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The Spectrum of Orofacial Clefting
The Spectrum of Orofacial Clefting
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.
FIG. 3. (Right) Incomplete bilateral cleft lip and (left) complete bilateral cleft lip– cleft palate.
malformations was 4.25 percent.5 With the re- cellular deficiency or failure of contact main-
markable improvements in perinatal care and tenance in one or several components of this
prenatal medical technology, it seems likely six-piece midfacial convergence results in the
that more of these fetuses will survive to term variations in clinical presentations that are
and require treatment. In a recent population- commonly seen (Figs. 2 and 3). Simonart’s
based sample from California, the birth preva- band, which can be seen at the posterosuperior
lence of all orofacial clefts was 0.17 percent, aspect of some lip clefts (Fig. 4, left), may well
with isolated clefting constituting roughly two- illustrate a rupture of contact (lack of contact
thirds of these patients; the remainder were a maintenance) rather than failure to make con-
mixture of sequences, chromosomal aberra- tact between the processes and may be the
tions, associations, and unknown causes.6 An primary developmental problem in many
increased awareness and understanding of clefts.7 This residual fibrous band is found in
these unique facial clefting anomalies is partic- the approximate location of the embryonic
ularly pertinent to the plastic surgeon. union of the maxillary and median nasal pro-
cesses that constitute the primary palate and is
often associated with a narrower cleft defect
EMBRYOLOGY than those clefts in which it is not found. Var-
Virtually all cases of cleft lip– cleft palate are ious other webs or synechiae can occasionally
attributable to the failure of the medial nasal be seen attached to the cleft, indicating inad-
process to either contact or maintain contact vertent adhesion of structures from surround-
with the lateral nasal and maxillary processes.7 ing facial processes (Fig. 4, right).
The embryologic pattern of neural crest cell In addition to the importance of merging
migration and subsequent merging is now ap- and fusion, the size of the facial processes af-
preciated to be a complex interplay of move- fects facial morphology and cleft susceptibility.
ments initiated when the inferior edge of the An inherently smaller median nasal process, as
medial nasal process joins the maxillary pro- would be suspected in Asians because of their
cess at approximately day 30 in the human smaller midfaces, tendency for class III occlusal
embryo. A significant morphogenetic move- relationships, and flatter nasal structures, may
ment of the nasal placode (rotation and ad- partially account for their relatively high rates
vancement) then permits its lateral nasal pro- of clefting. Conversely, some African Ameri-
cess to sweep over the maxillary process a few cans have broad, larger noses, increased facial
days later to join with the medial nasal process widths, and a tendency for maxillary dentoal-
to collectively form the upper lip-nasal unit.8 A veolar protrusion, all of which indicate the
104e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
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 II
presence of well-developed median nasal pro- Genetic Links to Nonsyndromic Orofacial Clefts*
cesses and a decreased clefting frequency.
The cause of cleft lip– cleft palate is complex
Gene Locus
and multifactorial, involving both genetic and
environmental factors (Tables I through SKI/MTHFR 1p36
TGFb2 1q41
IV).9,10 Transmission of the cleft phenotype in a TGFa 2p13
simple mendelian fashion, as is seen in many MSX1 4p16, 1q31, 6p23
other hereditary disorders, rarely occurs. This PVRL1 11q23
TGFb3 14q24
is supported by studies of cleft monozygotic GABRb3 15q11
twins that show a 30 to 60 percent concordance RARa 17q21
rate.9,11 When compared with the 1.0 to 4.7 BCL3 19q13
percent concordance rate for dizygotic twins, * Adapted from Murray, J. C. Gene/environment causes of cleft lip and/or
palate. Clin. Genet. 61: 250, 2002.
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 defect is 9 percent.12 In addition to genetics,
lip– cleft palate child, the chance that a second environmental factors (Table III), such as
child will be born with a similar defect is 3 to 4 smoke exposure and use of steroids, phenyt-
percent; if two children have the defect, the oin, and retinoids, have also been implicated
chance of a third child being born with the in the development of cleft lip– cleft palate.13–20
More recently, a complex interplay between
TABLE I genetic and environmental factors has been
Genetic Links to Syndromic Orofacial Clefts* unfolding.
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.
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 107e
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 of merging and
fusion, the holoprosencephalic median lip clefts
are caused by a failure of development. The lat-
FIG. 6. Median cleft lip in orofacial-digital syndrome, eral aspects of the face are produced separately
which is often associated with polylobed tongue, lingual tu- by the brachial arches and, as a result, are nor-
mors, and absence of central maxillary incisors.
mal. Although the facies of holoprosencephaly
are syndromic and present as two separate en- are different and parallel that of brain develop-
tities: the median cleft lip with hypotelorism ment (cyclopia, type I; ethmocephaly, type II;
(holoprosencephaly) and median cleft lip with and cebocephaly, type III),51,52 the median cleft
hypertelorism (median cleft face syndrome). lip with hypotelorism (type IV) is characterized
When medial cleft lip occurs without holo- by absence of the crista galli, nasal and premax-
prosencephaly, head circumference is within illary bones, and nasal septum. The hypoplastic
two standard deviations of the mean and nor- ethmoids accompany but are not the cause of the
motelorism is usual.31 orbital hypotelorism, which is primarily a brain
Holoprosencephaly (cyclopia-rhinencephaly) defect (Fig. 7). It is important to note that other
results from deficient anterior neural plate devel- forms of median cleft lip exist that appear very
opment. If the original holospheric telencepha- similar to holoprosencephaly but without cere-
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.
108e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005
bral involvement, and that have varying degrees plete midline merging of the facial processes,
of vomero-septal-prolabial hypoplasia.53 An intact with varying degrees of lateralization of their con-
ethmoid, nasal bone, and crista galli appear to tents. Forebrain morphogenesis is rarely in-
represent the key anatomical differences in these volved, and subsequent brain development is
patients as compared with classic holoprosen- usually normal.58,59 Thus, frontonasal dysplasia is
cephaly (Fig. 8). strikingly different from holoprosencephaly and
A group of “syndromic”-appearing patients presents in its extreme with a median cleft lip
who have traditionally been assigned a place and palate, bifid nose, orbital hypertelorism, in-
on the “normal” end of the holoprosencephaly feriorly displaced V-shaped frontal hairline, and
spectrum54,55 has recently been described by cranium bifidum occultum (Fig. 9). Unlike ho-
Mulliken et al.56 These patients have nasomax- loprosencephaly, the premaxillary segment is
illary hypoplasia, orbital hypotelorism, and an usually present, although it is clefted and maxil-
associated unilateral and bilateral cleft lip– lary incisor eruption can be expected.
cleft palate. Because these patients have nor- Mutations in several genes have been linked
mal head circumference and intelligence, they to holoprosencephaly. These include sonic
cannot belong on a continuum with holo- hedgehog (SHH),60 TGIF,61 SIX3,62 ZIC2,63 and
prosencephaly.31 To differentiate these pa- PTCH (Table IV).64 The only comparable ani-
tients from those with holoprosencephaly, au- mal model for holoprosencephaly (cyclopia)
thors have historically labeled these patients as occurs in the offspring of sheep that ingest
“false” or “pseudomedian” cleft lips. Other au- plant alkaloid.65,66 This finding is unique because
thors have denoted this entity as a Binder of the specificity and reproducibility of the defect
anomaly,57 which is associated with chondro- by this teratogen. Although nonspecific craniofa-
dysplasia punctata, cervical spine anomalies, cial malformations, including median cleft lip,
and fetal exposure to warfarin. The patients in have been produced by numerous other agents
the study by Mulliken et al. did not have any of in animals, specific teratogenic sources for me-
these characteristic findings or exposures and dian defects in humans have not been reported.
therefore cannot be classified as having Binder Alcohol—specifically, fetal alcohol syndrome—
anomalies. Mulliken et al. prefer to refer to has been associated with midline developmental
these patients as binderoid.56 defects, including the median facial cleft in rare
The median cleft face syndrome or frontona- cases.67
sal dysplasia appears to be the result of incom-
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
FIG. 8. Vomero-septal-prolabial hypoplasia can be con- cleft nos. 3 through 5, occur in slightly differ-
fused with holoprosencephaly, but there is no upper cranio- ent regions of the lateral midface (cleft nos. 1
facial involvement. and 2 are best described as paramedian or
Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 109e
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.
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.