Clefts in Pediatric Practice: Genetic Considerations
by Beth A. Pletcher, MD, March 2000

Cleft lip (CL), cleft palate (CP) or a combination of the two represent some of the most common birth defects encountered in pediatric practice. As an isolated finding, cleft lip with or without cleft palate (CL +/- CP) occurs about twice as often in children of Asian decent (almost 1 in 500) compared to 1 in 1000 Caucasians. The very highest incidence is in the Native American population (1 in 280) and the lowest in the African-American population (1 in 2500). Cleft palate as an isolated finding occurs a little less frequently with an estimated risk of 1 in 2000-2500 in both Caucasian and African-American populations. A more subtle manifestation of palatal clefting, known as a submucous cleft, is often not diagnosed until later childhood or even adulthood and is seen in about 1 in 1200 adults. A forme fruste of CP (bifid uvula) is seen in up to 1 in 50 Caucasians. Unilateral CL occurs on the left side twice as often as the right and soft tissue connections known as Simonart's bands help preserve the contour of the nares in about a quarter of the cleft lip cases. CL +/- CP occurs twice as often in males compared to females whereas CP shows a female predominance.

Many genetic models have been examined to see what factors contribute to cleft formation. For most isolated clefts, there appear to be a number of genetic and environmental factors that influence the occurrence of these defects. Twin studies have suggested a stronger genetic influence in CL +/- CP compared to CP alone, but for either there is still significant discordance, even for monozygotic twins.

Parents or prospective parents frequently wish to know recurrence risks for clefts in their offspring if they themselves have a history of orofacial clefting or have previously given birth to an affected child. Empiric data suggest that for a parent who has CL +/- CP him or herself, risks to offspring are approximately 4% compared to 3% for isolated CP. These numbers are actually very similar for a couple with a previously affected child, but recurrence risks jump to 14% for CL +/- CP and 13% for CP if a couple has two prior affected children.

Even though most clefts are isolated defects, it is essential for the primary care provider to reasonably rule out the possibility of a Mendelian disorder, cytogenetic abnormality or syndromic association in any infant or child with a cleft. In the newborn period it is important to perform a very careful clinical examination looking for other major or minor malformations. Associated anomalies are seen more frequently with isolated CP (about 30%) compared to CL +/- CP (about 8%). Conservative estimates suggest that there may be more than 250 syndromes described in which orofacial clefts are seen. Therefore, it behooves each medical provider to look closely for syndromic "clues" before assuming that a newborn or child simply has an isolated cleft. Below are a few helpful hints that might come in handy when you are seeing a child for the first time with CL, CP or CL +/- CP.

• In addition to the careful physical exam of the child, ask the parents if there is a family history of similar birth defects. This history should also include questions about family members with other birth defects, learning difficulties or mental retardation as well as stillbirths or recurrent miscarriages.

• If there are possibly other relatives with clefts (cousins, aunts, uncles, grandparents), think about the possibility of van der Woude syndrome. This autosomal dominant condition may be manifested only by lip pits or bumps in some family members while others may exhibit severe clefts. If the family history is suggestive, parental lip exams are simply done and quite useful.

• If the affected child has IUGR, dysmorphic features or other anomalies in addition to the cleft(s), cytogenetic studies should be considered.

While many of the genetic syndromes associated with clefts will be quite obvious in the newborn (i.e. presence of craniosynostosis, short limbs, ectodermal dysplasia, extra digits, micrognathia, microcephaly or joint contractures), below are several syndromes associated with CP that may be rather subtle in the newborn.

• Stickler syndrome is a variable autosomal dominant condition associated with mild micrognathia, CP and severe myopia. The eye problems may not be apparent in the newborn period unless an eye exam is recommended, but in a subset of affected individuals, undiagnosed myopia can lead to retinal detachment and subsequent visual loss. Arthropathy is common in older children and adults with this condition and may be helpful from a family history perspective.

• Velocardiofacial syndrome (VCFS) frequently occurs as a sporadic event in a family and many affected individuals have a detectable deletion of genetic material on the long arm of chromosome 22 by FISH analysis. There are some subtle yet unique facial features that may be associated with VCFS including: a high forehead, broad/prominent nasal root and upslanting palpebrae. Cardiac defects may or may not be present and can include isolated VSD, left sided aortic arch or more serious defects such as tetralogy of Fallot. Some affected individuals may not have a CP, but instead may exhibit signs of velopharyngeal incompetence. This may result in significantly hypernasal speech. Mild mental retardation or learning disabilities are also common in VCFS with a substantial risk for the occurrence of psychiatric disorders in affected young adults.

When counseling a couple who has given birth to a child with a CL, CP or both, it is important to provide reassurance and at the same time make sure there is no evidence of a syndromic association or cytogenetic disorder. Most parent are concerned about causation and they need to be told that these relatively common defects occur during early fetal development and are rarely the result of a fetal exposure or recognized in utero event. Referral to a plastic or maxillofacial surgeon who may work as a part of a multidisciplinary craniofacial team will assist the parents in dealing with this diagnosis and planning for their child's future care. A feeding specialist can assist parents who may be struggling with feeding problems and can often provide devices, special nipples or feeding strategies for families who have a child with a cleft. With advances in surgical care for children and adults with clefts, the future is indeed bright and there are a number of parent support groups that may provide information to families and providers. One group, The Cleft Palate Foundation can be reached at (919) 933-9044. They are located in North Carolina at 104 South Estes Drive- Suite 204, Chapel Hill, NC 27514 and online at http://www.cleft.com.

REFERENCES

Cohen MM Jr.: "Syndromes with cleft lip and cleft palate" Cleft Palate J 15: 306-328, 1978.

Crawford FC, Sofaer JA: "Cleft lip with or without cleft palate: Identification of sporadic cases with a high level of genetic predisposition" J Med Genet 24: 163-167, 1987.

Farrall M, Holder S: "Familial recurrence-pattern analysis of cleft lip with or without cleft palate" Am J Hum Genet 50: 270-277, 1992.

Gorlin RJ, Cohen MM Jr., Levin LS: Syndromes of the Head and Neck. 3rd Ed. Oxford University Press, New York, 1990.

Silva Fiho O, Christavao RM, Semb G: "Prevalence of a soft tissue bridge in a sample of 2014 patients with complete unilateral clefts of the lip and palate" Cleft Palate J 31: 122-124, 1994.

Wharton P, Mowrer DE: "Prevalence of cleft uvula among school children in kindergarten through grade five" Cleft Palate J 29:10-14, 1992.