common with a deep temporal motor branch, between the middle and posterior heads. An additional deep motor branch emerged posterior to the lateral pterygoid (Fig. 11D). A small nerve, independent of and medial to the mandibular, was seen coming through the foramen ovale. Its fibers became entangled with those of the mandibular nerve, especially the posterior deep motor branch. Although no proper otic ganglion could be discerned and the patient lacked parotid glands, it seems most likely that this nerve was the lesser petrosal from the tympanic plexus. The facial nerve entered the internal auditory meatus as usual and coursed laterally. At the normal position of the genu, the greater petrosal nerve was given off, but the facial nerve did not turn posteriorly and inferiorly. Instead it immediately emerged from the skull (Fig. 11C). Its position as it emerged was deep to the branching maxillary artery, inferior to the presumed stapedius muscle, superior and slightly anterior to the stapedialstyloid cartilage. The chorda tympani did not leave the skull separately, but was a branch of the interconnection of facial and auriculotemporal nerves. The motor branches of the facial nerve were normal. The greater petrosal nerve was traced to the pterygopalatine ganglion and appeared normal. The 8th-12th cranial nerves and the cervical plexus were not dissected in detail, but appeared normal. A minor exception was the course of the external laryngeal branch of the vagus, which was described with laryngeal musculature. Salivary Glands

The submandibular and sublingual glands were present and of normal size and histologic structure, although the submandibular appeared very high in position because of the smallness of the mandible. Neither parotid gland nor parotid duct was found. DISCUSS ION Comparison With Other Cases External manifestations. One aspect of MFD which has been thoroughly examined is external appearance. A table of diagnostic criteria was presented by Axellson et a1 [1963] and has been used by most subsequent workers. According to this table, our patient had typical MFD. There were no findings that were atypical of the condition. Skull. Neurocranium. Most discussions of MFD have concentrated on branchial arch derivatives to the exclusion of the rest of the skull. However, when closely inspected, the neurocranium has proved to be abnormal. Kyphosis of the cranial base has been reported previously by Garner [1967] , Dahl et a1 [1975], and Behrents et a1 [1977]. Increased cranial base flexion characterizes a number of primary developmental defects of skeletal tissue, including cleidocranial dysostosis [Bjork, 19721 . The cause is said to be deficient growth at the sphenooccipital synchondrosis [Sperber, 19761. The presence of a general skeletal defect is also suggested by the persistent intrasphenoidal synchondrosis, confirming the observations of Behrents et a1 [ 19771 . Similarly, large numbers of sutural bones

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often accompany abnormalities of ossification [El-Najjar and Dawson, 19771 and have been observed before in MFD by Lockhart [I9291 and McKenzie and Craig [1955]. Premature closure of the metopic suture has not been mentioned before, but digital impressions were found by Campbell [1954] . Middle clinoid processes have not been reported previously in MFD but represent a fairly common anomaly [Lang, 19771. Almost all of the ear anomalies of our patient, as well as gross normality of the inner ear [Hutchinson et al, 1977; Sando et al, 19681 , have been seen before: abnormal stapes with apparent absence of the other ossicles [Sando et al, 1968; Fernandez and Ronis, 19641 , constricted tympanic cavity with absence of external auditory meatus and tympanum [Cliff et al, 19691 , direct lateral exit of facial nerve with fusion of promontory and outer skull [Sando et al, 19681 ,and blind Eustachian tube [Behrents et al, 19771. However, two bilateral anomalies have not been reported before; the continuity of the styloid process with what seems to be the stapes and its articulation with the carotid canal, and the extracranial location of the presumed middle ear muscles and ossicles. The failure of previous studies to identify these structures cannot be taken to indicate that our subject is unique, since earlier investigators did not look for them in such unconventional positions. A small squamous bone without a zygomatic process has been observed by all workers who have examined the skull [Lockhart, 1929; McKenzie and Craig, 1955; Dahl et al, 19751 . An articular eminence is never present, but the mandibular fossa has been variously described as “upwardly displaced” [Cliff et al, 19691 and “shallow” [Lockhart, 1929;McKenzie and Craig, 195.51 . However, the descriptions provided by Dahl et a1 [I9751 and Lockhart [I9291 make it ciear that the articular area is atypically medial, as in the present subject, and probably not homologous to a true mandibular fossa. Exostoses in the region of the infratemporal crest have not been specifically described, but this crest was evidently well developed in the skulls studied by Dahl et a1 [1955] and by Lockhart [ 19291. The sphenoid bone has been described previously only by Dahl et a1 [ 19751, although Lockhart [ 19291 mentions it briefly. Both authors noted marked hypoplasia of the pterygoid process, especially the lateral plate, as was observed in our subject. The Dahl specimen and our patient were deficient in the infratemporal and orbital surfaces of the greater wing and lacked a well-defined pterygopalatine fossa. Also, both subjects had essentially normal sphenoid bodies and lesser wings. Viscerocranium. The mandible of our patient showed most of the changes which have been reported previously; obtuseness, antegonial notching, short neck with small, abnormally shaped condyle [Garner, 1967; Roberts et al, 19751. Interestingly, these defects appear to be more pronounced in our patient, the infant described by McKenzie and Craig [1955], and the fetus of Behrents et a1 [I9771 than in the older individuals studied by other authors. There are additional similarities between our patient and the fetus of Behrents et a1 [ 19771. 1) The anterior inferior border of the mandible shows the same strong eversion. This abnormality is also evident in the radiograms published by Roberts et a1 [ 19751. 2) There was no temporomandibular joint (TMJ) in the fetus, and the cartilaginous condyle (found on one side only) was separated from the cranium by temporalis musculature. This was present bilaterally in our patient. 3) Finally, the only apparent functioning articulation between upper and lower jaws was between Meckel’s cartilage and cartilages in the middle ear region. This area corresponds t o the location of the articulation in our specimen and supports the identification of the “medial condyle” as an ossification around Meckel’s cartilage. If this thesis, viz, that the craniomandibular joint represents the primary first branchial arch joint and not the TMJ, is correct, the question arises as to the


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situation in other reported MFD patients. Since previous papers have evidently not considered this possibility, the needed information is difficult to extract. The following points are germane : 1. A lateral condyle in addition t o the jaw articulation has not been seen in MFD except in our patient and that of Behrents et al. However, in the Behrents fetus, this structure was absent unilaterally, suggesting that the lateral, or true, condyle may not form at all. Even when formed, it is possible that this largely functionless structure could be resorbed postnatally. Interestingly, Pruzansky [ 19691 has illustrated mandibular spicules in a comparable position on the affected side in hemifacial microsomia. 2 . The condyle is always abnormal in form and somewhat resembles abnormal secondary condyles developed after trauma [Bjork, 19721. However, this fact does not clarify the developmental origin of the condyle. 3. As noted above, the squamous articular area described by Dahl et a1 and by Lockhart is more medial than expected, in a position which corresponds better to Meckel’s cartilage than t o the condylar cartilage. 4 . Superior views of the mandible in McKenzie and Craig [1955, Fig. 31 and Lockhart [ 1929, Fig. 11 indicate that the condyles are positioned unusually medially with respect to the coronoid process and the mandibular foramen. However, a comparable view in Dahl et a1 [1975, Fig. 41 does not show a medial position. 5. If the jaw articulation is primary, the head of the malleus is expected to form the condyle, while the body of the incus would form the cranial surface of the joint [Fawcett, 19241. Thus these ossicles should not be in the middle ear. The malleus and incus are variable in the specimens reported. They were absent or exceedingly abnormal in the cases of Lockhart and McKenzie and Craig. However, in the Dahl et a1 subject, the ossicles were absent on one side but normal on the other, yet the articulations were not reported to be asymmetrical. Thus the evidence suggests that the condyle in the patients of Lockhart, Behrents et al, and McKenzie and Craig, and our case,may be derived from Meckel’s cartilage. The Dahl patient does not fit this pattern. To the extent that “ontogeny recapitulates phylogeny,” this situation represents a developmental arrest at a stage of jaw-ear differentiation that is less than mammalian [Allin, 19751. The development of the zygomatic process of the maxilla varies among the cases described. This variation is probably related to the presence and size of the zygomatic bone. which also varies. The deficiency in our subject is more severe than in any case in the literature, since there is no trace of a zygomatic bone on either side, and the zygomatic process of the maxilla is reduced to a diminutive nubbin. The other maxillary defects in our patient are typical of MFD, except for the absence of the infraorbital foramen. The latter condition presumably stems from the abnormal distribution of the infraorbital nerve and artery to the palate. Dahl et a1 [1975] remark that the infraorbital foramen is small in their patient’s skull, and it also looks small in the illustration of McKenzie and Craig [1955, Fig. 41. The area is difficult to observe in Lockhart’s photographs, but no infraorbital foramen can be seen. Anomalous palatal foramina may be present. Thus, absence of the foramen in our subject may be an extreme manifestation of a typical MFD trait. Agenesis of the palatine bones has occasionally been reported in MFD, but closer inspection of the literature suggests this is not the case. The original such report seems to be that of Campbell [1954], who described inadequate vertical dimension of the palatines and inaccurately applied the word “agenesis,” which has been cited by later authors. In the present case the vertical portions of the palatines were short but otherwise normal, and the horizontal portions very small due to the cleft.

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Choanal atresia is considered an infrequent finding in MFD [Axellson et al, 19631, but only Behrents et a1 [1977] report malformations of the conchae. Our results agree with this observation. The hyoid and larynx have not previously been described in MFD. Muscles. Facial. The only mention of facial muscles in the MFD literature is the remark of McKenzie and Craig that they were “unusually well developed, there being many extra muscle bundles in the facio-platysma sheet.” The figures of Behrents et a1 [1977] illustrate generally that the size and position of the facial muscles are similar to those of a normal fetus. One possible exception to this normality is in their Figure 4, in which fibers of the buccal region concentrate heavily on the angle of the mouth in the MFD subject but are more dispersed in the normal control. This observation, if real, may relate to the situation in our patient, in which the upper lip muscles inserted only on the angle of the mouth, none reaching the upper lip. Although further comparison with MFD subjects is not feasible, an interesting perspective can be gained by contrasting our findings with those of Bersu and Ramirez-Castro [1977] in 18-trisomy. The trisomy infants had hypoplastic frontal, auricular, and nasal muscles, apparently more severe than in our case of MFD. In addition the lip muscles were extensively fused near the angle of the mouth and there was a supernumerary muscle between the corner of the mouth and the occiput. The former condition was also seen in the present study, the latter was not. Suprahyoid, The suprahyoid musculature in MFD has not been described previously, but an important point is illustrated in Figures 11 and 1 2 of Behrents et a1 [1977]. In their Figure 12, the mylohyoid clearly takes origin from the perichondrium of Meckel’s cartilage, in contrast t o the normal fetus,in which the muscle has transferred its attachment t o membrane bone above the cartilage. This perhaps is another indication of increased importance of Meckel’s cartilage in MFD. Variations of the suprahyoid muscles are common even in normal individuals. The trisomy 18 studies [Bersu and Ramirez-Castro, 19771 revealed a concentration of defects in the stylohyoid and posterior diagastric, as in the present study, although the specific abnormalities were not the same. Trigeminal. McKenzie and Craig [ 19551 remarked on the tendency of the masticatory muscles to become confluent. Behrents et a1 [1977] refer generally to “masseter muscle deficiency and abnormal muscle attachment” (p 25) without going into detail. In addition they found an abnormal attachment of the lateral pterygoid, inferior head, to the body of the mandible below the condylar neck with apparent fusion of the superior head and temporalis. A comparison of their Figure 10 with our findings suggests that their undifferentiated superior head of lateral pterygoid corresponds t o the deep temporalis of the present description. We prefer our interpretation because the muscle inserts on the coronoid process, as is typical for temporalis. The variations of temporalis, lateral, and medial pterygoids shown in the Behrents Figure 10 are very similar to our findings except for the absence of bone formation around Meckel’s cartilage. Partial attachment of lateral and medial pterygoids to Meckel’s cartilage is known in early developmental stages, but normally disappears by eight weeks gestation [Yuodelis, 19661. Lockhart [I9291 described the masseter and temporalis in some detail. Comparison between his subject and ours is difficult because his patient had a single condyle, which probably corresponds t o the medial condyle of our case. The following similarities appear to obtain: 1) The superficial masseter has partial origin from the stump representing the zygomatic process of the maxilla; 2) the temporalis lies lateral to the (medial) condyle; and 3) deep temporalis origin is quite low


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on the squama. The major difference between the two individuals is the absence in ours of Lockhart’s “deep masseter,” which arose from the superficial tempordis and articular disk and attached t o the masseteric fossa. In our patient, instead of a muscle in this position there was a ligament between the temporalis and masseter which was interrupted by the lateral condyle. The fiber orientation was the same as Lockhart’s “deep masseter.” Possibly the interference of the lateral condyle prevented the differentiation or maturation of the mesenchyme of this area into the muscle. None of the previous discussions of MFD have dealt with the tensor veli palatini, but comparisons can be made with other cleft palate dissections. Except for the very horizontal orientation of the belly, tensor structure generally resembled that found in other cleft palate cases [Dickson et al, 19741. The tensor tympani muscle may be well developed in MFD [Lockhart, 1929; Sando et al, 19681 or it may be absent [Sando et al, 19681. The muscle may be present even when the malleus is not and in such a case may insert on the lateral wall of the tympanic cavity [Lockhart, 19291 or the bony mass in the cavity [Sando et al, 19681. Sando et a1 pointed out that in their specimen the muscle was not enclosed by bone. This was also the case for the presumed tensor tympani in the present subject. In addition, the muscle did not enter the tympanic cavity. The possibility of incomplete differentiation of tensor tympani from the pterygoids has not been suggested by previous authors, and on the basis of temporal bone histology alone the muscle would surely have been thought missing. Other. Apparently only Sando et a1 [ 19681 have looked for stapedius in MFD, and they did not find it. However, as with the tensor tympani, an extracranial location of the muscle has not previously been considered. Palatal and pharyngeal muscles have not been described before in MFD, but comparisons with cleft palate subjects are again possible [Dickson et al, 19741. Our case resembled these patients in the attachment of palatopharyngeus and levator veli palatini to the cleft edges of the hard palate but differed from them in the horizontal orientation of the levator. No comparisons are available for the musculature of the larynx. Vessels and nerves. Arteries. The arterial circulation in MFD was described only by McKenzie and Craig [1955]. Like them, we found that the maxillary artery was severely modified, while remaining vessels were normal. However, there were specific differences between the two subjects, and our case was different on right and left sides. The salient features of the comparison are as follows: 1. McKenzie and Craig report normal middle meningeal vessels. In our subject an abnormally posterosuperior middle meningeal artery entered the ear region on both sides. On the left side there was a second meningeal branch well anterior to the foramen ovale. 2. McKenzie and Craig observed the sphenopalatine artery leaving the maxillary trunk near the inferior alveolar branch point, traveling through the infratemporal fossa beneath the lateral pterygoid until the pterygopalatine fossa. We observed nearly the same pattern on the right side of our subject, but on the left side the sphenopalatine artery stemmed normally from the termination of the maxillary. 3. McKenzie and Craig could not trace the maxillary artery farther than the infratemporal space and stated that the infraorbital artery was a branch of the ophthalmic. We were able to trace the maxillary artery into the apex of the orbit even on the right side, which otherwise showed a branching pattern similar to that of McKenzie and Craig’s specimen. We did not attempt to demonstrate the connection between maxillary and infraorbital on the right side but did so on the left.

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4. McKenzie and Craig made no reference t o the highly abnormal distribution of the infraorbital artery t o the palate which we observed. However, since their infraorbital artery was derived from the ophthalmic, the possibility of the terminal branches of the maxillary being distributed to the palate remains open. 5. Other anomalies in the maxillary artery branching patterns of the two MFD subjects are not infrequent in normal persons. This includes the “aberrant anastomotic” endocranial branch of the middle meningeal, which is given considerable weight in McKenzie and Craig’s discussion. According to “Gray’s Anatomy” [Warwick and Williams, 19731 the middle meningeal normally supplies branches in this region to the trigeminal nerve and ganglion. We agree with the general observation of Behrents et a1 [1977] that the head in MFD is richly vascularized. Nerves. Behrents et a1 [ 19771 speculated that nervous system abnormalities might be primary in MFD but did not describe the cranial nerves. In the present study the infraorbital branch of the maxillary nerve probably resembled its accompanying artery in being abnormally distributed to the palate. As might have been expected from the altered topography of the infratemporal fossa, the mandibular nerve had an anomalous branching pattern, and there was extensive anastomosis with the facial nerve. The facial nerve’s petrosal course has been described by Sando et a1 [1968]. The present study confirms the absence of the horizontal and vertical parts of the facial canal and absence of the chorda tympani (although this nerve was identified in an extracranial location). In contrast to Sando et a1 we found the greater superficial petrosal nerve in its usual position. Salivary glands. Behrents et a1 [ 19771 found gross hyperplasia of parotid and submandibular glands. In our subject the submandibular gland was large but not abnormally so, and the parotid gland was absent. Parotid aplasia was also found by McKenzie and Craig [ 19551 and is frequent in hemifacial microsomia [Grabb, 19651. The absence of any trace of the parotid makes it seem unlikely that the gland and/or duct could have been present prenatally and then lost. A plausible explanation for the sporadic presence or absence of the parotid gland has been given by Grrineberg and Wickramaratne [ 19741. Working with mouse mutants, these authors noted that the parotid duct is formed just behind the angle of the mouth, in line with the commissure. If the curvature of the commissure is abnormal, the duct is not initiated. An analogous situation holds for human branchial malformations, in which the orientation of the commissure and position of the angle are often abnormal. Clinical Correlations and Function

A number of the findings of this study have bearing on the disability of MFD patients. One of the most pervasive difficulties in the management of this syndrome is maintaining the airway, especially during feeding. Several findings help explain this difficulty. 1) The airway itself is very much reduced anteroposteriorly at the level of the vocal ligaments. Any movement of the hyolaryngeal apparatus might tend t o close off the narrow passageway completely. 2) It is known that the tongue impinges on the airway because it is relatively too large for a small oral cavity;in addition glossoptosis was reported in this patient. A likely explanation for the glossoptosis is the hypoplasia of the geiiiohyoid muscle, the major protrusor of the hyoid and root of the tongue. 3) Because of extreme kyphosis of the cranial base, the palatal levator pulls backwards rather than upwards, possibly causing further interference with the airway. The abnormal vocal quality in patients with MFD may also be related to malformations affecting the vocal tract (Peterson-Falzone, personal communication, 1978).


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Because of surprising absence of the elevators of the upper lip, a brief examination of facial muscle function was made on three patients at the University of Illinois Center for Craniofacial Anomalies-two with MFD and one with hemifacial microsomia (HFM). The patients were asked to smile (zygomaticus major), raise their eyebrows (frontalis), and elevate the upper lip. The MFD patients had no trouble with the first two tasks, indicating adequate motor function and confirming the normality of the muscles, but had trouble with the third task. One was unable to produce any movement of the upper lip, while the other raised his upper lip slightly by tensing it. This action is more likely due to orbicularis oris than to levator labii superioris. The same patient had no difficulty in performing a comparable movement with his lower lip. In contrast, the HFM patient easily performed the upper lip task, although he showed some asymmetry in frontalis function. This limited series of clinical tests appears to indicate that deficiency of the upper lip elevators is characteristic of MFD. Another point of clinical interest concerns the abnormal course of several nerves and the problem of local anesthesia in dental and minor surgical procedures. An attempt at an infraorbital nerve block on a patient similar t o ours would be doomed t o failure, but similar results might be achieved by injection into one of the abnormal palatal foramina. An inferior alveolar block would probably be feasible if the altered relation of mandibular foramen to condyle were accounted for, but the lingual nerve, embedded in the medial pterygoid muscle, tniglit not be anesthetiLed. Finally, the modified shape of the jaws and attachments of the masticatory muscles must strongly affect jaw mechanics in MFD patients. Mobility of the mandible has not yet been studied in them, but the structure of the temporal articulation surface suggests that anteroposterior translation might be restricted. This in turn would limit the possible extent of both lateral deviation and jaw opening. A second factor that would limit anterior excursion is the comparatively vertical orientation of the lateral pterygoid muscle, which is usually considered the major jaw protrusor. The anterior position of the joint and shortness of the mandible should further limit jaw opening, since for the same rotation at the condyle, less movement will occur at the anterior end of the jaw. With the exception of the lateral pterygoid, the normal lines of action of the masticatory muscles are generally retained. However, these vectors of muscle pull have altered positions with reference to the condyle, which means that the mechanical advantage of the muscles will differ from normal. The most distinct example of this is the medial pterygoid muscle inserting at the level of the joint instead of on the angular process. The moment arm of this muscle around the joint is very much reduced, causing a diminished contribution to masticatory force. These brief comments have been based primarily on the anatomy of a single case, and their application to other cases is yet to be demonstrated. Nonetheless, this type of analysis serves to direct clinical attention t o areas where problems can be anticipated. Several of our suggestions could be easily tested in the clinic: for example, direct measurement of the mandible’s envelope of motion or assessment of masticatory force with pressure transducers. Interpretation

In searching for a general pattern which might explain the great variety of anatomic aberrations found in MFD, we have found that most of the aberrations can be sorted into three categories: 1) retarded skeletal growth; 2) misplacement of the branchial arch derivatives in relation to the neurocranium; and 3 ) small size and abnormal distribution of the maxillary division of the trigeminal nerve.

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Skeletal growth. Retarded development of the skeleton was indicated by open synchondroses and kyphosis of the cranial base, sutural bones in the squamous and lambdoid sutures, digital impressions, and poor ossification of the greater wing of the sphenoid. Possibly the abnormalities of the laryngeal skeleton can also be related to this effect, especially the anteroposterior shortness of the thyroid lamina and its perforation by the external laryngeal nerve, which suggests that the cartilage may have formed late, after the nerve was already in position. These defects are not limited t o bones derived from neural crest cells, nor even to membrane bones. Moreover, an effect of long duration is indicated, rather than some brief embryonic event. It is notable that although extracraniofacial malformations are not characteristic of MFD, it is a general clinical impression that such patients are slighter than average (Pruzansky, unpublished observation). A more precise analysis of this finding is currently under way. Skeletal retardation may, therefore, be general. Malpositioning of branchial arch derivatives. The viscerocranium is hafted to the neurocranium more anteriorly than usual, producing a very acute angulation. This effect is shown by the acute cranial base angle, the shortness of the vertical plate of the palatines, the “downward” posterior slope of the orbital surface of the maxillary, and the increased distance between the branchial structures and the inner ear and facial nerve. Some insight into this effect is yielded by a close examination of the mouse model of MFD produced by hypervitaminosis A [Poswillo, 19751. In Figure 8 (p 13) of that paper an experimental 1 1-day fetus is compared to a normal one. In describing the affected specimen, Poswillo points out the general reduction of cephalic mesenchyme and displacement of the otocyst. The illustration also shows that the 1st and 2nd branchial arches are partially fused proximally and are acutely angled relative to the neurocranial primordium. In addition, cephalic flexure is increased, although this may be due to individual variation. The overall appearance strongly resembles that in man and suggests that the misorientation of the branchial arches is one of the earliest manifestations of MFD. Concentrating on the small size of the arches, Poswillo postulated neural crest cell death as the primary defect. However, more recent work on vitamin A suggests a modified view (see Hassell et al, [ 19771 , and references cited). According to these authors, the major target of vitamin A is the biochemical makeup of the intercellular matrix and/or cell surface glycoproteins. The effect on neural crest is indirect, consisting of inhibition of migration. Hassell et a1 observed crest cells accumulating at the base of the arches, which would account for the small size of the arches, their proximal fusion, and the separation of arches and otocyst (or more likely, failure of the otocyst to migrate from its original position). Incomplete crest migration could also account for the angulation of the arches, since at least in the chick, crest cells migrate dong an oblique path, going caudally as well as ventrally [Noden, 19731. An anteriorly positioned, angulated viscerocranium thus appears to be an ontogenetically early manifestation of MFD. A number of other MFD characteristics can be interpreted as sequelae of this essential malposition and are discussed below. Although these suggestions are speculative, they are based on established facts of descriptive embryology and developmental biology. Nearly all can be tested, using either experimental techniques on animal models or predicted clinical correlations for syndromes other than MFD. 1. Middle ear differentiation. According to Hanson et a1 [ 19621, the differentiation of the proximal portions of the 1st and 2nd branchial blastemata is intimately related to the branching pattern of the facial nerve. In particular, the trunk of the seventh cranial nerve splits the blastema of the 2nd arch into a stapes primordium plus laterohyale (which forms the lateral wall of the facial canal) and Reichert’s cartilage (styloid process plus parts of hyoid), the intervening section becoming the tendon of stapedius. The branching


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point of the chorda tympani nerve then separates the primordium of the long processes of incus and malleus from Reichert’s cartilage, while the chorda tympani itself separates the long crus of the incus from the manubrium of the malleus. In the “scenario” proposed for MFD, the branchial apparatus is placed anteriorly, out of contact with the inner ear and facial nerve. The nerve, uninfluenced by the developing blastemata, takes the shortest possible course to its destination. The branchial structures, isolated from the nerve, fail to differentiate. The stapes, long crus of the incus, and manubrium of the malleus remain fused with Reichert’s cartilage; the stapedius muscle lacks a tendon and does not attach to the stapes. These events would be more or less complete, depending on the completeness of isolation of the otocyst from the branchial arches. The failure of the external auditory meatus may be secondary to the middle ear failure, but also may be a direct result of the total or partial obliteration of its precursor, the proximal part of the first external branchid groove. 2. Maxillary artery branching pattern. The two most unusual arterial findings of this study were the posterior position of the middle meningeal artery and the proximal branch point of the sphenopalatine artery. The middle meningeal artery is formed from the distal portion of the stapedial artery and the trunk of the stapedial’s former maxillomandibular branches [Padget, 19481. A posterior position of the middle meningeal therefore implies that the maxillomandibular trunk (and therefore the jaws) was closer to the middle ear region than usual, which is the arrangement observed. There is no information in the literature that speaks to the branch point of the sphenopalatine artery. However, since the definitive branching pattern develops gradually from an arterial network around the pterygoid musculature, which is abnormal in MFD, perhaps the proximal origin of the sphenopalatine is also a secondary result of branchial malpositioning. 3 . Mandible, Meckel’s cartilage, and jaw joint. The condylar process grows backwards from the mandibular condensation while the squamous condensation, formed subdermally in relation to the mandibular nerve, grows forward [Yuodelis, 19661. The evidence from the present study is that both of these events were initiated. However, because of the “buckled” skull, the mandibular nerve, and thus the zygomatic root, are placed anteriorly, so that the latter lies in the territory of the alisphenoid. The growing condyle therefore meets with nothing but developing temporalis, and no TMJ is formed. The existing articulation between Meckel’s cartilage (head of malleus) and skull (body of incus) is the only functioning jaw joint and must be solely responsible for absorbing the stresses produced by early masticatory muscle contractions. Bone growth in response to a stressful environment is a well-known phenomenon and could account for extension of membranous ossification around Meckel’s cartilage, for the retention of primitive pterygoid and mylohyoid muscle attachments t o Meckel’s cartilage, and for the failure of the articulating end to differentiate into the malleolar head. Similarly, it is possible to account for the absence of a zygomatic ossification. The mesenchymal primordium of the zygomatic is present in the form of the aponeurotic origin of superficial masseter and zygomaticus major muscles. This aponeurosis is attached to the three anchorage points of the bone: zygomatic processes of frontal, maxillary, and squamous (or alisphenoid in this case). The problem is therefore failure t o ossify rather than absence. Ossification of the zygomatic bone normally begins in the seventh to the eighth week of gestation, just after the anlagen of condyle and glenoid become juxtaposed. It seems possible that the compressive stresses produced by embryonic jaw movements are instrumental in evoking this ossification. Then in the absence of the TMJ, the only stresses would be tensile forces from muscular attachments, and ossification might not take place. In this connection, Bassett and Herrmann

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[I961 J have shown that fibroblasts in vitro with high oxygen levels will form bone under pressure but only fibrous tissue under tension. Further, Oxnard [1971] has suggested that bone is never found under conditions of net tension. If these suppositions are correct, defects of zygomatic ossification should always accompany failure of TMJ formation. 4. Other skeletal malformations. The geometric position and possibly the form of the mandible may be a direct reflection of its peculiar articulation with a kyphotic cranial base. The most severely affected bone in terms of ossification is the greater wing of the sphenoid. It lies in the center of the buckled area of the skull and so has unusual relations with neighboring structures, notably the lateral pterygoid muscle. Also, the greater wing of the sphenoid is closely associated with the TMJ and might, like the zygomatic, be mechanically affected by its absence. From the foregoing i t is clear that both form and function are affected by the anomaly complex, and it is difficult to unravel independent influences on the resultant phenotype. Maxillary nerve. Since the branches of the trigeminal nerve develop before the arterial branches [Padget, 19481, we assume that the nerve rather than the artery is responsible for the aberrant distribution of the infraorbital neurovascular bundle. The nerve also precedes the mesenchymal condensation that becomes the maxilla, so it cannot be considered that its path was somehow blocked by an abnormal skeleton. Apparently there is nothing wrong with nerve growth per se, since no other nerve is affected in this way. Current theories on nerve branching emphasize two factors as important for determining nerve pathways: 1) an interaction between the nerve and its target, probably involving growthpromoting substances produced by the target [Marx, 1974; Pollack and Liebig, 19771 ; and 2) a spatial effect with reference to body coordinates [Diamond, 19761, which could be determined by any of the mechanisms proposed for positional information [Wolpert, 19711. Regarding the first factor, it is interesting to note that the “target” of the infraorbital nerve, primarily the skin of the midface, is involved in MFD. The resultant anomalies affect derivatives of the lower eyelid ectoderm: coloboma, misplaced and hypoplastic lashes, and absence of lacrimal canaliculus. Another possible association involves the facial muscles in the upper lip area. These muscles receive motor innervation from the facial, not the maxillary nerve, but there is usually extensive anastomosis among the finer branches of these nerves, and it is possible that the sensory supply of the muscles is trigeminal. Although these midface anomalies may be correlated with the absence of a normal infraorbital nerve, they are so disparate as to suggest that they are the effects, rather than the causes, of that absence. The second factor in nerve growth, position effect, may be of greater significance, since it was shown above that the branchial arches are out of place and could conceivably have misdirected the infraorbital nerve to the palate. Pathogen esi s

Theories of MFD pathogenesis have been recently summarized by Behrents et a1 [ 19771 . Most can be grouped into three categories. The first is the abnormality of the stapedial artery proposed by McKenzie and Craig [ 19551 and McKenzie [ 19581. This model was rejected by Poswillo [ 19731 on the basis that it is unlikely that such a mechanism could work symmetrically. Behrents et a1 [ 19771 also objected to the model, since the stapes is usually the least affected ossicle and since they observed no paucity of vascularization. We can add further evidence against the arterial model, because the arterial abnormalities in our subject differed importantly from those described by McKenzie and Craig [1955] ;moreover, they could be explained as secondary results of abnormalities of branchial arch position.


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The second pathogenetic category is deficiency of mesenchyme, particularly neural crest (see Poswillo [ 19751 and many earlier writers). The neural crest model is generally accepted, but has been critized by McKenzie and Craig [ 19551 for not explaining why the zygomatic region is greatly affected while midline areas are not. Behrents et al [1977] have also pointed out that other neural crest derivatives such as teeth are comparatively normal, while many skeletal parts not derived from neural crest are abnormal. It is important t o note that the neural crest theory is based in large part on the hypervitaminosis A mouse model [Poswillo, 19751. The vitamin A experiments are excellent mimics of MFD but, as mentioned above, vitamin A probably does not act by specifically killing neural crest cells, but by altering migration perhaps via the intercellular matrix. Behrents et a1 [1977] proposed a third pathogenetic model-that of defective nervous development, possibly sympathetic, on the basis of the salivary gland hyperplasia observed in their subject. As they point out, problems with this model include the lack of any postnatally observed nerve defects and the absence of similar salivary gland findings in other patients. In addition this model is not very satisfactory on an operational level, since it does not specifically account for the particular defects of MFD such as the missing zygoma . At the present time the best resolution of the problem may lie in accepting the hypervitaminosis A model as affecting primarily the intercellular matrix, rather than neural crest. That would account for separate effects on skeletal growth and cellular migration. The formation and growth of cartilage and bone are known to depend on matrix [Glenister, 1976; Jande and Belanger, 19731, and reduction in amount or change in quality of the matrix could conceivably cause general skeletal retardation. Since this effect occurs postnatally as well as prenatally, the matrix defect might persist and might be detectable biochemically. During development the diminished or altered matrix could act to inhibit or retard cell migration. A correlation between amount of matrix and the shape of the epithelium has in fact been observed in rat embryos by Morris and Solursh [ 19783. Although the defect is not restricted to the cranial region, the branchial arches would be most affected, since they depend most on cells migrating long distances through the matrix. The resulting abnormal size and position of the arches are in turn linked to the malformation of the middle ear, jaw joint, zygomatic arch, maxillary artery, and possibly infraorbital nerve. An altered matrix environment could also have separate effects on salivary gland growth (Behrents et al, 19771 . The apparent timing of the pathogenetic “event” at seven weeks in utero would then be a simple result of the appearance at this time of the developmental consequences of improper migration. Earlier morphogenetic movements are probably due to differential cell and tissue growth, rather than the migration of individual cells. This generalized mechanism for pathogenesis supports the notion of MFD as a developmental field complex with a cellular defect as its basis. ACKNOWLEDGMENTS

This work was supported in part by a grant from the National Institutes of Health (DE-02872), Department of Health, Education and Welfare. The illustrations were drawn by Lynn Gambill, and the skull was photographed by William Winn. We are grateful to Dr. Thomas Lakars for histologic studies, to Dr. Walter Greaves for reading the manuscript, and to Dr. Celia Kaye for several helpful suggestions. Dr. Rolf Behrents generously lent prints of the 15-week MFD fetus.

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Edited by John M . Opitz

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