8
Facial Bones
Karen Gripp and Luis Fernando Escobar
H umans are very adept at recognizing one another. This ability
is largely based on the identification of faces. The uniqueness
of each human face, with the possible exception of monozygotic
twins, allows for identification and recognition of an individual
with deeper implications in human interaction and, more impor-
tant, in social functioning. The recognition of an individual face,
whose combination of features is remembered as belonging to a
certain person, may be compared to the recognition of a syndrome
diagnosis based on certain characteristics of the facial structures.
The shape of individual facial structures can be recognized, but
the combination of findings may lead to the identification of a
facial ‘‘gestalt’’ that may be associated with a genetic syndrome.
On a more formal level, anthropometric measurements of facial
structures may be taken, and profiles of these measurements can
be constructed. Facial indexes such as those developed by Blumenbach
and Camper in the eighteenth century demonstrate the fascination
that the facial bones provoked in early ‘‘dysmorphologists.’’ At-
tempts to objectively recognize the abnormal from the normal facial
appearance have led to the development of dysmorphic indexes.1
Today, computer-driven facial recognition uses the correlation of the
measurements to identify individual faces or to identify a pattern
known to be characteristic for a specific syndrome. Based on consistent
patterns of age-dependent growth and maturation of facial structures,
facial photographs may be manipulated to predict the changes
with age.
The human facial form results from the interaction between
the skeletal and soft tissue elements. The skeletal framework pro-
vides the structural support of the face and is largely responsible for
size, shape, and proportions of each facial structure.2,3 Anomalies
such as cyclopia or proboscis are clearly associated with structural
abnormalities of the facial skeleton; however, more subtle facial
anomalies may lack evident skeletal findings that would be identi-
fiable only on facial radiographs or other imaging studies. Consistent
differences in the facial bony structures may underlie the character-
istic facial findings that would allow syndrome recognition.
The face may be conveniently divided into thirds—the upper,
middle, and lower—delimited by horizontal planes passing through
the pupils of the eyes and the rima oris. The three parts corre-
spond generally to the embryonic frontonasal, maxillary, and
mandibular processes, respectively. The upper third of the face is
predominantly of neurocranial composition. The middle third is
skeletally complex, composed in part of the cranial base, and in-
volves both the nasal extension from the upper third of the
face (frontonasal process) and the maxillary processes from the first
branchial arch. The lower third is composed skeletally of the
mandible.
Although these three segments develop through similar em-
bryologic processes, their individual origins differ. The form
of the facial bones is not as dependent on brain development as
are the calvarial bones. Anencephaly, for example, presents with
no calvarial bones but relatively good formation of the cranial
base and skeletal facial structures. The various facial bones are
derived as portions of the neurocranium, chondrocranium, or
viscerocranium. These skeletal elements have neural crest or
paraxial mesodermal origins.
The chondrocranium is the cartilaginous precursor of the
cranial base and the capsules surrounding the nasal and auditory
organs. The base of the skull becomes part of the neurocranium,
the bony tissue that surrounds the brain. The cranial base ossifies
endochondrally, while the vault undergoes intermembranous
ossification.
The viscerocranium is comprised of neural crest-derived
bones of the jaws (maxilla and mandible) as well as the zygoma
(part of the temporal bone), nasal, and lacrimal bones.
The teeth, with the exception of their enamel, which is ec-
todermally derived, are also comprised of neural crest cells.
Craniofacial development is an extremely complex process
that requires a perfectly organized interaction and integration be-
tween multiple specialized tissues, such as ectoderm, neural crest,
mesoderm, and pharyngeal endoderm. The complex mechanisms
and molecular cascades continue to be an enigmatic process. It has
not been until recent years that molecular biologists have been able
to focus on specific mechanisms involved in craniofacial develop-
ment.4–6 We are beginning to understand some of these mecha-
nisms, such as those that involve fibroblast growth factor or nodal
signaling and the role of homeobox genes. The complex interplay of
numerous signaling cascades controls the proliferation and differ-
entiation of specific cell populations. A thorough understanding of
these developmental events is essential to defining the basis for the
patterning of individual facial bones and their relative positioning.
This chapter includes information regarding the most
common defects that affect the facial skeleton. We review their
267
268 Craniofacial Structures

frequency and their involvement in specific syndromic disorders. into a triangular shape, leading to trigonocephaly. The orbits
We limit our discussion to the frontal bones, orbits, zygomas, the assume an excessively mesial position, which may be apparent as
nasal skeletal area, the maxillary structures, and the mandible. ocular hypotelorism.

References Diagnosis

1. Escobar LF, Bixler D, Padilla LM: Quantitation of craniofacial
anomalies in utero: fetal alcohol, Crouzon syndromes and Thanato-
phoric dysplasia. Am J Med Genet 45:25, 1993.
2. Friede H: Normal development and growth of the human neuro-
cranium and cranial base. Scand J Plast Reconstr Surg 15:163, 1981.
3. Lavelle CL: An analysis of foetal craniofacial growth. Ann Hum Biol
1:269, 1974.
4. Trainor PA: Making headway: the roles of hox genes and neural crest
cells in craniofacial development. Scientific WorldJournal 3:240, 2003.
5. David NB, Saint-Etienne L, Tsang M, et al.: Requirement for endoderm
and FGF3 in ventral head skeleton formation. Development 129:4457,
2002.
6. Couly G, Creuzet S, Bennaceur S, et al.: Interactions between Hox-negative
cephalic neural crest cells and the foregut endoderm in patterning the facial
skeleton in the vertebrate head. Development 129:1061, 2002.
8.1
Premature Metopic Sutural Synostosis
Definition
Premature metopic sutural synostosis is the premature fusion of
the metopic suture in utero. It deforms the anterior cranial fossa
Premature metopic sutural synostosis is characterized by the
presence of a keel-like ridge at the site of the metopic suture. The
head, viewed from above, appears triangular (Fig. 8-1). Physical
examination of the affected individual may show a vertical bony
ridge of the forehead that coincides with the anatomic midline.
Due to bony hypotelorism, the superolateral aspect of the orbits is
positioned more mesially and posteriorly than normal. The oc-
ciput bulges with compensatory expansion to accommodate brain
growth.1
In patients in whom metopic synostosis is suspected, radio-
logic confirmation is obligatory. Hypotelorism characterizes the
anteroposterior skull films, in addition to low-set lateroinferior
orbital angles. The roof of the orbits seems to be highly placed in
relation to the horizontal plate of the ethmoid bone. Computer-
ized tomography (CT) may show compression of the anterior
cranial fossa and the cribriform plate in the midline.1 When 3-D
CT study is used to identify metopic synostosis, it is important to
note that physiologic metopic closure occurs between 3 and
9 months of age; closure earlier than 3 months should be sus-
pected abnormal.2 The spectrum of facial morphology associated
with metopic synostosis is broad, from minor prominence of the
forehead to severe aesthetic deformity.

Fig. 8-1. A. Preoperative right lateral, frontal, and top views of the craniofacies in a patient with isolated
premature metopic synostosis. B. Right lateral, frontal, and top views of patient 3 months after surgical
correction. Note the reduction of hypotelorism. (From Marsh and Vannier.1)
 Facial Bones 269

Two types of premature metopic sutural synostosis can be
recognized. Isolated metopic synostosis occurs at a rate of ap-
proximately 0.3 per 1000 live births and is usually sporadic. In the
second type, metopic synostosis is associated with multiple con-
genital anomalies.3 These anomalies include aortic stenosis, tetralogy
of Fallot, omphalocele, cleft palate, hypospadias, multiple hemi-
vertebrae, congenital abducens nerve palsies, absence of the corpus
callosum, and agenesis of the septum pellucidum.1 It is not clear at
present whether the different phenotypical combinations seen in
these patients represent different conditions or belong together in a
wide spectrum of abnormalities with a single etiology. Mental re-
tardation is rarely seen as part of isolated early metopic sutural
synostosis. There is no evidence that a disturbance in brain growth as
a result of the cranial deformity contributes to the retardation oc-
casionally seen. Syndromes that include metopic synostosis are listed
in Table 8-1.
Etiology and Distribution
As with any other type of early synostosis, early metopic fusion may
lead to a sequence of developmental abnormalities. In this case,
striking changes in the facial skeleton may result. Unfortunately,
the mechanism that prematurely initiates this normal process of
development is unknown. During fetal life the two frontal bones
are separated by a sutural space, which consists of fibrous tissue and
mesenchymal cells responsible for the growth of the frontal bones.
This mesenchymal tissue has the potential to differentiate either
into bone or into secondary cartilage.12 For the metopic suture, it is
suggested that closure of the sutural space is due to the differen-
tiation of the mesenchyme into chondroid tissue instead of bone.
The chondroid tissue, then, is responsible for the growth of each
frontal bone toward the other and constitutes the first bridge of
union between the two bones.13 Active bone resorption prevents
this primary union from closing prematurely. Any interruption
either during mesenchymal differentiation or in the maintenance
of an open sutural space can lead to premature metopic synostosis.
It has been suggested that absence of interosseous movement might
lead to sutural fusion. Experimental evidence seems to support this;
immobilization of adjacent bone by cyanoacrylate glue, bone
grafting, or periosteal grafting induces synostosis.14 This also
would be consistent with the occurrence of metopic synostosis in
infants with intrauterine constraint of the cranium due to uterine
malformation or twinning.15 Teratogens causing trigonocephaly
include valproic acid and hydantoin (Table 8-1).7,16 Metopic syn-
ostosis constitutes 4–10% of all cases of craniosynostosis,1,17,18 and
male to female ratios of 3:4 and 2:3 have been reported.17
Prognosis, Treatment, and Prevention
Early surgical intervention strikingly improves the growth of the
facial skeleton in isolated metopic synostosis.19–21 Bicoronal cra-
niectomies can be helpful to free the frontal bones, with excision
of the keel down to the frontonasal suture. Orbital advancement
may be necessary to restore a normal brow contour. Straightening
of the supraorbital bar and reshaping of the forehead using var-
iations according to the deformity are very satisfactory. Following
this procedure, hypotelorism tends to disappear clinically and
diminishes radiologically.21
Recent forensic findings in Salzburg, Austria, suggest that the
great musician Wolfgang Amadeus Mozart had premature syn-
ostosis of the metopic suture.22 This was characterized, in his case,
by mild hypotelorism, reduction of the orbital volume, and a
supraglabellar sulcus divided in the midline by a small protu-
berance that formed a ridge near the nasion.
The prognosis of affected individuals is very encouraging, and,
unless seen in multiple anomaly syndromes, metopic synostosis should

Table 8-1. Syndromes associated with premature metopic suture synostosis

Causation
Syndrome Prominent Features Gene/Locus

Baller-Gerold4
Chromosome abnormalities5
Deletion 9p6
Hydantoin, prenatal7
Jacobsen8
Opitz-C9
Saethre-Chotzen10
Trigonocephaly-short stature-
developmental delay11
Trigonocephaly, isolated5
Growth deficiency, craniosynostosis, radial aplasia/hypoplasia, short curved ulna, AR (218600)
missing small bones of the hands, imperforate anus, anteriorly placed anus, mental
deficiency (50%)
Multiple congenital anomalies, learning differences Abnormal karyotype
Craniosynostosis, trigonocephaly, midfacial hypoplasia, short nose, anteverted nares, (158170)
long philtrum, poorly formed ears, extra digital flexion creases, excess in whorl patterns, Abnormal karyotype
heart defect
Growth deficiency, ocular hypertelorism, broad nasal bridge, short nose, clefting, (132810)
hypoplasia of distal phalanges, low arch dermal ridges, digitalized thumb, short neck, rib Hydantoin teratogenesis
anomalies, variable mental function
Low-set ears, ptosis, congenital heart disease, hypospadias, labial and clitoral hypoplasia, (147791)
joint contractures, hypotonia, mental retardation, thrombocytopenia Monosomy
11q23-qter
Craniosynostosis, narrow bifrontal diameter, microcornea, short broad nose, long (211750)
philtrum, thin lips, high arched palate, micrognathia, rhizomelic shortening Unknown
and postaxial hexadactyly of all limbs, thin ribs, humeral and femoral shortening
Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, AD (101400)
hallux valgus TWIST, 7p21
Marked frontal vertical ridge, narrow forehead, hypertelorism, growth retardation, XL (314320)
variable mental development
Craniosynostosis limited to the metopic region, giving a prow appearance to the AD (190440, 275600)
forehead, normal brain development
270 Craniofacial Structures
be considered a relatively benign form of craniofacial synostosis. No
reports of prenatal diagnosis of metopic synostosis can be found in the
literature, but ultrasonography may be helpful in detecting this ab-
normality via fetal cephalometry and detection of unusual craniofacial
shape. Prevention methodology is limited to prenatal counseling.
References (Premature Metopic Sutural Synostosis)
1. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care
for Craniofacial Deformities. JL Marsh, MW Vonnier, WG Stevens,
eds. CV Mosby, St. Louis, 1985, p 154.
2. Vu HL, Panchal J, Parker EE, et al.: The timing of physiologic
closure of the metopic suture: a review of 159 patients using recon-
structed 3D CT scans of the craniofacial region. J Craniofac Surg 12:
527, 2001.
3. Lajeunie E, Le Merrer M, Marchac D, et al.: Syndromal and
nonsyndromal primary trigonocephaly: analysis of a series of 237
patients. Am J Med Genet 75:211, 1998.
4. Cohen MM Jr, Toriello HV: Is there a Baller-Gerold syndrome? Am
J Med Genet. 61:63, 1996.
5. Azimi C, Kennedy SJ, Chitayat D, et al.: Clinical and genetic aspects of
trigonocephaly: a study of 25 cases. Am J Med Genet 117A:127, 2003.
6. Deroover J, Fryns JP, Parloir C, et al.: Partial monosomy of the short
arm of chromosome 9: a distinct clinical entity. Hum Genet 44:195,
1978.
7. Hanson JW, Myrianthopoulos NC, Sedgwick MHA, et al.: Risks to the
offspring of women treated with hydantoin anticonvulsants, with
emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976.
8. Penny LA, Dell’Aquila M, Jones MC, et al.: Clinical and molecular
characterization of patients with distal 11q deletions. Am J Hum Genet
56:676, 1995.
9. Lalatta F, Clerici Bagozzi D, Salmoiraghi MG, et al.: ‘C’ trigonocephaly
syndrome: clinical variability and possibility of surgical treatment. Am
J Med Genet 37:451, 1990.
10. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic hetero-
geneity of Saethre-Chotzen syndrome, due to TWIST and FGFR
mutations. Am J Hum Genet 62:1370, 1998.
11. Say B, Mayer J: Familial trigonocephaly associated with short stature
and developmental delay. Am J Dis Child 135:711, 1981.
12. Hall BK: Tissue interactions and chondrogenesis. In: Cartilage:
Development, Differentiation and Growth, vol. 2. BK Hall, ed.
Academic Press, New York, 1983, p 188.
13. Manzanares MC, Goret-Nicaise M, Dhem A: Metopic sutural closure
in the human skull. J Anat 161:203, 1988.
14. Engstrom C, Kiliaridis S, Thilander B: Facial suture synostosis related
to altered craniofacial bone remodelling induced by biochemical forces
and metabolic factors. In: Normal and Abnormal Bone Growth: Basic
and Clinical Research. AD Dixon, BG Sarnat, eds. Alan R. Liss, Inc.,
New York, 1985, p 379.
15. Graham JM Jr, Smith DW: Metopic craniosynostosis as a consequence
of fetal head constraint: two interesting experiments of nature. Pediatrics
65:1000, 1980.
16. Lajeunie E, Barcik U, Thorne JA, et al.: Craniosynostosis and fetal
exposure to sodium valproate. J Neurosurg 95:778, 2001.
17. Cohen MM Jr: Craniosynostosis and syndromes with craniosynostosis:
incidence, genetics, penetrance, variability and new syndrome updat-
ing. Birth Defects Orig Artic Ser XV(5B):13, 1979.
18. Shuper A, Merlob P, Grunebaum M, et al.: The incidence of
isolated craniosynostosis in the newborn infant. Am J Dis Child 139:
85, 1985.
19. Dhellemmes P, Pellerin PH, Lejune JP, et al.: Surgical treatment of
trigonocephaly. Childs Nerv System 2:228, 1986.
20. Anderson FM, Gwinn JL, Todt JC: Trigonocephaly: identity and surgical
treatment. J Neurosurg 19:723, 1962.
21. Marchac D: Early surgery in craniofacial synostosis. In: Craniofacial
Surgery. EP Caronni, ed. Little, Brown and Co., Boston, 1985, p 246.
22. Puech B, Puech PF, Tichy G, et al.: Craniofacial dysmorphism in
Mozart’s skull. J Forensic Sci 34:487, 1989.
8.2
Orbital Hypotelorism
Definition
Orbital hypotelorism is the decreased measurement between the bony
orbits, determined by decreased bony interorbital measurement and
decreased interpupillary measurement. Cyclopia represents the most
severe form of orbital hypotelorism.
Diagnosis
Orbital hypotelorism encompasses a wide spectrum of abnor-
malities ranging from mild reduction of the interorbital mea-
surement to complete fusion of the orbits. Even though simple
clinical inspection can detect orbital hypotelorism in the majority
of cases, inner canthal measurements are very useful in the rec-
ognition of mild forms (Fig. 8-2).1 In contrast to orbital hy-
pertelorism, inner canthal measurements are very helpful as an
indicator of reduced space between interorbital walls. More ac-
curate measurements can be made from the posteroanterior ra-
diographs of the skull when direct evaluation is possible.
Orbital hypotelorism can result from abnormalities in several
developmental events. Although it may be seen as an isolated
feature reflecting one end of the spectrum of continuous variation
in facial structure, the clinician should methodically search for
associated anomalies. Since orbital hypotelorism is consistently
found in association with holoprosencephaly, this possibility
should always be considered.2,3
Additional facial findings associated with holoprosencephaly
include absence of the upper frenulum and a single upper medial
incisor. These subtle findings can be present in otherwise healthy
carriers of mutations predisposing to holoprosencephaly, for ex-
ample, in sonic hedgehog (SHH), and may allow the identification
of affected family members, suggesting an autosomal dominant
inheritance pattern.
The most severe form of orbital hypotelorism is seen in
cyclopia, ethmocephaly, and cebocephaly, which are among the ar-
rhinencephalic defects.4 Cyclopia is the fusion of the orbits into a
single ring, which may encircle a wide range of intraorbital anomalies
(Fig. 8-3). Several chromosomal abnormalities have been associated
with cyclopia, including del 18p,5 del 2p,6 partial trisomy 3p, and
partial trisomy 7q.7 In ethmocephaly, severe ocular hypotelorism
occurs together with a blind-ended proboscis located between the
eyes; this differs from cebocephaly, which presents with a blind-ended
single nostril nose.
In addition to the association with holoprosencephaly, orbital
hypotelorism can be seen in maternal phenylketonuria, Coffin-
Siris, Langer-Giedion, Meckel-Gruber, and Williams syndromes
(Table 8-2). Chromosomal abnormalities such as trisomy 13 and
trisomy 20p have also been associated with reduction of the inter-
orbital measurement.16
In some cases, clefting disorders (cleft lip and palate) are
associated with some degree of orbital hypotelorism.17 An auto-
somal dominant form of ocular hypotelorism with submucosal
cleft palate and hypospadias was recognized by Shilbach and
Rott18 in a five-generation family with 10 affected individuals.
Pashayan and Lewis19 described a patient with hypotelorism,
nasomaxillary hypoplasia, and cleft lip and palate. The patient had
normal neurologic structures and development. Another case was
reported by Joss et al. in 2002.20 This rare entity was confirmed by
Stark,21 who reported a similar case.
 Facial Bones 271

Fig. 8-2. Standard curves for outer canthal, inner canthal, and interpupillary measurements. Data from
a study population of 2403 newborns to children 14 years of age (56% male, 44% female; 2006 white,
206 black, 43 Asian). (From Feingold and Bossert.12)

Other developmental abnormalities that involve mechanical Etiology and Distribution

influences on the final position of the orbits include craniosyn- Hypotelorism results from excessive medial migration of the or-
ostotic processes such as premature closure of the metopic bits due to inadequate development of the frontal-cribriform area,
suture. as a result of either metopic craniosynostosis or neural hypoplasia
272 Craniofacial Structures

Fig. 8-3. Hypotelorism associated with holoprosencephaly, absent nasal structures, and median cleft in
trisomy 13 (left). At right is an infant with cyclopia and proboscis. (Courtesy of Dr. Will Blackburn and Nelson
Reede Cooley, Jr.)

Table 8-2. Syndromes with orbital hypotelorism

Causation
Syndrome Prominent Features Gene/Locus

Coffin-Siris8 Growth deficiency, variable mental development, mild microcephaly, (135900)

coarse facies with full lips, hypoplastic to absent fifth finger,
radial dislocation at elbow, coxa valga, general hirsutism
Holoprosencephaly9 Deficit of midline facial development, incomplete morphogenesis Heterogeneous, including
of the forebrain, cyclopia, olfactory placodes consolidated into maternal diabetes
single tubelike proboscis above the eye (600725) SHH, 7q36
(603073) ZIC2, 13q32
(603714) SIX3, 2p21
(602630) TGIF, 18p11.3
Langer-Giedion10 Growth deficiency, mild to severe mental deficiency, microcephaly, AD (150230)
heavy eyebrows, deep-set eyes, sparse scalp hair, redundancy of the skin, microdeletion
cone-shaped epiphyses, brittle nails, multiple exostoses, syndactyly, 8q24.11-q24.13
tendency to fractures
Phenylketonuria, maternal11 Mental deficiency, growth deficiency, round facies, strabismus, smooth Maternal metabolic
philtrum, small upturned nose, mandibular hypoplasia, congenital disturbance
heart disease
Kallmann12 Anosmia, hypogonadotropic hypogonadism, short stature, sensorineural Heterogeneous
hearing loss, mental retardation (147950, 308700, 244200)
FGFR1, 8p11
Meckel-Gruber13 Growth deficiency, posterior encephalocele, microcephaly, cerebellar (AR 249000)
hypoplasia, microphthalmia, cleft palate, ear anomalies, polydactyly, 17q22-q23 and other loci
bile duct proliferation, fibrosis and cysts of the kidneys and liver,
cryptorchidism, incomplete development of external and/or internal genitalia
Smith-Lemli-Opitz14 Elevated 7-dehydrocholesterol, microcephaly, epicanthus, ptosis, cardiac AR (270400)
defects, postaxial polydactyly, increase of whorls on dermatoglyphic pattern, DHCR7, 11q12-q13
hypospadias, syndactyly of toes 2 and 3, failure to thrive, mental retardation
Trisomy 1315 Holoprosencephaly, microcephaly, iris colobomata, microphthalmia, retinal dysplasia, Abnormal karyotype
cleft lip and palate, distal proximal triradii, camptodactyly, congenital heart disease,
cryptorchidism, bicornuate uterus
 Facial Bones
(the holoprosencephaly series). Since orbital hypotelorism is of-
ten part of a multiple congenital anomalies disorder, the inci-
dence, sex ratio, and recurrence risk are variable, depending on
the underlying cause. When hypotelorism occurs as part of the
holoprosencephaly spectrum, the underlying cause for the holo-
prosencephaly may be identifiable. A chromosome anomaly or gene
mutation may be identified, allowing for testing of at-risk fam-
ily members and appropriate counseling. Human teratogens
causing holoprosencephaly include maternal diabetes, alcohol, re-
tinoic acid, and possibly drugs interfering with cholesterol metab-
olism.22,23 The autosomal recessive Smith-Lemli-Opitz syndrome,14
due to an enzymatic block of the last step of cholesterol biosyn-
thesis, represents a rare cause of holoprosencephaly (Table 8-2).
Prognosis, Treatment, and Prevention
Patients affected with cyclocephalic disorders have severe mal-
formations of the brain that result in developmental delay. De-
pending on the extent of the defect, these individuals may not
survive the neonatal period or infancy. The mild forms of orbital
hypotelorism do not cause visual impairment and have few clinical
implications. They usually do not require surgical correction, ex-
cept for aesthetic reasons.
Prenatal diagnosis is possible by ultrasonography, by inter-
orbital measurement.6 The presence of orbital hypotelorism should
alert the ultrasonographer to search for other fetal anomalies.
Reproductive genetic counseling is the only means of prevention
and should be individualized to each case. Recurrence figures can be
estimated according to the inheritance pattern of the primary defect.
References (Orbital Hypotelorism)
1. Feingold M, Bossert WH: Normal values for selected physical param-
eters. Birth Defects Orig Artic Ser X(13):1, 1974.
2. Sedano HO, Gorlin RJ: The oral manifestations of cyclopia. Oral Surg
Oral Med Oral Pathol 16:823, 1963.
3. Roulatt V, Pruzansky S: Premaxillary agenesis, ocular hypotelorism,
holoprosencephaly and extracranial anomalies in an infant with a
normal karyogram. Cleft Palate J 17:197, 1980.
4. Cohen MM Jr: An update of holoprosencephalic disorders. J Pediatr
101:865, 1982.
5. Klein VR, Harrod MJE, Brown CEL, et al.: Prenatal diagnosis of
cyclopia. Proc Greenwood Genet Center 6:138, 1987.
6. Grundy HO, Niemeyer P, Rupani MK, et al.: Prenatal detection of cyclopia
associated with interstitial deletion 2p. Am J Med Genet 34:268, 1989.
7. Burrig KF, Gebaner J, Terinde R, et al.: Case of cyclopia with an
unbalanced karyotype attributable to a balanced 3/7 translocation. Clin
Gen 35:262, 1989.
8. Carey JC, Hall BD: The Coffin-Siris syndrome: five cases including
two siblings. Am J Dis Child 132:667, 1978.
9. Cohen MM Jr: Malformations of the craniofacial region: evolutionary,
embryonic, genetic, and clinical perspectives. Am J Med Genet 115:
245, 2002.
10. Ludecke HJ, Wagner MJ, Nardmann J: Molecular dissection of a
contiguous gene syndrome: localization of the genes involved in the
Langer-Giedion syndrome. Hum Molec Genet 4:31, 1995.
11. Sweeney E, Fryer A: Nasomaxillary hypoplasia and severe orofacial
clefting in a child of a mother with phenylketonuria. J Inherit Metab
Dis 25:77, 2002.
12. Dode C, Levilliers J, Dupont JM, et al.: Loss-of-function mutations in
FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet
33:463, 2003.
13. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic
heterogeneity in Meckel syndrome. Hum Genet 101:88, 1997.
14. Cunniff C, Kratz LE, Moser A, et al.: Clinical and biochemical
spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and
abnormal cholesterol metabolism. Am J Med Genet 68:263, 1997.
273
15. Delatycki M, Gardner RJ: Three cases of trisomy 13 mosaicism and a
review of the literature. Clin Genet 51:403, 1997.
16. Taybi H: Radiology of Syndromes and Metabolic Disorders, ed 2. Year
Book Medical Publishers, Chicago, 1983, p 444.
17. Ben-Hur N, Ashur H, Mieurreri M: An unusual case of median cleft lip
with orbital hypotelorism—a missing link in the classification. Cleft
Palate J 15:365, 1978.
18. Shilbach U, Rott HD: Ocular hypotelorism, submucosal cleft palate
and hypospadias: a new autosomal dominant syndrome. Am J Med
Genet 31:863, 1980.
19. Pashayan HM, Lewis MB: Hypotelorism, nasomaxillary hypoplasia and
cleft lip and palate in a patient with normocephaly and normal
intelligence—a case report. Cleft Palate J 17:62, 1980.
20. Joss SK, Paterson W, Donaldson MD, et al.: Cleft palate, hypotelorism, and
hypospadias: Schilbach-Rott syndrome. Am J Med Genet 113:105, 2002.
21. Stark DB: Hypotelorism, nasomaxillary hypoplasia and cleft lip and
palate in a patient with normocephaly and normal intelligence, a case
report (letter). Cleft Palate J 17:262, 1980.
22. Cohen MM, Shiota K: Teratogenesis of holoprosencephaly. Am J Med
Genet 109:1, 2002.
23. Edison RJ, Muenke M: Central nervous syndrome and limb anomalies
in case reports of first-trimester statin exposure. N Engl J Med 350:
1579, 2004.
8.3
Orbital Hypertelorism
Definitions
Orbital hypertelorism is the excessive separation of the medial
walls of the bony orbits. As with other growth parameters, the
interorbital measurement is age-related, with an increase from
approximately 16 mm at birth to approximately 27 mm in adult
life. Orbital hypertelorism is present when the interorbital mea-
surement exceeds 2 standard deviations (SD) above the mean. In
the adult, the upper limit of normal is approximately 30 mm.
Ocular Hypertelorism
Ocular hypertelorism is the increased space between the eyes as
determined by interpupillary measurement. Determination of oc-
ular hypertelorism using interpupillary measurement requires that
the eyes be properly aligned. Alternatively, ocular hypertelorism can
be assumed if the interorbital measurement is greater than 2 SD
above the mean and the eyes are of normal size.
Telecanthus
Telecanthus is the increased measurement between the inner
canthi but with normally spaced eyes. Telecanthus results from
lateral displacement of the inner canthus and lacrimal punctae.
The iris is shifted medially from its normally central position
in the palpebral aperture. Graphs with the normal range of in-
traorbital, interpupillary, and inner canthal measurements have
been prepared by several groups of investigators (Fig. 8-2).1–6
Diagnosis
The term hypertelorism was probably introduced in 1924 by Greig7
to describe a discrete condition with excessive separation of the
eyes. It is often used indiscriminately to convey the impression
that the eyes are widely spaced. The experienced observer can
usually detect true orbital hypertelorism and ocular hypertelorism
by simple inspection (Fig. 8-4).
This, however, is not always the case. The clinician can
be confused by the impression of hypertelorism produced by
274 Craniofacial Structures
Fig. 8-4. Isolated ocular hypertelorism in a 9-year-old male without
associated defects (Greig hypertelorism).
telecanthus in the presence of normal interorbital and interpupil-
lary measurements. Diagnosis of orbital hypertelorism requires
radiologic studies to confirm the presence of a wide separation of
the orbits. Because of involvement of soft tissue, the determination
of the measurement between the bony orbital walls is difficult.
Several quantitative methods such as inner canthal measurement,
interpupillary measurement, canthal index, and circumference
interorbital index have been used in an attempt to establish the
position of the orbits in relation to each other.1 Of the various
methods for determining orbital hypertelorism, the preferable one
probably is the interorbital measurement as determined directly
from posteroanterior skull radiographs.4 Values 2 SD or greater
above the mean compared with Tessier data are diagnostic of or-
bital hypertelorism.
The use of computed tomography (CT) to measure inter-
orbital space has been investigated.8 However, the high cost may
limit its use for assessment of orbital hypertelorism. On the other
hand, CT scanning allows study of the orbital contents with re-
spect to the bony orbit. It allows independent measurement for
each globe, which is necessary to uncover asymmetric displace-
ment that could lead to binocular stereoscopic vision and other
visual complications.
Orbital hypertelorism may be an isolated craniofacial char-
acteristic, but this is uncommon.9,10 Usually it is a component
of one of numerous multiple congenital anomaly syndromes
(Fig. 8-5). It often represents the mildest form of midline facial
clefting. Over 200 malformation syndromes include orbital hy-
pertelorism; Table 8-3 lists the most common of these syndromes.
Orbital and ocular hypertelorism usually coexist. It is possi-
ble, however, for the eyes to be displaced laterally by encroach-
ment into the orbital space by tumor, neural tissue, or ethmoid air
cells, with normal interorbital measurement.35
Etiology and Distribution
During early stages of embryonic life, the eyes extend laterally as
evaginations of the forebrain. Differential growth, occurring prior
to ossification of the bones of the skull, results in convergence
toward the facial midline from this primitive lateral position.
Aberrations in this differential growth affect the position of the
orbits.
Since orbital hypertelorism is a characteristic finding in
several craniofacial malformation syndromes that involve differ-
ent pathogenicities, there is no identifiable single mechanism that
leads to the disorder. Three main mechanisms have been postu-
lated to produce orbital hypertelorism.4,36 The first possible
mechanism is a time-specific deficiency in differential growth, with
a primary effect on the forebrain and optic primordia or their
supporting tissues. The second possible mechanism is migration
being interrupted due to the presence of a midline lesion, such as a
nasoencephalocele, which inhibits the progressive medial approx-
imation of the orbits. A third proposed mechanism is the occur-
rence of a parallel pathologic process on the cranial base (secondary
to craniosynostosis, for example) that could separate the orbits
during intrauterine life and persist through early postnatal growth.
Isolated hypertelorism is rare and usually occurs in a spo-
radic form. Apparently dominant and recessive cases have been
reported; however, the sexes appear to be equally affected. Syn-
dromic hypertelorism has many causes (Table 8-3), and the re-
currence risks depend on the cause. As the genes causally involved
in these syndromes are identified, it becomes clear that many of
them encode transcription factors active in early embryologic
development. The gene product encoded by the cleidocranial
dysplasia gene is a transcription factor essential for cell prolifer-
ation and differentiation,37 whereas the transcription factor en-
coded by the Greig syndrome gene (GLI3) acts as a repressor of
signaling through FGF838 and sonic hedgehog (see Section 8.2).
Of note, the protein product encoded by the gene involved in
Gorlin syndrome (Table 8-3) is a cell membrane bound receptor
for sonic hedgehog. In contrast to these molecules involved in
transcription and the sonic hedgehog signaling pathway, muta-
tions affecting proteins involved in the cytoskeletal organization,
such as filamin A (OPD spectrum disorders, Table 8-3), are
more likely to result in structural malformations by abnormal
cell migration.29
In a review of patients with a primary presenting diagnosis of
hypertelorism, excluding patients with syndromic craniosynostosis
or cleft lip, the most common cause was frontonasal dyspla-
sia, followed by craniofrontonasal dysplasia.39 Numerous chro-
mosome aberrations cause orbital hypertelorism. These include
XXXXY syndrome, trisomy 22, trisomy 13, deletion 4p, deletion
5p, and deletion 17p. Teratogenic exposures associated with hy-
pertelorism include hydantoin, warfarin, and aminopterin.
Prognosis, Treatment, and Prevention
The prognosis of the patient with bony orbital hypertelorism
depends on the primary defect. Multiple congenital anomaly
 Facial Bones 275

Fig. 8-5. Ocular hypertelorism in a 26-month-old male with Aarskog syndrome showing triangular face,
broad forehead, and widow’s peak (A); in an infant girl with bifid nose (B); in an infant girl with median cleft
face (C); and in an adult with frontonasal dysplasia showing broad nose and widow’s peak (D). (B and C
courtesy of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

syndromes that severely affect the orbital area may represent major
surgical challenges requiring multiple interventions.
Orbital hypertelorism is classified into three different cate-
gories according to the interorbital measurement. Each category is
treated surgically in a different manner. First-degree orbital hy-
pertelorism (interorbital distance [IOD] between 30 and 34 mm)
can be corrected by rhinoplasty, correction of the epicanthal folds,
or both. Second-degree orbital hypertelorism (IOD between 34
and 40 mm) can be corrected by extracranial osteotomy. Third-
degree orbital hypertelorism (IOD greater than 44 mm) requires
an intracranial approach.40 Surgical correction rests on transpo-
sition of the portion of the orbit that must be moved to effect a
movement of the globe. This procedure can be done with excellent
results during early infancy. Early intervention results in a normal
appearance, which minimizes the psychological problems for the
patient. Prognosis should be individualized according to the pri-
mary defect involved.
Prenatal diagnosis of orbital hypertelorism is possible with
real-time ultrasonography. Normal standards have been estab-
lished by different investigators, with similar results.41–43
Figure 8-6 shows a coronal section of the fetal craniofacies at
18 weeks gestation from our normal sample. Landmarks for de-
termining the interorbital measurement have been identified. In
the presence of fetal orbital hypertelorism, along with an accurate
last menstrual period date, the clinician should investigate the
possibility of associated birth defects.
Table 8-3. Syndromes associated with orbital hypertelorism
Causation
Syndrome Prominent Features Gene/Locus

Aarskog11 Moderate short stature, rounded facies, ptosis, slight downward-slanting XL (305400)
palpebral fissures, small nose, anteverted nostrils, hypodontia, brachydactyly, FGD1, Xp11.21
mild interdigital webbing, mild pectus, shawl scrotum
Acrocallosal12 Growth and mental deficiency, agenesis of the corpus callosum, preaxial AR (200990)
polydactyly, syndactyly, prominent forehead and occiput, hypoplastic
midface
Acrodysostosis13 Growth deficiency and mental deficiency, brachydactyly, low nasal bridge, (101800)
upturned small nose, short and broad hands
Cat eye14 Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, (115470)
anal atresia, rectovesicular fistula, renal agenesis Partial tetrasomy
22 due to inv dup (22)(q11)
Cleidocranial dysplasia15 Wide, late-closing fontanel; depressed nasal bridge; supernumerary teeth; AD (119600)
hypoplastic clavicles; minor skeletal abnormalities; mild short stature CBFA1(RUNX2), 6p21
Craniofrontonasal16 Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and XL (304110)
splits in nails EFNB1, Xq12
Coffin-Lowry17 Downslanting palpebrae, open mouth with thick lips, growth and mental deficiency, XL (303600)
pectus anomalies, wide hands with tapering digits, hyperextensible joints, drop attacks RSK2, Xp22.2-p22.1
Donnai-Barrow18 Diaphragmatic hernia, exomphalos, absent corpus callosum, iris coloboma, myopia, AR (222448)
sensorineural deafness
Escobar19 Small stature, inner canthal folds, micrognathia, cleft palate, expressionless face, AR (265000)
multiple large joint pterygia, camptodactyly, syndactyly, cryptorchidism
Frontonasal dysplasia20 Lateral displacement of inner canthi, widow’s peak, broad nasal bridge, hypoplasia to (136760)
absence of the prolabium, premaxilla
Gorlin21 Macrocephaly, odontogenic keratocysts, basal cell nevi, palmar pits, mental AD (109400)
retardation, medulloblastoma PTCH, 9q22.3
Greig High forehead, frontal bossing, macrocephaly, broad nasal root, postaxial polydactyly, AD (175700)
cephalopolysyndactyly22 broad thumbs, syndactyly, preaxial polydactyly of toes GLI3, 7p13
Killian/Teschler-Nicola23 Obesity, short stature, seizures, hypotonia, deafness, sparse anterior scalp hair, Tetrasomy 12p
delayed dental eruption, large ears, flat broad nasal root, coarse face, long
philtrum, thin upper lip, short neck, broad hands with short digits,
diaphragmatic hernia
Larsen24 Flat facies; depressed nasal ridge; prominent forehead; dislocations of elbow, wrist, Heterogeneous
and knee; dysplastic epiphyseal centers; spatulate thumbs; short nails; short (150250, 245600, 245650)
metacarpals; talipes equinovarus; cervical vertebrae hypoplasia 3p21.1-p14.1 for AD form
Lenz-Majewski25 Short stature, variable mental development, prominent forehead, late closure of (151050)
fontanels, proptosis, choanal stenosis, cutis laxa, cutaneous syndactyly, sparse hair,
dysplastic enamel, proximal symphalangism, absent middle phalanges, long and
flared metaphyses
Multiple lentigines Lentigines, prominent ears, ptosis, short neck, pulmonic stenosis, ECG abnormalities, AD, allelic to Noonan (151900)
(LEOPARD)26 short stature PTPN11, 12q24.1
Neu-Laxova27 Microcephaly, lissencephaly, absence of corpus callosum, absence of olfactory bulbs, AR (256520)
absence of lids, flattened nose, gaping mouth, micrognathia, short neck, transparent
scaling skin, ichthyosis, short limbs, syndactyly of fingers and toes, poorly mineralized
bones, cataracts, microphthalmia, absence of eyelashes and scalp hair
Noonan28 Short stature, variable mental impairment, epicanthal folds, ptosis, downslanting AD (163950)
palpebrae, low-set and abnormally shaped ears, webbed neck, shield chest, Heterogeneous
pectus carinatum and/or excavatum, cubitus valgus, pulmonary valve stenosis, PTPN11, 12q24.1
cryptorchidism, bleeding tendency, multiple giant cell lesions
Oto-palato-digital (OPD) OPD type 2: growth deficiency, large anterior fontanel, wide sutures, prominent XL (311300, 304120, 309350,
spectrum29 forehead, flat nasal bridge, small mouth, cleft palate, small mandible, flexed 305620)
overlapping fingers, short thumbs, syndactyly, bowed long bones, subluxed Allelic to Melnick-Needles,
joints, narrow chest frontometaphyseal dysplasia,
and periventricular heterotopia
FLNA, Xq28
Hypertelorism-hypospadias Variable mental development, widow’s peak, laryngeal abnormalities, hypospadias, AD (145410)
(Opitz)30 cryptorchidism, bifid scrotum, hernias 22q11.2
XL (300000)
MID1, Xp22.3
(continued )

276
 Facial Bones 277

Table 8-3. Syndromes associated with orbital hypertelorism (continued)

Causation
Syndrome Prominent Features Gene/Locus

Robinow31 Moderate short stature, macrocephaly, frontal bossing, proptosis, small triangular AD (180700)
mouth, micrognathia, hyperplastic alveolar ridges, short forearms, AR (268310)
hemivertebrae, small penis or clitoris, cryptorchidism Allelic to brachydactyly type B
ROR2, 9q22
Sotos32 Overgrowth, macrocephaly, prominent forehead, prognathism variable mental AD (117550)
development, large hands and feet, accelerated phalangeal centers, premature NSD1, 5q35
eruption of teeth
Teebi33 Heavy eyebrows, downslanting palpebrae, depressed nasal bridge, short nose, mild AD (145420)
syndactyly, shawl scrotum
Weaver34 Accelerated growth and maturation, long philtrum, large ears, mild hypertonia, AD (277590)
spasticity, camptodactyly, broad thumbs, thin deep-set nails, limited elbow and knee Unknown in most; NSD1, 5q35
extension, relatively loose skin, thin hair, umbilical hernia point mutation in some cases

7. Greig DM: Hypertelorism: a hitherto undifferentiated congenital

Fig. 8-6. Coronal ultrasonographic view of the fetal facial skeleton
at 18 weeks of gestation. Note localization of landmarks for
evaluation of interorbital measurement.
References (Orbital Hypertelorism)
1. Feingold M, Bossert WH: Normal values for selected physical param-
eters. Birth Defects Orig Artic Ser X(13):1, 1974.
2. Merlob P, Sivan Y, Reisner SH: Anthropometric measurements of the
newborn infant (27 to 41 gestational weeks). Birth Defects Orig Artic
Ser XX(7):1, 1984.
3. Laestadius ND, Aase JM, Smith DW: Normal inner canthal and outer
orbital dimensions. J Pediatr 74:465, 1969.
4. Tessier P: Orbital hypertelorism. 1. Successive surgical attempts, mate-
rials and methods. Causes and mechanisms. Scand J Plast Reconstr Surg
6:135, 1972.
5. Hall JG, Froster-lskenius UG, Allanson JE: Handbook of Normal
Physical Measurements. Oxford University Press, Oxford, 1989.
6. Saul RA, Stevenson RE, Rogers RC, et al.: Growth references from
conception to adulthood. Proc Greenwood Genet Center, Suppl 1,
1988.
craniofacial deformity. Edinburgh Med J 31:350, 1924.
8. Costaras M, Pruzansky S, Broadbent BH Jr.: Bony interorbital distance
(BIOD), head size, and level of the cribriform plate relative to orbital
height: I. Possible pathogenesis of orbital hypertelorism. J Craniofac
Genet Dev Biol 2:5, 1982.
9. Myrianthopoulos NC: Epidemiology of craniofacial malformations:
foundations of craniofacial genetics. In: Clinical Dysmorphology of
Oral-Facial Structures. M Melnick, ED Shields, NJ Burzynski, eds. John
Wright, PSG, Boston, 1982, p 12.
10. Morin JD, Hill JC, Anderson MC, et al.: A study of growth in the
interorbital region. Am J Ophthalmol 56:895, 1963.
11. Fryns JP: Aarskog syndrome: the changing phenotype with age. Am J
Med Genet 43:420, 1992.
12. Koenig R, Bach A, Woelki U, et al.: Spectrum of the acrocallosal
syndrome. Am J Med Genet 108:7, 2002.
13. Robinow M, Pfeiffer RA, Gorlin RJ, et al.: Acrodysostosis: a syndrome
of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am
J Dis Child 121:195, 1971.
14. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’: decentric
small marker chromosome probably derived from a 22 (tetrasomy
22pter;q11) associated with a characteristic phenotype. Report of 11 pa-
tients and delineation of the clinical picture. Hum Genet 57:148, 1981.
15. Cooper SC, Flaitz CM, Johnston DA, et al.: A natural history of
cleidocranial dysplasia. Am J Med Genet 104:1, 2001.
16. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofronto-
nasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996.
17. Hunter AGW: Coffin-Lowry syndrome: a 20-year follow-up and review
of long-term outcomes. Am J Med Genet 111:345, 2002.
18. Gripp KW, Donnai D, Clericuzio CL, et al.: Diaphragmatic hernia-
exomphalos-hypertelorism syndrome: a new case and further evidence
of autosomal recessive inheritance. Am J Med Genet 68:441, 1997.
19. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes:
a review and report of eleven patients. Am J Med Genet 12:377, 1982.
20. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia.
J Pediatr 76:906, 1970.
21. Evans DGR, Ladusans EJ, Rimmer S, et al.: Complications of the
naevoid basal cell carcinoma syndrome: results of a population based
study. J Med Genet 30:460, 1993.
22. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig
cephalopolysyndactyly syndrome: clinical and radiological findings in 4
independent families and 3 sporadic cases with identified GLI3 muta-
tions. Am J Med Genet 120A:49, 2003.
23. Schaefer GB, Jochar A, Muneer R, et al.: Clinical variability of
tetrasomy 12p. Clin Genet 51:102, 1997.
24. Larsen LJ, Schottstaedt ER, Bost FC: Multiple congenital dislocations
associated with characteristic facial abnormality. J Pediatr 37:574, 1950.
278 Craniofacial Structures
25. Robinow M, Johanson AJ, Smith TH: The Lenz-Majewski hyperostotic
dwarfism: a syndrome of multiple congenital anomalies, mental
retardation, and progressive skeletal sclerosis. J Pediatr 91:417, 1977.
26. Digilio MC, Conti E, Sarkozy A, et al.: Grouping of multiple-
lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
Am J Hum Genet 71:389, 2002.
27. Neu RL, Kajii T, Gardner LI, et al.: A lethal syndrome of microcephaly
with multiple congenital anomalies in three siblings. Pediatrics 47:
610, 1971.
28. Allanson JE, Hall JG, Hughes HE, et al.: Noonan syndrome: the
changing phenotype. Am J Med Genet 21:507, 1985.
29. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum
Disorders Clinical Collaborative Group: Localized mutations in the gene
encoding the cytoskeletal protein filamin A cause diverse malformations
in humans. Nat Genet 33:487, 2003.
30. Opitz JM: G syndrome (hypertelorism with esophageal abnormality and
hypospadias, or hypospadias-dysphagia, or ‘Opitz-Frias’ or ‘Opitz-G’
syndrome)—perspective in 1987 and bibliography. Am J Med Genet
28:275, 1987.
31. Robinow M, Silverman FN, Smith HD: A newly recognized dwarfing
syndrome. Am J Dis Child 117:645, 1969.
32. Allanson JE, Cole TRP: Sotos syndrome: evolution of facial phenotype
subjective and objective assessment. Am J Med Genet 65:13, 1996.
33. Teebi AS: New autosomal dominant syndrome resembling cranio-
frontonasal dysplasia. Am J Med Genet 28:581, 1987.
34. Weaver DD, Graham CB, Thomas IT: A new overgrowth syndrome
with accelerated skeletal maturation, unusual facies, and camptodac-
tyly. J Pediatr 84:547, 1974.
35. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care
for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 184.
36. DeMyer W: The median cleft face syndrome. Differential diagnosis of
cranium bifidum occultum and hypertelorism in median cleft nose, lip
and palate. Neurology 17:961, 1967.
37. Coffman JA: Runx transcription factors and the developmental balance
between cell proliferation and differentiation. Cell Biol Int 27:315, 2003.
38. Aoto K, Nishimura T, Eto K, et al.: Mouse GLI3 regulates Fgf8 expression
and apoptosis in the developing neural tube, face, and limb bud. Dev Biol
251:320, 2002.
39. Tan ST, Mulliken JB: Hypertelorism: nosologic analysis of 90 patients.
Plast Reconstr Surg 99:317, 1997.
40. Psillakis JM: Surgical treatment of hypertelorbitism. In: Craniofacial
Surgery. EP Caronni, ed. Little, Brown and Company, Boston, 1985, p 190.
41. Mayden KL, Tortora M, Berkowitz RL: Orbital diameters: a new
parameter for prenatal diagnosis and dating. Am J Obstet Gynecol
144:289, 1982.
42. Jeanty P, Cantraine F, Cousaert E, et al.: The binocular distance: a new
way to estimate fetal age. J Ultrasound Med 3:241, 1984.
43. Escobar LF, Bixler D, Padilla M, et al.: Fetal craniofacial morphomet-
rics in utero. Evaluation at 16 weeks of gestation. Obstet Gynecol
72:677, 1988.
8.4
Midline Facial Skeletal Clefting
Definition
Midline facial skeletal clefting is a sagittally oriented fissure di-
viding the craniofacial structures at the midline. Midline facial
clefts result from failure of the facial processes to fuse during the
embryonic stage.
Diagnosis
Midline facial clefting (MFC) is classified according to the
morphologic characteristics. Table 8-4 lists the different types of
facial bone involvement as shown by computed tomography
Table 8-4. Facial bone abnormalities in midline facial clefts
Tessier1
type
0 Keel-shaped maxillary alveolus, reduction of median and
paramedian midfacial height, thickening of the nasal septum,
broad and flat maxilla, orbital hypertelorism, widening of
anterior cranial fossa
1 Clefting of the maxilla with or without cleft palate, maxillary
hypoplasia, flattening of the nasal dorsum, asymmetry of
the ptyrigoid plates, keel-shaped alveolus
2 Alveolar cleft that extends to soft and hard palate, deviation of
the nasal septum
3 Deviation of the nasal septum, no septation between nasal cavity
and the cleft side of the maxilla, cleft extending to the medial
portion of the orbital floor and into the inferior orbital rim, orbit
and anterior cranial fossa inferiorly displaced
4 Palatal cleft from the maxilla to the infraorbital foramen, medial
septation separating the nasal cavity from the orbit, maxillary
sinus and mouth present
5 From narrow to broad cleft of the maxilla to the infraorbital
foramen and maxillary sinus, cleft entering the inferolateral
orbital rim
12 Flattening of the frontal process of the maxilla, orbital
hypertelorism, flattening of the frontal bone, obtuse
nasofrontal angle
13 Bony cleft beginning in the region of the nasal bone and
extending superiorly through the full height of the frontal bone;
posteriorly, cleft extends through the cribiform plate and
ethmoid sinus as far as the lesser wing and body of the sphenoid
14 Median frontal cleft defect sometimes with herniation of a
frontal encephalocele, flattened glabella, shortening of the
anterior dimension of the middle cranial fossa
Tessier types 6–11 involve regions other than the craniofacial midline.
Therefore, they are not included here. Further information is given by David et al.2
(CT) scanning. Initially recognized by soft tissue abnormalities,
midline facial clefts vary from mild broadening of the philtrum,
or a true medial cleft lip (MFC 0), to severe orbital hypertelor-
ism, with anterior cranium bifidum occultum. Recognition of the
degree of skeletal involvement requires radiologic techniques
such as CT. CT and tridimensional reconstruction are essential in
evaluating accurately the severity of the defect and in planning
reconstructive procedures (Fig. 8-7). In addition, cephalometric
analysis of the skeletal craniofacies is helpful in delineating
skeletal morphology.
Midline facial clefts are characterized by the combination of
two or more of the following: (1) true ocular hypertelorism,
(2) broadening of the nasal root, (3) median facial cleft affecting
the nose or both nose and upper lip and at times the palate,
(4) unilateral or bilateral clefting of the alae nasi, (5) lack of for-
mation of the nasal tip, (6) anterior cranium bifidum occultum,
and (7) V-shaped hair prolongation onto the forehead, generally
over the area of the cranium bifidum.3
Distinction has to be made between median and paramedian
craniofacial clefts and also between median clefts and the group of
frontoethmoidal meningoencephaloceles, which are associated
with a normal craniofacial skeleton that is displaced in position
(Fig. 8-8).4,5 However, encephaloceles are sometimes associated
with true craniofacial clefts with markedly abnormal skulls.
Since frontoethmoidal meningoencephaloceles lack the frontal
 Facial Bones
Fig. 8-7. Three-year-old patient with facial cleft. Note the facial
skeletal defect as seen via 3-D CT reformat sequence. (From David
et al.2)
hairline indicator, this sign may be helpful in distinguishing the two
entities.
Other entities that include ocular hypertelorism must be
carefully differentiated from mild forms of midline facial clefts.
Syndromes including ocular hypertelorism usually affect other
areas of the body in addition to the midline of the face.
Etiology and Distribution
Severe midline facial clefting is associated with gross malforma-
tions of the head and rarely presents in an isolated form. As sug-
gested by Sedano and Gorlin3 in 1988, frontonasal malformation
may represent the reaction of part, or parts, of an embryo as a unit
to both normal and abnormal stimuli. The spectrum of frontonasal
malformations involves individual entities that may include mid-
facial clefts as a major characteristic (Table 8-5). Examples are
craniofrontonasal dysplasia, ophthalmofrontonasal dysplasia, and
Greig cephalopolysyndactyly. Midline craniofacial clefting has been
reported to occur in hemifacial microsomia (sporadic), Treacher
279
Fig. 8-8. Ten-month-old female with frontoethmoidal meningoen-
cephalocele. She was exposed prenatally to hydantoin and had a
unilateral constriction ring of the arm and nail hypoplasia.
Collins syndrome (autosomal dominant), and acrofrontofacionasal
dysostosis (autosomal recessive). In addition, it can be seen as part
of some multiple congenital anomaly syndromes or can represent a
single developmental event in a malformation sequence, as was
suggested by Toriello and collaborators.11
Midline facial clefting appears to result from insult during
the embryonic period.3 The developmental basis for these defects
was investigated by Darab and coworkers.12 They were able to
produce a spectrum of defects ranging from narrow midline
nasal-groove defects to frank midfacial clefting in mouse embryos
exposed to methotrexate during day 9 of pregnancy (correspond-
ing to week 4 of human gestation). Affected embryos showed di-
lation and congestion of blood vessels in the frontonasal process,
suggesting that vascular damage may be responsible for initiating
the sequence of events leading to midline facial clefting. Caution is
suggested, since mice may be highly sensitive to teratogenic clefting
and this may not be the case in humans.
The majority of midline facial clefts are sporadic, with a
somewhat low recurrence risk. The recurrence risk, however, can be
substantial if the clefts are associated with other anomalies in a rec-
ognized malformation syndrome. A particularly interesting example
is the craniofrontonasal syndrome, due to mutations in the EFNB1
gene located in the pericentromeric region of the X chromosome.13
In contrast to other X-linked disorders, craniofrontonasal syndrome
affects females more severely, and males show milder manifestations,
such as hypertelorism only.
Prognosis, Treatment, and Prevention
The child with midfacial cleft should be approached by a multi-
disciplinary team of professionals. The evaluation and treatment of
these children should include audiology, genetics, maxillofacial
prosthetics, neurology, neurosurgery, ophthalmology, oral and
maxillofacial surgery, orthodontics, pediatrics, psychiatry, psy-
chology, radiology, social work, and speech pathology. Some cen-
ters have the advantage of including physical anthropology. This
‘‘team’’ approach has greatly improved the prognosis for the child
with midfacial clefts. Surgical reconstruction in childhood has
become routine at a few centers. Initially, surgeons were reluctant
to do major reconstructive surgery on young children, preferring to
wait until most of the facial growth had occurred. The current
change to earlier surgery has probably been motivated by concern
for the patient’s psychological adjustments. However, depending
280 Craniofacial Structures

Table 8-5. Syndromes associated with midline facial skeletal clefting

Causation
Syndrome Prominent Features Gene/Locus

Craniofrontonasal6
Facio-auriculo-vertebral spectrum7
Frontonasal dysplasia8
Oto-palato-digital (OPD)
spectrum9
Greig cephalopolysyndactyly10
Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal XL (304110)
grooves and splits in nails EFNB1, Xq28
Macrostomia, microtia, periauricular tags, hemivertebrae or hypoplasia Unknown, sporadic
of vertebrae, malfunction of soft palate, hypoplasia of one side of face (164210, 257700)
Ocular hypertelorism, lateral displacement of inner canthi, widow’s peak, Unknown, sporadic
deficit in midline frontal bone, notched broad nasal tip, medial cleft lip, (136760)
broad nasal root, nasal tags, mental deficiency
Frontometaphyseal dysplasia: coarse facies; prominent supraorbital ridges; XL (305620, 311300,
partial anodontia; high palate; small mandible; wide foramen magnum; 304120, 309350)
flared pelvis; mixed conductive and sensorineural hearing loss; flexion FLNA, Xq28
defects of fingers, wrists, elbows, knees, and ankles Allelic to Melnick-Needles,
OPD types 1 and 2, and
periventricular heterotopia
High forehead, frontal bossing, macrocephaly, hypertelorism, broad nasal AD (175700)
root, postaxial polydactyly of hands, broad thumbs, preaxial polydactyly GLI3, 7p13
of feet, broad halluces, syndactyly

on the severity of the defects, multiple procedures may be required.
This process may take from a few months to years. Between 15%
and 20% of patients with midfacial clefts have some degree of
developmental delay. This can, in most cases, be reasonably at-
tributed to other causes, such as extreme prematurity, perinatal
difficulties, or multiple other congenital anomalies.14
Prevention of midline facial clefting is limited to reproduc-
tive genetic counseling and prenatal testing for pregnancies at risk.
Prenatal diagnosis by ultrasonography has been accomplished in
the past, and ultrasonography is a relatively good indicator of the
severity of the defect.15,16 Since no chromosomal abnormality has
been identified, amniocentesis has limited diagnostic value. In
specialized centers, fetoscopy remains as an important backup
procedure for confirmation of midline facial clefts.
References (Midline Facial Skeletal Clefting)
1. Tessier P: Anatomical classification facial, cranio-facial and latero-
facial clefts. J Maxillofac Surg 4:69, 1976.
2. David DJ, Moore MH, Cooler RD: Tessier clefts revisited with a third
dimension. Cleft Palate J 26:163, 1989.
3. Sedano HO, Gorlin RJ: Frontonasal malformation as a field defect and
in syndromic associations. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 65:804, 1988.
4. David DJ, Sheffield L, Simpson D, et al.: Frontoethmoidal meningoen-
cephaloceles, morphology and treatment. Br J Plast Surg 37:271, 1984.
5. Moore MH, David DJ, Cooler RD: Hairline indicators of craniofacial
clefts. Plast Reconstr Surg 82:589, 1988.
6. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Craniofronto-
nasal syndrome: study of 41 patients. Am J Med Genet 61:147, 1996.
7. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia:
progress in understanding the genetic basis of a complex malformation
syndrome. Hum Genet 109:638, 2001.
8. Sedano HO, Cohen MM Jr, Jirasek J, et al.: Frontonasal dysplasia.
J Pediatr 76:906, 1970.
9. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum
Disorders Clinical Collaborative Group: Localized mutations in the
gene encoding the cytoskeletal protein filamin A cause diverse mal-
formations in humans. Nat Genet 33:487, 2003.
10. Debeer P, Peeters H, Driess S, et al.: Variable phenotype in Greig
cephalopolysyndactyly syndrome: clinical and radiological findings in
4 independent families and 3 sporadic cases with identified GLI3
mutations. Am J Med Genet 120A:49, 2003.
11. Toriello HV, Radecky LL, Sharda J, et al.: Frontonasal ‘‘dysplasia,’’
cerebral anomalies, and polydactyly. Report of a new syndrome and
discussion from a developmental field perspective. Am J Med Genet
(suppl)2:89, 1986.
12. Darab DJ, Minkoff R, Sciote J, et al.: Pathogenesis of median clefts in
mice treated with methotrexate. Teratology 36:77, 1987.
13. Wieland I, Jakubiczka S, Muschke P, et al.: Mutations of the Ephrin-B1
gene cause craniofrontonasal syndrome. Am J Hum Genet 74:1209,
2004.
14. Stewart RE: The value of establishing the genetic component in
etiology of craniofacial anomalies. Birth Defects Orig Artic Ser XVI(5):
27, 1980.
15. Chevernak FA, Tortora M, Mayden K, et al.: Antenatal diagnosis of
median cleft syndrome: sonographic demonstration of cleft lip and
hypertelorism. Am J Obstet Gynecol 149:94, 1984.
16. Gianluigi P, Reece EA, Romero R, et al.: Prenatal diagnosis of cranio-
facial malformations with ultrasonography. Am J Obstet Gynecol 155:
45, 1986.
8.5
Absence and Hypoplasia of the Zygoma
Definition
Absence and hypoplasia of the zygoma is the impaired develop-
ment of the zygomatic bone leading to deficiency of the midface
and orbital floor. Hypoplasia/aplasia of the zygoma represents an
anomaly of the first branchial arch and has wide phenotypic
variability.
Diagnosis
Hypoplasia of the malar bones and zygomatic arches is usually
recognizable on simple clinical inspection of the affected indi-
vidual (Fig. 8-9). Striking deficiency of the midface in the zygo-
matic area is characteristic. The deficient facial skeleton is
reflected in soft tissue abnormalities such as tongues of hair
protruding onto the cheeks, lateral canthal colobomas, downward
obliquity of the palpebral fissures, lower lid colobomas, lower
lid ciliary agenesis, and a small face with prominent nose. Facial
anomalies of this type are usually seen in well-defined entities such
as Treacher Collins syndrome and ablepharon-macrostomia.1,2
 Facial Bones
Fig. 8-9. Top: Frontal (A) and lateral (B) view of patient with
hypoplasia of zygomatic bone. Bottom: Frontal view of 13-month-old
female with Treacher Collins syndrome showing downslanting
palpebral fissures, sagging (cleft) lower lids, and hypoplasia of the
zygoma. (A and B from Jackson et al.2)
Due to the wide spectrum of abnormalities associated with
absence or hypoplasia of the zygoma, radiologic studies are es-
sential in establishing the areas involved and in evaluating the
extent of the defect. This is best accomplished by the Waters
radiologic view and frontal tomograms that demonstrate defi-
ciency of the malar bones and partial or complete absence of the
zygomatic arches. In addition, modification of the orbital shape
with an inferolateral elongation can be observed.
The hypoplasia can be described in relation to the three artic-
ulations of the zygoma: zygomaticotemporal, zygomaticofrontal,
and zygomaticomaxillary. Impairment in the development of the
temporal process of the zygoma, in conjunction with impairment
of the zygomatic process of the temporal bone, results in partial
to complete absence of the zygomatic arch. Impairment of the
frontal process causes absence of the anterior portion of the lateral
orbital wall. Impairment along the maxillary articulation results in
281
a defect of the inferior rim and floor of the orbit, with inferolateral
herniation.3,4
Total absence of the zygomatic bones and zygomatic arches is
rare, and, in many cases, a remnant of zygomatic bone can be
found appended to the sphenoid tubercle, without connection to
the maxilla or the frontal or temporal bone. Zygomatic absence is
responsible for the absence of the lateral orbital rim, with for-
mation of the lateral orbital wall by the hypoplastic greater wing
of the sphenoid.5
In the ablepharon-macrostomia syndrome, radiologic studies
may show profound hypoplasia of the malars, infraorbital rims,
and lateral walls and absent zygomatic arches. Other entities that
include zygomatic hypoplasia or absence are Goldenhar (hemi-
facial microsomia), Nager (preaxial acrofacial dysostosis), and
Miller (postaxial acrofacial dysostosis) syndromes (Table 8-6).
Clinical caution is suggested since the occurrence of incomplete
and or asymmetric forms may lead to diagnostic difficulties.
Etiology and Distribution
It is important to emphasize that absence or hypoplasia of the
zygoma does not occur as an isolated malformation. It is the result
of a deficient growth and aberrant tissue interaction between
several embryologic craniofacial structures. Opitz21 suggested that
these abnormalities constitute part of the mandible, zygoma, ear
ossicles developmental field (MZEDF), which may imply that
whenever one of the three structures becomes anomalous, ab-
normal growth will occur in the other two. Positive statistical
correlations exist between the frequency of aberrant development
of these three structures, supporting a developmental field con-
cept.22 This idea is particularly attractive when one observes the
close clinical linkage between syndromes that affect the structures
derived from the first branchial arches. These include mandibu-
lofacial dysostosis; ablepharon-macrostomia; otocephaly; and Gold-
enhar, Miller, and Nager syndromes.
Etiologically, the primary developmental defect that leads to
abnormalities of the zygoma is unknown; however, damage to the
stapedial artery has been suggested to cause failure of migration of
the neural crest cells, leading to deficient growth of the zygomatic
structures.23 This appears to be a plausible explanation, but it fails
to account for the occurrence of bilateral defects. Nevertheless, the
possibility that some cases of first branchial arch deficiency are due
to this mechanism or to similar mechanisms of vascular origin
cannot be dismissed. If the vascular theory holds true, this may lead
to excessive and/or premature deficiencies in the amounts of cell
death in the first and second arch. Among the cell populations that
may be particularly affected are the first arch epithelial placode
cells.24
The appearance of single ossification centers for each of the
zygomatic bones at approximately the 8th week of gestation has
led to the suggestion that any arrest in chondrogenesis could
result in absence or hypoplasia of the zygoma.2 This suggested
mechanism would support the idea of failure of cell differentiation
due to the absence of an appropriate extracellular matrix during the
early developmental stages.25 The gene causally involved in man-
dibulofacial dysostosis has been identified as TCOF1. It encodes a
nucleolar phosphoprotein named treacle, whose biologic function
remains poorly defined. Investigation of a mouse model showed
that heterozygous Tcof1 deletion leads to perinatal death from
severe craniofacial anomalies caused by a massive increase of
apoptosis in the prefusion neural folds. These studies, in combi-
nation with the mutations identified in patients with Treacher
Table 8-6. Syndromes associated with absence or hypoplasia of the zygoma
Causation
Syndrome Prominent Features Gene/Locus

Bloom6 Growth deficiency, microcephaly, dolichocephaly, small nose, butterfly AR (210900)

Chondrodysplasia punctata7
Deletion 22q11.28
Diamond-Blackfan anemia-
microtia-cleft palate9
Facio-auriculo-vertebral
spectrum10
Hallermann-Streiff11
Marshall12
Miller13
Mohr14
Nager15
Oto-palato-digital (OPD)
spectrum16
Pycnodysostosis 17
Seckel18
Townes-Brocks19
Treacher Collins20
telangiectatic erythema involving the midface region exacerbated by sunlight RECQL3, 15q26.1
Growth deficiency, short limbs, epiphyseal stippling, low nasal bridge, Multiple loci
downward-slanting palpebral fissures, variable joint contractures, XL (302960)
scoliosis, follicular atrophoderma, ichthyosis EBP, Xp11.23
XL (302950)
ARSE, Xp22.3
AD (118650)
AR (215100)
PEX7, 6q22-q24
Cleft palate, conotruncal heart malformation, thymic hypoplasia, (192430)
abnormal external ear, prominent nasal tip, hypoplastic alae Microdeletion, 22q11.2
nasi, learning difficulties
Macrocytic anemia, short stature, downslanting palpebral fissures, AD (606164)
microtia, cleft palate, micrognathia
Macrostomia, unilateral hypoplasia of malar and mandibular region, Unknown, sporadic
microtia, periauricular tags, epibulbar dermoid, hemivertebrae or (164210, 257700)
hypoplasia of vertebrae, malfunction of soft palate, cardiac and renal
malformation
Small stature, brachycephaly, frontal bossing, thin calvarium, delayed Unknown, sporadic
ossification of sutures, micrognathia, anterior displacement of the (234100)
temporomandibular joint, microphthalmia, cataracts, small nose with
hypoplasia of the cartilage, microstomia, hypoplasia of the teeth,
partial anodontia
Short stature, depressed nose with flat nasal bridge, anteverted nares, AD (154780)
flat midface, myopia, cataracts, calvarial thickening, irregular distal Allelic to Stickler type 2
femoral and proximal tibial epiphyses, bowing of the radius and ulna COL1A11, 1p21
Downslanting palpebral fissures, eyelid coloboma, ectropion, micrognathia, AR (263750) Most sporadic,
cleft lip and/or palate, postaxial limb deficiencies, syndactyly, AD rarely reported
accessory nipple
Short stature, conductive deafness, low nasal bridge, broad nasal tip, AR (252100)
slightly bifid, midline cleft of tongue, hypoplasia of the maxilla and body
of the mandible, duplication of hallux and first metatarsals, duplication
of tarsal bones, polydactyly, metaphyseal flaring
Normal intelligence, short stature, conductive deafness and articulation AD, AR (154400)
problems, downslanting palpebral fissures, micrognathia, absence of the
lower eyelashes, periauricular tags, atresia of external ear canal,
hypoplasia to aplasia of the thumb, proximal radioulnar synostosis,
short forearms
OPD type 1: variable mental deficiency, short stature, moderate conductive XL (311300, 304120,
deafness, thick base of skull, facial bone hypoplasia, absence of frontal and 309350, 305620)
sphenoid sinuses, partial anodontia, impacted teeth, small trunk, pectus FLNA, Xq28
excavatum, small iliac crests, joint contractures, broad distal phalanges, Allelic to Melnick-Needles,
accessory ossification center at the base of the second metatarsal frontometaphyseal dysplasia
and periventricular heterotopia
Small stature, osteosclerosis with tendency toward transverse fracture, AR (265800)
delayed closure of sutures, persistence of anterior fontanel, lack of CTSK, 1q21
frontal sinus, facial hypoplasia, irregular permanent teeth, dysplasia to
loss of acromion of the clavicle, acro-osteolysis of distal phalanges,
wrinkled skin over dorsa of distal fingers
Growth deficiency, mental deficiency, microcephaly, receding forehead, AR (210600)
prominent nose, downward-slanting palpebral fissures, clinodactyly ATR, 3q22-q24
of fifth finger, proximal radial hypoplasia with dislocation of heterogeneous
radial head, hypoplasia of proximal fibula
Hemifacial microsomia with preauricular tags, abnormal ear shape, AD (107480)
sensorineural hearing loss, thumb anomalies, imperforate anus, renal SALL1, 16q21.1
malformations
Downslanting palpebral fissures, cleft in zygomatic bone, lower lid AD (154500)
coloboma, partial to total absence of lower eyelashes, malformed TCOF1, 5q32-q33
auricles, external ear malformation, conductive deafness, cleft palate,
extension of scalp hair onto lateral cheek

282
 Facial Bones
Collins syndrome, suggest that the protein is crucial for the survival
of cephalic neural crest cells, and that haploinsufficiency is disease
causing.26
Prognosis, Treatment, and Prevention
The prognosis for patients with zygomatic anomalies and related
disorders is very good. In a small number of cases, neonatal
complications cause insults to the central nervous system, but the
majority of patients have normal intelligence.
Treatment of these anomalies is primarily surgical and is de-
signed to build the zygomatic bones and zygomatic arches. If other
anomalies are involved, the correction can be made at the same
time these are corrected depending on the degree of involvement.
These procedures are usually performed during childhood with
excellent results. Jackson and collaborators1 have used bilateral
full-thickness vascularized skull grafts raised on the anterior
one-third of the temporalis muscle to correct the skeletal anomalies
in the ablepharon-macrostomia syndrome. The grafts are con-
toured to form the zygomatic arch and to augment the lateral
orbital wall. Only cranial bone grafts may be used on the anterior
aspect of the orbital rim. Considering that, in most severe
forms, two malar bones and two zygomatic arches have to be re-
constructed and that partial resorption may occur, the donor sites
for bone grafts may be insufficient. In such cases, cranial vault and
tibia are used to preserve ribs and iliac crest for additional proce-
dures that may be required. Distraction osteotomy may be used as a
primary procedure or after bone grafting.27
As was mentioned previously, zygomatic deficiency is not an
isolated birth defect, and careful consideration of syndromic as-
sociations must be made. Recurrence figures must be calculated
for the primary diagnosis. In mandibulofacial dysostosis, for ex-
ample, the recurrence risk for the offspring of an affected indi-
vidual will be 50%, with high penetrance and equal distribution
between sexes.
Prenatal diagnosis of zygomatic hypoplasia in association
with mandibulofacial dysostosis has been accomplished via fe-
toscopy and ultrasonography.28,29 Fetal cephalometry with ultra-
sound should be attempted to establish the degree of deficient
growth. Prenatal counseling is at present the only means of pre-
vention.
References (Absence and Hypoplasia of the Zygoma)
1. Jackson IT, Shaw KE, Pinal-Matorras F: A new feature of the able-
pharon macrostomia syndrome: zygomatic arch absence. Br J Plast Surg
41:410, 1988.
2. Kay ED, Kay CN: Dysmorphogenesis of the mandible, zygoma and
mandible, ear ossicles in hemifacial microsomia and mandibulofacial
dysostosis. Am J Med Genet 32:27, 1989.
3. Tessier P: Anatomical classification of facial, craniofacial and latero-
facial clefts. J Maxillofac Surg 4:69, 1976.
4. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care
for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens,
eds. CV Mosby, St. Louis, 1985, p 256.
5. Raulo Y: Treacher Collins syndrome: analysis and principles of surgery.
In: Craniofacial Surgery. EP Caronni, ed. Little, Brown and Co,
Boston, 1985, p 372.
6. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum
Molec Genet 5:1457, 1996.
7. Spranger JW, Opitz JM, Bibber U: Heterogeneity of chondrodysplasia
punctata. Hum Genet 11:190, 1971.
8. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and micro-
deletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet
44:261, 1992.
283
9. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral
microtia and cleft palate in cousins with Diamond-Blackfan anemia.
Am J Med Genet 101:268, 2001.
10. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia:
progress in understanding the genetic basis of a complex malformation
syndrome. Hum Genet 109:638, 2001.
11. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med
Genet 41:488, 1991.
12. Griffith AJ, Sprunger LK, Sirko-Osadsa DA, et al.: Marshall syndrome
associated with a splicing defect at the COL11A1 locus. Am J Hum
Genet 62:816, 1998.
13. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis
syndrome. J Pediatr 95:970, 1979.
14. Toriello HV: Heterogeneity and variability in the oral-facial-digital
syndromes. Am J Med Genet (suppl)4:149, 1988.
15. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: male-
to-male transmission in 2 families. Am J Med Genet 41:83, 1991.
16. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum
Disorders Clinical Collaborative Group: Localized mutations in the gene
encoding the cytoskeletal protein filamin A cause diverse malformations
in humans. Nat Genet 33:487, 2003.
17. Gelb BD, Shi GP, Chapman HA, et al.: Pycnodysostosis, a lysosomal
disease caused by cathepsin K deficiency. Science 273:1236, 1996.
18. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation
affecting expression of ataxia-telangiectasia and Rad3-related protein
(ATR) results in Seckel syndrome. Nat Genet 33:497, 2003.
19. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the
SALL1 putative transcription factor gene cause Townes-Brocks
syndrome. Nat Genet 18:81, 1998.
20. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection rate in
TCOF1 among Treacher Collins syndrome patients reveals clustering of
mutations and 16 novel pathogenic changes. Hum Mutat 16:315, 2000.
21. Opitz JM: The developmental field concept in clinical genetics.
J Pediatr 101:805, 1982.
22. Kumakawa K, Funasaka S: Middle ear malformation with normal external
meatus; correlation of ossicular anomalies with anomalies of auricle, jaw
and face. Nippon Jibiinkoka Gakkai Kaiho 88:30, 1985.
23. Poswillo D: The embryological basis of craniofacial dysplasia. Postgrad
Med J 53:517, 1977.
24. Sulik KK, Johnson MC, Smiley SJ, et al.: Mandibulofacial dysostosis
(Treacher Collins syndrome): a new proposal for its pathogenesis. Am
J Med Genet 27:359, 1978.
25. Herring SW, Powlatt UF, Pruzansky S: Anatomical abnormalities in
mandibulofacial dysostosis. Am J Med Genet 3:225, 1979.
26. Dixon J, Brakebush C, Fassler R, et al.: Increased levels of apoptosis in
the prefusion of neural folds underlie the craniofacial disorder,
Treacher Collins syndrome. Hum Mol Genet 9:1473, 2000.
27. McCarthy JG, Hopper RA: Distraction osteogenesis of zygomatic bone
grafts in a patient with Treacher Collins syndrome: a case report.
J Craniofac Surg 13:279, 2002.
28. Nicolaides KH, Johanston D, Donnai D, et al.: Prenatal diagnosis of
mandibulofacial dysostosis. Prenat Diagn 4:201, 1984.
29. Crane JP, Beaver HA: Midtrimester sonographic diagnosis of mandi-
bulofacial dysostosis. Am J Med Genet 25:251, 1986.
8.6
Midface Retrusion and Hypoplasia
Definition
Midface retrusion and hypoplasia is the underdevelopment or
posterior positioning of the midface. Affecting the inferior por-
tion of the orbits, nasal bones, and maxilla, the human midface
growth deficiency gives these individuals a semilunar configura-
tion of the anterior portion of the craniofacial profile.1 Retrusion
or hypoplasia of the midface suggests a complex growth deficiency
involving neural tissue, cranial base, and branchial arches.
284 Craniofacial Structures
Diagnosis
For practical purposes, the facial skeleton is divided into three
main areas: the upper face, composed of the frontal bones and
upper part of the orbits; the midface, composed of the lower
portion of the orbits, nasal bones, and maxilla; and the lower face,
consisting mainly of the mandible. Abnormalities in any one of
these areas distort the normal shape of the craniofacies as a whole.
Each is a unique area of growth and development, with relatively
independent clinical delineation. Of the three facial areas, the
midface may be the most fascinating multistructural complex of
facial development. It represents the central point of union of the
growing and migrating craniofacial processes (branchial arches),
with the final developmental result based on normal growth of the
cranial base and brain. In some instances, pathologic processes of
the upper and lower skeletal face will modify the shape of the
midface (Fig. 8-10). Acrocephalosyndactyly syndromes are good
examples of such modification.2
The middle one-third of the skeletal face constitutes the struc-
tural support of the nose, which is an important element in facial
aesthetics. Alterations of the anteroposterior dimensions of the
midface lead to changes in facial convexity and in dental occlusion.1
Evaluation of patients with midface retrusion includes exter-
nal measurements, lateral radiographs, cephalometry, and study of
dental occlusion. A complete dimensional study of the whole face is
necessary not only to analyze the relationship between the maxilla
and the rest of the facial skeleton but also to determine alterations
of the upper or lower one-third of the face.3
Cephalometry is an accurate method of assessing alterations
in the anterior projection of the face. It also provides documen-
tation of the preoperative and postoperative findings in affected
individuals. Fixed anatomic points, such as the cranial base, the
Frankfurt plane, and other facial planes, are used in the regular
cephalometric evaluation. Excellent normative data have recently
been published for all postnatal ages.4 Dental models have been
used to confirm the cephalometric measurements; these may help
the clinician to evaluate malocclusion problems and to plan cor-
Fig. 8-10. Preoperative (A) and postoperative (B) profile of patient with midface retrusion. (From Ortiz-
Monasterio and Musolas.1)
rective surgical procedures. The cast is cut and different segments
are mobilized to determine what type of procedure will produce the
most favorable result.1
Midfacial hypoplasia or retrusion may cause obstruction of
the nasal airway and inability to feed adequately. This is seen in
syndromes such as the Antley-Bixler syndrome, in which patients
show choanal atresia and feeding difficulties.5 Since the infant is
usually a nose breather, obstruction of the nasal airway in the
neonatal period requires rapid recognition and treatment. Oro-
tracheal intubation is usually required.
Some patients with midface hypoplasia and/or retrusion have
isolated hypoplasia of the maxilla, which provides support to the
upper lip. This is usually a hereditary feature (autosomal dominant)
and is commonly associated with prognathism. The majority of cases
of maxillary hypoplasia result from congenital anomaly syndromes,
such as Crouzon, Apert, and Binder syndromes6 (Table 8-7).
Etiology and Distribution
Midface hypoplasia or retrusion is seen not as an isolated finding
but only as part of a multiple congenital anomaly syndrome. In
the absence of a traumatic or infectious cause, a genetic or en-
vironmental origin should be investigated.28 The inheritance of
midface hypoplasia should be considered in the context of the
entity with which it is seen.
The growth and development of the midface are not com-
pletely understood. It has been suggested that the three areas of
the face (upper, middle, and lower one-third) may have relatively
independent mechanisms of growth and development, the mid-
face being the most complex of the three.29 Insufficient infor-
mation is available at present to define a single mechanism that
results in midface hypoplasia; perhaps it would be unwise to seek
a single cause. This fascinating area of structures may be a de-
velopmental field in which growing parts of an embryo are con-
trolled and coordinated in a spatially ordered, temporally synchronized,
and epimorphically hierarchical manner.
Several authors have attempted to delineate a developmental
field by anthropometric analysis. This attempt is based on the
Table 8-7. Syndromes associated with midface retrusion and hypoplasia
Causation
Syndrome Prominent Features Gene/Locus

Achondroplasia7 Rhizomelia, megalocephaly, small foramen magnum, short cranial base, low nasal bridge, AD (100800)
prominent forehead, narrowing of lumbar interpedicular distance, lumbar lordosis, short FGFR3, 4p16.3
trident hand
Angelman8 Growth deficiency, mental retardation, ataxia, seizure disorder, inappropriate laughter, (105830)
microbrachycephaly, widely spaced teeth Mat del 15q11-q13
Pat UPD 15q
UBE3A
Antley-Bixler9 Growth deficiency, variable mental development, brachycephaly, choanal stenosis/atresia, AR (207410)
craniosynostosis, depressed nasal bridge, radiohumeral synostosis, arachnodactyly, Abnormal steroid
femoral bowing, femoral fractures biogenesis in some
cases
Apert10 Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal groove, AD (101200)
shallow orbits, hypertelorism, severe syndactyly hands and feet, broad distal phalanges FGFR2, 10q26
of thumb, mental retardation
Cohen11 Truncal obesity, hypotonia, high nasal bridge, short philtrum, downslanting palpebral AR (216550)
fissures, prominent maxillary central incisors, large ears, chorioretinal dystrophy, narrow COH1, 8q22
hands and feet
Deletion 1p3612 Mental retardation, expressive language most severely affected, deep-set eyes, prominent Subtelomeric deletion
supraorbital ridges, seizure disorder
Deletion 18q13 Mental retardation, hypotonia, behavior problems, short stature, narrow external ear Monosomy for
canal, microcephaly, hypoplastic labia majora, cryptorchidism variable 18q region
Deletion 22q11.214 Cleft palate, conotruncal heart malformation, thymic hypoplasia, abnormal external ear, (192430) 22q11.2
prominent nasal tip, hypoplastic alae nasi, learning difficulties microdeletion
Crouzon15 Bicoronal or pansynostosis, proptosis, beaked nose AD (123500)
FGFR2, 10q26
Facio-auriculo-vertebral Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, hemivertebrae or Unknown, sporadic
spectrum16 hypoplasia of vertebrae, malfunction of soft palate (164210, 257700)
Prenatal alcohol17 Growth deficiency, fine motor dysfunction, poor eye-hand coordination, variable Teratogen
microcephaly, short palpebral fissures, short nose, smooth philtrum, thin smooth upper
lip, joint anomalies, small distal phalanges
Prenatal valproate18 Narrow bifrontal diameter, high forehead, epicanthal folds, low nasal bridge, short nose, Teratogen
congenital heart disease, long and thin fingers and toes, meningomyelocele, cleft lip
Prenatal fluconazole19 Phenocopy of Antley-Bixler syndrome Teratogen,
interference with
steroid biogenesis
Hallermann-Streiff 20 Small stature, brachycephaly with parietal bossing, thin calvarium, delayed ossification AD (234100)
of the sutures, microphthalmia, small nose, microstomia, hypoplasia of the teeth, atrophy
of the skin, hypotrichosis
Pfeiffer21 Brachycephaly, coronal synostosis, hypertelorism, broad distal phalanges of the thumb, AD (101600)
medial deviation of thumbs and broad first toes FGFR1, 8p11
FGFR2, 10q26
Rieger22 Iris dysplasia, short philtrum, thin upper lip, hypodontia, failure of involution of AD (180500)
periumbilical skin PITX2, 4q25-q26
Rubinstein-Taybi23 Short stature, small cranium, palpebral downslant, beaked nose, epicanthal folds, (180849)
strabismus, malformed auricles, broad thumbs, broad toes, cryptorchidism, mental Microdeletion or
retardation mutation
CREBBP, 16p13.3
Saethre-Chotzen24 Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue syndactyly, (101400)
hallux valgus TWIST, 7p21
Stickler25 Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard and/soft palate, AD (108300, 604841,
micrognathia, deafness, retinal detachment, cataracts, hypotonia, marfanoid habitus, 184840)
flat vertebrae COL2A1, 12q31
COL11A1, 1p21
COL11A2, 6p21
Trisomy 2126 Hypotonia, short stature, brachycephaly, upslanting palpebral fissures, small ears, cardiac Abnormal karyotype,
defects, single palmar crease, clinodactyly trisomy 21
Turner27 Small stature, ovarian dysgenesis, transient congenital lymphedema, broad chest, widely Abnormal karyotype,
spaced nipples, pectus excavatum, abnormal auricles, inner canthal folds, excessive 45,X
pigmented nevi, renal malformation, congenital heart disease

285
286 Craniofacial Structures
concept of spatial relationship between structures belonging to the
same growth field, which represents an area of convergence and
concentration of several growth forces.30,31 Positive results were
obtained by Siebert,29 who suggested a positive delineation of the
midface developmental field. However, the representative variables
used (inner canthal measurement, outer orbital measurement, nose
breadth, and mouth width) are soft tissue measurements that
probably do not truly reflect the growth of the skeletal midface.
More studies are needed to elucidate the mechanisms involved in
the aberrant growth of the middle one-third of the skeletal face.
Prognosis, Treatment, and Prevention
The treatment of hypoplasia of the midface is surgical, and the
central section of the face must be advanced; a horizontal os-
teotomy of the maxilla closely following the trace of a LeFort I
fracture is indicated.
When the facial hypoplasia extends to the floor of the orbit, to
the nose, and to the malar eminence, the osteotomy varies ac-
cording to the amount of advancement required and the particular
areas of the face that must be mobilized. Ortiz-Monasterio and
Musolas1 have suggested the use of Tessier osteotomies types 2.4
and 5, which follow the course of a LeFort III fracture. These
procedures are complemented by cartilage or bone grafts to the
pyriform area that will be useful in the restoration of the facial
convexity. Distraction osteogenesis has been used in combination
with LeFort procedures to increase the amount of midfacial ad-
vancement in a single surgical procedure.32,33 Further refinement
of this technique allows for distraction in more than one plane.34
Midface advancement is a rewarding technique, with excellent
functional correction and improvement of facial aesthetics. The
prognosis must be individualized according to the associated
congenital malformations, but in general it is considered very good.
Prenatal studies of the midface have rarely been reported.29
Recent advances in ultrasonography have raised the possibility of
accurately measuring the midface at early gestational ages.35 The
presence of midface hypoplasia during a fetal sonogram should
alert the ultrasonographer to the possibility of associated fetal
anomalies.
Midface hypoplasia is not an independent entity. Prevention
of this condition is related to the individual situation, with pre-
natal counseling apparently the only method available at present.
References (Midface Retrusion and Hypoplasia)
1. Ortiz-Monasterio F, Musolas A: Midface retrusion. World J Surg
13:410, 1989.
2. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care
for Craniofacial Deformities. CV Mosby, St. Louis, 1985, p 209.
3. Ricketts RM: Divine proportion in facial esthetics. Symposium on
maxillo-facial surgery. Clin Plast Surg 9:401, 1982.
4. Saksena SS, Bixler D, Yu PL: A Clinical Atlas of Roentgencephalometry
in Norma Lateralis. Alan R. Liss, Inc., New York, 1987, p 5.
5. Escobar LF, Bixler D, Sadove M, et al.: Antley-Bixler syndrome from a
prognostic perspective: report of a case and review of the literature.
Am J Med Genet 29:829, 1988.
6. Gross-Kieselstein E, Har-Even Y, Navon P, et al.: Familial variant of
maxillonasal dysplasia? J Craniofac Genet Dev Biol 6:331, 1986.
7. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al.: Achondroplasia is defined
by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368, 1995.
8. Buntinx IM, Hennekam RCM, Brouwer OF, et al.: Clinical profile of
Angelman syndrome at different ages. Am J Med Genet 56:176, 1995.
9. Antley RM, Bixler D: Trapezoidocephaly, midface hypoplasia and
cartilage abnormalities with multiple synostoses and skeletal fractures.
Birth Defects Orig Artic Ser XI(2):397, 1975.
10. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results
from localized mutations of FGFR2 and is allelic with Crouzon
syndrome. Nat Genet 9:165, 1995.
11. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with
hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb
anomalies. J Pediatr 83:280, 1973.
12. Heilstedt HA, Ballif BC, Howard LA, et al.: Physical map of 1p36,
placement of breakpoints in monosomy 1p36, and clinical character-
ization of the syndrome. Am J Hum Genet 72:1200, 2003.
13. Kline AD, White ME, Wapner R, et al.: Molecular analysis of the 18q-
syndrome—and correlation with phenotype. Am J Hum Genet 52:895,
1993.
14. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and
microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med
Genet 44:261, 1992.
15. Reardon W, Winter RM, Rutland P, et al.: Mutations in the fibroblast
growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet
8:98, 1994.
16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia:
progress in understanding the genetic basis of a complex malformation
syndrome. Hum Genet 109:638, 2001.
17. Jones KL, Smith DW: The fetal alcohol syndrome. Teratology 12:1, 1975.
18. Kozma C: Valproic acid embryopathy: report of two siblings with
further expansion of the phenotypic abnormalities and a review of the
literature. Am J Med Genet 98:168, 2001.
19. Aleck KA, Bartley DL: Multiple malformation syndrome following
fluconazole use in pregnancy: report of an additional patient. Am J
Med Genet 72:253, 1997.
20. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med
Genet 41:488, 1991.
21. Cohen MM Jr: Pfeiffer syndrome update, clinical subtypes, and
guidelines for differential diagnosis. Am J Med Genet 45:300, 1993.
22. Semina EV, Reiter R, Leysens NJ, et al.: Cloning and characterization
of a novel bicoid-related homeobox transcription factor gene, RIEG,
involved in Rieger syndrome. Nat Genet 14:392, 1996.
23. Hennekam RCM, Tilanus M, Hamel BCJ, et al.: Deletion at chromosome
16p13.3 as a cause of Rubinstein-Taybi syndrome: clinical aspects. Am J
Hum Genet 52:255, 1993.
24. Pantke OA, Cohen MM Jr, Witkop CJ Jr, et al.: The Saethre-Chotzen
syndrome. Birth Defects Orig Artic Ser XI(2):190, 1975.
25. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler
syndrome. J Med Genet 36:353, 1999.
26. Korenberg JR, Chen XN, Schipper R, et al.: Down syndrome
phenotypes: the consequences of chromosomal imbalance. Proc Nat
Acad Sci 91:4997, 1994.
27. Saenger P: Turner’s syndrome. N Engl J Med 335:1749, 1996.
28. Hopkin GB: Hypoplasia of the middle third of the face associated
with congenital absence of the anterior nasal spine, depression of the
nasal bones, and angle class III malocclusion. Br J Plast Surg 16:146,
1963.
29. Siebert JR: Prenatal growth of the median face. Am J Med Genet
25:369, 1986.
30. Lauder GV: Form and function: structural analysis in evolutionary
morphology. Paleobiology 7:430, 1981.
31. Cheverud JM: Phenotypic, genetic, and environmental morphology inte-
gration in the cranium. Evolution 36:499, 1982.
32. Alonso N, Munhoz AM, Fogaca W, et al.: Midfacial advancement by bone
distraction for treatment of craniofacial deformities. J Craniofac Surg
9:114; discussion 119, 1998.
33. Toth BA, Kim JW, Chin M, et al.: Distraction osteogenesis and its
application to the midface and bony orbit in craniosynostosis syndromes.
J Craniofac Surg 9:100; discussion 119, 1998.
34. Satoh K, Mitsukawa N, Hosaka Y: Dual midfacial distraction
osteogenesis: Le Fort III minus I and Le Fort I for syndromic
craniosynostosis. Plast Reconstr Surg 111:1019, 2003.
35. Escobar LF, Bixler D, Padilla LM, et al.: A morphometric analysis of
the fetal craniofacies by ultrasound: fetal cephalometry. J Craniofac
Genet Dev Biol 10:19, 1990.
 Facial Bones
8.7
Agnathia
Definition
Agnathia is the complete absence of the mandible. This rare
condition can be viewed as the most severe form of micrognathia
(reduction in mandibular size). However, agnathia and micro-
gnathia probably have different etiologies.
Diagnosis
Using simple clinical inspection, the dysmorphologist is fre-
quently able to detect changes in mandibular shape and size. In
agnathia, the missing lower one-third of the facial skeleton causes
striking morphologic changes (Fig. 8-11). Affected individuals
have severe soft tissue anomalies, such as microstomia, cleft lip
and/or palate, and ear abnormalities ranging from absence or
misplacement of the external auricle to abnormalities of the inner
ear. Some patients also have holoprosencephaly and upper res-
piratory tract anomalies.1
Two groups of patients with agnathia are now recognized:
those who have varying degrees of cyclopia, with holoprosence-
phalic brain, and those without cyclopialike facial malformations.2
The former is a rare lethal condition that has been reported to
occur in association with microstomia, aglossia, synotia, and brain
Fig. 8-11. Infant with agnathia without holoprosencephaly.
287
malformations. It usually occurs with developmental abnormalities
of other systems that lead to early neonatal death.1 The second
group is considered less severe and consists of agnathia without
holoprosencephaly. Affected patients usually have microstomia,
aglossia, blind mouth, middle ear anomalies, cleft lip, cleft palate,
and downward-slanting palpebral fissures (Fig. 8-11).
Most pregnancies with agnathic fetuses are associated with
polyhydramnios, which probably result from fetal inability to
swallow because of persistence of the oropharyngeal membrane.
As a consequence, premature labor is frequent, with only rare
cases reaching 38 weeks of gestation. The neonate shows a blind-
ending mouth, which impedes the passing of an oropharyngeal
tube to establish an airway. Early recognition of this situation may
prompt the clinician to perform a tracheostomy.
Ear positioning is variable, and the use of the term otocephaly
does not seem justified. Patients with fusion of the ears in the
midline are rare.3 Inner ear anomalies have been reported to occur
in about 40% of cases.4
Etiology and Distribution
It seems possible that two different mechanisms are responsi-
ble for agnathia holoprosencephaly and agnathia without brain
anomalies (otocephaly).1,5,6 Agnathia is considered to be a defect
in the ventral portion of the first branchial arch and may be
secondary to defective neural crest migration or proliferation or
to a mesodermal deficiency in the arch itself.6 Persistence of the
oropharyngeal membrane occurs. Bixler and collaborators1 have
suggested that a defect in prechordal mesoderm formation and/or
its interactions accounts for agnathia-holoprosencephaly. Subse-
quent effects on neural crest cells may result. A graded series of
defects resulting from abnormal formation of the prosencephalon
and the mandible occurs.
Agnathia without holoprosencephaly is a very rare abnor-
mality, with sporadic occurrence. Autosomal recessive inheritance
has been suggested by Pauli et al.2 based on their observation of two
affected stillborn siblings. However, an unbalanced chromosome
abnormality was later identified in this family.7 Animal models
(mouse and guinea pig) have also indicated the existence of an
inherited type of agnathia without holoprosencephaly; however,
this evidence is not conclusive at the present time.8
Agnathia with holoprosencephaly seems to have a higher
incidence than agnathia without holoprosencephaly, with only
24 cases of the latter identified in the 25 years prior to 1985.1 In
patients with agnathia with holoprosencephaly, situs inversus may
also be present.9 Sex ratios are equal, and excessive incidence has
not been described in any racial group.
Prognosis, Treatment, and Prevention
As was mentioned previously, agnathia without holoprosence-
phaly seems to carry a better prognosis than agnathia with ho-
loprosencephaly. In general, the prognosis in both situations is
poor; however, there are no adequate data concerning survival
rates. In the presence of airway obstruction, the clinician should
consider a tracheostomy, since this is the only means of ensuring
good ventilatory support. Once the patient is stable, evaluation for
surgical correction of associated anomalies is indicated, with the
planning of feeding methods to support the child.
Reports of prenatal diagnosis of this condition can be found
in the literature.10,11 The authors used prenatal radiographs to
identify agnathia and polyhydramnios. The use of ultrasonogra-
phy, which can demonstrate polyhydramnios and agnathia with
288 Craniofacial Structures
holoprosencephaly, has been found to be preferable. Computer
tomography has also been used for prenatal diagnosis.12
Since most of the cases are sporadic, no biochemical, DNA,
or chromosomal markers have been useful in the diagnosis of
agnathia. There appears to be no effective means of prevention at
present.
References (Agnathia)
1. Bixler D, Ward R, Gale DD: Agnathia-holoprosencephaly: a develop-
mental field complex involving face and brain. Report of 3 cases.
J Craniofac Genet Dev Biol 1:241, 1985.
2. Pauli RM, Pettersen JC, Arya S, et al.: Familial agnathia-holoprosen-
cephaly. Am J Med Genet 14:677, 1983.
3. Johnson W, Cook JB: Agnathia associated with pharyngeal isthmus
atresia and hydramnios. Arch Pediatr 78:211, 1961.
4. Le Marec B, Bourdiniere J, Le Clech G, et al.: A propos d’un cas
d’tocephalie (A case of otocephaly). J Genet Hum 24(suppl):253, 1976.
5. Opitz JM: Letter to the editor. Clin Genet 17:238, 1980.
6. Johnston MC, Sulik KK: Some abnormal patterns of develop-
ment in the craniofacial region. Birth Defects Orig Artic Ser XV(8):
23, 1979.
7. Krassikoff N, Sekhon GS: Familial agnathia-holoprosencephaly caused
by an inherited unbalanced translocation and not autosomal recessive
inheritance. Am J Med Genet 34:255, 1989.
8. Juriloff DM, Sulik KK, Roderick TH, et al.: Morphogenesis of sponta-
neously occurring otocephaly in a newly developed mouse mutant.
Teratology 21:47A, 1980.
9. Ozden S, Bilgic R, Delikara N, et al.: The sixth clinical report of a rare
association: agnathia-holoprosencephaly-situs inversus. Prenat Diagn
22:840, 2002.
10. Ursell W: Hydramnios associated with congenital microstomia, agnathia
and synotia. J Obstet Gynecol Br Commonwealth 79:185, 1972.
11. Cayea PD, Bieber FR, Ross MJ, et al.: Sonographic findings in otocephaly
(synotia). J Ultrasound Med 4:377, 1985.
12. Ebina Y, Yamada H, Kato EH, et al.: Prenatal diagnosis of agnathia-
holoprosencephaly: three-dimensional imaging by helical computed
tomography. Prenat Diagn 21:68, 2001.
8.8
Micrognathia
Definition
Micrognathia is the reduction in size of one or all parts of the
mandible. Micrognathia should be differentiated from retro-
gnathia, in which the mandible is of normal size but is posteriorly
positioned in relation to the skull base.
Diagnosis
Malformations of the mandible are among the most common
malformations known to humans. Among these, micrognathia may
be the most common.1 Severe micrognathia can be detected by
the clinician by simple inspection (Fig. 8-12). Mild forms may be
difficult to detect, however, and can be easily confused with ret-
rognathia. Roentgenocephalometry is extremely helpful in the
differentiation between true micrognathia and retrognathia, and it
also provides a substantial amount of information necessary for
objective decisions concerning treatment.
Mandibular hypoplasia may induce other anomalies, as is the
case in the Pierre Robin sequence. Here, acting as a single initi-
ating defect, the small mandible keeps the tongue in a posterior
location, impairing the closure of the posterior palatal shelves in
the midline. This results in cleft palate.
Rarely seen as an isolated characteristic, hypoplasia of the
mandible can be familial.2 However, it is more common as part of
a multiple congenital anomaly syndrome, with which it follows
the corresponding mode of inheritance. More than 130 syn-
dromes and 47 chromosomal anomalies have been reported to
include micrognathia as a consistent feature (Table 8-8).
Etiology and Distribution
Micrognathia is believed to result from hypoplasia of the neural
crest cell population in the first branchial arch. The bony elements
of the lower jaw are neural crest-derived. From two different ossi-
fication centers that appear at about the 6th week of gestation, each
side of the mandible is formed by posteroanterior ossification
spreading over the framework provided by Meckel’s cartilage. At
birth, the mandible consists of two halves, with a fibrous union at
the symphysis. Complete ossification of the mandible and the fi-
brous union occurs within the 1st year of life. Evidence for the
supportive role of Meckel’s cartilage during growth of the mandi-
ble is shown by the effects of the lathyrogen B-aminoproprionitrile
(BAPN) on facial growth.39 Administration of BAPN to pregnant
rats at about day 15 of gestation reduces the length of the mandible
in the fetuses.
In some instances, micrognathia may be due to mechanical
influences during growth and development. The best example of
this situation is the mandibular hypoplasia seen in the oligohy-
dramnios sequence, in which compression impedes normal
growth and development of the mandible.
Teratogenic factors also have been suggested to play a role in
the etiology of micrognathia. Observations in fetuses of mothers
who received radiotherapy during pregnancy showed an increased
incidence of mandibular hypoplasia.40 Administration of the
antiniacin agent 6-aminonicotinamide and the glutamine ana-
logue diazo-oxo norleucine to rats during gestational day 15
produced severe growth retardation of Meckel’s cartilage, thereby
producing an inadequate framework for mandibular develop-
ment.41
Anomalies of the mandible with or without ear abnormalities
are considered to occur with a frequency greater than one of every
100 newborn babies.1 Micrognathia does not follow a sex pref-
erential pattern. The mode of inheritance, if any, should be
evaluated in the context of the disorder of which micrognathia
constitutes a part.
Prognosis, Treatment, and Prevention
The prognosis of the patient with mandibular hypoplasia depends
on associated birth defects. Cases of isolated micrognathia or even
Pierre Robin sequence have an excellent prognosis. The neonate
with airway obstruction may require tracheotomy and feeding
gastrostomy. Surgical mandibular advancement was previously not
recommended for use during infancy.42 This has changed due to
the availability of distraction osteogenesis. This technique has been
used successfully in children as young as 6 months.43 As the dis-
traction devices become smaller, they can be implanted in even
younger infants. This technique may be used to prevent tracheot-
omy or to allow for decannulation in tracheotomy-dependent
patients.44 When there is a stable airway and nutrition can be
maintained, orthognathic surgery can be deferred until mid- to late
adolescence depending on the sex, since females can undergo such
surgery earlier.
Micrognathia has been clearly identified in the prenatal
period via ultrasonography.45,46 The routine ultrasonographic
 Facial Bones 289

Fig. 8-12. Mild micrognathia in a 12-year-old male with MPS 1-H/I-S compound (A), moderate
micrognathia in an infant with cerebrocostomandibular syndrome (B and C), and severe micrognathia
associated with radial reduction defects in a 5-year-old boy with Nager syndrome (D). (B and C courtesy
of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

examination between 16 and 18 gestational weeks should allow
delineation of the morphology of the mandible. Prenatal recog-
nition of micrognathia is helpful in that it allows the neonatolo-
gist, facial surgeon, otolaryngologist, and anesthetist to be prepared
for possible complications during and after delivery.
References (Micrognathia)
1. Melnick M: Anomalies of branchial-arch-derived otomandibular
structures. In: Clinical Dysmorphology of Oral-Facial Structures.
M Melnick, ED Shields, NJ Burzmski, eds. John Wright, PSG, Boston,
1982, p 336.
2. Warkany J: Congenital Malformations. Notes and Comments. Year
Book Medical Publishers, Chicago, 1971, p 622.
3. Hall JG, Reed SD, Driscoll EP: Part 1. Amyoplasia: a common, sporadic
condition with congenital contractures. Am J Med Genet 15: 571, 1983.
4. Ellis NA, German J: Molecular genetics of Bloom’s syndrome. Hum
Molec Genet 5:1457, 1996.
5. Wagner T, Wirth J, Meyer J, et al.: Autosomal sex reversal and
camptomelic dysplasia are caused by mutations in and around the
SRY-related gene SOX9. Cell 79:1111, 1994.
6. Dignan PSJ, Martin LW, Zenni EJ Jr: Pierre Robin anomaly with an
accessory metacarpal of the index fingers: the Catel-Manzke syndrome.
Clin Genet 29:168, 1986.
7. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’:
Decentric small marker chromosome probably derived from a 22
(tetrasomy 22pter;q11) associated with a characteristic phenotype.
Report of 11 patients and delineation of the clinical picture. Hum
Genet 57:148, 1981.
8. Plotz FB, van Essen AJ, Bosschaart AN, et al.: Cerebro-costo-mandibular
syndrome. Am J Med Genet 62:286, 1996.
9. Pena SDJ, Shokeir MHK: Autosomal recessive cerebro-oculo-facio-
skeletal (COFS) syndrome. Clin Genet 5:285, 1974.
10. Cohen MM Jr, Hall BD, Smith DW, et al.: A new syndrome with
hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb
anomalies. J Pediatr 83:280, 1973.
Table 8-8. Syndromes associated with micrognathia
Syndrome
Amyoplasia congenita3
Bloom4
Campomelic dysplasia5
Catel-Manzke6
Cat eye7
Cerebro-costo-mandibular8
Cerebro-oculo-
facio-skeletal (COFS)9
Cohen10
Cornelia de Lange11
Deletion 22q11.212
Diamond-Blackfan
anemia-microtia-
cleft palate13
Dubowitz14
Escobar15
Facio-auriculo-vertebral
spectrum16
Hallermann-Streiff17
Lethal multiple
pterygium18
Marshall-Smith19
Meckel-Gruber20
290
Causation
Prominent Features Gene/Locus
Round face; small upturned nose; midline capillary hemangioma; severe Unknown, sporadic
flexion contractures at metacarpophalangeal joints, with mild (108110)
contractures at interphalangeal joints, hips usually dislocated,
adducted, or abducted
Growth deficiency, mild microcephaly with dolichocephaly, small nose, AR (210900)
facial telangiectatic erythema that involves the butterfly midface region RECQL3, 15q26.1
exacerbated by sunlight
Growth deficiency, large brain with gross cellular disorganization, AR (211970)
small flat-appearing face, cleft palate, short palpebral fissures, anterior SOX9, 17q24-q25
bowing of tibiae, short fibula, absence of mineralization of the sternum,
hypogenitalism, XY gonadal dysgenesis
Hyperphalangy of index finger, postnatal growth deficiency, cleft palate, (302380)
malformed ears, cardiac defects, clinodactyly Majority of cases are
sporadic affected males
Cognitive delay, mild hypertelorism, inferior coloboma of the iris, (115470)
preauricular pits and tags, cardiac defects (TAPVR), imperforate partial tetrasomy 22
anus, renal agenesis (isochromosome 22pter-q11)
Cognitive delay, growth deficiency, glossoptosis, cleft soft palate, AD (117650)
bell-shaped small thorax, anomalous rib insertion with ‘‘rib gaps’’
Reduced white matter of brain with gray mottling, microcephaly, large AR (214150, 126340)
pinnae, blepharophimosis, microphthalmia, cataracts, nystagmus, ERCC6, 10q11
camptodactyly, flexion contractures of elbows and knees, hirsutism, kyphosis ERCC2, 19q13
Truncal obesity, hypotonia, high nasal bridge, short philtrum, AR (216550)
downslanting palpebral fissures, prominent maxillary central incisors, COH1, 8q22
large ears, chorioretinal dystrophy, narrow hands and feet
Short stature, cognitive delay, initial hypertonicity, low-pitched weak cry, AD (122470)
long curly eyelashes, small nose, bushy eyebrows, synophrys, hirsutism, Most cases sporadic
micromelia, genital anomalies NIPBL, 5p13.1
Cleft palate, conotruncal heart malformation, thymic hypoplasia, (192430)
abnormal external ear, prominent nasal tip, hypoplastic alae microdeletion 22q11.2
nasi, learning difficulties
Macrocytic anemia, short stature, downslanting palpebral fissure, microtia, Dominant (606164)
cleft palate, micrognathia
Prenatal growth deficiency, variable mental deficiency, short attention AR (223370)
span, microcephaly, short palpebral fissures, round nasal tip, prominent
dysplastic ears, eczema
Multiple pterygia, short stature, inner canthal folds, cleft palate, AR (265000)
emotionless face, scoliosis, camptodactyly, syndactyly, genital
anomalies
Macrostomia, unilateral facial hypoplasia, microtia, periauricular tags, Unknown, sporadic
hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate (164210, 257700)
Small stature, brachycephaly with parietal bossing, thin calvarium, Unknown, sporadic
delayed ossification of the sutures, microphthalmia, small nose, (234100)
microstomia, hypoplasia of the teeth, atrophy of the skin,
hypotrichosis
Generalized amyoplasia, multiple pterygia, contractures, growth AR (253290)
deficiency, epicanthal folds, ocular hypertelorism, flat nose, Heterogeneous
cryptorchidism, mild neck edema and loose skin
Accelerated linear growth and skeletal maturation, long cranium, Unknown
prominent forehead, bluish sclerae, broad proximal and middle (602535)
phalanges with narrow distal phalanges, hypertrichosis, respiratory
problems
Growth deficiency, occipital encephalocele, microcephaly, ear anomalies, AR, multiple loci
cleft palate, microphthalmia, polydactyly, cystic renal dysplasia, (606361) 8q24
cryptorchidism (603194) 11q13
(249000) 17q22-q23
(continued )
Table 8-8. Syndromes associated with micrognathia (continued)

Causation
Syndrome Prominent Features Gene/Locus

Melnick-Needles Melnick-Needles: prominent eyes, late closure of fontanels, short upper XL (309350, 311300,
(Oto-palato- arms and distal phalanges, bowing of radius and tibia, coxa valga, 304120, 305620)
digital spectrum)21 small thoracic cage, pectus excavatum, iliac flaring; often male lethal FLNA, Xq28
Allelic to OPD1, OPD2,
frontometaphyseal dysplasia,
periventricular heterotopia
Miller22 Downslanting palpebral fissures, eyelid coloboma, ectropion, cleft lip AR (263750)
and/or palate, postaxial limb deficiencies, syndactyly, accessory nipple Most sporadic, AD rarely
reported
Miller-Dieker23 Lissencephaly, heterotopias, absent or hypoplastic corpus callosum, (247200)
small brain stem, hypotonia, seizures, microcephaly, small nose, late Microdeletion 17p13.3
eruption of primary teeth, cryptorchidism
Moebius24 Mask-like facies with sixth and seventh nerve palsy, hypoplasia to (157900)
absence of the central brain nuclei, myopathy Majority of cases
sporadic, few familial
Nager25 Normal intelligence, short stature, conductive deafness and articulation AD, AR (154400)
problems, malar hypoplasia, palpebral downslant, absence of lower
eyelashes, periauricular tags, atresia of external ear canal, hypoplasia
to aplasia of the thumb, proximal radioulnar synostosis, short
forearms
Nijmegen breakage26 Microcephaly, short stature, palpebral upslant, long nose, immune AR (251260)
dysfunction, chromosome breakage, malignancies, neurodegeneration NBS1, 8q21
Pallister-Hall27 Hypothalamic hamartoblastoma, hypopituitarism, flat midface, anteverted AD (146510)
nares, laryngeal cleft, bifid epiglottis, multiple frenuli, abnormal lung GLI3, 7p13
lobation, nail dysplasia, postaxial polydactyly, anal defects Allelic to Greig
Progeria28 Alopecia, hypoplasia of nails, loss of subcutaneous fat, periarticular AD (176670)
fibrosis, skeletal hypoplasia, dysphasia, dental anomalies, atherosclerosis LMNA, 1q21.2
Prenatal accutane29 Bilateral microtia, anotia, U-shaped palatal cleft, ocular hypertelorism, Teratogen
conotruncal heart defects, hydrocephaly, cerebellar hypoplasia, agenesis
of the vermis, thymic abnormalities
Seckel30 Prenatal growth deficiency, microcephaly, receding forehead, prominent AR, heterogeneous
nose, mental retardation (210600) ATR, 3q22
(606744) 18p11-q11
Splenogonadal fusion31 Fused spleen and gonad, limb defects, deep and narrow palate, multiple (183300)
unerupted teeth Sporadic, mostly males,
possibly due to vascular event
Stickler32 Flat facies, depressed nasal bridge, epicanthal folds, clefts of hard AD
and/soft palate, deafness, retinal detachment, cataracts, hypotonia, (108300) COL2A1, 12q31
marfanoid habitus, flat vertebrae (604841) COL11A1, 1p21
(184840) COL1A2, 6p21
Treacher Collins33 Downslanting palpebral fissures, cleft in zygomatic bone, lower lid AD (154500)
coloboma, partial to total absence of lower eyelashes, external TCOF1, 5q21-q33
ear malformation, conductive deafness, cleft palate, extension of scalp
hair onto lateral cheek
Trisomy 834 Variable cognitive deficiency, strabismus, hypertelorism, full lips, Abnormal karyotype
cupped ears, camptodactyly, limited supination, long slender trunk,
narrow pelvis
Trisomy 935 Growth deficiency, severe mental deficiency, narrow bifrontal diameter, Abnormal karyotype
prominent upper lip, low-set ears, joint anomalies, hypoplastic
phalanges, congenital heart disease
Trisomy 1836 Growth deficiency, hypertonicity, prominent occiput, small mouth, Abnormal karyotype
clenched hand, overlapping fingers, cardiac defects, renal
malformation, rocker-bottom feet
Deletion 4p37 Growth deficiency, hypotonia, severe mental deficiency, strabismus, Abnormal karyotype
hypertelorism, prominent glabella, posterior midline scalp defects,
periaurcular tags, clefting, genital anomalies
Deletion 13q38 Growth deficiency, mental deficiency, microcephaly, hypertelorism, Abnormal karyotype
microphthalmia, retinoblastoma, webbed neck, congenital heart
disease, hypospadias, lumbar agenesis

291
292 Craniofacial Structures
11. Allanson JE, Hennekam RCM, Ireland M: De Lange syndrome:
subjective and objective comparison of the classical and mild pheno-
types. J Med Genet 34:645, 1997.
12. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and
microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med
Genet 44:261, 1992.
13. Gripp KW, McDonald-McGinn DM, La Rossa D, et al.: Bilateral
microtia and cleft palate in cousins with Diamond-Blackfan anemia.
Am J Med Genet 101:268, 2001.
14. Tsukahara M, Opitz JM: Dubowitz syndrome: review of 141 cases
including 36 previously unreported patients. Am J Med Genet 63:277, 1996.
15. Hall JG, Reed SD, Rosenbaum KN, et al.: Limb pterygium syndromes:
a review and report of eleven patients. Am J Med Genet 12:377, 1982.
16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia:
progress in understanding the genetic basis of a complex malformation
syndrome. Hum Genet 109:638, 2001.
17. Cohen MM Jr: Hallermann-Streiff syndrome: a review. Am J Med
Genet 41:488, 1991.
18. Chen H, Immken L, Lachman R, et al.: Syndrome of multiple pterygia,
camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic
hygroma, and skeletal anomalies: delineation of a new entity and
review of lethal forms of multiple pterygium syndrome. Am J Med
Genet 17:809, 1984.
19. Williams DK, Carlton DR, Green SH, et al.: Marshall-Smith syndrome:
the expanding phenotype. J Med Genet 34:842, 1997.
20. Paavola P, Salonen R, Baumer A, et al.: Clinical and genetic heteroge-
neity in Meckel syndrome. Hum Genet 101:88, 1997.
21. Robertson SP, Twigg SR, Sutherland-Smith AJ, et al.: OPD-spectrum
Disorders Clinical Collaborative Group: Localized mutations in the
gene encoding the cytoskeletal protein filamin A cause diverse mal-
formations in humans. Nat Genet 33:487, 2003.
22. Miller M, Fineman R, Smith DW: Postaxial acrofacial dysostosis
syndrome. J Pediatr 95:970, 1979.
23. Allanson JE, Ledbetter DH, Dobyns WB: Classical lissencephaly
syndromes: does the face reflect the brain? J Med Genet 35:920,
1998.
24. Baraitser M: Genetics of Moebius syndrome. J Med Genet 14:415,
1977.
25. Aylsworth AS, Lin AE, Friedman PA: Nager acrofacial dysostosis: male-
to-male transmission in 2 families. Am J Med Genet 41:83, 1991.
26. Van der Burgt I, Chrzanowska KH, Smeets D, et al.: Nijmegen
breakage syndrome. J Med Genet 33:153, 1996.
27. Kang S, Allen J, Graham JM Jr, et al.: Linkage mapping and phenotypic
analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet
34:441, 1997.
28. Eriksson M, Brown WT, Gordon LB, et al.: Recurrent de novo point
mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
Nature 423:293, 2003.
29. Sulik KK, Cook CS, Webster WS: Teratogens and craniofacial
malformations: relationships to cell death. Development 103(suppl):213,
1988.
30. O’Driscoll M, Ruiz-Perez VL, Woods CG, et al.: A splicing mutation
affecting expression of ataxia-telangiectasia and Rad3-related protein
(ATR) results in Seckel syndrome. Nat Genet 33:497, 2003.
31. Bonneau D, Roume J, Gonzalez M, et al.: Splenogonadal fusion limb
defect syndrome: report of five new cases and review. Am J Med Genet
86:347, 1999.
32. Snead MP, Yates JRW: Clinical and molecular genetics of Stickler
syndrome. J Med Genet 36:353, 1999.
33. Splendore A, Silva EO, Alonso LG, et al.: High mutation detection
rate in TCOF1 among Treacher Collins syndrome patients reveals
clustering of mutations and 16 novel pathogenic changes. Hum Mutat
16:315, 2000.
34. Riccardi VM: Trisomy 8: an international study of 70 patients. Birth
Defects Orig Artic Ser XIII(3C):171, 1977.
35. Cantu ES, Eicher DJ, Pai GS, et al.: Mosaic vs. nonmosaic trisomy 9:
report of a liveborn infant evaluated by fluorescence in situ hybrid-
ization and review of the literature. Am J Med Genet 62:330, 1996.
36. Baty BJ, Blackburn BL, Carey JC: Natural history of trisomy 18 and
trisomy 13: I. Growth, physical assessment, medical histories, survival,
and recurrence risk. Am J Med Genet 49:175, 1994.
37. Battaglia A, Carey JC, Cederholm P, et al.: Natural history of Wolf-
Hirschhorn syndrome: experience with 15 cases. Pediatrics 103:830,
1999.
38. Tranebjaerg L, Nielsen KB, Tommerup N, et al.: Interstitial deletion
13q: further delineation of the syndrome by clinical and high-
resolution chromosome analysis of five patients. Am J Med Genet
29:739, 1988.
39. Diewert VM: Correction between alterations in Meckel’s cartilage and
induction of cleft palate with B-aminoproprionitrile in the rat. Teratology
24:43, 1981.
40. Fogh-Andersen P: Rare clefts of the face. Acta Chir Scand 129:275, 1965.
41. Diewert VM: Contributions of differential growth of cartilages to
changes in craniofacial morphology. In: Factors and Mechanisms
Influencing Bone Growth. Alan R. Liss, Inc, New York, 1982, p 229.
42. Marsh JL, Vannier MW: Cranial deformities. In: Comprehensive Care
for Craniofacial Deformities. JL Marsh, MW Vannier, WG Stevens,
eds. CV Mosby, St Louis, 1985, p 260.
43. Denny AD, Talisman R, Hanson PR, et al.: Mandibular distraction
osteogenesis in very young patients to correct airway obstruction. Plast
Reconstr Surg 108:302, 2001.
44. Perlyn CA, Schmelzer RE, Sutera SP, et al.: Effect of distraction
osteogenesis of the mandible on upper airway volume and resistance in
children with micrognathia. Plast Reconstr Surg 109:1809, 2002.
45. Malinger G, Rosen N, Achiron R, et al.: Pierre Robin sequence
associated with amniotic band syndrome ultrasonographic diagnosis
and pathogenesis. Prenat Diagn 7:455, 1987.
46. Rotten D, Levaillant JM, Martinez H, et al.: The fetal mandible: a 2D
and 3D sonographic approach to the diagnosis of retrognathia and
micrognathia. Ultrasound Obstet Gynecol 19:122, 2002.
8.9
Congenital Asymmetry of the Facial Skeleton
Definition
Congenital asymmetry of the facial skeleton is a quantitative dis-
crepancy in size between the right and left sides of the facial skel-
eton. The facial midline is determined by the sagittal line drawn
from the vertex (highest midpoint of the craniofacies) through the
nasion and subnasale points to the gnathion (lowest medial point
of the mandible).
Diagnosis
Asymmetry of the facial skeleton and of the human skull as a
whole to a degree that can be readily appreciated is so common
that it has to be recognized as the rule.1 Such normal or anatomic
asymmetry must be distinguished from pathologic asymmetry
(Fig. 8-13). This difficult task is facilitated by quantitative pro-
cedures that can validate clinical observations. Useful techniques
include anthropometry, cephalometry, tridimensional computed
tomography (CT), and for the prenatal period fetal cephalometry
via ultrasound. These techniques not only describe the severity of
the asymmetry but provide information necessary to plan ade-
quate corrective treatment.
During the neonatal period, one should be particularly
careful in distinguishing between facial asymmetry resulting from
molding of the cranial bones during the birth process and true
malformation of the facial skeleton. Facial asymmetry resulting
from excessive molding of the cranium or from displacement of
the mandible during breech or face presentations is very common
and is usually self-correcting. Morphometric analysis of the face is
helpful in establishing the role of skeletal abnormalities in facial
 Facial Bones 293

Fig. 8-13. Facial asymmetry in a 31-month-old male with hemifacial microsomia (A), an infant with
asymmetric crying face (B), and a teenage girl with Parry-Romberg syndrome (C and D). (Courtesy
of Dr. Charles I. Scott, Jr, A. I. duPont Hospital for Children, Wilmington, DE.)

asymmetry. However, the precise diagnosis requires roentgeno-
graphic examination of the craniofacial skeleton, and sometimes
more sophisticated technology such as CT, tridimensional imag-
ing (TDI), and magnetic resonance imaging (MRI). With the
anteroposterior radiographs of the skull, one can use cephalo-
metric measurements to quantify the extent of the defect and the
particular facial areas involved. CT, TDI, and MRI are very useful
in distinguishing between congenital (‘‘developmental’’) skeletal
facial asymmetry and acquired skeletal facial asymmetry due to
pathologic processes and trauma.
Radiologic analysis assessing asymmetry of the facial skeleton
should include three planes as described by Murray and collabora-
tors.2 The frontal plane view, which is evaluated with an ante-
roposterior cephalometric radiograph, demonstrates asymmetry of
the mandible, maxilla, pyriform apertures, and orbits. This radio-
graphic view also discloses obliquity and rotation of the plane
formed by the two mandibular midlines, dental and skeletal. The
dental midline is rotated toward the normal side, while the skeletal
midline is rotated toward the abnormal side. The sagittal plane view
can demonstrate discrepancies in the ramus height and relationships
of the maxilla, mandible, and base of the skull. A panoramic view
may reveal anomalies in height and shape of the mandibular rami
and the temporomandibular joint (TMJ). The transverse plane is
evaluated with a submental vertex radiologic plate to demonstrate
the shape and width of the mandibular body, asymmetry in the
zygomatic arches, and medial and anterior displacement of the TMJ.
The most common cause of congenital facial asymmetry
probably is the group of disorders known as the otocraniofacial
294 Craniofacial Structures

syndromes.3 These involve unilateral and bilateral developmental

malformations of the skeletal craniofacial structures that may arise
from a growth deficiency of the first and second branchial arches.
They include conditions such as mandibulofacial dysostosis and
hemifacial microsomia. With an incidence of one in 4000,
hemifacial microsomia represents a wide spectrum of abnormal-
ities of the facial skeleton.4 Different classifications have been
suggested according to the severity of the defects.5 In type I, the
malformation of the facial skeleton is slight and mandibular
growth is compromised; however, the anatomic development of
the TMJ is not impaired. Type II shows a pronounced mal-
formation of the facial skeleton. The body and ramus of the lower
jaw, along with the TMJ, are underdeveloped on the affected side.
Rudiments of the condylar and coronoid processes are situated
below the malar arch and frontally to the site of the natural po-
sition of the articular fossa. Underdevelopment of the temporal
bone, the mastoid process, and the articular fossa and tubercle
also can be observed. Type III is also characterized by pronounced
malformation of the facial skeleton. The body of the mandible on
the affected side is underdeveloped and ends in a rudiment of the
ramus. The TMJ is absent. Radiologic studies usually show pro-
nounced asymmetry and disfigurement of the facial skeleton. The
underdeveloped side of the face is flattened, involving the orbit,
malar bone, and frontal and occipital bones. The affected malar
bone is considerably lower than the analogous bone on the intact
side. The body of the lower jaw is hypoplastic and deformed, and
the ramus appears as a pointed rudiment.
Etiology and Distribution
Asymmetry of the facial skeleton rarely occurs as an isolated
anomaly. In the majority of cases, it represents one component of a
multiple anomaly syndrome, usually resulting from an insult in the
early development of the branchial arches or brain. One must
understand that in the human, various insults to the fetus can
produce unilateral facial skeletal defects.
Growth of the facial skeleton is influenced by multiple factors,
including brain growth.6 Asymmetrical growth of the brain pro-
duces rotation of the face on the cranium, which progresses with
age and further growth. As the temporal lobes of the cerebrum
show a greater asymmetric development, increased displacement of
the nasomaxillary segment on the affected side occurs, and this in
turn produces a rotation of the face. This seems to apply to a few
conditions that include facial asymmetry in their phenotype;
however, it cannot be generalized.
Vascular theories to explain unilateral birth defects have gained
popularity.7–9 Robinson and collaborators7 suggested that a vascular
accident interrupting the blood flow to developing facial structures
could result in tissue ischemia, necrosis, or both. The severity of the
resulting defects would be directly proportional to the magnitude
and duration of tissue injury, allowing for a wide phenotypic vari-
ability. It has been suggested that a lesion in the stapedial artery, the
second aortic arch vessel, can produce unilateral craniofacial defects.
Animal models seem to support this theory.9 Vascular theories
may also be supported by the increased incidence of hemifacial

Table 8-9. Syndromes associated with congenital asymmetry of the facial skeleton
Causation
Syndrome Prominent Features Gene/Locus

Apert13
Craniofrontonasal14
Cat eye15
Facio-auriculo-vertebral
spectrum16
Hemimaxillofacial
dysplasia17
Hemifacial hyperplasia
with strabismus18
Hemifacial microsomia
with radial defects19
McCune-Albright20
Muenke21
Saethre-Chotzen22
Townes-Brocks23
Wildervanck24
Craniosynostosis, high forehead, flat facies, irregular supraorbital horizontal AD (101200)
groove, shallow orbits, hypertelorism, severe syndactyly hands and feet, broad FGFR2, 10q26
distal phalanges of thumb, mental retardation
Broad nasal root, bifid nasal tip, narrow shoulders, longitudinal grooves and XL (304110)
splits in nails EFNB1, Xq12
Mental deficiency, inferior coloboma of the iris, micrognathia, cardiac defects, (115470)
anal atresia, rectovesicular fistula, renal agenesis Partial tetrasomy
22 due to inv dup (22)(q11)
Macrostomia, unilateral facial hypoplasia, micrognathia, microtia, periauricular Unknown, sporadic
tags, hemivertebrae or hypoplasia of vertebrae, malfunction of soft palate, (164210, 257700)
renal and cardiac abnormalities
Unilateral enlargement of maxillary alveolar bone and gingival, hypoplastic Unknown
teeth, hypertrichosis of ipsilateral facial skin
Abnormal growth of the facial skeleton, zygomatic deficiency, convergent AD (141350)
strabismus, amblyopia of the affected side, submucous cleft palate
Similar facial findings to those seen in hemifacial microsomia, periauricular AD (141400)
pits or skin tags, shortening of the mandibular ramus, radial limb defects,
triphalangeal thumbs, duplication of the thumb
Fibrous dysplasia in bone, irregular patches of pigment of trunk, precocious (174800)
puberty, hyperthyroidism, hyperparathyroidism, acromegaly, Cushing, GNAS1, 20q13.2
hyperprolactinemia, short stature
Uni- or bicoronal synostosis, macrocephaly, hearing loss, learning differences AD (602849)
FGFR3, 4p16.3
Coronal synostosis, ptosis, small rounded ears, brachydactyly, soft tissue AD (101400)
syndactyly, hallux valgus TWIST, 7p21
Hemifacial microsomia with preauricular tags, abnormal ear shape, sensorineural AD (107480)
hearing loss, thumb anomalies, imperforate anus, renal malformations SALL1, 16q21.1
Ear anomalies, preauricular tags, pseudopapilledema, Duane anomaly, (314600)
Klippel-Feil anomaly Sporadic, most cases female
 Facial Bones
microsomia in offspring of diabetic mothers10,11 and in products of
twin or higher-order multiple pregancies.12
Several single-gene defects are known to cause skeletal facial
asymmetry as part of the clinical picture (Table 8-9). An autosomal
dominant form of isolated facial asymmetry has been described in
the past; however, in this case the asymmetry is localized to the
maxillomandibular region, without involvement of the upper
face and midface.25 Other causes of congenital facial asymmetry
include premature unilateral closure of the coronal suture, other
craniosynostosis, TMJ anomalies, coronoid process hyperplasia,
septic processes of the mandible, and trauma.9
Since skeletal facial asymmetry is not a primary birth defect,
its occurrence is usually dependent on another underlying defect
in facial embryogenesis. At present, no conclusive studies of sex
distribution are available.
Prognosis, Treatment, and Prevention
Advancements in surgical methodology have improved the prog-
nosis for patients with facial asymmetry. Mildly affected individ-
uals in whom there is no concern regarding appearance during
childhood need no treatment until adolescence. At this time an
assessment of the residual asymmetry at the end of growth can be
made and appropriate surgery undertaken.4 For many years it was
believed that the skeletal problems affecting the jaws and facial
skeleton, even in severe cases, should not be surgically corrected
until adolescence, mainly to avoid interference with growth. Sur-
gery in the adolescent patient has been directed most often to the
centralization of the mandible with bone grafting.
Recent years have seen increased interest in earlier restora-
tion of facial symmetry through surgery in the preschool period.
Surgical procedures may include the use of costochondral grafts.
These grafts with growth potential are placed into the vertical
ramus of the mandible to correct any deficiency. Osteotomies,
especially in the midface, are sometimes unavoidable. Distraction
osteotomy of the mandible has been used successfully in young
patients; however, on follow-up it became clear that the affected
side grew at a slower rate than the contralateral side, and initial
overcorrection was considered.26 A further definitive operation
may be required at the end of growth.
Prenatal diagnosis of this condition has been accomplished
with ultrasonography.27 Fetal craniofacial asymmetry may be the
first indication of a multiple congenital anomaly syndrome. At
16 weeks of gestation, an ultrasonographic coronal section may
identify differences between both sides of the facial skeleton. Level
two ultrasound may indicate the presence of other defects. Pre-
natal counseling should be available to all couples with a previ-
ously affected child.
References (Congenital Asymmetry of
the Facial Skeleton)
1. Brash JA: The Etiology of Irregularity and Malocclusion of the Teeth.
Dental Board of the United Kingdom, London, 1956, p 31.
2. Murray JE, Kaban LB, Mulliken JB, et al.: Analysis and treatment of
hemifacial microsomia. In: Craniofacial Surgery. E Caronni, ed. Little,
Brown and Co, Boston, 1985, p 377.
3. Pruzansky S: Otocraniofacial syndromes: clinical studies on mandibu-
lofacial dysostosis, hemifacial microsomia, and variants. In: Craniofacial
Surgery. E Caronni, ed. Little, Brown and Co, Boston, 1985, p 351.
4. Poole MD: Hemifacial microsomia. World J Surg 13:396, 1989.
5. Bezrukov VM, Plotnikov NA, Gun’ko VI, et al.: Surgical correction of
deformation of the facial skeleton in patients with hemifacial
microsomia. Acta Chir Plast 30:202, 1988.
295
6. Trenouth MJ: Asymmetry of the human skull during fetal growth.
Anat Rec 211:205, 1985.
7. Robinson LK, Hoyme HE, Edwards DK, et al.: Vascular pathogenesis
of unilateral craniofacial defects. J Pediatr 111:236, 1987.
8. Bavnick JNB, Weaver DD: Subclavian artery supply disruption sequence:
Hypothesis of vascular etiology for Poland, Klippel-Feil and Möbius
anomalies. Am J Med Genet 23:903, 1986.
9. Poswillo D: The pathogenesis of the first and second branchial arch
syndromes. Oral Surg 35:301, 1973.
10. Ewart-Toland A, Yankowitz J, Winder A, et al.: Oculoauriculovertebral
abnormalities in children of diabetic mothers. Am J Med Genet 90:303,
2000.
11. Wang R, Martinez-Frias ML, Graham JM Jr: Infants of diabetic moth-
ers are at increased risk for the oculo-auriculo-vertebral sequence: A
case-based and case-control approach. J Pediatr 141:611, 2002.
12. Lawson K, Waterhouse N, Gault DT, et al.: Is hemifacial microsomia
linked to multiple maternities? Br J Plast Surg 55:474, 2002.
13. Wilkie AOM, Slaney SF, Oldridge M, et al.: Apert syndrome results
from localized mutations of FGFR2 and is allelic with Crouzon
syndrome. Nat Genet 9:165, 1995.
14. Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al.: Cranio-
frontonasal syndrome: study of 41 patients. Am J Med Genet 61:147,
1996.
15. Schinzel A, Schmid W, Fraccaro M, et al.: The ‘cat eye syndrome’:
Decentric small marker chromosome probably derived from a 22
(tetrasomy 22pter;q11) associated with a characteristic phenotype. Report
of 11 patients and delineation of the clinical picture. Hum Genet 57:
148, 1981.
16. Kelberman D, Tyson J, Chandler DC, et al.: Hemifacial microsomia:
progress in understanding the genetic basis of a complex malformation
syndrome. Hum Genet 109:638, 2001.
17. Miles DA, Lovas JL, Cohen MM Jr: Hemimaxillofacial dysplasia: a
newly recognized disorder of facial asymmetry, hypertrichosis of the
facial skin, unilateral enlargement of the maxilla, and hypoplastic teeth
in two patients. Oral Surg Oral Med Oral Pathol 64:445, 1987.
18. Kurnit D, Hall JG, Shurtleff DB, et al.: An autosomal dominantly inherited
syndrome of facial asymmetry, esotropia, amblyopia, and submucous cleft
palate (Bencze syndrome). Clin Genet 16:301, 1979.
19. Moeschler J, Clarren SK: Familial occurrence of hemifacial microsomia
with radial limb defects. Am J Med Genet 12:371, 1982.
20. Schwindinger WF, Francomano CA, Levine MA: Identification of
a mutation in the gene encoding the alpha subunit of the stimulatory
G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc
Natl Acad Sci U S A 89:5152, 1992.
21. Gripp KW, McDonald-McGinn DM, Gaudenz K, et al.: Identification
of a genetic cause for isolated unilateral coronal synostosis: a unique
mutation in the fibroblast growth factor receptor 3. J Pediatr 132:714,
1998.
22. Paznekas WA, Cunningham ML, Howard TD, et al.: Genetic heteroge-
neity of Saethre-Chotzen syndrome, due to TWIST and FGFR muta-
tions. Am J Hum Genet 62:1370, 1998.
23. Kohlhase J, Wischermann A, Reichenbach H, et al.: Mutations in the
SALL1 putative transcription factor gene cause Townes-Brocks
syndrome. Nat Genet 18:81, 1998.
24. Balci S, Oguz KK, Firat MM, et al.: Cervical diastematomyelia in cervico-
oculo-acoustic (Wildervanck) syndrome: MRI findings. Clin Dysmor-
phol 11:125, 2002.
25. Burchfield D, Escobar V: Familial facial asymmetry (autosomal
dominant hemihypertrophy?). Oral Surg Oral Med Oral Pathol 50:
321, 1980.
26. Hollier LH, Kim JH, Grayson B, et al.: Mandibular growth after
distraction in patients under 48 months of age. Plast Reconstr Surg
103:1361, 1999.
27. Tamas DE, Mahony BS, Bowie JD, et al.: Prenatal sonographic diag-
nosis of hemifacial microsomia (Goldenhar-Gorlin syndrome). J Ultra-
sound Med 5:461, 1986.
This page intentionally left blank