El espectro de la hendidura orofacial eppley2005

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CME
The Spectrum of Orofacial Clefting
Barry L. Eppley, M.D., D.M.D., John A. van Aalst, M.D., Ashley Robey, M.D.,
Robert J. Havlik, M.D., and A. Michael Sadove, M.D.
Indianapolis, Ind.
Learning Objectives: After studying this article, the participant should be able to: 1. Describe the differing types of
congenital clefting defects that extend outward from the perioral region. 2. Define the sites of anatomical disruption and
deformities that these types of facial clefts cause. 3. Describe the cause and incidence, if known, of orofacial clefts and
their inheritance/transmission risks.
Background: Clefts of the orofacial region
are among the most common congenital
facial defects. The clinical presentation is
usually that of a lateral cleft of the lip
through the philtrum with or without ex-
tension through the palatal shelves. How-
ever, atypical forms of clefts with lip involve-
ment also occur in a variety of patterns,
some of which are embryologically predict-
able; others are not.
Methods: An overview of the embryology,
cause, and incidence of this diverse and
interesting group of congenital orofacial
clefts is presented.
Results: Clefts involving the lateral upper
lip; median upper lip; and oblique facial,
lateral facial, and median mandibular re-
gions are reviewed.
Conclusions: This review of orofacial mal-
formations describes clefting anomalies
that emanate from the mouth and lips. As
the causes of orofacial clefts are better un-
derstood, it is becoming clear that a com-
plex interplay between genetic and envi-
ronmental variables causes these clefts.
Future study of orofacial clefts will require
increasingly sophisticated methods of elu-
cidating these subtle interactions. (Plast.
Reconstr. Surg. 115: 101e, 2005.)
Orofacial clefting is a failure in developing
embryonic facial and palatal processes to ei-
ther completely merge or fuse, which results in
a predictable series of postnatal deformities.
What is frequently not appreciated is that these
congenital anomalies show a wide variety of
anatomical disruptions extending outward
from the oral cavity with varying frequencies
and association with other congenital malfor-
mations. As such, the term cleft lip– cleft palate
should be restricted to those clefts involving
the embryonic primary and secondary palate.
The variability of expression and decreased fre-
quency of the more unusual orofacial clefts
represent a set of more complex and etiologi-
cally distinct developmental problems.
CLASSIFICATION
A universally accepted classification scheme
that fully encompasses, accurately describes,
and integrates all the various types of orofacial
and craniofacial clefts does not exist. Van der
Meulen’s classification has an embryologic ba-
sis1 and Tessier’s classification has an anatom-
ical basis (Fig. 1).2 Tessier’s classification sys-
tem is commonly used by surgeons because it is
purely descriptive and makes no pretense at
causation and developmental relationships.
There is also an ease of correlation between
the anatomical defect and the required recon-
structive surgery. The Tessier classification in-
cludes numbered clefts from 0 (midline cleft of
the lip and nose) to 30 (a mandibular cleft).
Cleft nos. 1, 2, and 3 are through the lateral
margin of Cupid’s bow (corresponding with
From the Division of Plastic Surgery, Indiana University School of Medicine. Received for publication February 12, 2003; revised April 29,
2004.
DOI: 10.1097/01.PRS.0000164494.45986.91
101e
the more commonly seen cleft lip–cleft palate
deformities). Tessier cleft nos. 4, 5, and 6 are
oro-ocular clefts; however, cleft no. 6 does not
emanate from the oral cavity. Cleft nos. 7, 8,
and 9 are lateral facial clefts; among these
clefts, only cleft no. 7 emanates from the oral
cavity. The remaining clefts are above the pal-
pebral fissure (Figs. 2 and 3). Although this
classification system is of value for most cranio-
facial clefting problems, it is inadequate for the
commonly seen cleft lip–cleft palate deformity
(the typical cleft lip corresponds in part to
Tessier cleft nos. 1, 2, and 3).
A purely descriptive classification scheme is
used for this review of orofacial clefts and in-
cludes only those clefts that have an oral com-
ponent. In circumoral fashion, these clefts in-
clude the median cleft lip (Tessier cleft no. 0),
unilateral and bilateral cleft lip (primary pal-
ate; Tessier cleft nos. 1, 2, and 3), oblique facial
cleft (Tessier cleft nos. 4 and 5), lateral facial
cleft (Tessier cleft no. 7), and the median man-
dibular cleft (Tessier cleft no. 30).
INCIDENCE
According to recent studies, the frequency of
orofacial clefting is on the rise.3,4 In a study of
clefting frequency in spontaneously aborted
and stillborn fetuses, the incidence of facial
FIG. 2. Variability in presentation of the more common
cleft lip–cleft palate deformities. (Above) Microform cleft lip;
(center) incomplete unilateral cleft lip; (below) complete uni-
lateral cleft lip–cleft palate.
FIG. 1. Craniomaxillofacial clefting classification by
Tessier. Using the orbit, and specifically the palpebral fis-
sures, as central craniofacial landmarks, clefts are marked by
their lines of hard- and soft-tissue cleavage. The orofacial
clefts, nos. 0 through 7 and 30 (solid lines), occur primarily
inferior to the palpebral fissure. Craniofacial cleft nos. 9
through 14 (dashed lines) occur superior to the palpebral
level. (Adapted from Kawamoto, H. K., Jr. Rare craniofacial
clefts. In J. C. McCarthy (Ed.), Plastic Surgery, Vol. 4. Phila-
delphia: Saunders, 1990.)
102e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
malformations was 4.25 percent.5 With the re-
markable improvements in perinatal care and
prenatal medical technology, it seems likely
that more of these fetuses will survive to term
and require treatment. In a recent population-
based sample from California, the birth preva-
lence of all orofacial clefts was 0.17 percent,
with isolated clefting constituting roughly two-
thirds of these patients; the remainder were a
mixture of sequences, chromosomal aberra-
tions, associations, and unknown causes.6 An
increased awareness and understanding of
these unique facial clefting anomalies is partic-
ularly pertinent to the plastic surgeon.
EMBRYOLOGY
Virtually all cases of cleft lip–cleft palate are
attributable to the failure of the medial nasal
process to either contact or maintain contact
with the lateral nasal and maxillary processes.7
The embryologic pattern of neural crest cell
migration and subsequent merging is now ap-
preciated to be a complex interplay of move-
ments initiated when the inferior edge of the
medial nasal process joins the maxillary pro-
cess at approximately day 30 in the human
embryo. A significant morphogenetic move-
ment of the nasal placode (rotation and ad-
vancement) then permits its lateral nasal pro-
cess to sweep over the maxillary process a few
days later to join with the medial nasal process
to collectively form the upper lip-nasal unit.8 A
cellular deficiency or failure of contact main-
tenance in one or several components of this
six-piece midfacial convergence results in the
variations in clinical presentations that are
commonly seen (Figs. 2 and 3). Simonart’s
band, which can be seen at the posterosuperior
aspect of some lip clefts (Fig. 4, left), may well
illustrate a rupture of contact (lack of contact
maintenance) rather than failure to make con-
tact between the processes and may be the
primary developmental problem in many
clefts.7 This residual fibrous band is found in
the approximate location of the embryonic
union of the maxillary and median nasal pro-
cesses that constitute the primary palate and is
often associated with a narrower cleft defect
than those clefts in which it is not found. Var-
ious other webs or synechiae can occasionallybe seen attached to the cleft, indicating inad-
vertent adhesion of structures from surround-
ing facial processes (Fig. 4, right).
In addition to the importance of merging
and fusion, the size of the facial processes af-
fects facial morphology and cleft susceptibility.
An inherently smaller median nasal process, as
would be suspected in Asians because of their
smaller midfaces, tendency for class III occlusal
relationships, and flatter nasal structures, may
partially account for their relatively high rates
of clefting. Conversely, some African Ameri-
cans have broad, larger noses, increased facial
widths, and a tendency for maxillary dentoal-
veolar protrusion, all of which indicate the
FIG. 3. (Right) Incomplete bilateral cleft lip and (left) complete bilateral cleft lip–cleft palate.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 103e
presence of well-developed median nasal pro-
cesses and a decreased clefting frequency.
The cause of cleft lip–cleft palate is complex
and multifactorial, involving both genetic and
environmental factors (Tables I through
IV).9,10 Transmission of the cleft phenotype in a
simple mendelian fashion, as is seen in many
other hereditary disorders, rarely occurs. This
is supported by studies of cleft monozygotic
twins that show a 30 to 60 percent concordance
rate.9,11 When compared with the 1.0 to 4.7
percent concordance rate for dizygotic twins,
these results favor an important but not exclu-
sive role for genetics in the development of
cleft lip–cleft palate. In a family with a cleft
lip–cleft palate child, the chance that a second
child will be born with a similar defect is 3 to 4
percent; if two children have the defect, the
chance of a third child being born with the
defect is 9 percent.12 In addition to genetics,
environmental factors (Table III), such as
smoke exposure and use of steroids, phenyt-
oin, and retinoids, have also been implicated
in the development of cleft lip–cleft palate.13–20
More recently, a complex interplay between
genetic and environmental factors has been
unfolding.
GENETIC FACTORS
Cleft lip is a feature in 171 syndromes (15
percent of cleft lip–cleft palate cases are syn-
dromic)9–11,21–23 (Table I). Sixty-four are auto-
somal recessive, 35 are autosomal dominant,
and six are X-linked recessive.10 In a series
examining the association of malformations
with clefting, 13.6 percent of patients with cleft
lip, 36.8 percent of patients with both cleft lip
and cleft palate, and 46.7 percent of patients
FIG. 4. The importance of adhesion between developing facial processes can be seen in the fibrous bands that
are occasionally seen across or attached to the cleft. (Left) Simonart’s band serving as a residual tissue connection
between the medial and lateral lip processes. (Right) Band from lower lip attached to cleft.
TABLE I
Genetic Links to Syndromic Orofacial Clefts*
Syndrome Location Gene
Van der Woude 1q32–41
Ectrodactyly ectodermal dysplasia 3q27 P63
Margarita Island ectodermal dysplasia 11q23
Aicardi Xp22
Craniofrontonasal dysplasia Xp22
Hypertelorism-microtia-clefting 1q, 7p
Kallman Xp22 KAL1
Gorlin 9q22–31 LMX1B
Velo-cardio-facial 22q11
* Adapted from Prescott, N. J., Winter, R. M., and Malcolm, S. Nonsyn-
dromic cleft lip and palate: Complex genetics and environmental effects. Ann.
Hum. Genet. 65: 510, 2001.
TABLE II
Genetic Links to Nonsyndromic Orofacial Clefts*
Gene Locus
SKI/MTHFR 1p36
TGFb2 1q41
TGFa 2p13
MSX1 4p16, 1q31, 6p23
PVRL1 11q23
TGFb3 14q24
GABRb3 15q11
RARa 17q21
BCL3 19q13
* Adapted from Murray, J. C. Gene/environment causes of cleft lip and/or
palate. Clin. Genet. 61: 250, 2002.
104e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
with cleft palate alone had associated
malformations.22
Nonsyndromic cleft lip–cleft palate is a het-
erogeneous disease entity with candidate cleft-
ing loci on chromosomes 1, 2, 4, 6, 11, 14, 17,
and 19 (Table II). Chromosome 1 is associated
with nonsyndromic orofacial clefting by means
of a mutation in methylenetetrahydrofolate re-
ductase on 1q36.24 The short arm of chromo-
some 2 has a susceptibility gene in the 2p13
region found to be associated with cleft lip–
cleft palate.25 Studies have disagreed about
whether this site involves transforming growth
factor alpha26 or not.27 MSX1 located on chro-
mosome 4 (4q25) has been associated with
increased risk of cleft lip–cleft palate.28 Chro-
mosome 6 contains a likely gene responsible
for cleft lip–cleft palate at 6p23.29 Other chro-
mosomes with possible clefting loci include
chromosome 11, the transforming growth fac-
tor beta3 locus on chromosome 14, the reti-
noic acid receptor-� gene on chromosome 17,
the BCL3, and the transforming growth factor
beta locus on chromosome 19.30,31
ENVIRONMENTAL FACTORS
The list of environmental factors associated
with orofacial clefting is growing (Table III).
Any maternal alcohol consumption during
pregnancy increases the incidence of orofacial
clefting.32 Increased alcohol consumption re-
sults in further increases in the incidence of
developing both syndromic and nonsyndromic
clefts.33 An association between maternal ciga-
rette smoking and orofacial clefting is well es-
tablished,30 resulting in at least a doubling of
the incidence of cleft lip–cleft palate com-
pared with nonsmoking mothers. Further-
more, increased maternal smoking further in-
creases the odds of having a child with cleft
lip–cleft palate.34 The effect of maternal smok-
ing appears to be related to increased serum
carbon monoxide levels,15–17 which exert their
effect on cytochrome oxidase.7
Multiple studies have shown that folate defi-
ciency is associated with cleft lip–cleft pal-
ate.19,20 Prenatal folic acid supplementation has
been shown to decrease this risk35; high phar-
macologic doses (6 mg/day) are required for
the protective effect.36 At present, folic acid
supplementation is the only empiric preventa-
tive treatment shown to decrease the incidence
of facial clefting. Conversely, folic acid antago-
nists increase the incidence of orofacial cleft-
ing.18 These findings highlight the (as yet in-
completely understood) role of poor nutrition
in the development of orofacial clefts, and sug-
gest the reason for a link between increased
risk of orofacial clefting and low socioeco-
nomic status and the higher incidence of un-
usual orofacial clefts found in developing
countries.
Maternal corticosteroid use causes a 3.4-fold
increase in orofacial clefting.37 The increase
has been corroborated by other investigators in
nonsyndromic cleft lip–cleft palate.14 Anticon-
vulsants, including phenytoin, oxazolidinedio-
nes, and valproic acid, also cause cleft lip–cleft
palate. Phenytoin causes a nearly 10-fold in-
crease in the incidence of facial clefting11 and
exerts its effect by inhibiting enzymes in the
NADH dehydrogenase electron transport
chain.7 Other pharmacologic agents, including
retinoic acid, have also been implicated in oro-
facial clefting, but the exact mechanism of ac-
tion remains to be determined.18
GENETIC-ENVIRONMENTAL INTERACTIONS
Much of the literature on facial clefting has
examined environmental and genetic factors
in isolation. More recent work indicates that
there is a complex interplay between the
two.10,30 Smoking, for example, is known to
increase the incidence of orofacial clefting;
however, infants with the transforming growth
factor alpha genotype (also previously known
TABLE III
Environmental Causes of Orofacial Clefts*
Teratogen Cleft Type Genetic Link
Alcohol Cleft lip–cleft palate MSX1,TGFb3
Cigarette smoke Cleft lip–cleft palate TGFa
Folic acid Cleft lip–cleft palate TGFa, MTHFR
Steroids Cleft lip–cleft palate TGFb
Anticonvulsants Cleft lip–cleft palate GABA receptor b3
Altitude Cleft lip
TGFa/b, transforming growth factor alpha/beta.
* Adapted fromCarinci, F., Pezzetti, F., Scapoli, L., et al. Recent develop-
ments in orofacial cleft genetics. J. Craniofac. Surg. 14: 130, 2003.
TABLE IV
Genetic Mutations in Holoprosencephaly*
Gene
Chromosome
Map Location Reference
SHH 7q36 60
TGIF 18p11 61
SIX3 2p21 62
ZIC2 13q22 63
PTCH 9q22 64
* Adapted from Cohen, M. M., Jr. Perspectives on craniofacial anomalies,
syndromes, and other disorders. In K. Y. Lin, R. C. Ogle, and J. A. Jane (Eds.),
Craniofacial Surgery: Science and Surgical Techniques. Philadelphia: Saunders, 2002.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 105e
to be associated with orofacial clefting) have a
sixfold increase in orofacial clefting when com-
bined with maternal smoking.38 Maternal ciga-
rette smoking also interacts with an allelic vari-
ation of MSX1 that further increases the
incidence of orofacial clefting.39 Infants with
allelic variants at the MSX1 site born to moth-
ers who have more than four drinks per month
also show a higher incidence of clefting.39
Maternal folic acid deficiency has been asso-
ciated with orofacial clefting.40 This finding
may be explained by a variant in the maternal
5,10-methylene-tetrahydrofolate reductase en-
zyme, making the enzyme less efficient.41 Addi-
tional work suggests that maternal genotype
may also play a role in fetal folate status.42 With
increased understanding about the causes of
cleft lip–cleft palate, it is becoming more ap-
parent that subtle interactions between the en-
vironment and genetic background make in-
fants susceptible to clefting.
UNILATERAL AND BILATERAL CLEFT
LIP–CLEFT PALATE
Clefts of the embryonic primary (cleft lip)
and secondary palate (cleft palate) are over-
whelmingly the most frequently encountered
congenital facial defects, constituting nearly
two-thirds of major facial malformation and
nearly 80 percent of all orofacial cleft types
(Figs. 2 and 3).5,6 Differences in racial suscep-
tibility are well documented and are the result
of racial variations in the timing and coordina-
tion of cellular morphologic patterns, particu-
larly the development of the median nasal pro-
cess. As such, the frequency may range from an
incidence of one in 400 to 500 live births in
Asians and American Indians to one in 1500 to
2000 live births in African Americans. Cauca-
sian susceptibility is intermediate at one in 750
to 900 live births.6,43 The left side of the pri-
mary palate, for reasons as yet unclear (fetal
position and circulatory and neural anatomy
have all been implicated), is more often cleft
than the right.
MEDIAN CLEFT LIP
In contrast to clefts of the lateral lip, median
lip clefts are relatively rare. They are found in
less than one in 100 cases of cleft lip–cleft
palate, with a reported incidence of between
0.43 and 0.73 percent of cleft lip–cleft palate
cases.44,45 Median cleft lips occur in less than
0.0001 percent of all births. Racial and sex
differences have not been established.
Like all cleft lip processes, a graded spec-
trum of deformity occurs and is the result of
failure of the two medial nasal processes to
meet in the midline and fuse. However, me-
dian lip clefting raises concerns about the over-
lying face and brain not seen in the more
common lateral lip clefts. An incomplete me-
dian cleft (vermilion notch) may occur as an
isolated entity (Fig. 5) or as part of such syn-
dromes as orofacial-digital syndrome (Fig. 6),
which represents a spectrum of anomalies of
the face, head, hands, and feet (types I to
VI).46–48 More complete median cleft defects
FIG. 5. Incomplete median cleft lips. (Left) Vermilion notch, presence of central maxillary skeletal diastema, and
double frenulum; (right) wider median cleft lip extending through the alveolus to the palate.
106e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
are syndromic and present as two separate en-
tities: the median cleft lip with hypotelorism
(holoprosencephaly) and median cleft lip with
hypertelorism (median cleft face syndrome).
When medial cleft lip occurs without holo-
prosencephaly, head circumference is within
two standard deviations of the mean and nor-
motelorism is usual.31
Holoprosencephaly (cyclopia-rhinencephaly)
results from deficient anterior neural plate devel-
opment. If the original holospheric telencepha-
lon fails to develop lateral evaginations, the cere-
brum remains singular rather than hemispheric.
Therefore, the prosencephalic cavity remains as a
monoventricle.49 The associated median facial
abnormalities occur because of the sharing of
embryologic cellular tissue (mesenchymal pri-
mordium) and the prechordal mesoderm (me-
soderm between the prosencephalon and stomo-
deum) in conjunction with migrating neural
crest cells.50 The frontonasal prominence of the
prosencephalon then produces the median
craniofacial skeleton (crista galli, ethmoid,
vomer, nasal, and premaxillary bones) and the
cartilaginous septum. The overlying soft tissues
(forehead, nose, and prolabium) likewise arise
from these embryonic tissues. Unlike lateral lip
clefts, which represent a problem ofmerging and
fusion, the holoprosencephalic median lip clefts
are caused by a failure of development. The lat-
eral aspects of the face are produced separately
by the brachial arches and, as a result, are nor-
mal. Although the facies of holoprosencephaly
are different and parallel that of brain develop-
ment (cyclopia, type I; ethmocephaly, type II;
and cebocephaly, type III),51,52 the median cleft
lip with hypotelorism (type IV) is characterized
by absence of the crista galli, nasal and premax-
illary bones, and nasal septum. The hypoplastic
ethmoids accompany but are not the cause of the
orbital hypotelorism, which is primarily a brain
defect (Fig. 7). It is important to note that other
forms of median cleft lip exist that appear very
similar to holoprosencephaly but without cere-
FIG. 6. Median cleft lip in orofacial-digital syndrome,
which is often associated with polylobed tongue, lingual tu-
mors, and absence of central maxillary incisors.
FIG. 7. Holoprosencephalic facies with median cleft lip. (Left) Absence of entire prolabial unit;
(right) absence of complete premaxilla extending up to the crista galli.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 107e
bral involvement, and that have varying degrees
of vomero-septal-prolabial hypoplasia.53 An intact
ethmoid, nasal bone, and crista galli appear to
represent the key anatomical differences in these
patients as compared with classic holoprosen-
cephaly (Fig. 8).
A group of “syndromic”-appearing patients
who have traditionally been assigned a place
on the “normal” end of the holoprosencephaly
spectrum54,55 has recently been described by
Mulliken et al.56 These patients have nasomax-
illary hypoplasia, orbital hypotelorism, and an
associated unilateral and bilateral cleft lip–
cleft palate. Because these patients have nor-
mal head circumference and intelligence, they
cannot belong on a continuum with holo-
prosencephaly.31 To differentiate these pa-
tients from those with holoprosencephaly, au-
thors have historically labeled these patients as
“false” or “pseudomedian” cleft lips. Other au-
thors have denoted this entity as a Binder
anomaly,57 which is associated with chondro-
dysplasia punctata, cervical spine anomalies,
and fetal exposure to warfarin. The patients in
the study by Mulliken et al. did not have any of
these characteristic findings or exposures and
therefore cannot be classified as having Binder
anomalies. Mulliken et al. prefer to refer to
these patients as binderoid.56
The median cleft face syndrome or frontona-
sal dysplasia appears to be the result of incom-
plete midline merging of the facial processes,
with varying degrees of lateralization of their con-
tents. Forebrain morphogenesis is rarely in-
volved, and subsequent brain developmentis
usually normal.58,59 Thus, frontonasal dysplasia is
strikingly different from holoprosencephaly and
presents in its extreme with a median cleft lip
and palate, bifid nose, orbital hypertelorism, in-
feriorly displaced V-shaped frontal hairline, and
cranium bifidum occultum (Fig. 9). Unlike ho-
loprosencephaly, the premaxillary segment is
usually present, although it is clefted and maxil-
lary incisor eruption can be expected.
Mutations in several genes have been linked
to holoprosencephaly. These include sonic
hedgehog (SHH),60 TGIF,61 SIX3,62 ZIC2,63 and
PTCH (Table IV).64 The only comparable ani-
mal model for holoprosencephaly (cyclopia)
occurs in the offspring of sheep that ingest
plant alkaloid.65,66 This finding is unique because
of the specificity and reproducibility of the defect
by this teratogen. Although nonspecific craniofa-
cial malformations, including median cleft lip,
have been produced by numerous other agents
in animals, specific teratogenic sources for me-
dian defects in humans have not been reported.
Alcohol—specifically, fetal alcohol syndrome—
has been associated with midline developmental
defects, including the median facial cleft in rare
cases.67
OBLIQUE FACIAL CLEFTS
The term oblique facial cleft, occurring in a
variety of manifestations from the lip to the
orbit, is a vague designation.1 The cleft has also
been described by other equally nondescript
names, including meloschisis and vertical facial
and orbitofacial clefting. It really represents a
group of lateral midfacial dysplasias that con-
sist of distinct malformations involving differ-
ing points of origin from the lip and superior
extensions into the orbit. These clefts corre-
spond to the Tessier cleft nos. 3, 4, and 5; the
use of this nomenclature is of particular help
in this area (Figs. 2 and 3).2,43 Because of their
rarity (less than 0.25 percent among all facial
clefts) and incomplete case descriptions in the
literature, the actual incidence of these clefts
as a group and individually is not known.43,45,68
All known cases are sporadic, with no syn-
dromic association or sex predilection.
The oblique clefts, as indicated by Tessier
cleft nos. 3 through 5, occur in slightly differ-
ent regions of the lateral midface (cleft nos. 1
and 2 are best described as paramedian or
FIG. 8. Vomero-septal-prolabial hypoplasia can be con-
fused with holoprosencephaly, but there is no upper cranio-
facial involvement.
108e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
vertical facial clefts and are excluded from this
discussion). The most medial variety (cleft no.
3, also known as a naso-ocular or nasomaxillary
cleft) extends from the philtrum of the lip, as
occurs in the more common lateral cleft of the
lip, to the medial canthus of the eye, with
foreshortening of this distance.69 As a result, a
bony cleft occurs at the lateral incisor/canine
area of the alveolus, extending through the
frontal process of the maxilla to the lacrimal
groove of the medial orbit. Soft-tissue defects,
including colobomas of the nasal ala and lower
eyelid and an inferiorly displaced medial can-
thus and globe, are characteristic. Concurrent
absence or dysfunction of the nasolacrimal sys-
tem is predictably high (Fig. 10). More later-
ally, the cleft no. 4 (also known as an oro-
ocular cleft) spares the nose and extends
toward a more centric orbital position.70 The
lip origin of this cleft deviates from common
lip clefts and does not violate the philtral ridge.
At a point between the philtrum and commis-
sure, the cleft extends superiorly through the
nasolabial fold and passes into the orbit just
medial to the infraorbital foramen (Fig. 11). As
such, the medial canthal tendon and nasolac-
rimal duct are usually intact. However, a
marked coloboma of the lower eyelid is
present, and in some cases, varying degrees of
anophthalmos are present. The no. 5 cleft is
primarily distinguished from the more medi-
ally positioned cleft no. 4 by passing lateral to
the infraorbital foramen (Fig. 12). This skeletal
pathway difference has long been recognized
and has historically (pre-Tessier) been subdi-
vided into type I (no. 4) and type II (no. 5)
forms of oro-ocular clefting.71 The lateraliza-
tion of this cleft is also distinctly different at the
alveolar level by originating posterior to the
canine. The ocular findings, however, includ-
ing a severe lower eyelid coloboma, inferior
displacement, and partial prolapse of the or-
bital contents into the sinus and anophthal-
mos, are not unlike findings in a no. 4 cleft.
FIG. 10. Tessier no. 3 orofacial cleft. The lip has been
previously repaired.
FIG. 9. Two patients exhibiting differing degrees of expression of the median cleft
face syndrome. (Left) Incomplete median lip cleft with moderate widening of the
interorbital distance and nose. (Right) Increased severity with marked lateralization of
orbits and nose that has previously undergone primary lip repair.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 109e
The embryology of the oblique facial clefts is
difficult to explain by the known facial processes
of merging and fusion. The no. 3 cleft occurs
along the naso-optic groove, formed by the con-
fluence of the lateral aspects of the olfactory
placode and frontonasal process and the medial
edge of the maxillary process, and as such the
associated abnormalities are completely predict-
able. Cleft nos. 4 and 5, however, correspond to
no known embryologic grooves or plane of mes-
enchymally supported epithelium, and their ori-
gin currently remains speculative. The cause of
these clefts has loosely been ascribed to a primary
arrest of development, neurovascular insuffi-
ciency or necrosis, or a result of tears in the
developing maxillary process.72,73 This embryo-
logic mystery has defied explanation because an
experimental oblique cleft model has only been
produced inconsistently by maternal hypervita-
minosis A and salicylate intoxication.52 More re-
cent experimental work suggests that these mal-
formations are caused by a combination of
directly tethered tissue migration (such as from
amniotic bands) and increased local pressure
that produces cellular ischemia.74 As a result,
such clefting may occur later in fetal develop-
ment rather than during primary facial
morphogenesis.
LATERAL FACIAL CLEFTS
Lateral facial clefts, or commissural clefts,
are best thought of as a variable finding within
the broader congenital condition of hemifacial
microsomia (Tessier cleft no. 7). They are the
second most common orofacial cleft (second
to the common cleft lip), with an incidence less
than that of hemifacial microsomia (one in
3500 to 5000 live births) because of an incon-
sistent occurrence within the syndrome.75 Al-
though commissure clefts are not seen in every
case of hemifacial microsomia, their occur-
rence should initiate a search for involvement
of the ipsilateral ear, mandible, and facial
nerve and overlying facial soft-tissue deficien-
cies. These clefts also occur in the oculoauricu-
lovertebral spectrum (historically referred to as
Goldenhar syndrome), which has the addi-
tional features of epibulbar dermoids, verte-
bral anomalies, and central nervous system and
cardiopulmonary defects.76
The clinical findings of the lateral oral cleft
variably extend along a line from the commis-
sure to the tragus. Most commonly, a 1- to
3-cm-long cleft is present, with disruption of
the orbicularis and buccinator muscles and
with the cleft edges lined by vermilion.75 Only
rarely does a complete cleft extend posterior to
or beyond the anterior border of the masseter
muscle, although a groove or skin depression
continuing along the cleft line to the ear may
occasionally be seen (Fig. 13). Because of the
association between lateral oral clefts and
hemifacial microsomia, underlying deformities
of the mandibleare well appreciated. Less ap-
preciated but equally common, particularly in
severe expressions of the syndrome, is the zy-
gomatico-orbital dysplasia, marked by a disrup-
tion of the zygomatic arch and inferior dis-
placement of the lateral canthus caused by
variable amounts of accompanying zygomatic
hypoplasia and resultant orbital dystopia.
Lateral facial clefts are easy to understand
embryologically, as the commissure represents
the most anterior point of mesodermal merg-
FIG. 11. Tessier no. 4 orofacial cleft.
FIG. 12. Bilateral incomplete Tessier no. 5 clefts.
110e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
ing of the maxillary and mandibular processes.
Should the fusion process remain incomplete,
a variable spectrum from furrowing of the tis-
sues to complete anatomical separation per-
sists. The pathogenesis of the lateral facial cleft
appears to be heterogeneous. A vascular cause,
attributable to embryonic hematoma forma-
tion from disruption of the stapedial artery
stem, is one proposed mechanism.77 The sever-
ity of the condition subsequently depends on
the size of the hematoma and its time course of
resolution as brachial arch development oc-
curs.78 The cause of this embryonic hemor-
rhage has been speculated to range from vas-
cular flow anomalies, such as hypertension and
hypoxia, to pharmacologic agents, such as sa-
licylates and anticonvulsants.79 Intrauterine
compression secondary to oligohydramnios in
the embryonic head region has also been sug-
gested and may account for some cases of
hemifacial microsomia that occur with other
anomalies, such as limb reduction defects.80
MEDIAN MANDIBULAR CLEFTS
Clefting of the lower face (Tessier cleft no. 30)
(Fig. 1) almost universally occurs through the
midline of the lip and mandible. Although para-
median lower lip/mandibular clefting has been
reported, there are fewer than 70 reported cases
in the literature, appearing with less frequency
than the oblique facial clefts.11,81,82 Sex and racial
predilections remain indeterminate.
A range of inferior clefting has been reported
that extends from mild notching of the lower lip
and mandibular alveolus (Fig. 14) to complete
cleavage of themandible, extending into inferior
neck structures.81–85 Tongue involvement is typi-
cal though variable in expression, ranging from a
bifid anterior tip with ankyloglossia to the bony
cleft margins, to marked lingual hypoplasia. In-
ferior cervical defects (midline separation, hyp-
oplasia, and agenesis) of the epiglottis, strapmus-
cles, hyoid bone, thyroid cartilage, and sternum
may also be present, particularly when the cuta-
FIG. 13. Tessier no. 7 (commissure) clefts. (Above, left) Left-sided hemifacial microsomia with commissural cleft.
(Below, left) Right-sided hemifacial microsomia with commissural cleft extending to the anterior border of the
masseter. (Right) Bilateral commissural clefts without hemifacial microsomia.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 111e
neous cleft passes caudal to the gnathion point
on the chin.
The embryologic basis of median mandibu-
lar clefts lies in the failure of coaptation of the
free ends of the first visceral arches in the
midline. Once the arches are formed through
neural crest cell migration, vascularization,
and mesodermal myoblastic ingrowth, growth
centers are organized at their tips that are re-
sponsible for closing the final gap and coalesc-
ing the two sides.8 As the incisor teeth are
frequently missing along the medial mandibu-
lar margins, this suggests that partial or com-
plete failure of growth center differentiation
and development is responsible for such de-
fects rather than a simple merging and contact
maintenance. Because no animal models exist
for study of the median cleft lip, the cellular
basis for this defect may remain unknown for
some time. Presumably, however, more infe-
rior cervical defects would be caused by similar
mechanisms in the second and third visceral
arches. The occasional association of a supe-
rior midline defect (cleft palate) with a median
mandibular cleft is interesting because it sug-
gests that a broader defect in epithelial mesen-
chymal merging and fusion is occurring or that
the tongue abnormality affects palatal shelf clo-
sure in utero in these patients.86,87
SUMMARY
This review of orofacial malformations de-
scribes clefting anomalies that emanate from
the mouth and lips—the most common cleft
structure of the face. Some of these clefts are
relatively common, including the typical cleft
lip with or without cleft palate; others are ex-
tremely rare. As the causes of orofacial clefts
are better understood, it is becoming clear that
a complex interplay between genetic and envi-
ronmental variables causes these clefts. Future
study of orofacial clefts will require increas-
ingly sophisticated methods of elucidating
these subtle interactions. Orofacial clefts are of
particular relevance to plastic surgeons, who
set the world’s standard for care and recon-
struction of such facial congenital deformities.
Barry L. Eppley, M.D., D.M.D.
Division of Plastic Surgery
CranioFacial Program
Indiana University School of Medicine
702 Barnhill Drive, Suite 3540
Indianapolis, Ind. 46202
beppley@iupui.edu
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