The geneticist is responsible for identifying the etiology and/or pathogenesis of the cleft or craniofacial anomaly. The information is then used to discuss overall prognosis for the patient as well as recurrence risk for the parents, patient, and other family members. As with other birth defects, clefts and craniofacial disorders may be the result of chromosomal abnormalities, single gene disorders, and/or environmental factors/agents. Most commonly they are the result of multifactorial inheritance involving the interaction of an individual's genetic background with the environment.

Considerable progress has been made in the identification of causative factors over the past 10 years particularly in the area of single gene disorders. The genes responsible for several of the most well known genetically determined syndromes have been recently identified. However, at the time of this writing, molecular testing is infrequently utilized in clinical management. Working drafts of the human genome sequence have recently been published in Nature and Science. Several surprises have emerged. The number of human genes (roughly 30,000) is far less than originally estimated. Through a variety of genetic mechanisms including alternative splicing and regulation of transcription, the 30,000 genes code for an enormously complex array of proteins. Clearly, biology is no longer "one gene - one protein." It is now known that mutations in different genes may produce the same phenotype (e.g. FGFR1 and FGFR2 in Pfeiffer Syndrome). Different mutations in the same gene may result in different phenotyps (e.g. FGFR3 and achondroplasia, hypochondroplasia, thanatophoric dysplasia, and Crouzon Syndrome with acanthosis nigricans). The tissue distribution of a mutation may produce a range of phenotypes from a multisystem disorder to a tumor (e.g. GNAS1 and McCune-Albright Syndrome, fibrous dysplasia, and pituitary adenoma).

With respect to environmental factors, there are some agents, such as with the acne drug, Accutane, which are potent human teratogens with a high risk for craniofacial malformation in prenatally exposed fetuses, regardless of the infant or mother's genetic background. There are factors, such as cigarette smoking, that increase the risk for cleft lip with or without cleft palate only in susceptible individuals. However, the genes that confer susceptibility to most cleft and craniofacial conditions remain to be elucidated. There is currently considerable interest in folic acid as a pre- or peri-conceptual treatment that might reduce the risk for cleft lip and palate as it does for spina bifida. Further study is needed to confirm early reports.

Three types of genetic mutations are under investigation in craniofacial disorders:

1. Those that increase an individual's susceptibility for a given error in morphogenesis but produce a phenotype only through interaction with other genes or environmental factors;
2. Those that produce phenotypes directly; and
3. Those that modify expression of disease producing genes and thus alter the phenotype.

Genetic advances are likely to improve the ability to diagnose and test for syndromes impacting craniofacial development. Understanding of the molecular pathogenesis of a condition will hopefully translate into novel strategies for treatment through manipulation of cellular pathways. Recognition of the factors impacting susceptibility and risk may lead to more effective strategies for prevention.

1. Cleft lip with or without cleft palate (CL+P)
   1. Incidence in the general population is roughly 1:1000, but varies in different racial groups.
   2. Although the majority of CL+P occurs in an otherwise normal individual, between 10% and 20% of affected individuals have the condition as part of a syndrome with broader implications to the individual and family. These conditions need to be identified such that appropriate follow-up is instituted and accurate recurrence risk counseling is offered.
      1. The majority of syndromes are diagnosed clinically through history and physical examination.
      2. Chromosomal testing may be indicated when CL+P occurs with other malformations, growth deficiency, or developmental delay.
      3. Molecular (DNA) testing is available for a very few specific conditions.
   3. For isolated CL+P, multifactorial inheritance is likely. Empiric risk for recurrence for unaffected parents with one affected child is 4:100 or 4%. This risk also applies to the affected individual's own chance for similarly affected offspring.
   4. Prenatal diagnosis for isolated CL+P depends upon the ability of ultrasound to visualize the fetal face. For syndromes in which CL+P represents one feature, prenatal diagnosis should be tailored to the underlying etiology of the syndrome.
2. Cleft palate alone (CP alone)
   1. Incidence in the general population is roughly 1:2000.
   2. Although the majority of CP alone occurs in an otherwise normal individual, up to 50% of affected individuals have the condition as part of a syndrome with broader implications to the individual and family. These conditions need to be identified such that appropriate follow-up is instituted and accurate recurrence risk counseling is offered.
      1. The majority of syndromes are diagnosed clinically through history and physical examination.
      2. Chromosomal testing may be indicated when CP occurs with other malformations, growth deficiency, or developmental delay.
      3. Molecular (DNA) testing is available for a very few specific conditions.
      4. Stickler syndrome is a common enough disorder that ophthalmologic evaluation of at-risk individuals is recommended.
   3. For CP alone, multifactorial inheritance is likely. Empiric risk for recurrence for unaffected parents with one affected child is 3:100 or 3%. This risk also applies to the affected individual's own chance for similarly affected offspring. The risk is for an infant with CP alone, not CL+P.
   4. Prenatal diagnosis for CP alone is currently not possible.
3. Non-cleft craniofacial abnormalities
   1. This group of conditions is highly heterogeneous and runs the gamut from disorders of unknown etiology with a negligible recurrent risk (e.g., amnion rupture sequence) to those in which single gene mutations play the determining role (most of the syndromic craniosynostoses) with a substantial risk for recurrence in some families. Since prognosis and recurrence risk information is specific to each condition, genetic evaluation is encouraged in this population.
   2. Prenatal diagnosis may be possible for a few conditions depending upon the etiology, the phenotype produced, and the availability of chromosomal and molecular diagnosis.

Footer

©2007 American Cleft Palate-Craniofacial Association

website by Kilpatrick Design Studio