Chapter 13
Cleft Lip and Palate
BRAD ANGLE

INTRODUCTION
Orofacial clefts (cleft lip [CL], cleft palate [CP])
are among the most common of all major birth
defects. CL may occur either in association with
CP or in the absence of CP, and is generally re-
ferred to as “cleft lip with or without cleft palate”
(CL/P). CL/P is etiologically and genetically dis-
tinct from CP, which typically occurs without as-
sociated CL. CL/P and CP may occur as isolated
congenital anomalies (nonsyndromic orofacial
clefts) or as components of genetic disorders or
syndromes.

EPIDEMIOLOGY/ETIOLOGY
The overall incidence of CL with or without cleft
palate is approximately 1/1000, ranging from
1/500 to 1/2500 in different populations, vary-
ing with geographic location, ethnic group, and
socioeconomic conditions.1 CL may be unilat-
eral (80%) or bilateral (20%) and when unilat-
eral, it is more common on the left side (70%).
Approximately 85% of cases of bilateral CL and
70% of unilateral CL are associated with CP. The
incidence of isolated CP is approximately 1 in
25002 and Robin sequence occurs in approxi-
mately 1 in 14,000 live births.3
Both genetic and environmental factors are
thought to play important roles in the causation
93
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of orofacial clefts (multifactorial inheritance). It
is likely that there are multiple genes that may
play a role in cleft malformations. In addition to
single gene disorders that cause syndromic
forms of orofacial clefts, it has been estimated
that at least six genes, and possibly many more,
could be involved in the development of non-
syndromic orofacial clefts.4,5 It has been sug-
gested that causation does not involve “major
genes” but rather the combination of many genes,
each conferring only a small risk, in conjunction
with a significant environmental component.6
Results of a number of studies suggest that in-
volvement of the pathways of folate metabolism
may play a role in the etiology of orofacial clefts.5
Some studies have suggested that women with a
specific mutation (C677T) in the methylenete-
trahydrofolate reductase (MTHFR) gene have an
increased risk of having an offspring with an
orofacial cleft.7,8
Many epidemiological studies have demon-
strated a relation between specific environmen-
tal factors and teratogens and the development
of orofacial clefts. Environmental factors such as
cigarette smoking appear to play a role in the
occurrence of these malformations.5 Alcohol use
in pregnancy increases the risk of CL/P but not
CP only.9 The anticonvulsants phenytoin and
valproic acid are associated with an increased
risk for a variety of congenital anomalies includ-
ing orofacial clefts.10 It is unclear whether CP
94 PART III CRANIOFACIAL MALFORMATIONS
occurring in association with CL results from me-
chanical deformation or from genes or environ-
mental factors that affect development of both
the lip and palate.

EMBRYOLOGY
Between the fourth and eighth week of embry-
ologic development, the upper lip and palate
form from the migration and connection of three
bilateral processes (nasomedial, nasolateral, max-
illary) derived from cells of neural crest origin.
Clefting occurs when there is failure of fusion or
diminished mesenchymal penetration between
these migrating embryological processes.
The embryology of CL and CP is for the most
part distinct. CL is a unilateral or bilateral gap in
the upper lip and jaw, which form during the
third through seventh week of embryonic de-
velopment. CP is a gap in the hard or soft palate,
which forms from the 5th through 12th weeks
of development. CP may result from defective
growth of the palatine shelves or failure of ele-
vation or fusion of the shelves. In some cases,
hypoplasia of the mandibular area prior to 9 weeks
of development may allow the tongue to be
posteriorly located, impairing the closure of the
posterior palatal shelves and resulting in the
formation of a U-shaped CP (Robin sequence—
see later).

ASSOCIATED ANOMALIES AND
SYNDROMES
Cleft Lip with or without
Cleft Palate
Approximately 70% of cases of CL with or with-
out CP occur as isolated abnormalities (nonsyn-
dromic CL/P) and 30% as part of more than
300 multiple malformation syndromes, chromo-
some abnormalities, teratogenic conditions, and
inherited single-gene disorders.3 Some of the
more common genetic disorders and syndromes

TABLE 13-1 Genetic Disorders Associated
with Cleft Lip with or without Cleft Palate
Amnion rupture sequence
Crouzon syndrome
Deletion 4p syndrome
Ectrodactyly-ectodermal dysplasia (EEC)
syndrome
Fetal alcohol syndrome
Fetal hydantoin syndrome
Fetal valproate syndrome
Fryns syndrome
Hay-Wells ectodermal dysplasia
Oral-facial-digital syndrome
Trisomy 13
Van der Woude syndrome
in which CL/P frequently occur are listed in
Table 13-1.
Among the most common single-gene dis-
orders associated with CL/P, Van der Woude
syndrome (VWS) is an autosomal dominant dis-
order caused by mutations in the IRFG gene. In-
dividuals with VWS have congenital lower lip
fistulae (pits) or sometimes small mounds (usu-
ally bilateral), CL, or CP, each alone or in any
combination of the three anomalies (Fig. 13-1).
Orofacial clefts are a frequent occurrence in
a number of ectodermal dysplasia syndromes.
Figure 13-1. Pits in lower lip of individual with
Van der Woude syndrome. (Used with permis-
sion from Dr. Jeffrey Murray, University of Iowa.)

These disorders involve abnormalities of the
hair, teeth, and skin. Some ectodermal dys-
plasias also are associated with congenital limb
anomalies involving absence of fingers or toes
(ectrodactyly/split hands and feet). Mutations
in the TP63 gene cause the ectrodactyly, ecto-
dermal dysplasia, and cleft lip/palate (EEC)
syndrome and Hay-Wells anklyoblepharon-
ectodermal dysplasia–clefting (AEC) syndrome.
CL with or without palate may occur in a vari-
ety of chromosome abnormalities, particularly in
association with partial deletion of the short arm
of chromosome 4. Deletion 4p syndrome (4p- or
Wolf-Hirschhorn syndrome) is characterized by
ocular hypertelorism, broad or beaked nose, mi-
crocephaly, low-set ears, and CL and/or CP.
While the vast majority of CL malformations
are lateral clefts, median or midline clefts (through
the center of the upper lip) are very rare and rep-
resent approximately 0.5% of all CL defects. Me-
dian CL may occur as an isolated anomaly or as
part of a number of malformation syndromes.
The most common disorders associated with a
median CL are holoprosencephaly, Trisomy 13,
and oral-facial-digital (OFD) syndrome.
Holoprosencephaly is a malformation in
which impaired cleavage of the embryonic fore-
brain is the major feature. Typical craniofacial
features include hypertelorism, various degrees
of abnormal nasal development, and occasional
median CL. Infants with Trisomy 13 may have
holoprosencephaly and/or median CL.
Oral-Facial-Digital type 1 syndrome is an
X-linked dominant disorder affecting mainly
females, which is characterized by multiple
frenuli between the buccal mucous membrane
and alveolar ridge, median CL and/or CP, lobu-
lated or bifid tongue, and a variety of digital
anomalies including asymmetric digits, syn-
dactyly, and polydactyly.
As previously mentioned, a number of ter-
atogens may cause CL/P including alcohol,
phenytoin, and valproic acid. Each of these
teratogens is associated with characteristic
craniofacial features and a variety of congeni-
tal anomalies most commonly including digital
CHAPTER 13 CLEFT LIP AND PALATE 95

TABLE 13-2 Genetic Disorders Associated
with Cleft Palate
22q11.2 deletion syndrome and other
chromosome abnormalities
Fetal alcohol syndrome
Hay-Wells ectodermal dysplasia
Kniest dysplasia
Oto-Palato-digital syndrome
Robin sequence
Spondyloepiphyseal dysplasia congenita
Stickler syndrome
Treacher Collins syndrome
Van der Woude syndrome
abnormalities, congenital heart defects, and gen-
itourinary anomalies.
Cleft Palate
Approximately 15–50% of infants with CP without
CL have additional congenital abnormalities and
there are a number of specific genetic disorders
in which CP is a frequent finding (Table 13-2).
One of the disorders most frequently associ-
ated with CP is the 22q11.2 deletion syndrome.
This syndrome is caused by a submicroscopic
deletion of chromosome 22 detected by fluo-
rescence in situ hybridization (FISH). With an
incidence of 1/4000, 22q11.2 deletion syndrome
is the most common chromosome microdele-
tion syndrome and one of the most common of
all recognized genetic disorders. The most fre-
quently observed features of this disorder in-
clude congenital heart defects, particularly
conotruncal defects (tetralogy of Fallot, inter-
rupted aortic arch, ventricular septal defect),
palatal abnormalities (CP, abnormal velopha-
ryngeal musculature and function), hypocal-
cemia, immune deficiency, and characteristic fa-
cial features (Table 13-3).
The 22q11.2 deletion syndrome includes the
phenotypes previously described as DiGeorge
syndrome (heart defects, hypocalcemia, absent
or hypoplastic thymus) and velocardiofacial
96 PART III CRANIOFACIAL MALFORMATIONS

TABLE 13-3 Clinical Features of 22q11.2 Deletion Syndrome
Findings
Congenital heart defects (total)
Tetralogy of Fallot
Interrupted aortic arch
Ventricular septal defect
Truncus arteriosus
Other
Palatal abnormalities (total)
Overt cleft palate
Other
Immune defects
Hypocalcemia
Renal anomalies
Characteristic facial features
Minor ear anomalies
Prominent nose
Narrow palpebral fissures
Retruded mandible
Flattened malar area
Slender fingers
Feeding problems
Learning problems
syndrome (VCFS). More than 95% of individuals
with typical clinical features of 22q11.2 deletion
will have detectable deletions by FISH testing.
A small number of individuals with the 22q11.2
phenotype have a deletion of chromosome 10p13.
The 22q11.2 deletion syndrome is inherited in
an autosomal dominant fashion. Approximately
90% of affected individuals have a de novo (new)
deletion and 10% have an inherited deletion from
a parent. Offspring of affected individuals have a
50% chance of inheriting the deletion.
The combination of CP (frequently U-shaped),
micrognathia (small mandible), and glossopto-
sis (tongue retroposition into the pharyngeal
airway resulting in variable degrees of obstruc-
tion and respiratory distress) was first described
by Pierre Robin in 192311 and is referred to as
Pierre Robin syndrome or Robin sequence.
While the classic definition of Robin sequence
requires the presence of all three findings, var-
ious authors have advocated other definitions
% Affected
74%
22%
15%
13%
7%
17%
69%
11%
58%
77%
50%
37%
Majority
63%
30%
90%
allowing for the presence of only two findings,
most commonly micrognathia and CP without
glossoptosis.12
Robin sequence often occurs as an isolated
condition in otherwise normal individuals, but it
may also occur with additional nonspecific con-
genital anomalies or as one feature in more than
40 genetic disorders.13 In one study, Robin se-
quence occurred as an isolated finding in 48% of
cases, with additional anomalies in 17% of cases,
and as part of an identifiable syndrome in 35%
of cases.14 The most common genetic disorders
associated with Robin sequence are 22q11.2
deletion syndrome, Stickler syndrome, and
Treacher Collins syndrome (see Micrognathia).
Stickler syndrome is an autosomal dominant
connective tissue disorder caused by mutations in
one of the three collagen genes (COL2A1,
COL11A1, and COL11A2). The most common
features include ocular findings (myopia, cataract,
retinal detachment), hearing loss (conductive and
 CHAPTER 13 CLEFT LIP AND PALATE 97

sensorineural), midfacial underdevelopment, and
CP or Robin sequence. A mild spondyloepiphy-
seal dysplasia or early arthritis may develop dur-
ing later childhood and adulthood.
CP may be a finding in a number of skeletal
dysplasias and conditions with digital anomalies.
Spondyloepiphyseal dysplasia congenita and
Kniest dysplasia are autosomal dominant skele-
tal disorders characterized by disproportionate
short stature with vertebral and long bone ab-
normalities and variable non-skeletal anomalies
including CP. Oto-Palatal-Digital syndrome is an
X-linked disorder associated with deafness, broad
distal digits with short nails, and CP.

EVALUATION
The evaluation of an infant with an orofacial cleft
requires a detailed family and prenatal history and
physical examination. A family history of orofacial
clefts and/or lip pits may suggest the possibility of
a heritable form of clefting such as Van der Woude
syndrome. A prenatal history of maternal alcohol
use or treatment with anticonvulsant medications
should prompt an evaluation for other anomalies
associated with exposure to these teratogens.
An approach to the evaluation of CL/P is il-
lustrated in Fig. 13-2. In the cases of apparent
isolated CL/P without other anomalies, dysmor-
phic features, or known teratogenic exposures,
no additional evaluation or testing may be indi-
cated. Chromosome analysis should be obtained
in any infant with additional congenital anom-
alies or dysmorphic features. Evaluation for spe-
cific syndromes associated with CL/P should be
pursued based upon the clinical findings.
The general approach to the evaluation of an
infant with CP is similar to that of an infant with
CL/P with some additional considerations (Fig.
13-3). Due to the frequency and phenotypic vari-
ability of 22q11.2 deletion syndrome, FISH test-
ing should be considered in any infant with a CP,
including an infant with an isolated CP.

CL/P

Lip Pits or Family History of No Other Anomalies or Other Anomalies and/or

Pits and CL Dysmorphic Features Dysmorphic Features

Van der Woude Syndrome Isolated CL/P Obtain Chromosome Analysis

Abnormal Karyotype Normal Karyotype

Trisomy 13 Evaluate for

Deletion 4p Syndrome Specific Syndromes
Other Chromosome Based Upon Clinical
Abnormalities Findings

Figure 13-2. Algorithm for evaluation of an infant with cleft lip with or without cleft palate.
98 PART III CRANIOFACIAL MALFORMATIONS

CP

No Other Anomalies Isolated Robin Sequence CP or Robin Sequence +

Other Anomalies

Fish for 22q11.2 Deletion Fish for 22q11.2 Deletion Chromosome Analysis
Fish for 22q11.2 Deletion

Normal Abnormal Normal Abnormal: Normal:

22q.11 Deletion Evaluate
Other Chromosome for Other
Abnormalities Syndromes
Isolated 22q11.2 Deletion Eye Exam
CP Hearing Screen

Abnormal: Normal:
Stickler Syndrome Isolated CP

Figure 13-3. Algorithm for evaluation for an infant with cleft palate.

The diagnosis of 22q11.2 deletion should be
particularly considered in infants with a CP and a
congenital heart defect (with or without hypocal-
cemia), and in infants with Robin sequence. All in-
fants with a confirmed diagnosis of 22q11.2 dele-
tion should have particular baseline diagnostic
tests and evaluations (Table 13-4) and long-term
multidisciplinary follow-up. Any infant with Robin
sequence in which 22q11.2 deletion syndrome has
been excluded should have a baseline ophthal-
mology exam and hearing screening to evaluate
for abnormalities associated with Stickler syn-
drome. Molecular testing is available for confir-
mation of a suspected diagnosis.

MANAGEMENT AND PROGNOSIS

TABLE 13-4 Evaluation of Infant with
22q11.2 Deletion Syndrome
Echocardiogram
Renal ultrasound
Calcium level
Immunology evaluation including quantitative
and qualitative T and B cell studies
Hearing screening
Feeding evaluation if cleft present or
symptoms of feeding problems
Evaluation for early intervention services
during first few months of life
formed at 8–12 months of age. Infants with CP are
at risk for recurrent otitis media and conductive
hearing loss and should be monitored accordingly.

The clinical management of orofacial clefts re- GENETIC COUNSELING

quires a multidisciplinary approach involving cran-
iofacial surgeons, dentists, orthodontists, speech
therapists, otolaryngologists and clinical geneticists.
Surgical repair of CL is usually performed at 2–3
months of age while repair of CP is typically per-
Susceptibility to nonsyndromic CL/P and CP
likely involves a combination of many genes
and environmental components. Relatives of pa-
tients with nonsyndromic CL/P and CP are at an
increased risk of recurrence with the risk (in


TABLE 13-5 Recurrence Risks for Nonsyndromic Cleft Lip and Cleft Palate
Cleft Lip with or without Cleft Palate
Relationship to Index Case
Sibs (overall risk)
Bilateral cleft lip and palate
Unilateral cleft lip and palate
Unilateral cleft lip alone
Children
Second-degree relatives
Third-degree relatives
General population
cases of CL/P) declining as the degree of rela-
tionship decreases (Table 13-5). In addition, the
recurrence risk of CL/P varies based upon the
severity of the defect, with the greatest risk oc-
curring when the abnormality is bilateral with
CP and lower when there is only CL (Table 13-
5). Recurrence risks for syndromic forms of CL
and CP are based upon the inheritance pattern of
the specific disorder. Parental FISH testing should
be offered for any infant diagnosed with 22q11.2
deletion syndrome to identify a potentially mildly
affected and previously undiagnosed parent.
The use of multivitamins with folic acid is
currently recommended for all women of re-
productive age to reduce the risk of neural tube
defects in offspring and there is now evidence
from some studies that women taking multivit-
amins containing folic acid in early pregnancy
may also be at lower risk of having children
with orofacial clefts.5 However, other studies
have found no evidence that folic acid is in-
volved in preventing orofacial clefts, and the is-
sue remains unresolved.6
REFERENCES
1. Bender PL. Genetics of cleft lip and palate. J Pedi-
atr Nurs. 2000;15:242–9.
2. Natsume N, Kawai T, Kohama G, et al. Incidence
of cleft lip or palate in 30,338 Japanese babies born
between 1994 and 1995. Br J Oral Maxillfac Surg.
2000;38:605–7.
3. Printzlau A, Andersen M. Pierre-Robin sequence
in Denmark: a retrospective population-based
CHAPTER 13 CLEFT LIP AND PALATE 99
Isolated Cleft Palate
(%) (%)
4.0 1.8
5.7
4.2
2.5
4.3 3
0.6
0.3
0.1 0.04
epidemiological study. Cleft Palate Craniofac
J. 2004;41:47–52.
4. Farrell M, Holder S. Familial recurrence-pattern
analysis of cleft lip with or without cleft palate.
Am J Med Genet. 1992;50:270–7.
5. Carinci F, Pezzetti F, Scapoli L, et al. Recent devel-
opments in orofacial cleft genetics. J Craniofac
Surg. 2003;14:130–43.
6. Spritz R. The genetics and epigenetics of orofacial
clefts. Curr Opin Pediatr. 2001;13:556–60.
7. Mills JL, Kirke PN, Molloy AM, et al. Methylenete-
trahydrofolate reductase thermolabile variant and
oral clefts. AM J Med Genet. 1999;86:71–4.
8. Martinelli M, Scapoli L, Pezzetti F, et al. C677T vari-
ant form at the MTHFR gene and CL/P: a risk fac-
tors for mothers? Am J Med Genet. 2001;98:357–60.
9. Munger RG, Romitti PA, Daack-Hirsch S, et al. Ma-
ternal alcohol use and risk of orofacial cleft birth
defects. Teratology. 1996;54:2–33.
10. Azarbayjani F, Danielsson BR. Phenytoin-induced
cleft palate: evidence for embryonic cardiac brad-
yarrhythmia due to inhibition of delayed rectifier
K+ channels resulting in hypoxia-reoxygenation
damage. Teratology. 2001;63:152–60.
11. Robin P. La chute de la base de la langue consid-
érée comme une nouvelle cause de gene dans la
respiration naso-pharyngienne. Bull Acad Natl
Med. 1923;89:37–41.
12. Cohen MM. Craniofacial disorders. In: Rimoin DL,
Connor JM, Pyeritz RE, et al., eds. Principles and
Practice of Medical Genetics. 4th ed. New York,
Churchill Livingstone; 2002:3714.
13. Cohen MM. The Child with Multiple Birth Defects.
New York, Oxford University Press; 1997.
14. Holder-Espinasse M, Abadie V, Cormier-Daire V, et
al. Pierre Robin sequence: a series of 117 consecu-
tive cases. J Pediatr. 2001;139:588–90.
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