180 Cleft lip and/or palate (CL/CP) is the most common cranio- facial malformation with an estimated incidence of approxi- mately 1 in 700 to 1 in 1000 live births among Caucasians.
CL/CP may occur as an isolated finding or may be found in association with other congenital malformations.
GENETICS/BASIC DEFECTS
1. Environmental agents a. Cleft lip and cleft palate
i. Alcohol
ii. Anticonvulsants (phenytoin, sodium valproate) iii. Isotretinoin
iv. Steroids v. Methotrexate
vi. Maternal infections in the first trimester a) Rubella
b) Toxoplasmosis vii. Maternal smoking b. Isolated clefts
i. Little evidence linking to any single teratogenic agent, except anticonvulsant phenytoin
ii. Use of phenytoin during pregnancy is associated with a tenfold increase in the incidence of cleft lip c. Cleft lip: incidence of cleft lip in infants in mothers who smoke during pregnancy is twice that of those born to nonsmoking mothers
2. Genetic factors
a. Syndromic clefts associated with malformations involving other developmental regions
i. About 25% of neonates with CL/CP show asso- ciated malformations, syndromes or aneuploidy ii. Van der Woude syndrome: the most commonly
recognized syndrome associated with CL/CP, an autosomal dominant disorder characterized by CL/CP and blind sinuses or pits of the lower lip iii. Microdeletion of chromosome 22q11.2 (velocar- diofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome): currently the most common syndromic diagnoses among patients with clefts of the secondary palate alone iv. Other syndromes associated with clefts of the
secondary palate alone:
a) Stickler syndrome
b) Ectrodactyly-ectodermal clefting (EEC) syndrome
c) Popliteal pterygium syndrome b. Nonsyndromic cleft of the lip and/or palate
i. An embryopathy derived from failure in fusion of the nasal process and/or palatal shelves ii. Genetic factors play an important role in the eti-
ology of cleft lip and/or palate since one in five
patients in different populations has a positive family history of CL/CP
iii. Isolated CL/CP is considered multifactorial in origin and demonstrates strong familial aggrega- tion with a significant genetic component iv. No evidence of classic Mendelian inheritance
attributable to any single gene, although a num- ber of genes or loci have been implicated, including transforming growth factor-alpha, retinoic acid receptor alpha, BCL3, MSX-1 and several regions on chromosome 6p23-24 (OFC1), 2q13 (OFC2), 19q13.2 (OFC3), and other loci such as 4q25-4q31.3 and 17q21
CLINICAL FEATURES
1. Classification of different types of orofacial clefting a. Cleft lip with or without cleft palate (CL/CP)
i. Unilateral cleft lip
ii. Unilateral cleft lip and cleft palate iii. Bilateral cleft lip
iv. Bilateral cleft lip and cleft palate b. Cleft palate only
i. Cleft palate
ii. Submucous cleft palate iii. Velopharyngeal insufficiency
iv. Robin sequence and robin complexes c. Median clefts
i. Median cleft lip
ii. Persistent infranasal furrow iii. Median frenular cleft
iv. Median mandibular cleft
d. Alveolar clefts (oral-facial-digital syndromes) e. Tessier type clefts including lateral and oblique facial
clefts
2. Racial difference in CL/CP
a. Whites: approximately 1 in 1000 births b. African Americans: 0.41 per 1000 births c. Asians: approximately twice of whites
3. Sex difference in CL/CP and isolated clefts of the second- ary palate
a. Children born with CL/CP: 60–80% are males b. Isolated clefts of the secondary palate: more fre-
quently in females 4. Sites of clefts
a. Isolated cleft lip: 21%
b. CL/CP: 46%
c. Clefts of the secondary palate alone: 33%
d. Unilateral clefts
i. More common in the left than the right (2:1) ii. Much more common than bilateral (9:1) iii. Associated with palatal clefts in 68% of cases
e. Bilateral clefts of the lip: associated with palatal clefts in 86% of cases
5. Types of cleft lip a. Microform
i. Presence of a vertical groove and vermilion notching
ii. Associated with varying degrees of lip shorten- ing
b. Unilateral incomplete cleft lip
i. Present with varying degrees of lip disruption ii. Associated with an intact nasal sill or Simonart
band (a band of fibrous tissue from the edge of the red lip to the nostril floor)
c. Complete cleft lip: characterized by disruption of the lip, alveolus, and nasal sill
6. Secondary medical problems with the presence of cleft plate a. Difficulty in sucking
b. Inadequate intake of formula c. Aspiration
d. Deviated nasal septum (airway obstruction) e. Hearing impairment
f. Recurrent ear infections g. Malocclusion
h. Abnormal craniofacial growth
i. Inability to generate a pressure gradient between the oral and nasal chambers (hinders sucking in most infants)
j. Speech dysfunction
i. The most serious untoward consequence associ- ated with cleft palate
ii. Hypernasality or escape of sound into the nasal cavity associated with the production of many consonant phonemes and vowels in the English language except m, n, and ng
k. Cosmetic disfigurement associated with orofacial clefting
DIAGNOSTIC INVESTIGATIONS
1. Speech and hearing evaluation
2. Echocardiography for associated cardiac anomalies 3. Karyotyping if indicated, especially to detect
del(22)(q11.2)
4. Molecular genetic analysis for a known mutation in a syn- dromic CL/CP
GENETIC COUNSELING
1. Recurrence risk
a. Recurrence risk for nonsyndromic CL ± CP i. Unaffected parent
a) No previously affected child: about 0.1%
(general population risk)
b) With one previously affected child: about 4%
c) With two previously affected children:
about 14%
ii. One affected parent
a) No previously affected child: about 4%
b) With one previously affected child: about 12%
c) With two previously affected children:
about 25%
iii. Two affected parents
a) No previously affected child: about 35%
b) With one previously affected child: about 45%
c) With two previously affected children:
about 50%
b. Recurrence risk for nonsyndromic CP i. Unaffected parent
a) No previously affected child: about 0.04%
(general population risk)
b) With one previously affected child: about 3.5%
c) With two previously affected children:
about 13%
ii. One affected parent
a) No previously affected child: about 3.5%
b) With one previously affected child: about 10%
c) With two previously affected children:
about 24%
iii. Two affected parents
a) No previously affected child: about 2.5%
b) With one previously affected child: about 40%
c) With two previously affected children:
about 45%
c. Presence of a microform such as a form fruste cleft lip, submucous cleft palate, or bifid uvula suggest genetic factors within the family, which would alter the inheritance risks (e.g., striking association with lower-lip pits in the van der Woude syndrome) d. Recurrence risk for CL/CP with associated anomalies
i. Mendelian diseases and syndromes
a) Autosomal dominant inheritance (e.g., Apert syndrome)
b) Autosomal recessive inheritance (e.g., Smith-Lemli-Opitz syndrome)
c) X-linked inheritance (e.g., oto-palato-digital syndrome)
ii. Chromosome disorders (e.g., trisomy 13) 2. Prenatal diagnosis
a. Prenatal ultrasonography
i. CL/CP not reliably diagnosed until the soft tis- sues of the fetal face become distinct by 13–14 weeks by transabdominal (TA) sonography and by transvaginal (TV) sonography slightly earlier ii. Fetal palate best seen in the axial plane
iii. Fetal lips optimally visualized in the coronal view iv. To demonstrate isolated CL/CP
v. To demonstrate associated anomalies (limb and spine anomalies, most common with 33%; car- diovascular anomalies, 24%)
b. Fetal echocardiography in case of fetal cardiac anom- alies
c. Fetal karyotyping in case of associated fetal anomalies 3. Management
a. Medical
i. A highly specialized multidisciplinary approach from birth to adulthood
ii. Airway management iii. Establishment of feeding
iv. Speech, hearing, and language therapies b. Surgical
i. Primary surgery on the lip: usually carried out around the age of 3 months followed by palatal repair at around 6 months
ii. Preventative and restorative dental care iii. Orthodontics
iv. Secondary surgery in the form of alveolar bone grafting
v. Pharyngeal flap or sphincter pharyngoplasty for velopharyngeal incompetence
c. Psychological issues i. Parental stress
ii. Parent-child relationship
iii. Behavioral and emotional adjustment iv. Self-concept and personality
v. Cosmetic disfigurement vi. Social functioning
vii. Congnitive development and adjustment viii. Cleft Lip and Palate Association (CLAPA), a
helpful source of support and information for both families and professionals
d. Recent observation suggests beneficial effects of folic acid supplementation during pregnancy in the preven- tion of facial clefting
REFERENCES
Bergé SJ, Plath H, Van de Vondel PT, et al.: Fetal cleft lip and palate: sonographic diagnosis, chromosomal abnormalities, associated anomalies and postnatal outcome in 70 fetuses. Ultrasound Obstet Gynecol 18:422–431, 2001.
Bonaiti-Pellié C, Briand ML, Feingold J, et al.: An epidemiological and genetic study of facial clefting in France. I. Epidemiological and frequency in rel- atives. J Med Genet 11:374–377, 1982.
Burdi AR: Epidemiology, etiology, and pathogenesis of cleft lip and palate.
Cleft Palate J 14:14:262–269, 1977.
Carinci F, Pezzetti F, Scapoli L, et al.: Genetics of nonsyndromic cleft lip and palate: a review of international studies and data regarding the Italian population. Cleft Palate Craniofac J 37:33–40, 2000.
Chen H: Medical Genetics Handbook. St Louis: Warren H Green, 1988, pp 320–321.
Cockell A, Lees M: Prenatal diagnosis and management of orofacial clefts.
Prenat Diagn 20:149–151, 2000.
Cohen MM Jr: Craniofacial disorders. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds): Emery and Rimoin’s Principles and Practice of Medical Genetics. 4th ed, London, Churchill Livingstone, 2002, Chapter 142, pp3689–3727.
Curtis E, Fraser F, Warburton D: Congenital cleft lip and palate: risk figures for counselling. Am J Dis Child 102:853–857, 1961.
De La Pedraja J, Erbella J, McDonald WS, et al.: Approaches to cleft lip and palate repair. J Craniofac Surg 11:562–571, 2000.
Endrica MC, Kapp-Simon KA: Psychological issues in craniofacial care: state of the art. Cleft Palate-Craniofac J 36:3–11, 1999.
Farrall M, Holder S: Familial recurrence-pattern analysis of cleft lip with or without cleft palate. Am J Hum Genetics 50:270–277, 1992.
Fraser FC: The genetics of cleft lip and palate. Am J Hum Genet 22:336–352, 1970.
Fraser GR, Calnan GS: Cleft lip and palate: Seasonal incidence, birth weight, birth rank, sex, site, etc. Arch Dis Child 36:420, 1961.
Habib Z: Factors determining occurrence of cleft lip and cleft palate. Surg Gynecol Obstet 146:105–110, 1978.
Habib Z: Genetic counseling and genetics of cleft lip and palate. Obstet Gynecol Surv 33:441–447, 1978.
Hartridge T: The role of folic acid in oral clefting. Br J Orthodontics 26:115–120, 1999.
Hibbert SA, Field JK: Molecular basis of familial cleft lip and palate. Oral Dis 2:238–241, 1996.
Kirschner RE, LaRossa D: Cleft lip and palate. Otolaryngol Clin N Amer 33:1191–1215, 2000.
Lee W, Kirk JS, Shaheen KW, et al.: Fetal cleft lip and palate detection by three-dimensional ultrasonography. Ultrasound Obstet Gynecol 16:
314–320, 2000.
Lynch HAT, Kimberling WJ: Genetic counseling in cleft lip and cleft palate.
Plast Reconstr Surg 68:800–815, 1981.
Matthews MS, Cohen M, Viglione M, et al.: Prenatal counseling for cleft lip and palate. Plast Reconstr Surg 101:1–5, 1998.
Melnick M, Bixler D, Fogh-Anderson P, et al.: Cleft ± cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968. Am J Med Genet 6:83–97, 1980.
Milerad J, Larson O, Hagberg C, et al.: Associated malformations in infants with cleft lip and palate: a prospective, population-based study. Pediatrics 100:180–186, 1997.
Mitchell LE, Risch N: Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genetics 51:323–332, 1992.
Mulliken JB, Benacerraf BR: Prenatal diagnosis of cleft lip. What the sinolo- gist needs to tell the surgeon. J Ultrasound Med 20:1159–1164, 2001.
Murray JC: Gene/environment causes of cleft lip and/or palate. Clin Genet 61:248–256, 2002.
Nyberg D, Sickler G, Hegge F, et al.: Fetal cleft lip with and without cleft palate: US classification and correlation with outcome. Radiology 195:
677–684, 1995.
Prescott NJ, Winter RM, Malcolm S: Nonsyndromic cleft lip and palate: complex genetics and environmental effects. Ann Hum Genet 65:505–515, 2001.
Stark RB: The pathogenesis of harelip and cleft palate. Plast Reconstr Surg 13:20–39, 1954.
Stein J, Mullikan JB, Stal S, et al.: Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 mutigenerational families. Am J Hum Genet 57:257–272, 1995.
Tolarova M, Harris J: Reduced occurrence of orofacial clefts after periconcep- tional supplementation with high-dose folic acid and multivitamins.
Teratology 51:71–78, 1995.
Tolarova M, Cervenka J: Classification and birth prevalence of orofacial clefts.
Am J Med Genet 75:126–137, 1998.
Wyszynski DF, Beaty TH: Review of the role of potential teratogens in the origin of human non-syndromic oral clefts. Teratology 53:309–317, 1996.
Wyszynski DF, Beaty TH, Maestri N: Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J 33:406–417, 1996.
Fig. 1. Two infants with bilateral cleft lips and cleft palate.
Fig. 2. An infant with unilateral cleft lip and cleft palate.
Fig. 3. An infant and a boy with cleft palate.
Fig. 4. A boy with high-arched palate.
Fig. 5. An infant with bilateral CL/CP associated with trisomy 13.
Fig. 6. A stillborn with CL/CP and other multiple congenital anom- alies including massive cystic hygroma.
