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Oculoauriculovertebral dysplasia (Goldenhar's syndrome)
Oral pathology American
Academy
of Oral
Pathology
Donald Kerr, Editor
Oculoauriculovertebraldysplasia (Goldenhar’s syndrome) Milton
D. Be&man,
DEPARTMENTS SCHOOL
OF
08
D.M.D., and Murray
ORAL
PATHOLOGY
DENTAL
MEDICINE,
UNIVERSITY
SCHOOL
OF MEDICINE
HOSPITALS
(BOSTON
FLOATING
AND AND
Peingold, M.D., Boston, Mass.
ORAL
PEDIATRICS,
DEPARTMENT
AND
THE
HOSPITAL
NEW
TUFTS
OF
TUFTS
MEDICAL
CENTER
ENGLAND
FOR INFANTS
UNIVERSITY
PEDIATRICS,
AND
CHILDREN)
0
culoauriculovertebral dysplasia was first described by von Arltl in 1845, and the eponym dates from a description published by GoldenhaP in 1952. Gorlin and associates3 suggested the more descriptive title of ocubauricukovertebral dysplasia, which delineates the three major components of the syndrome and the pathologic process. The major manifestations of this syndrome are eye, ear, and vertebral anomalies. The eye anomalies consist of epibulbar dermoid tumors, lipodermoid tumors, and coloboma of the upper eyelid (Fig. 1). The epibulbas dermoid tumor is most frequently bilateral and usually is located at the limbus or cornea1 margin of the lower outer quadrant of the eye (Fig. 2). Occasionally a lipodermoid cyst is found in the upper outer quadrant, where it may occur alone or accompany a dermoid cyst. The ear may be small, low-set, or abnormally shaped, with stenosis or atresia of the external auditory meatus. A constant finding is the presence of bilateral preauricular fleshy appendages, which are usually multiple, often pedunculated, located anterior to the tragus, and found along the line from the tragus to the corner of the mouth. Blind fistulas are often found in the same area, but these are not always bilateral. The vertebral anomalies include occipitalization of the atlas, fusion of one or more of the vertebrae, hemivertebrae, supernumerary vertebrae, spina bifida, and scoliosis, plus other abnormalities. Oral and facial anomalies associated with this condition are unilateral hypoplasia of the mandible and maxilla, micrognathia, ogy,
Presented at the twenty-first Miami Beach, Fla., April
annual 7, 1967.
This investigation was supported 33, 341-02 from the National Institute
408
meeting
of
the
American
Academy
of Oral Pathol-
in part by Public Health Service Fellowship 5-FZ-DEof Dental Research and the National Foundation.
Oculonuriculoz~ertebral
Volume 25 Number 3
Pig. 1. Coloboma quadrant.
of upper
eyelid
Fig. 3. Patient R. D:, showing metry of nostrils, and mmrognathia.
and epibulbar
epibulbar
dermoid
dermoid
tumors,
tumor
dysplasia
located
preauricular
in lower
appendices,
409
outer
asym-
macrostomia, high arched palate, cleft lip and palate, malocclusion, and/or open-bite, as well as other dental malformations. The purpose of this article is to report four cases of Coldenhar’s syndrome and to demonstrate the variations in this symptom complex, with emphasis on the oral manifestations. CASE REPORTS CASE
1
Patient B. C., ii-year-old white girl, was admitted to the Boston Floating Hospital for Infants and Children for evaluation of a facial asymmetry which had been present since birth. The patient was the product of a full-term, uncomplicated pregnancy and delivery of
410
Be&man
and Peingold
O.S., O.M. & O.P. March, 1968
a 21-year-old mother. There was no history of infections or medications during the pregnancy. Birth weight was 7 pounds, 12 ounces. At birth, the child was noted to have a cleft palate and asymmetry of the face, with the left side smaller than the right. Additional abnormalities included ptosis of the left eyelid, weakness of the left lateral rectus muscle, dermoid cyst of the sclera on the left, bifid lobe and protrusion of the left ear, preauricular and infraauricular skin appendages, and a clubfoot. Otoplasty and excision of the auricular appendages were performed when the patient was 5 months old and the cleft palate was repaired a month later, with no complications. There was no family history of birth defects or consanguinity. The parents and a 4-year-old sibling were in good health. Physical examination revealed a well-developed, well-nourished white girl in no distress. The vital signs were normal. The child was in the seventy-fifth percentile for height and weight. There was hypoplasia of the forehead, palpebral fissure, zygoma, maxilla, mandible, and tongue on the left side. Ptosis of the left eyelid and an open-bite on the left side were also noted. There was a 4 mm. episcleral dermoid tumor in the lower outer quadrant of the left eye, which covered a small portion of the iris and conjunctiva. There was bilateral lateral rectus muscle weakness, which was more marked on the left than on the right. Convergence was decreased and diplopia was present on lateral gaze. The fundi were normal. The inferior aspect of the left ear was rotated anteriorly, and the external auditory meatus and canal were steno&L On the left side there was a preauricular skin tag anterior to the left tragus, and incisional scars secondary to removal of other preauricular tags were also present. There was a Grade 3/a ejection systolic murmur, heard best at the left sternal border at the second and third intercostal spaces. The left clavicle was more prominent than the,right. There was a slight cervicothoracic scoliosis, with concavity toward the right. There were no gross or focal neurologic signs other than the aforementioned eye findings.
Fig. 3’. Types of malocclusion. B, Patient B. C., demonstrating lateral open-bite. B, Patient P. J., with anterior overbite and posterior cross-bite. C, Patient 8. B., demonstrating anterior open-bite and protrusion of maxillary anterior teeth.
Volume 25 Number 3
Oculo~uriculovertebrnl
dysplasia
411
Oral examination disclosed a slight maerostomia on the left. The left side of the tongue was hypoplastic and deviated to the left on protrusion. There was a high-arched palate, with slight scarring in the area of the soft palate secondary to cleft palate repair. The left maxillary and mandibular deciduous canines, first molars, and second molars did not occlude (Fig. 3, A). There was no asymmetry of the nose. X-ray studies showed that the mastoid and zygomatic bones and the ramus and body of the mandible were hypoplastic on the left side. The left temporomandibular fossa was small, with anterior displacement of the condyle. The teeth appeared normal in size. There was widening of the interpedicular spaces, especially of the lower cervical vertebrae. On flexion and extension of the cervical spine, the atlas remained fixed in relation to the occiput, although there was no evidence of bony union. The odontoid process of the axis was unusually long, and articulation of the atlas was remote from the body of the second cervical vertebra, representing a supernumerary vertebra at the atlantoaxial level. There was slight curvature of the dorsolumbar spine. Spina bifida involving the lower rervir.al vertebrae and the upper three dorsal vertebrae was present. Audiometric examination revealed that the patient’s hearing in the right ear was within normal limits. The left ear demonstrated moderate sensorineural hearing loss at frequencies less than 1,000 cycles per second but no hearing loss at the higher frequencies, Speech discrimination in the right ear was better than in the left. CASE 2
Patient R. D., a 3-month-old white boy, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. The infant was a product of a full-term, uncomplicated pregnancy and delivery of a 35.year-old gravida V, para 4, abortus 1 mother. The birth weight was 8 pounds, 14
Fig. 4. Posteroanterior radiogram of Patient dible and hypoplasia of ramus on right.
P. J., showing
marked
asymmetry
of man-
412
Berkmm
and Feingold
O.S., O.M. & O.P. March, 1968
ounces. Pregnancy was uneventful until the last month, when the mother was placed on diuretic therapy for ankle edema. There was no family history of birth defects or consanguinity, but a paternal great aunt was said to be retarded. The parents and three siblings were in good health. Eye, ear, and facial deformities were noted at birth. The child had had no difficulty since birth. Physical examination revealed a well-developed, well-nourished white male infant in no distress. The vital signs were normal. The child was in the fiftieth percentile for height, There was slight hypoplasia of the left side of the face. weight, and head circumference. A coloboma was present in the middle of the left upper lid. A 6 by 6 mm. whitish, round, epibulbar dermoid tumor was noted in the lower outer quadrant of the right eye, and an 8 by 8 mm. whitish, round, epibulbar dermoid tumor was seen in the lower outer quadrant of the left eye. The fundi were normal. The left ear had a slightly misshapen pinna; the tragus W&S absent and the coneha was enlarged. Multiple ear tags were present in the right and left preauricular regions. A small fistula was noted in the left preauricular region. There was a large, pedunculated skin tag on the right cheek, midway between the tragus and the corner of the mouth. The right nostril was asymmetric, and a tab of tissue covered with nasal mucosa was attached to the medial wall of the right nostril. A cherry-red hemangioma was noted on the right flank. There were no gross or focal neurologic signs, and the mental and motor development was normal for the patient’s age. The remainder of the physical examination was also normal. Oral examination disclosed that the child had slight to moderate micrognathia and a moderately high-arched palate. No teeth were present at the time of examination. The buccal mucosa, tonsils, and pharynx were normal. On x-ray examination, the zygoma and mandible were found to be slightly hypoplastic. The ramus and condyle on the left were underdeveloped in comparison to those on the right. There was incomplete fusion of the posterior portion of the neural arch from the fifth cervical through the fifth dorsal vertebrae. There was no evidence of abnormal segmentation. Audiometric examination indicated that the patient’s hearing was within normal limits. CASE 3
Patient P. J., a 3x-year-old white girl, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. The child was born following a pregnancy that was uneventful until term, at which time the mother developed vaginal bleeding. The patient was delivered by cesarean section, at which time an abruptio placenta was found. There was no history of infections or medications during pregnancy. The birth weight was 5 pounds, 12% ounces. At birth, the patient’s right ear was malformed and the external auditory meatus was absent. Hypoplasia and facial paralysis were noted on the right side, and there was a cleft palate. X-ray films at birth showed hypoplasia of the right zygoma, maxillary sinus, orbit, and mandible, as well as hemivertebrae and fusion of the cervical vertebrae. The patient also experienced feeding difficulties during the neonatal period. The cleft palate was repaired when the child was 15 months old, and bilat.eral inguinal hernias were repaired when she was 21 months of age. There was no family history of consanguinity, but two siblings had syndactyly of the toes. The mother, father, and three siblings were in good health. Physical examination revealed a small white girl in the third percentile for height and weight. Vital signs were normal. There was severe hypoplasia of the right forehead, palpebral fissure, malar area, maxilla, and mandible. Also on the right side, there were ptosis of the eyelid, questionable superior reetus muscle weakness, and anti-mongoloid obliquity. There were no dermoid tumors or colobomas. The right ear was low set and aplastic, with no external auditory m&us. A pedunculated supernumerary ear tag was present anterior to the aplastic right ear. The left ear was normal. The remainder of the physical examination findings were within normal limits. Oral examination disclosed slight microstomia, asymmetry of the right side of the mouth, and an elongated philtrnm. The palate was constricted, and there was moderate scarring secondary to cleft palate repair, The soft palate was short and underdeveloped, and movement
Volume 25 Number 3
Oculoauriculovertebral
dysplasia
413
of the palatal muscles was limited. The tongue was hypoplastic on the right side, and there was slight mierognathia on the right. The right side of the maxillary arch was hypoplastic, and the entire arch was V-shaped, with crowding of maxillary deciduous teeth and overlapping of the deciduous central incisors. Three mandibular incisors were present. A deep anterior overbite and a severe posterior cross-bite on the right were present (Fig. 3, B). There were several carious teeth. X-ray examination showed that the temporal bone and zygoma were hypoplastic. on the right side. The orbits were slightly asymmetrical, with the right one lower than the left. The posterior fossa was slightly deeper on the right than on the left. The right maxillary sinus and right maxilla were smaller than those on the left side. There was marked asymmetry of the mandible, with shortening of the body on the right. The ramus on the right was hypoplast,ie and shorter than on the left, and the right temporomandibular joint was infantile in development (Fig. 4). The cervical spine showed abnormal segmentation, fusion, and hemivertebrae. The remainder of the skeletal survey revealed congenital fusion of the bodies of fourth and fifth lumbar vertebrae and asymmetry of the upper dorsal spine on the right at the level of the second and third thoracic vertebrae. Audiometric and speech examination indicated that the patient’s hearing on the left side was within normal limits. On the right there was a conductive loss of 60 to 70 d&h&, as a result of the absence of the external auditory meatus. The patient demonstrated distortions of sibilant sounds and nasal speech which was related to the cleft palate. CASE 4
Patient 8. B., a white boy 9 years 3 months of age, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. This child was the product of a full-term, uncomplicated pregnamy and delivery of a 30-year-old gravida V, para 4, abortus 1 mother. There was no history of infections or medications during the pregnancy, and there was no family history of consanguinity or birth defects. The parents and four siblings were in good health. Several eye abnormalities, facial asymmetry, preauricular skin tags, atresia of t,he left ear, and a heart murmur were noted at birth. Chromosomal analysis was normal. The preauricular skin tags and those on the cheek were removed when the patient was 3ji2 months of age. A coloboma on the middle third of the right upper eyelid was repaired when he was 18 months old, and an epibulbar dermoid tumor in the right eye was partially removed when he was 4 years of age. Plastic repair of a coloboma of the right eyebrow was performed when the boy was 5, and when he was 6% years old the macrostomia of the left side of the mouth was repaired and the micrognathia was improved with a silicone implant. Physical examination revealed a well-developed, well-nourished, white boy who was in the fiftieth percentile for height and weight. Vital signs were normal. There was hypoplasia of the forehead, palpebral fissure, malar area, and mandible on the left side. A large protruding epibulbar dermoid tumor was present in the lower outer quadrant of the left eye. The left, eye also had a slight anti-Mongoloid slant. The right eye revealed plastic repair of coloboma of the lid and eyebrow. There was opacification of the right cornea in the lower outer quadrant, where the epibulbar dermoid tumor had been partially removed, The left pinna was poorly developed and abnormally shaped, and the external auditory meatus was absent on the left side. Scars were present secondary to plastic repair of the left pinna and removal of preauricular skin tags. Cardiac examination revealed a Grade 3/u blowing, pansystolic murmur, heard best, at the third and fourth left intercostal spaces and at the apex. The murmur also radiated to the back. The remainder of the physical examination findings were within normal limits. Oral examination disclosed a small scar at the corner of the mouth on the left, secondary to plastic repair of the macrostomia. There was severe micrognathia and slight hypoplasia of the left side of the tongue, with deviation of the tongue to the left on protrusion. The palate was high and arched. The buccal mucosa was normal, and the gingiva was bluish red, spongy, and enlarged. The teeth had whitish spots which did not fluoresce. The maxillary left deciduous lateral incisor was overretained, and the mandibular right decidous first molar was submerged
414
Berkmm
and Fe&gold
O.S.,O.M.&O.P. March, 1968
and ankylosed. The right mandibular second premolar was congenitally missing. There was a class 11 malocclusion with severe anterior open-bite and protrusion of maxillary anterior teeth (Fig. 3, C). X-ray examination revealed hypoplasia of the temporal bone and zygomatic arch on the left. The mandible was small, particularly on the left, and receded anteriorly. The first rib on the right was hypoplastic. There were no abnormalities of the cervical vertebrae. X-ray films of the chest showed the heart to be slightly enlarged on the right, with normal pulmonary vasculature. The patient scored a mental age of 10 years 8 months on the Peabody Picture Vocabulary Test for receptive language ability. Formal articulation testing demonstrated good articulation of all sounds, with the exception of sibilant distortion which was complicated by the severe anterior open-bite. General articulation was intelligible.
DISCUSSION At the present time, the etiology of oculoauriculovertebral dysplasia cannot be explained on a genetic, familial, or chromosomal basis. Go&n and coworkeq3 in their review of more than forty cases in the literature and two new cases of their own, found no evidence of a hereditary pattern, although Saraux and associates* described the syndrome in sisters. In Bock’s5 case, the syndrome was present in one of identical twins, and in ManfrediniY case the patient’s great-grandmother and grandfather had lipodermoid tumors without any other manifestations of the syndrome. Smithells reported a case of Goldenhar’s syndrome with an associated tetralogy of Fallot. The congenital malformations of the facial structures arise from the embryonic first and second branchial arches, the first pharyngeal pouch, the first branchial cleft, and the primordia of the temporal bone. McKenzie8 related mandibulofacial malformation to failure of the embryonic blood supply during critical periods in the development of the face. The time from the third to the fifth week is a critical period for the normal blood supply of the first arch. It is during this period, between the disappearance of the first aortic arch and the full development of the external carotid artery, that a delay in the blood supply may result in poor oxygenation of the embryonic facial tissues that are undergoing growth and differentiation. Although this circulatory failure occurs before the presence of ossification centers in the mandible and maxilla, McKenzie believed that it could cause abnormal bone formation. The external and middle ear anomalies and defects of the mandibular ramus and condyle probably are related to an abnormal vascular supply to the first branchial arch. The inner ear escapes malformation because of its embryonic origin from the auditory placode adjacent to the neural plate which is separate from the branchial arches. Mann8 speculated that the epibulbar dermoid tumors arise from abnormal differentiation of pluripotential embryonic cells located between the edges of the optic cup and the ectoderm. In many cases there is simultaneous occurrence of the epibulbar dermoid tumors and an upper-lid coloboma (Cases 2 and 4), and Gorlin and associa.tes3 suggest that the dermoid tumor may represent the missing piece of the upper lid. The eitology and embryology of the ocular defects are not understood at this time. The vertebral anomalies appear to arise during the fifth week of gesta-
Vohlme 25 Number 3
OculoauricuEovertebral
dysplasia
415
tion. These malformations are thought to involve the parachordal mesoblasts, the precursor of the nervous system and its protective tissues.l” Hemivertebrae result from asymmetric hypoplasia of one of the paired fetal chondrification centers in the vertebral body. When this occurs in the thoracic region, there are errors in rib segmentation .3 The vertebral anomalies usually do not present any clinical symptoms. Grabb,l’ in his study of 102 patients with the first and second branchial arch syndrome, noted that the most common congenital malformations associated with this syndrome were malformations of the vertebrae and ribs (11 per cent), eye and/or eyelid (10 per cent), and cleft lip and/or palate (7 per cent). Epibulbar dermoid tumors were seen in four patients. GalloeheP suggested that in approximately 10 per cent of the children with Goldenhar’s syndrome there is a mild degree of mental retardation. The manifestations of our four cases are summarized in Table I. Three patients (B. C., R. D., and S. B.) showed the major manifestations of epibulbar dermoid tumors, auricular appendices, ear deformities, and vertebral anoma.lies. Table I. Review of the manifestations dysplasia
of four
cases of oculoauriculovertebral Patients
Manif e&&ions Ocular A. Epibulbar dermoid tumor B. Coloboma of upper eyelid C. Coloboma of eyebrow D. Ptosis of eyelid E. Anti-Mongoloid obliquity Auricular A. Microtia B. Aurieular appendices C. Atresia or stenosis of external auditory meatus D. Blind-ended fistulas Oral A. Micrognathia B. Unilateral facial hypoplasia C. Aplasia or hypoplasia of the ramus and condyle D. Maxillary hypoplasia E. High-arched palate F. Macrostomia G. Cleft palate H. Malocclusion 1. Open-bite Musculoskeletal A. Hemivertebrae B. Spina bifida C. Scoliosis D. Vertebral spinal fusion E. Supernumerary vertebrae F. Hypoplastic ribs G. Inguinal hernia H. Congenital heart defect I. Clubfoot
416
Berkfimn
and Pehigold
OS., ox & O.P. March, 1968
Although Patient P. J. did not have an epibulbar dermoid or coloboma of the upper lid, she did have ptosis of the eyelid, unilateral anti-Mongoloid obliquity, auricular anomalies, unilateral facial hypoplasia, and vertebral anomalies and, therefore, should be classified as having Goldenhar’s syndrome. The syndrome bears a resemblance to both mandibulofacial dysostosis (Treacher Collins syndrome) and hemifacial microsomia and should be differentiated from these two conditions. The characteristic features of mandibulofacial dysostosis are (1) anti-Mongoloid obliquity, (2) lower-lid colobomas (in contrast to upper-lid coloboma in Goldenhar’s syndrome), (3) malar and/or maxillary hypoplasia, (4) microtia and deficiency of external auditory meatus, (5) supernumerary ear tags, and (6) malocclusion. Mandibulofacial dysostosis is a bilateral condition, and vertebral anomalies are generally absent, It is thought to be inherited as an autosomal dominant trait.13 Hemifa,cial microsomia is a variant of mandibulofacial dysostosis and oculoauriculovertebral dysplasia. It consists of (1) microtia, (2) maerostomia, and (3) failure of formation of the mandibular ramus and condyle. There is no evidence that this syndrome is inherited. I3 The three syndromes represent involvement of the first and second branchial arches, but in the case of Goldenhar’s syndrome there is also involvement of the vertebrae and the eye. Early diagnosis of Goldenhar’s syndrome is important. When a severe hearing loss is found early, the patient’s hearing can be improved by the use of a hearing aid because the loss is mainly a conductive defect. Plastic surgery can improve the facial appearance by removal of preauricular skin tags and plastic reconstruction of the ear. Ear surgery is usually deferred until the child is older and the growth of the ear is completed. The epibulbar dermoid cysts should be removed, but this should not be done too early because of the possibility of damaging the thin &era. The vertebral abnormalities usually cause no difficulty. Treatment of the oral problems requires the cooperation of the pediatrician, the dentist, the orthodontist, and the oral surgeon. If the child has a cleft lip and/or palate, our approach is to insert a neonatal orthopedic appliance to assist in feeding and to help improve the alignment of the maxillary arch. Subsequently, the cleft lip and palate are repaired. The dentist must be cognizant of the orthodontic problems that can be associated with this syndrome. The malocclusion is related to several factors: (1) unilateral hypoplasia or aplasia of the condyle and ramus of the mandible, (2) micrognathia and/or hypoplasia of the maxilla, and (3) cleft lip and palate. The treatment of the orthodontic problems in many cases requires surgical intervention accompanied by movement of teeth. In addition, the dentist and the plastic surgeon must work together to improve the unilateral hypoplasia of the face and micrognathia. Thus, this syndrome presents many complex problems in treatment and requires an integrated multidisciplinary approach. SUMMARY
Four cases of oculoauriculovertebral dysplasia (Goldenhar’s syndrome), consisting of epibulbar dermoid tumors, preauricular appendices, ear deformi-
Volume 25 Number 3
Oculoa.~~iciclovertebraZ
dysplasia
417
ties, and vertebral anomalies, are described. The oral manifestations of the syndrome are enumerated in each case. The differential diagnosis of oeuloaurieulovertebral dysplasia, mandibulofacial dysostosis (Treacher Collins syndrome) , and hemifacial microsomia is outlined. The multidisciplinary treatment of the eye, ear, face, and oral abnormalities is discussed. REFERENCES 1. Van
2. ,.9 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Duyse, D.: Bride dermoide oculo-palpebrale et coloboma partiel de la paupierr avec remarques sur la genese de cas anomalies, Ann. ocul. 88: 101-132, 1882. Goldenhar, M.: Associations malformations de l’oeil et de l’oreille en particulier IR syndrome dermoide enibulbaire-annendices auricularies-fistula auris coneenita et scs relations avec la dysostose mandib;io-faciale, J. genet. hum. 1: 243-282, 1932. Gorlin, R. J., Jue. K. L., Jacobsen. IT., and Goldschmidt. E.: Oculoauriculovertebral Dvsalasia. J. ‘Pedist. 63: 991-999. 1963. familiale de &r&x, H., Grignon, J. L., and’ Dhermy, P.: K propos dune observation syndrome de Franceschetti-Goldenhar, Bull. Sot. onhthal. franc. 63: 705-707. 1963. Bock, R. H.: Ein Fall von epibulbarem Dermolipom mit ‘Missbildung’ einer Gesichtshalfte, Diskordantes Vorkommen bei einem eineiigen Zwillingspaar, Ophthalmologica 122: 86-90, 1951. Manfredini? U.: Le Cosidette Sindromi de1 Primo Arco Branchiale (Su di un case (Ii sindromi dl Goldenhar associata a disostosi oto-mandibolare), Ann. ottal. 91: 689.To4, 1965. Smithells, R. W.: Oculoauriculovertebral Syndrome (Goldenhar’s Syndrome), Develop. Med. Child. Neurol. 6: 406-407, 1964. McKenzie, J.: The First Arch Syndrome, Arch. Dis. Childhood 33: 477-486 1958. Mann, I.: Developmental Abnormalities of the Eye, ed. 2, Philadelphia, 1957, J. Ii. Lippincott Company. Neimann, N., Cordier, J., Manciaux, M., and Barrucand, D.: Syndrome de Frances. chetti assoeie au syndrome de Goldenhar et % des malformations vertebra@ Semairm h8p. Paris 36: 2632-2644. 1960. Grabb, W. C.: The First and Second Branchial Arch Syndrome, Plast. R- Reconst,ruct. Surg. 36: 485508, 1965. Gallocher, M. G. M. P.: Contribution L I’etude de la dysostose mandibulofaciale ou syndrome de Franceschetti (2 observations typiquesj, Thesis, Bourdeaux, No. 6!5, I-X, 1950. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the Head and Neck, New Pork. 1964, McGraw-Hill Book Company.
Academy
of Oral
Pathology
Donald Kerr, Editor
Oculoauriculovertebraldysplasia (Goldenhar’s syndrome) Milton
D. Be&man,
DEPARTMENTS SCHOOL
OF
08
D.M.D., and Murray
ORAL
PATHOLOGY
DENTAL
MEDICINE,
UNIVERSITY
SCHOOL
OF MEDICINE
HOSPITALS
(BOSTON
FLOATING
AND AND
Peingold, M.D., Boston, Mass.
ORAL
PEDIATRICS,
DEPARTMENT
AND
THE
HOSPITAL
NEW
TUFTS
OF
TUFTS
MEDICAL
CENTER
ENGLAND
FOR INFANTS
UNIVERSITY
PEDIATRICS,
AND
CHILDREN)
0
culoauriculovertebral dysplasia was first described by von Arltl in 1845, and the eponym dates from a description published by GoldenhaP in 1952. Gorlin and associates3 suggested the more descriptive title of ocubauricukovertebral dysplasia, which delineates the three major components of the syndrome and the pathologic process. The major manifestations of this syndrome are eye, ear, and vertebral anomalies. The eye anomalies consist of epibulbar dermoid tumors, lipodermoid tumors, and coloboma of the upper eyelid (Fig. 1). The epibulbas dermoid tumor is most frequently bilateral and usually is located at the limbus or cornea1 margin of the lower outer quadrant of the eye (Fig. 2). Occasionally a lipodermoid cyst is found in the upper outer quadrant, where it may occur alone or accompany a dermoid cyst. The ear may be small, low-set, or abnormally shaped, with stenosis or atresia of the external auditory meatus. A constant finding is the presence of bilateral preauricular fleshy appendages, which are usually multiple, often pedunculated, located anterior to the tragus, and found along the line from the tragus to the corner of the mouth. Blind fistulas are often found in the same area, but these are not always bilateral. The vertebral anomalies include occipitalization of the atlas, fusion of one or more of the vertebrae, hemivertebrae, supernumerary vertebrae, spina bifida, and scoliosis, plus other abnormalities. Oral and facial anomalies associated with this condition are unilateral hypoplasia of the mandible and maxilla, micrognathia, ogy,
Presented at the twenty-first Miami Beach, Fla., April
annual 7, 1967.
This investigation was supported 33, 341-02 from the National Institute
408
meeting
of
the
American
Academy
of Oral Pathol-
in part by Public Health Service Fellowship 5-FZ-DEof Dental Research and the National Foundation.
Oculonuriculoz~ertebral
Volume 25 Number 3
Pig. 1. Coloboma quadrant.
of upper
eyelid
Fig. 3. Patient R. D:, showing metry of nostrils, and mmrognathia.
and epibulbar
epibulbar
dermoid
dermoid
tumors,
tumor
dysplasia
located
preauricular
in lower
appendices,
409
outer
asym-
macrostomia, high arched palate, cleft lip and palate, malocclusion, and/or open-bite, as well as other dental malformations. The purpose of this article is to report four cases of Coldenhar’s syndrome and to demonstrate the variations in this symptom complex, with emphasis on the oral manifestations. CASE REPORTS CASE
1
Patient B. C., ii-year-old white girl, was admitted to the Boston Floating Hospital for Infants and Children for evaluation of a facial asymmetry which had been present since birth. The patient was the product of a full-term, uncomplicated pregnancy and delivery of
410
Be&man
and Peingold
O.S., O.M. & O.P. March, 1968
a 21-year-old mother. There was no history of infections or medications during the pregnancy. Birth weight was 7 pounds, 12 ounces. At birth, the child was noted to have a cleft palate and asymmetry of the face, with the left side smaller than the right. Additional abnormalities included ptosis of the left eyelid, weakness of the left lateral rectus muscle, dermoid cyst of the sclera on the left, bifid lobe and protrusion of the left ear, preauricular and infraauricular skin appendages, and a clubfoot. Otoplasty and excision of the auricular appendages were performed when the patient was 5 months old and the cleft palate was repaired a month later, with no complications. There was no family history of birth defects or consanguinity. The parents and a 4-year-old sibling were in good health. Physical examination revealed a well-developed, well-nourished white girl in no distress. The vital signs were normal. The child was in the seventy-fifth percentile for height and weight. There was hypoplasia of the forehead, palpebral fissure, zygoma, maxilla, mandible, and tongue on the left side. Ptosis of the left eyelid and an open-bite on the left side were also noted. There was a 4 mm. episcleral dermoid tumor in the lower outer quadrant of the left eye, which covered a small portion of the iris and conjunctiva. There was bilateral lateral rectus muscle weakness, which was more marked on the left than on the right. Convergence was decreased and diplopia was present on lateral gaze. The fundi were normal. The inferior aspect of the left ear was rotated anteriorly, and the external auditory meatus and canal were steno&L On the left side there was a preauricular skin tag anterior to the left tragus, and incisional scars secondary to removal of other preauricular tags were also present. There was a Grade 3/a ejection systolic murmur, heard best at the left sternal border at the second and third intercostal spaces. The left clavicle was more prominent than the,right. There was a slight cervicothoracic scoliosis, with concavity toward the right. There were no gross or focal neurologic signs other than the aforementioned eye findings.
Fig. 3’. Types of malocclusion. B, Patient B. C., demonstrating lateral open-bite. B, Patient P. J., with anterior overbite and posterior cross-bite. C, Patient 8. B., demonstrating anterior open-bite and protrusion of maxillary anterior teeth.
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Oral examination disclosed a slight maerostomia on the left. The left side of the tongue was hypoplastic and deviated to the left on protrusion. There was a high-arched palate, with slight scarring in the area of the soft palate secondary to cleft palate repair. The left maxillary and mandibular deciduous canines, first molars, and second molars did not occlude (Fig. 3, A). There was no asymmetry of the nose. X-ray studies showed that the mastoid and zygomatic bones and the ramus and body of the mandible were hypoplastic on the left side. The left temporomandibular fossa was small, with anterior displacement of the condyle. The teeth appeared normal in size. There was widening of the interpedicular spaces, especially of the lower cervical vertebrae. On flexion and extension of the cervical spine, the atlas remained fixed in relation to the occiput, although there was no evidence of bony union. The odontoid process of the axis was unusually long, and articulation of the atlas was remote from the body of the second cervical vertebra, representing a supernumerary vertebra at the atlantoaxial level. There was slight curvature of the dorsolumbar spine. Spina bifida involving the lower rervir.al vertebrae and the upper three dorsal vertebrae was present. Audiometric examination revealed that the patient’s hearing in the right ear was within normal limits. The left ear demonstrated moderate sensorineural hearing loss at frequencies less than 1,000 cycles per second but no hearing loss at the higher frequencies, Speech discrimination in the right ear was better than in the left. CASE 2
Patient R. D., a 3-month-old white boy, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. The infant was a product of a full-term, uncomplicated pregnancy and delivery of a 35.year-old gravida V, para 4, abortus 1 mother. The birth weight was 8 pounds, 14
Fig. 4. Posteroanterior radiogram of Patient dible and hypoplasia of ramus on right.
P. J., showing
marked
asymmetry
of man-
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ounces. Pregnancy was uneventful until the last month, when the mother was placed on diuretic therapy for ankle edema. There was no family history of birth defects or consanguinity, but a paternal great aunt was said to be retarded. The parents and three siblings were in good health. Eye, ear, and facial deformities were noted at birth. The child had had no difficulty since birth. Physical examination revealed a well-developed, well-nourished white male infant in no distress. The vital signs were normal. The child was in the fiftieth percentile for height, There was slight hypoplasia of the left side of the face. weight, and head circumference. A coloboma was present in the middle of the left upper lid. A 6 by 6 mm. whitish, round, epibulbar dermoid tumor was noted in the lower outer quadrant of the right eye, and an 8 by 8 mm. whitish, round, epibulbar dermoid tumor was seen in the lower outer quadrant of the left eye. The fundi were normal. The left ear had a slightly misshapen pinna; the tragus W&S absent and the coneha was enlarged. Multiple ear tags were present in the right and left preauricular regions. A small fistula was noted in the left preauricular region. There was a large, pedunculated skin tag on the right cheek, midway between the tragus and the corner of the mouth. The right nostril was asymmetric, and a tab of tissue covered with nasal mucosa was attached to the medial wall of the right nostril. A cherry-red hemangioma was noted on the right flank. There were no gross or focal neurologic signs, and the mental and motor development was normal for the patient’s age. The remainder of the physical examination was also normal. Oral examination disclosed that the child had slight to moderate micrognathia and a moderately high-arched palate. No teeth were present at the time of examination. The buccal mucosa, tonsils, and pharynx were normal. On x-ray examination, the zygoma and mandible were found to be slightly hypoplastic. The ramus and condyle on the left were underdeveloped in comparison to those on the right. There was incomplete fusion of the posterior portion of the neural arch from the fifth cervical through the fifth dorsal vertebrae. There was no evidence of abnormal segmentation. Audiometric examination indicated that the patient’s hearing was within normal limits. CASE 3
Patient P. J., a 3x-year-old white girl, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. The child was born following a pregnancy that was uneventful until term, at which time the mother developed vaginal bleeding. The patient was delivered by cesarean section, at which time an abruptio placenta was found. There was no history of infections or medications during pregnancy. The birth weight was 5 pounds, 12% ounces. At birth, the patient’s right ear was malformed and the external auditory meatus was absent. Hypoplasia and facial paralysis were noted on the right side, and there was a cleft palate. X-ray films at birth showed hypoplasia of the right zygoma, maxillary sinus, orbit, and mandible, as well as hemivertebrae and fusion of the cervical vertebrae. The patient also experienced feeding difficulties during the neonatal period. The cleft palate was repaired when the child was 15 months old, and bilat.eral inguinal hernias were repaired when she was 21 months of age. There was no family history of consanguinity, but two siblings had syndactyly of the toes. The mother, father, and three siblings were in good health. Physical examination revealed a small white girl in the third percentile for height and weight. Vital signs were normal. There was severe hypoplasia of the right forehead, palpebral fissure, malar area, maxilla, and mandible. Also on the right side, there were ptosis of the eyelid, questionable superior reetus muscle weakness, and anti-mongoloid obliquity. There were no dermoid tumors or colobomas. The right ear was low set and aplastic, with no external auditory m&us. A pedunculated supernumerary ear tag was present anterior to the aplastic right ear. The left ear was normal. The remainder of the physical examination findings were within normal limits. Oral examination disclosed slight microstomia, asymmetry of the right side of the mouth, and an elongated philtrnm. The palate was constricted, and there was moderate scarring secondary to cleft palate repair, The soft palate was short and underdeveloped, and movement
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of the palatal muscles was limited. The tongue was hypoplastic on the right side, and there was slight mierognathia on the right. The right side of the maxillary arch was hypoplastic, and the entire arch was V-shaped, with crowding of maxillary deciduous teeth and overlapping of the deciduous central incisors. Three mandibular incisors were present. A deep anterior overbite and a severe posterior cross-bite on the right were present (Fig. 3, B). There were several carious teeth. X-ray examination showed that the temporal bone and zygoma were hypoplastic. on the right side. The orbits were slightly asymmetrical, with the right one lower than the left. The posterior fossa was slightly deeper on the right than on the left. The right maxillary sinus and right maxilla were smaller than those on the left side. There was marked asymmetry of the mandible, with shortening of the body on the right. The ramus on the right was hypoplast,ie and shorter than on the left, and the right temporomandibular joint was infantile in development (Fig. 4). The cervical spine showed abnormal segmentation, fusion, and hemivertebrae. The remainder of the skeletal survey revealed congenital fusion of the bodies of fourth and fifth lumbar vertebrae and asymmetry of the upper dorsal spine on the right at the level of the second and third thoracic vertebrae. Audiometric and speech examination indicated that the patient’s hearing on the left side was within normal limits. On the right there was a conductive loss of 60 to 70 d&h&, as a result of the absence of the external auditory meatus. The patient demonstrated distortions of sibilant sounds and nasal speech which was related to the cleft palate. CASE 4
Patient 8. B., a white boy 9 years 3 months of age, was referred to the Boston Floating Hospital National Foundation Birth Defect Evaluation Center for evaluation of multiple congenital anomalies. This child was the product of a full-term, uncomplicated pregnamy and delivery of a 30-year-old gravida V, para 4, abortus 1 mother. There was no history of infections or medications during the pregnancy, and there was no family history of consanguinity or birth defects. The parents and four siblings were in good health. Several eye abnormalities, facial asymmetry, preauricular skin tags, atresia of t,he left ear, and a heart murmur were noted at birth. Chromosomal analysis was normal. The preauricular skin tags and those on the cheek were removed when the patient was 3ji2 months of age. A coloboma on the middle third of the right upper eyelid was repaired when he was 18 months old, and an epibulbar dermoid tumor in the right eye was partially removed when he was 4 years of age. Plastic repair of a coloboma of the right eyebrow was performed when the boy was 5, and when he was 6% years old the macrostomia of the left side of the mouth was repaired and the micrognathia was improved with a silicone implant. Physical examination revealed a well-developed, well-nourished, white boy who was in the fiftieth percentile for height and weight. Vital signs were normal. There was hypoplasia of the forehead, palpebral fissure, malar area, and mandible on the left side. A large protruding epibulbar dermoid tumor was present in the lower outer quadrant of the left eye. The left, eye also had a slight anti-Mongoloid slant. The right eye revealed plastic repair of coloboma of the lid and eyebrow. There was opacification of the right cornea in the lower outer quadrant, where the epibulbar dermoid tumor had been partially removed, The left pinna was poorly developed and abnormally shaped, and the external auditory meatus was absent on the left side. Scars were present secondary to plastic repair of the left pinna and removal of preauricular skin tags. Cardiac examination revealed a Grade 3/u blowing, pansystolic murmur, heard best, at the third and fourth left intercostal spaces and at the apex. The murmur also radiated to the back. The remainder of the physical examination findings were within normal limits. Oral examination disclosed a small scar at the corner of the mouth on the left, secondary to plastic repair of the macrostomia. There was severe micrognathia and slight hypoplasia of the left side of the tongue, with deviation of the tongue to the left on protrusion. The palate was high and arched. The buccal mucosa was normal, and the gingiva was bluish red, spongy, and enlarged. The teeth had whitish spots which did not fluoresce. The maxillary left deciduous lateral incisor was overretained, and the mandibular right decidous first molar was submerged
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and ankylosed. The right mandibular second premolar was congenitally missing. There was a class 11 malocclusion with severe anterior open-bite and protrusion of maxillary anterior teeth (Fig. 3, C). X-ray examination revealed hypoplasia of the temporal bone and zygomatic arch on the left. The mandible was small, particularly on the left, and receded anteriorly. The first rib on the right was hypoplastic. There were no abnormalities of the cervical vertebrae. X-ray films of the chest showed the heart to be slightly enlarged on the right, with normal pulmonary vasculature. The patient scored a mental age of 10 years 8 months on the Peabody Picture Vocabulary Test for receptive language ability. Formal articulation testing demonstrated good articulation of all sounds, with the exception of sibilant distortion which was complicated by the severe anterior open-bite. General articulation was intelligible.
DISCUSSION At the present time, the etiology of oculoauriculovertebral dysplasia cannot be explained on a genetic, familial, or chromosomal basis. Go&n and coworkeq3 in their review of more than forty cases in the literature and two new cases of their own, found no evidence of a hereditary pattern, although Saraux and associates* described the syndrome in sisters. In Bock’s5 case, the syndrome was present in one of identical twins, and in ManfrediniY case the patient’s great-grandmother and grandfather had lipodermoid tumors without any other manifestations of the syndrome. Smithells reported a case of Goldenhar’s syndrome with an associated tetralogy of Fallot. The congenital malformations of the facial structures arise from the embryonic first and second branchial arches, the first pharyngeal pouch, the first branchial cleft, and the primordia of the temporal bone. McKenzie8 related mandibulofacial malformation to failure of the embryonic blood supply during critical periods in the development of the face. The time from the third to the fifth week is a critical period for the normal blood supply of the first arch. It is during this period, between the disappearance of the first aortic arch and the full development of the external carotid artery, that a delay in the blood supply may result in poor oxygenation of the embryonic facial tissues that are undergoing growth and differentiation. Although this circulatory failure occurs before the presence of ossification centers in the mandible and maxilla, McKenzie believed that it could cause abnormal bone formation. The external and middle ear anomalies and defects of the mandibular ramus and condyle probably are related to an abnormal vascular supply to the first branchial arch. The inner ear escapes malformation because of its embryonic origin from the auditory placode adjacent to the neural plate which is separate from the branchial arches. Mann8 speculated that the epibulbar dermoid tumors arise from abnormal differentiation of pluripotential embryonic cells located between the edges of the optic cup and the ectoderm. In many cases there is simultaneous occurrence of the epibulbar dermoid tumors and an upper-lid coloboma (Cases 2 and 4), and Gorlin and associa.tes3 suggest that the dermoid tumor may represent the missing piece of the upper lid. The eitology and embryology of the ocular defects are not understood at this time. The vertebral anomalies appear to arise during the fifth week of gesta-
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tion. These malformations are thought to involve the parachordal mesoblasts, the precursor of the nervous system and its protective tissues.l” Hemivertebrae result from asymmetric hypoplasia of one of the paired fetal chondrification centers in the vertebral body. When this occurs in the thoracic region, there are errors in rib segmentation .3 The vertebral anomalies usually do not present any clinical symptoms. Grabb,l’ in his study of 102 patients with the first and second branchial arch syndrome, noted that the most common congenital malformations associated with this syndrome were malformations of the vertebrae and ribs (11 per cent), eye and/or eyelid (10 per cent), and cleft lip and/or palate (7 per cent). Epibulbar dermoid tumors were seen in four patients. GalloeheP suggested that in approximately 10 per cent of the children with Goldenhar’s syndrome there is a mild degree of mental retardation. The manifestations of our four cases are summarized in Table I. Three patients (B. C., R. D., and S. B.) showed the major manifestations of epibulbar dermoid tumors, auricular appendices, ear deformities, and vertebral anoma.lies. Table I. Review of the manifestations dysplasia
of four
cases of oculoauriculovertebral Patients
Manif e&&ions Ocular A. Epibulbar dermoid tumor B. Coloboma of upper eyelid C. Coloboma of eyebrow D. Ptosis of eyelid E. Anti-Mongoloid obliquity Auricular A. Microtia B. Aurieular appendices C. Atresia or stenosis of external auditory meatus D. Blind-ended fistulas Oral A. Micrognathia B. Unilateral facial hypoplasia C. Aplasia or hypoplasia of the ramus and condyle D. Maxillary hypoplasia E. High-arched palate F. Macrostomia G. Cleft palate H. Malocclusion 1. Open-bite Musculoskeletal A. Hemivertebrae B. Spina bifida C. Scoliosis D. Vertebral spinal fusion E. Supernumerary vertebrae F. Hypoplastic ribs G. Inguinal hernia H. Congenital heart defect I. Clubfoot
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Although Patient P. J. did not have an epibulbar dermoid or coloboma of the upper lid, she did have ptosis of the eyelid, unilateral anti-Mongoloid obliquity, auricular anomalies, unilateral facial hypoplasia, and vertebral anomalies and, therefore, should be classified as having Goldenhar’s syndrome. The syndrome bears a resemblance to both mandibulofacial dysostosis (Treacher Collins syndrome) and hemifacial microsomia and should be differentiated from these two conditions. The characteristic features of mandibulofacial dysostosis are (1) anti-Mongoloid obliquity, (2) lower-lid colobomas (in contrast to upper-lid coloboma in Goldenhar’s syndrome), (3) malar and/or maxillary hypoplasia, (4) microtia and deficiency of external auditory meatus, (5) supernumerary ear tags, and (6) malocclusion. Mandibulofacial dysostosis is a bilateral condition, and vertebral anomalies are generally absent, It is thought to be inherited as an autosomal dominant trait.13 Hemifa,cial microsomia is a variant of mandibulofacial dysostosis and oculoauriculovertebral dysplasia. It consists of (1) microtia, (2) maerostomia, and (3) failure of formation of the mandibular ramus and condyle. There is no evidence that this syndrome is inherited. I3 The three syndromes represent involvement of the first and second branchial arches, but in the case of Goldenhar’s syndrome there is also involvement of the vertebrae and the eye. Early diagnosis of Goldenhar’s syndrome is important. When a severe hearing loss is found early, the patient’s hearing can be improved by the use of a hearing aid because the loss is mainly a conductive defect. Plastic surgery can improve the facial appearance by removal of preauricular skin tags and plastic reconstruction of the ear. Ear surgery is usually deferred until the child is older and the growth of the ear is completed. The epibulbar dermoid cysts should be removed, but this should not be done too early because of the possibility of damaging the thin &era. The vertebral abnormalities usually cause no difficulty. Treatment of the oral problems requires the cooperation of the pediatrician, the dentist, the orthodontist, and the oral surgeon. If the child has a cleft lip and/or palate, our approach is to insert a neonatal orthopedic appliance to assist in feeding and to help improve the alignment of the maxillary arch. Subsequently, the cleft lip and palate are repaired. The dentist must be cognizant of the orthodontic problems that can be associated with this syndrome. The malocclusion is related to several factors: (1) unilateral hypoplasia or aplasia of the condyle and ramus of the mandible, (2) micrognathia and/or hypoplasia of the maxilla, and (3) cleft lip and palate. The treatment of the orthodontic problems in many cases requires surgical intervention accompanied by movement of teeth. In addition, the dentist and the plastic surgeon must work together to improve the unilateral hypoplasia of the face and micrognathia. Thus, this syndrome presents many complex problems in treatment and requires an integrated multidisciplinary approach. SUMMARY
Four cases of oculoauriculovertebral dysplasia (Goldenhar’s syndrome), consisting of epibulbar dermoid tumors, preauricular appendices, ear deformi-
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ties, and vertebral anomalies, are described. The oral manifestations of the syndrome are enumerated in each case. The differential diagnosis of oeuloaurieulovertebral dysplasia, mandibulofacial dysostosis (Treacher Collins syndrome) , and hemifacial microsomia is outlined. The multidisciplinary treatment of the eye, ear, face, and oral abnormalities is discussed. REFERENCES 1. Van
2. ,.9 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Duyse, D.: Bride dermoide oculo-palpebrale et coloboma partiel de la paupierr avec remarques sur la genese de cas anomalies, Ann. ocul. 88: 101-132, 1882. Goldenhar, M.: Associations malformations de l’oeil et de l’oreille en particulier IR syndrome dermoide enibulbaire-annendices auricularies-fistula auris coneenita et scs relations avec la dysostose mandib;io-faciale, J. genet. hum. 1: 243-282, 1932. Gorlin, R. J., Jue. K. L., Jacobsen. IT., and Goldschmidt. E.: Oculoauriculovertebral Dvsalasia. J. ‘Pedist. 63: 991-999. 1963. familiale de &r&x, H., Grignon, J. L., and’ Dhermy, P.: K propos dune observation syndrome de Franceschetti-Goldenhar, Bull. Sot. onhthal. franc. 63: 705-707. 1963. Bock, R. H.: Ein Fall von epibulbarem Dermolipom mit ‘Missbildung’ einer Gesichtshalfte, Diskordantes Vorkommen bei einem eineiigen Zwillingspaar, Ophthalmologica 122: 86-90, 1951. Manfredini? U.: Le Cosidette Sindromi de1 Primo Arco Branchiale (Su di un case (Ii sindromi dl Goldenhar associata a disostosi oto-mandibolare), Ann. ottal. 91: 689.To4, 1965. Smithells, R. W.: Oculoauriculovertebral Syndrome (Goldenhar’s Syndrome), Develop. Med. Child. Neurol. 6: 406-407, 1964. McKenzie, J.: The First Arch Syndrome, Arch. Dis. Childhood 33: 477-486 1958. Mann, I.: Developmental Abnormalities of the Eye, ed. 2, Philadelphia, 1957, J. Ii. Lippincott Company. Neimann, N., Cordier, J., Manciaux, M., and Barrucand, D.: Syndrome de Frances. chetti assoeie au syndrome de Goldenhar et % des malformations vertebra@ Semairm h8p. Paris 36: 2632-2644. 1960. Grabb, W. C.: The First and Second Branchial Arch Syndrome, Plast. R- Reconst,ruct. Surg. 36: 485508, 1965. Gallocher, M. G. M. P.: Contribution L I’etude de la dysostose mandibulofaciale ou syndrome de Franceschetti (2 observations typiquesj, Thesis, Bourdeaux, No. 6!5, I-X, 1950. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the Head and Neck, New Pork. 1964, McGraw-Hill Book Company.