Relationship Between the Mandibulofacial Dysostosis Syndrome of Franceschetti and the Oculo-Auriculo-Vertebral Dysplasia Syndrome of Goldenhar

RELATIONSHIP BETWEEN THE MANDIBULOFACIAL DYSOSTOSIS SYNDROME OF FRANCESCHETTI A N D T H E OCULO-AURICULOVERTEBRAL DYSPLASIA SYNDROME OF GOLDENHAR H. SAUL SUGAR, M.D. AI rD MARTIN BERMAN, M.D. Detroit, Michigan

The great interest and rapid expansion of knowledge concerning genetically and nongenetically caused syndromes has created a need for more specific identification and, perhaps, clarification of definite relationships between some of these syndromes. DukeElder states that the syndrome of Goldenhar is sometimes associated with mandibulofacial dysostosis and cites a number of such cases. On the other hand, Gorlin and Pindborg consider the two syndromes to be entirely distinct, particularly since vertebral anomalies almost always occur in Goldenhar's syndrome and are absent in mandibulofacial dysostosis, and since, according to their view, no unilateral form of mandibulofacial dysostosis exists. 1

2

After having studied a number of cases of both the mandibulofacial dysostosis syndrome of Franceschetti and the oculo-auriculo-vertebral dysplasia syndrome of Goldenhar, we encountered a patient who showed certain manifestations common to both syndromes, suggesting a possible relationship between the two. Other cases of this kind in the literature tend to strengthen the conviction that the two syndromes are connected by certain common manifestations but are definitely separated by the presence or absence of dermoids and/or lipodermoids. Our patient was a 14-year-old-Caucasian boy born without complication after a normal pregnancy. His birth weight was 8 pounds 5 ounces. At the age of 2 years he was treated surgically for cleft palate ; at age 7 years he had cosmetic surgery for protruding ears. Hearing had been poor since birth; the external ears were moderately deformed. In 1963, at the age of 10 years planography of a

From the Department of Ophthalmology, Wayne State University, School of Medicine, and Sinai Hospital.

the middle ear showed no sign of ossicles on the left side but the possibility of their presence on the right side could not be ruled out. Exploratory tympanotomy showed malformation of the right middle ear with no normal structures present. There was bilateral atresia of the auditory canals. Ophthalmoscopic examination revealed visual acuity of 20/20, corrected with +2.75 sph+0.50 cyl ax 110 in the right, and +2.75 sph + 0.50 cyl ax 75 in the left. There was hypoplasia of each maxilla and the mandible, mild ectropion of each lower lid, and a notch in each lower lid at the junction of the middle and lateral thirds. Ductions were full; there was an exophoria of 4 prism diopters for near. Ophthalmoscopic and slitlamp examinations showed normal findings. Schijftz tension was 17 mm Hg in both eyes. X-rays revealed spina bifida occulta of the first sacral vertebra, a small maxilla, and hypoplasia of the right frontal sinus, and indicated that the left maxillary antrum was directed more medially than the right (figs. 1 and 2 ) . There was no family history of consanguinity and there were no other familial instances of the syndrome. Chromosome studies (Dr. Molly L o ) showed normal karyotype and count. Mandibulofacial dysostosis was probably first described by Thomson in 1847, was reintroduced by Berry in 1889 and Collins in 1900 ; it was again extensively studied by Franceschetti * in 1944 and 1949. In its socalled complete form the syndrome consists of the following : 1. Sloping antimongoloid palpebral fissures with a notch in the outer part of the lower lids, sometimes with associated anomalous cilia and atrophy of the orbicularis and tarsal tissue. 4

5

7

8

6

VOL. 6 6 , NO. 3 2. Small often

MANDIBULOFACIAL DYSOSTOSIS

and

incomplete

asymmetrical,

malar

frequently

511

SYNDROME

bones,

producing

moderate facial asymmetry. T h e zygomatic process of the temporal bone m a y be lacki n g ; the body and rami of the mandible are often

hypoplastic.

The

palate

is

highly

arched or cleft, and the teeth are irregular. Malocclusion

and

abnormal

dentition

are

frequently found. 3. Underdeveloped, often

deformed, with

small

external

ears,

frequent absence

of

the external auditory canal, sometimes with anomalies

of

the

middle

and

inner

Preauricular appendages and blind

ear.

fistulae

between the external ear and the angle o f the mouth m a y be present. 4. M a c r o s t o m i a 5. A b s e n c e of the nasofrontal angle 6. Hyperplasia of the frontal sinuses and absence of mastoid cells m a y occur 7. A

patch of

hair growing toward the

cheek in front of the ear 8. Facial clefts a n d skeletal deformation 9. Rarely, such anomalies as macroglossia, absence of the parotid, internal h y d r o -

Fig. 2 (Sugar and Berman). Side view of patient. cephalus, lesions of the heart and great vessels,

the

tracheobronchial

tree,

cryptorchi-

dism, a n d mental deficiency. Franceschetti

described incomplete, abor-

tive, unilateral and atypical f o r m s in addition to the typical f o r m . Incomplete f o r m s include cases with oblique antimongoloid fissures, and malar and mandibular atrophy, without

auricular

malformation.

Abortive

f o r m s are considered to have only lid anomalies. I n atypical f o r m s there is substitution of one of the principal characteristics b y an anomaly, such as microphthalmia, for the lid deformity. T h e oculo-auriculo-vertebral dysplasia synd r o m e of Goldenhar consists of the following: 1. Epibulbar

dermoids

or

epidermoids,

often associated with coloboma of the upper lids. 2. Auricular blind

fistulas,

appendages

and

pretragal

microtia, disturbance of

the

external auditory meatus and deafness. 3. Vertebral column anomalies, Fig. 1 (Sugar and Berman). Patient with mandibulofacial dysostosis.

including

occipitalization o f the atlas, cuneiform vertebrae, cervical vertebral synostosis,

supernu-

512

AMERICAN JOURNAL OF O P H T H A L M O L O G Y

merary thoracic or lumbar vertebrae, aplasia of sacral vertebra, anomalous ribs, sacral fovea, and others. Macrostomia and mild micrognathia are frequent. Hemifacial hypoplasia associated with a fibrous band between the angle of the mouth and the tragus often occurs (as in all three of my reported cases). High vaulted palate, bifid tongue, cleft lip, cleft palate, malocclusion and dental anomalies have been described. A number of cases described as mandibulofacial dysostosis now must be reevaluated in light of the above criteria. Surely they will be found to be examples of the Goldenhar syndrome : Jorio described a patient with facial asymmetry, malar and mandibular hypoplasia, coloboma of the right upper lid, bilateral bulbar epidermoids, and right preauricular and auricular deformities. Tranos described a patient with hypoplasia of the mandible, bilateral lipodermoids, right auricular agenesis, absence of the external auditory canal and a fibrous band between the tragus and the mouth comissure. Slight antimongoloid shape of the palpebral fissures was described but the photographs show no notching. Malar and mandibular hypoplasia was present. A second patient, described as having Franceschetti's syndrome, is a typical Goldenhar case with only antimongoloid shape of the palpebral fissure added. 9

10

Paufique and associates described a patient with antimongoloid obliquity of the eyelids, hypoplasia of the malar and mandibular bones, and right dermoid and bilateral auricular anomalies. Neimann and co-workers described a patient with antimongoloid obliquity of the palpebral fissures, a moderate malar hypoplasia, marked mandibular hypoplasia and the typical Goldenhar syndrome, including right superior palpebral coloboma, bilateral limbal tumors, deformity of the tragus, right auricular fistula, left auricular appendage, macrostomia, dental malocclusion, arched palate 11

12

S E P T E M B E R , 1968

and multiple vertebral malformations from the atlas to the second dorsal vertebra in the form of spina bifida occulta or unilateral aplasia. Neimann and his associates concluded that their case and the cases described by the three authors mentioned above merited the syndrome name of FranceschettiGoldenhar since they considered them to have both syndromes. Vannas described a patient with unilateral Franceschetti syndrome and bilateral lipodermoid, bilateral auricular appendages and fistula auris in the left pinna. Her second patient had anophthalmos on one side and a dermoid and auricular appendage in the left, together with cervical vertebral anomalies. This case was considered an atypical form of Franceschetti syndrome. 13

Boudet reported a patient with hemifacial hypoplasia and an epibulbar dermoid, together with solid block fusion of the atlas and third cervical vertebra. Blodi described a case of craniofacial dysostosis in which there was a unilateral small left mandible and flattening of the left side of the face due to a band between the ear and mouth angle. A n antimongoloid slant was present in the left lower lid. No notching was described. A left lipodermoid was present as well as extra tragi and a preauricular fistula. 14

16

Rousseau's case, described as a Franceschetti syndrome, is one of a typical Goldenhar syndrome. Similarly, Hoffmann-Egg and Velissaropoulos considered their last three patients to have mandibulofacial dysostosis because of modified maxillary or malar hypoplasia but they, too, were typical Goldenhar syndrome cases with bulbar epidermoids. In each of the above, descriptions were obviously of the Goldenhar syndrome with the addition of malar and mandibular hypoplasia and antimongoloid obliquity of the lower lid without notching. The presence of a unilateral facial flattening associated with a fibrous band in the cheek, a frequent component of the Goldenhar syndrome, probably 18

17

V O L . 66, N O . 3

MANDIBULOFACIAL DYSOSTOSIS SYNDROME

produces a lid slant that is usually unilateral and only simulates a true antimongoloid slant. This suggests that an antimongoloid slant without notching or other evidence of lower lid involvement should not be considered characteristic of the Francheschetti syndrome. It is likely that the hypoplasia of facial bones is a feature common to both syndromes. The question of whether one may use the presence of spinal anomalies as a criterion for the Goldenhar syndrome can be given a qualified answer. Since such anomalies are not always present in typical cases (see Case 2 in previous paper ) they are not absolutely necessary. On the other hand, the case described in this paper is characteristic of the Franceschetti syndrome with the addition of a sacral spina bifida, a fairly common spinal anomaly, previously described in this condition by Gallocher. It might be most accurate to say that usually there are no spinal anomalies in Franceschetti's syndrome whereas they usually are present in Goldenhar's. Franceschetti and associates described a case of unilateral mandibulofacial dysostosis with slight obliquity of the right palpebral fissure, microtia and hypacousia, hemifacial hypoplasia, agenesis of the right frontalis muscle and clonic right torticollis with skeletal anomalies, including bilateral paramastoid process, two vertebral synostoses, two cuneiform vertebrae, spina bifida and unilateral sacralization with neoarthrodesis. This case suggests an incomplete Goldenhar type rather than a true Franceschetti syndrome, especially if one accepts the relationship between hemifacial hypoplasia and ipsilateral obliquity of the palpebral fissure. 3

24

18

Let us now consider the pathogenesis of the gross anomalies common to both syndromes : the ear defects, the highly arched or cleft palate, and hypoplasia of the malar bones. According to Mann, the basic defect is a defective gene which leads to defective ossification of the facial bones derived from the first visceral arch, probably after the sev19

513

enth week of fetal life (Hövels considers it to arise earlier). The defects of the ear and lids result from the facial bone maldevelopment. The blind fistulae result from noncoalescence of the first groove. The pinna develops from the dorsal surface of the first branchial cleft about the fifth week and is complete by the end of the second month. According to Keerl, and second branchial arch is also involved in the ear anomalies since defects of the small bones of the inner ear are found. He reported a case with defects of the incus processes and deformity of the stapes, causing middle-ear deafness. He believed that the rod form of the stapes indicates the influence of the stapedius artery, as shown by McKenzie and Craig. 20

21

22

The vertebral anomalies arise during the fifth week in utero, when the crown-rump length of the embryo is 12 to 14 mm. From the genetic viewpoint, mandibulofacial dysostosis appears to be irregularly dominant. A study of three generations by Debusmann suggested a lethal effect of the mutated gene since three involved infants in the third generation died during the first six months of life. There is no known hereditary pattern for Goldenhar's syndrome. Chromosome counts have been normal. 23

SUMMARY

The Franceschetti and Goldenhar syndromes arise at about the same period of embryonic development, the first as a genetic manifestation, the second apparently unrelated to heredity. Because of the time of origin, the two syndromes have in common certain ear deformities and, often, malar and mandibular hypoplasia and palatal anomalies. They differ absolutely in the presence of epibulbar dermoids or epidermoids (only in the Goldenhar syndrome) and, usually, in the absence of vertebral anomalies in the Franceschetti syndrome. The source of much confusion in the literature is the unilateral antimongoloid slant in cases of Goldenhar's syndrome with hemifacial hypoplasia. Here

514

AMERICAN JOURNAL OF OPHTHALMOLOGY

the lid slant is probably the result of the facial asymmetry and should not be considered a manifestation of Franceschetti's syndrome. Our case is considered typical of Franceschetti's syndrome. 970 Fisher Building (48202) REFERENCES 1. Duke-Elder, S. : System of Ophthalmology. Congenital deformities. S t Louis, Mosby, 1963, vol. 3, pt. 2, p. 1021. 2. (a) Gorlin, R. J. and Pindborg, J. J.: Syndromes of the Head and Neck. New York, McGraw-Hill, 1964, p. 419. (b) Gorlin, R. J., Jue, K. L., Jacobsen, U. and Goldschmidt, E. Oculo auriculo vertebral dysplasia. J. Pediat. 63:99, 1963. 3. (a) Sugar, H . S. : The oculo auriculo vertebral dysplasia syndrome of Goldenhar. Am. J. Ophth. 62:678, 1966. (b) An unusual example of the oculo-auriculo-vertebral dysplasia syndrome of Goldenhar. J. Ped. Ophth. 4:9,1967. 4. Thomson, A . : Notice of several cases of malformation of the external ear together with experiments on the state of hearing in such persons. Monthly J. Med. Sei. (Edin.) 7:420, 1947. 5. Berry, G. A . : Note on a congenital defect (coloboma?) of the lower lid. Roy. London Ophth. Hosp. Rep. 12:255, 1889. 6. Collins, E . T. : Case with symmetrical congenital notches in the outer part of each lower lid and defective development of the malar bones. Tr. Ophth. Soc. U.K. 20:190, 1900. 7. Franceschetti, A . and Zwahlen, P. Un syndrome nouveau: la dysostose mandibulofaciale. Bull. Suisse d'med. 1:60, 1944. 8. Franceschetti, A . and Klein, D. : The mandibulofacial dysostosis: A new hereditary syndrome. Acta Ophth. 27:143, 1949. 9. Jorio, S. : Sui tumori congenital epibulbari (a tipo familiäre, od associate a malformazioni facciale multiple). Rasseg. d'Ottal. 17:259, 1936. 10. Tranos, L. : Mandibulofacial dysostosis associated with dermolipoma of the conjunctiva. Am. J. Ophth. 37:354, 1954. 11. Paufique, L., Etienne, R. and Moreau, P. G. :

S E P T E M B E R , 1968

Un cas de dysostosis mandibulofaciale avec dermoide de la cornee (syndrome de Franceschetti). Bull. Soc. Ophtal. Fr. 81-84,1952. 12. Neimann, N., Cordier, J., Manciaux, M. and Barrucane, D. : Syndrome de Franceschetti associé au syndrome de Goldenhar et a des malformations vertebrales. Ann. de Pédiat. 36:2632, 1960. 13. Vannas, S.: La dysostose mandibulo-faciale associée à des malformations oculaires particulières. J. Genêt. Hum. 4 =234,1955. 14. Boudet, G : Anomalies oculaires congénitales et malformations craniofaciales associées. Montpelier Med. 53:704, 1958. 15. Blodi, F. C. : Developmental anomalies of the skull affecting the eye. Arch. Ophth. 57:593, 1957. 16. Rousseau, M . R. : Dysostose mandibulo-faciale avec dermoide de la cornee (syndrome de Franceschetti). Rev. d'Oto-Neuro-ophth. 27:220, 1955. 17. Hoffmann-Egg, L. and Velissoropoulos, P.: Malformations oculo auriculaires (lipodermoide epibulbaire, appendice pre-auriculaire, colchóme de la paupière supérieure) et leurs relations avec la dysostose mandibulo-faciale. Ann Ocul. 186:155, 1953. 18. Franceschetti, A., Brocher, J. E. W . and Klein, D. : Dysostose mandibulo-faciale unilaterale avec deformations multiples du squelette (processus paramastoide, Synostose des vertebres, sacralisation, etc torticolis clonique). Ophthalmologica 118:796, 1949. 19. Mann, I. : Deficiency of the malar bones with defect of the lower lids. Brit. J. Ophth. 27:13, 1943. 20. Hövels, O. : Zur Pathogenese der Missbuldengen des 1. Visceralbogens. Z. Kinderh. 73:568, 1953. 21. Keerl, G. : Zur formalen und causalen Genese der Dysostosis Mandibulofacialis. Ophthalmologica 143:5, 1962. 22. McKenzie, J. and Craig, J. : Mandibulofacial dysostosis (Treacher-Collins Syndrome). Arch. Dis. Childhood. 30:391, 1955. 23. Debusmann: Familiäre kombinierte Gesichts missbilding im Bereich des ersten Viszeralbogens. Arch. f. Kinderh. 120:133,1940. 24. Gallocher, M. G. M . P. : La dysostose mandibulofaciale ou syndrome de Franceschetti. Thesis, University of Bordeaux, 1950.