June, 1970 T h e j o u r n a l of P E D I A T R I C S
Frontonasal dy lasia Frontonasal dysplasia is" a nongenetic, congenital disorder in which manifestations are limited to the head. Four types of facies can be distinguished based upon embryologie considerations. Clefting of the lip and~or palate is associated with two of these facies.
H e d d i e O. Sedano, D.D.S., M. M i c h a e l Cohen, Jr., D . M . D . , J a n Jirasek, M . D . , a n d R o b e r t J. Gorlin, D.D.S. ~ MINNEAPOLIS, MINN.
S I N c s. t h e m i d d l e of the eighteenth century, frontonasal dysplasia has been r e p o r t e d in the literature u n d e r a variety of names. T h e a n o m a l y consists of: (a) ocular hypertelorism, (b) b r o a d e n i n g of the nasal root, (c) m e d i a n facial cleft affecting the nose o r both the nose a n d the u p p e r lip and, at times, the palate, (d) uni- or bilateral clefting of the ala nasl, (e) lack of f o r m a t i o n of the nasal tip, (f) anterior c r a n i u m bifidum occultum, a n d (g) V - s h a p e d h a i r p r o l o n g a tion onto t h e forehead, g e n e r a l l y over the a r e a of the c r a n i u m bifidum. T h e condition presents variable clinical combinations. T h e most t h o r o u g h recent review of this a n o m a l y is t h a t of D e M y e r , 1 who called the condition the m e d i a n cleft face syndrome. CASE REPORTS
Case 1. The patient, a Caucasian male 7month-old infant, was the product of a 43 week From the Division of Oral Pathology, University of Minnesota. This study was made possible in part by United States Public Health Service Program Grant In Oral Pathology DE-1770. ~Address: Division of Oral Pathology, University o[ Minnesota, Minneapolis, Minnesota 55455.
Vol. 76, No. 6, pp. 906-913
gestation. The 20-year-old mother gained 20 pounds and vomited throughout the entire pregnancy. The father's age at time of conception was unknown. There were no other siblings and no history of miscarriage or abortion. Consanguinity was denied and the family history was noncontributory. The mother allegedly took LSD. At the time of examination, the patient revealed a grossly deformed face which maintained fetal proportions (Fig. 1). True ocular hypertelorism was evident with a canthal index of 70.7 (upper limit of normality 38). Canthal index ~
inner canthal distance x 100. outer canthal distance
Epicanthal folds and blepharophimosis were present, causing the eyes to appear smaller than normal. The medial canthal area partly covered the cornea. The external nares were small and wide and the alar cartilages were hypoplastic. The nasal root was absent. A soft, rMsed protuberance was present in the midfacial region, extending from the nasal area to the forehead. Skull roentgenograms revealed anterior cranium bifidum with a widely open metopic suture. There was right talipes calcaneovarus and the right lower extremity was shorter than the left. In addition, a supernumerary bifid hallux and an extra metatarsal were present on the right foot. The testes were undescended. Dermato-
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Fig. 1. Case 1. Note fetal appearance of facies characterized by marked ocular hypertelorism, horseshoe-shaped prominence, pronounced separation of nostrils, and notching of upper lip.
glyphic analysis revealed arch patterns on the second and third digits bilaterally and transitional simian creases. The karyotype was normal (46,XY). According to our classification this case corresponds to type D frontonasal dysplasia. Case 2. The patient, a Caucasian female, was born in 1960 after an uneventful pregnancy. The age of the mother at the time of conception was 35 years. The father's age was unknown. At birth, head circumference, body length, and weight were within normal limits. There were three other normal siblings and no history of miscarriage or abortion. The paternal grandfather and a paternal uncle were reported to have had bilateral microphthalmia. There was no parental consanguinity. Physical examination revealed bilateral clefting of the alae nasi, right anophthalmia, and left microphthalmia, the child being totally blind. A protuberance was present in the midfrontal region (Fig. 2). Skull roentgenograms showed an anterior cranium bifidum corresponding to this area (Fig. 3). The nasal root was markedly broad and ocular hypertelorism was present with a canthaI index of 45.9. No other abnormalities were present. Der-
Fig. 2. Case 2. Patient had right anophthalmia, left microphthalmia, and bilateral colobomas of alae nasi. Note broad basal root.
matoglyphic analysis was within normal limits. The karyotype was normal (46,XX). According to our classification this case corresponds to type C frontonasal dysplasia. LITERATURE
Review of the literature yielded more than 70 cases of the frontonasal dysplasia (Tables I to V ~ ) . E a r l i e r case reports such as those of H o p p e , ~ Liebrecht, ~ a n d KredeI, ~ which p r o b a b l y represent examples of the condition, were not i n c l u d e d in t h e present series because p h o t o g r a p h i c or other illustrative description was not given. D o u b t f u l cases a n d those presenting no clinical or photog r a p h i c information were also eliminated f r o m o u r review: reference 5 (Cases 1 a n d 2), reference 6 (Figs. 4 a n d 5 ) , references 7 to 11, a n d reference 12 (Case 8). Several instances of double r e p o r t i n g were
*For Tables II to V, order Document No. NAPS-00934 from ASIS National Auxiliary Publications Service, in care of CCM Information Sciences, Inc., 909 3rd Ave., New York, N. Y. 10022, remitting ~;2.00 for each m~crofiche copy or $5.00 for each photocopy.
Sedano et al.
The Journal o[ Pediatrics June 1970
Anomaly Mental retardation Brachycephaly Hydrocephalus Webbing of neck Low-set ears Conduction deafness Preauricular tags Absent tragus Synostosis of coronal sutures Hypertrophy of ethmoidal
Facies A (re[. No.) 12 17 18 14 21 12 22 23
(Case 7) (Case 1) (Case 2)
Facies B (re[. No.)
Facies C (re[. No.)
12 (Case 4)
2O (Case 7)
(Case 2) --12 (Case 7) 12 (Case 7)
24 (Fig. 6)
Facies D (re[. No.) 19
-----25, 26 ----
-__ ---9, 27, 64 19 ---
16 (Case 1 28 (Case 1 29, 30
Hypoplastic frontal sinuses Bilateral anophthalmia Microphthalmia Epibulbar dermoid Coloboma of upper eyelid Congenital cataracts Nose tags Clinodactyly Bilateral camptodaetyly Syndactyly Polydactyly Genu valgum Enlarged epiphysis Spina bifida oculta Hypoplasia of pectoral muscles Umbilical hernia Cryptorchidism
12 18 12 17 17 14 14
------(Case (Case -(Case (Case (Case
31 (Case 3) 26 25 26 -32 7) 2)
3O 7) 1) 1)
14 17 (Case 1) 1 (Case 6)
n o t e d . S i n c e t h e m e t h o d of a s c e r t a i n m e n t is n o t of i m p o r t a n c e i n t h i s a n o m a l y , o n l y t h e first r e p o r t w a s t a b u l a t e d a n d a d d i t i o n a l data added when noted in the second report. CLASSIFICATION The anomaly presents marked clinical v a r i a b i l i t y . T h e c l a s s i f i c a t i o n o f D e M y e r 1 is based upon: (a) the presence of true ocular hypertelorism and (b) median facial malf o r m a t i o n s , e s s e n t i a l l y s y m m e t r i c a l . H e exc l u d e d f r o m his s u r v e y all p a t i e n t s i n w h i c h the mental status was not documented. This last p a r a m e t e r w a s n o t i n c l u d e d i n o u r req u i r e m e n t s . O u r c l a s s i f i c a t i o n also differs f r o m t h a t of D e M y e r as e x p l a i n e d b e l o w i n t h a t w e h a v e v i e w e d m e d i a n f a c i a l clef r i n g
64 27, 64 19 -1 (Case 2) __
-12 (Case 7)
--__ __ 34 --
-1 (Case 2)
a n d l a t e r a l n o t c h i n g of t h e a l a n a s i as t w o different components based upon independent embryological development. Conseq u e n t l y , o u r f o u r facies d i f f e r f r o m t h o s e of D e M y e r as follows:
Facies I A Facies I B Facies I A (not illustrated) Facies I I B Facies I I C Facies I I I (not illustrated) Facies I V
Facies B Facies D Facies D (probably) Facies"B Facies C Facies B (probably) Facies A
W e h a v e classified t h e cases i n t o f o u r closely r e l a t e d g r o u p s , b a s e d u p o n a m o d i fied c o n c e p t of e m b r y o l o g i c a l d e v e l o p m e n t
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Fig. 3. Case 2. Roentgenogram showing reduced size of right orbit as well as anterior cranium bifidum occultum.
Fig. 4. Head of an embryo 10.2 mm. long, 42 days of age (Streeter horizon X V I ) . Nasal ridges (arrows) are present; no frontal process can be recognized.
Fig. 5. Head of an embryo 15.5 ram. long, 45 days old (Streeter horizon X V I I I ) . Primary nasal passages are formed. The cartilaginous nasal capsule begins to develop. T h e apex and dorsum nasi are inconspicuous. Nasal alore (arrows) can be clearly recognized. The infranasal groove is present. Note resemblance to facies D.
Fig. 6. Facies A. Marked ocular hypertelorism, broad nasal root, and absence of nasal tip. (Courtesy of F. Burian, Prague, Czechoslovakia.)
Sedano et al.
of the face, conceived of by one of us (J. E. J.). In a previous study, 50 human embryos were analyzed by direct observation and by histologic examination. In no case was it possible to identify the classical frontonasal process (Figs. 4 and 5). In its place an unpaired forebrain area was recognized. In 22day-old (2 to 3 ram. long) embryos the following structures can be seen around the stomadeum: two maxillary areas, two mandibular arches, and the unpaired forebrain area. The wall of the forebrain area is formed by neuroectoderm of the brain vesicle mesenchyme and is covered by surface ectoderm. The eyes develop laterally in this area between the twenty-fifth and thirtyseventh days of gestation. In 33-day-old embryos, approximately 7 mm. long, the olfactory placodes begin to develop medially and rostrally in the brain area. A mesenchymal nasal ridge covered with ectoderm elevates as a horseshoe-shaped ridge around each olfactory placode, changing it into an olfactory pit. On each nasal ridge, a premaxillary (globular) part, a medial part, and a lateral part may be distinguished. The premaxillary parts of both nasal ridges are separated by the infranasal furrow, the lateral parts from the maxillary area by a nasomaxillary (nasolacrimal) furrow. The maxillary area is separated from the premaxillary part of the nasal ridge by an epithelial plate. The development of the nose depends on the formation of the cartilaginous nasal capsule induced by the olfactory epithelium. The nasal capsule is part of the chondrocranium and has a sagittal septal part and a horizontal part. The sagittal part elevates the tip of the nose and turns the external nares caudally. The horizontal part separates the nasal cavity from the brain and contributes to the formation of the dorsum nasi. If the nasal capsule fails to develop, the dorsum and the tip of the nose will not be present; the unpaired brain area may extend caudally, filling the space between the two nasal ridges. As a consequence, the individ-
The Journal o[ Pediatrics June 1970
ual will present with: (a) ocular hypertelorism, because the eyes have failed to move toward the midline, (b) two independent and rudimentary nares with lack of formation of the nasal tip and dorsum, and (c) marked, uni- or bilateral frontal prominence, representing protrusion of the brain vesicle in this area (cranium bifidum occulture). The lateral notching of the ala nasi, present in some of the variants of frontonasal dysplasia, is easily explained by failure of fusion of the medial and lateral parts of the nasal ridge. Frontonasal dysplasia is clearly understood using these concepts of embryogenesis. Whatever the etiological agent, the time at which it acts upon the developing cranium and face probably can explain the variability of the clinical manifestations. METHODS
All case reports which the authors considered representative of the condition were analyzed photographically (clinical photographs printed in the original reports were duplicated a n d / o r enlarged in all those cases in which communication with the authors failed to obtain the original prints). Cases were thus grouped according to the various types of alterations, as specified below. Ocular hypertelorism was considered the invariable component of the anomaly and, in order to determine, the presence of true hypertelorism, the following procedure was used: The inner and outer canthal distances were measured with metric needlepoint calipers on frontal view photographs. All other photos were excluded. Since the photographs were of varied sizes, only the ratio of inner canthal distance to outer canthal distance was used for comparative purposes. Accordingly, canthal indices were obtained. RESULTS
Four basic facies were identified as follows: facies A: Ocular hypertelorism, broad nasal roots, median nasal groove with absence of the nasal tip. True clefting of the midline is not present, facies B: Ocular hy-
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Fig. 7. Facies B. Newborn infant: Notice the rectangular oronasal opening and the absence of an intermaxillary segment, the so-called pseudomedian cleft lip. (Courtesy of DeMyer, W., Neurology 17: 961, t967.)
pertelorism, broad nasal root, deep median facial groove or true cleft affecting the nose or both the nose and the upper lip. T h e palate may also be cleft, facies C: Ocular hypertelorism, broad nasal root, uni- or bilateral notching of the ala nail. facies D: Combination of facies B and C. Anterior cranium bifidum occultum can be present in all four types. A typical example of facies A is illustrated in Fig. 6. Family histories were noncontributory in most cases. Two reports stated that the mother was "hyperteloric. "is' 14 In two instances the patient was a dizygotic twin, the other twin being normal and of the opposite sex (reference 12, Case 7, and reference 15). Fig. 7 represents an example of facies B. Family histories were negative except for Case 1 of Pettersson, ~ in which an uncle presented cleft lip-palate and a twin brother of the patient presented cleft nose, but without ocular hypertelorism. Facies C is illustrated in Fig. 2. No family history of similar or other malformations was noted in any case. Our Case 1 (Fig. 1) is an example of
Fig. 8. Facies D. Girl illustrating more marked changes than illustrated in Fig. 1. (Courtesy of C. M. Carter , Orlando, Florida.)
facies D. Another example is seen in Fig. 8. The majority of the reports do not state whether there were other abnormalities among relatives of affected individuals, Table I shows a variety of reported anomalies associated with the different facies of frontonasal dysplasia. DISCUSSION Careful analysis of frontonasal dysplasia suggests no genetic basis f o r the condition. The anomaly is probably produced by interference with the normal embryologic development of the face, especially the nose. This i n t e r f e r e n c e t a k e s place at different stages of development, producing the four closely related clinical types. The varied and sporadic associated anomalies reported in some cases suggest that these abnormalities are adventitious fin~lings unrelated to the condition. We believe that the pathology in this anomaly is confined to the face. Cleft lip a n d / o r cleft palate is not associated with facies A. In facies B, the following results were noted: cleft lip with or without cleft palate, 14 cases; cleft palate, 2 cases;
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The Journal of Pediatrics June 1970
negative, 8 cases; a n d not stated, 2 cases. I n facies C, only one of 17 cases presented with cleft lip. O f 18 cases w i t h facies D, 13 presented with cleft lip with o r without cleft palate, 1 with cleft palate, 3 negative, a n d 1 not stated. Bifid uvula was r e p o r t e d in only one case? s T h e association of clefting with facies B a n d D is self-evident. DIFFERENTIAL
6. 7. 8.
Frontonasal dysplasia should be differentiated from nasal glioma. T h e l a t t e r presents a n o r m a l configuration of the tip a n d alae of the nose a n d true o c u l a r hypertelorism is not present. W e consider frontonasal dysplasia a n d h o l o p r o s e n c e p h a l y to be at opposite ends of the " s p e c t r u m " o f m i d f a c e malformations. H o l o p r o s e n c e p h a l y is associated with the facies of cyclopia, ethmocephaly, cebocephaly, p r e m a x i l l a r y agenesis, a n d p a r t i a l p r e m a x i l l a r y agenesis. I n holop r o s e n c e p h a l y etiologic factors affect the developing c r a n i u m a n d face at a n earlier embryonal stage than t h a t assumed for frontonasal dysplasia a n d affected individuals would present ocular hypotelorism. I n dividuals with frontonasal dysplasia constantly manifest true, o c u l a r hypertelorism.
9. I0. 11.
t4. 15. 16.
Permission was granted from Sonoma State Hospital, Sonoma, California, to publish Case 1. The authors thank Dr. C. H. Carter, Orlando, Florida, for collaborative assistance, and Mr. LeRoy P. Christenson and Mr. Verne K. Greenlee, Division of Photography, University of Minnesota, School of Dentistry, for their aid. REFERENCES
1. DeMyer, W.: The median cleft face syndrome. DifferentiM diagnosis of cranium bifidum occuhum, hypertelorlsm, and median cleft nose, lip, and palate, Neurology 17: 961, 1967. 2. Hoppe, I.: Eine angeborene Spaltung der Nase, Med. Ztg. d. Ver. f. Heilk. in Preussen 2: 164, 1859. 3. Liebrecht, P.: Observation d'un cas de difformit~ eong~nitale du nez avec quelques r~flexions sur l'influence des impressions maternelles sur la malformation du foetus, J. Med. (Bruxelles) 63: 10, 109, 1876. 4. Kredel, L. : Die angeborenen Nasenspalten und ihre Operation, Deutsch. Z. Chir. 47: 237, 1898. 5. Borges, A. F., and Alexander, J. E.: Plastic
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26. Tillman, H. H.: Mandibulofaclal dysostosis. Report of three cases, Oral Surg. 23: 638, 1967. 27. Lexer, E.: Angeborene mediane Spaltung der Nase, Arch. Klin. Chit. 62: 360, 1900. 28. Galanti, S.: Rata malformazlone congenlta del naso. (Due casi di naso bifido), Ann. Laring. 60: 583, 1961. 29. Kazanjian, V., and Holmes, E.: Treatment of median cleft lip associated with bifid nose and hypertelorism, Plast. Reconstr. Surg. 24: 582, 1959. 30. Von Viezens, A., and Willenberg, W.: Zwei seltene Gesichtsmissbildungen im Hals- NasenOhrenbereieh: Doppelnase und Dysostosis mandibulofacialis, Deutsch. Med. J. 7- 457, 1956. 31. Berndorfer, A.: Ober die seitliche Nasenspalte, Acta Otolaryng. (Stockholm) 55: 163, 1962. 32. Rohasco, S. A., and Massa, J. L.: Frontonasal syndrome, Brit. J. Plast. Surg. 21: 244, 1968. 33. Bougon and Derocque: Fissure m6diane de la face, Rev. Chir. Orthop. 9: 219, 1908. 34. Ritter, W.: Kraniofaziale Dysplasien und St6rungen der Zahnentwicklung, Stuttgart, 1968, G. Fischer, p. 35. 35. Pickerill, H. P.: Hypertelorism. Notes on three cases, Brit. J. Surg. 26: 588, 1938/39. 36. Witzel, O.: Ober die angeborene mediane Spaltung der oberen Gesichtsh~ilfte, Arch. Klin. Chir. 27: 893, 1882. 37. Trendelenburg, F.: Verletzungen und chirurgische Krankheiten des Gesichts, Deutsch. Chit. 33: 16, 1886-1913. 38. Nasse, D.: Zwei F~ille yon angeborener medianer Spaltung der Nase, Arch. Klin. Chir. 49: 767, 1895. 39. Wilkinson, G.: A case of bifid nose, J. Laryng. 37: 560, 1922. 40. Bumba, F., and Lucksch, F.: Ein Fall yon Doggennase, Virchow. Arch. Path. Anat. 264: 554, 1927. 41. Lagos, G. A.: Labio leporino median0 y nariz bifida, Sem. Med. 51": 237, 1944. 42. Weaver, D., and Bellinger, D.: Case reports. Bifid nose associated with midline cleft of the upper lip, Arch. Otolaryng. 44: 480, 1946. 43. Kitlowski, E. A.: Congenital anomaly of the face: Case report. Inclusion cyst arising from mucous membrane of pharynx with deformity of nose and cleft lip and palate, Plast. Reconstr. Surg. 23: 64, 1959. 44. Birrel, J. F.: The ear, nose and throat disease of children, London, 1960, Cassell & Co., Ltd., p. 94. 45. Baibak, G., and Bromberg, B. E.: Congenital
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