Eric A. Wulfsberg
The discovery of an oral cleft (OC) in a baby or young child is a distressing event for the family. Parents who have been visualizing a healthy child throughout pregnancy are often shocked by the significant physical and cosmetic abnormalities that accompany an OC. Following the discovery of the OC, the parents will appropriately have many questions, which may be divided into two general categories: the first addresses diagnosis and prognosis of the condition, involving questions such as “What is wrong?,” can be done about it?,” and “What does it mean for the future?”; the second addresses etiology and recurrence risk, typically including questions such as “Why did it happen?,” “Will it happen again?,” and “What are our reproductive options in the future?” These questions can be answered only after accurately determining the abnormalities that are present and establishing the etiology of the OC. When a genetic syndrome with associated mental retardation is the cause of cleft, the developmental prognosis may be more important to the ultimate function of the individual than the specific anatomic issues surrounding the OC and its repair. Thus, this section discusses issues related to the general and orofacial evaluation of the OC patient with emphasis on clues to differentiate syndromic from nonsyndromic OCs.
While the majority of individuals with OCs have no other physical abnormalities and are developmentally normal, a significant number have associated malformations, possibly as part of a genetic or chromosomal syndrome. Most studies looking for associated abnormalities or syndromes among individuals with facial clefts have been done in craniofacial or cleft palate (CP) clinic populations. This tends to underestimate the incidence of the most severe or lethal malformation syndromes as these children often do not survive the neonatal period. Using these populations has the advantage that craniofacial clinics often include a dysmorphologist or clinical geneticist, resulting in a more thorough morphological evaluation. A study of this type from the CP clinic in San Diego, which does not include early lethal syndromes, showed a 14% incidence of associated malformations in individuals with cleft lip (CL) with or without CP (CL/P), a 40% incidence of associated malformations among individuals with CP, and a 78% incidence of associated malformations among individuals with velopharyngeal insufficiency (Jones, 1993, 2000). For comparison, a French population-based study utilizing a birth defects registry showed a 37% incidence of associated malformations in individuals with CL/P, a 47% incidence of associated malformations among individuals with CP, and a 14% incidence of associated malformations among individuals with CL (Stoll et al., 2000). In the French study, approximately 13% of the patients with CL/P, 14% with CP, and 6% CL had recognized multiple malformation syndromes (Stoll et al., 2000). Thus, results from these two different patient populations suggest that the type of OC can heighten or lower concerns for associated malformations or genetic syndromes. Similarly, the severity of the OC appears to be important. Bilateral CL/P is almost twice as likely to be associated with a multiple malformation syndrome than unilateral CL/P (Milerad et al., 1997).
While surgeons evaluate OC patients with reference to the best technique for good cosmetic and functional repair, the goal of the medical evaluation is to categorize the abnormality into one of three groups: (1) part of a multiple malformation syndrome with possible associated developmental disabilities and/or mental retardation and a recurrence risk as high 25% to 50%, (2) a nonsyndromic abnormality with presumed good developmental outcome and lower recurrence risk, or (3) one of a number of associated malformations not representing a known or recognized syndrome, with guarded developmental outcome depending on the nature and severity of the associated abnormalities an unknown recurrence risk. These distinctions are critically important for counseling but may not be immediately obvious at the initial evaluation of OC patient. Therefore, evaluation of the OC patient is often an ongoing process that may need to be repeated over a period of time to accurately categorize the nature and etiology of an individual OC and, thus, provide important treatment, long-term prognosis, and recurrence risk counseling information. As in other areas of medicine, this clinical evaluation should include a detailed medical and family history, a careful physical examination, and appropriate diagnostic studies.
Evaluation of an individual with an OC begins by gathering medical and family history information. The pregnancy history should include the ages of the parents as chromosomal abnormalities are more frequent with advanced maternal age and new gene mutations are more frequent with advanced paternal age. Maternal health and any medications taken during the pregnancy may give clues to exposure potential teratogens. In particular, personal habits, such as alcohol or cigarette use during the pregnancy, should be ascertained. The occupations of both parents may also suggest potential teratogen exposures. Pregnancy complications, such as maternal illnesses or premature delivery, may add important clues. Perinatal history, especially any nursery complications and feeding difficulties, is often important. While feeding difficulties may be due to the OC itself, they may also indicate associated neurodevelopmental abnormalities suggestive of a syndromic etiology. Over time, child's growth and neurodevelopment are perhaps the two best measures of good health and normality. Abnormalities in these vital areas should raise concern of a syndromic etiology for the OC.
The family history is best done by constructing a three-generation pedigree, looking for individuals with OCs as well as other congenital and developmental abnormalities. The family history may identify other members with apparent nonsyndromic OCs, supporting a nonsyndromic etiology for the OC and altering the recurrence risk counseling. Because of the phenotypic variability of many OC syndromes, the family history may also identify individuals with other abnormalities, leading to the diagnosis of a familial OC syndrome. Updating the family history at subsequent clinic visits is important as additional information may be learned from other family members after the discovery of the individual OC and new affected individuals may be added to the family over time.
The physical examination needs to be comprehensive and thorough because extracranial as well craniofacial abnormalities may be major components of an OC syndrome. Some dysmorphologists begin their physical examinations away from the OC and craniofacial region so as not to overlook minor abnormalities of the hands, feet, genitalia, and other body parts. The important extracranial abnormalities seen in clefting syndromes will be discussed elsewhere in this book. An important general concept to remember is that those structures with complex embryonic development, such as the brain, heart, face, and hands, are the most likely to show associated abnormalities (Stoll et al., 2000). Examination for minor abnormalities in the parents, and sometimes in other family members, is an important part of the evaluation. This may uncover features of a clefting syndrome not present in the affected individual.
When trying to understand how a structural abnormality such as an OC develops, it is important for the physician to have a thorough knowledge of the normal embryology of facial development, as described earlier in this book. The most common abnormal embryological processes that can lead to an OC include malformations and disruptions. The majority of OCs are malformations, meaning that an error in early development prevented completion of normal developmental processes, resulting in the OC (Jones, 1997). Primary malformation OCs can be nonsyndromic, part of a multiple malformation syndrome, or part of a number associated but nonsyndromic malformations. malformation OCs are most commonly (1) paramedian CL or CLP occurring at the junction of lateral branchial arch derivatives and the frontonasal process, (2) isolated CP, or (3) medial facial clefts involving deficiency of the frontonasal process. A smaller number of OCs are the result of disruptions, meaning that lip and palate structures were developing normally until they were interfered with by an extrinsic force such as a swallowed amniotic strand, or of a chemical teratogen such as in fetal alcohol syndrome (Jones, 1997). Clefts caused by swallowed amniotic strands are most likely to be atypical appearing oro-orbital or oroauricular clefts, but the amniotic strands can interfere with subsequent normal development and result in an oroorbital or oroauricular cleft together with a typical appearing paramedian OC (Eppley et al., 1998).
Careful physical evaluation of the type and severity of an OC can alter the concern for associated abnormalities and syndromes. As previously discussed, CL/P, CP, median facial clefts, and velopharnygeal insufficiency are developmentally separate abnormalities showing different patterns of inheritance, recurrence risks, and syndrome associations. While typical unilateral or bilateral CL/P occurs at the boundary of embryonic frontonasal process and lateral branchial arch derivatives, care must be taken on oral examination to recognize the occasional severe unilateral CL/P, which may mimic a less common median OC. Identification of frontonasal derivatives such as the philtral columns or prolabial segment will allow this important distinction to be made as midline structures may have been distorted and shifted to one side by a large unilateral CL/P. Identification of median OCs involving failure formation or hypoplasia of the frontonasal process almost always signifies disturbances in underlying forebrain development with a guarded developmental prognosis and often an early lethal outcome (DeMyer, 1975). Aberrant oral frenulae are seen in a number of disorders, including Ellis-van Creveld syndrome, and are combined with midline upper lip notches in the orofaciodigital syndromes. It is likely that these disorders are embryologically different from midline OCs due to absence or hypoplasia of the frontonasal process as underlying forebrain abnormalities are not present. Paramedian lower lip pits, which contain the openings of labial mucous glands or accessory salivary glands, are found in fewer than 1 % of individuals with CL/P, but are highly associated with Van der Woude's syndrome, an autosomal dominant clefting syndrome (Cervenka et al., 1967). The lip pits in Van der Woude's syndrome can occur without a CL/P so the finding of this abnormality in the parent of a child with a CL/P increases the recurrence risk for this syndrome to 50% in future offspring. In contrast to lower lip pits, upper pits or commissural pits, located at the angles of mouth, have no association with CL/P or other anomalies (Lettieri, 1993). Oroauricular and oro-orbital clefts are the least common types of OC and rarely have a genetic etiology. As discussed above, oro-orbital and oroauricular clefts often result from swallowed amniotic strands, which either cause disruptions of normally formed tissues or interfere with subsequent normal lip and palate closure. Lateral oroauricular clefts, which indicate incomplete merging of the maxillary and mandibular processes, are found in Treacher Collins syndrome, the oculoauriculovertebral spectrum (including hemifacial microsomia as well Goldenhar's syndrome), and the acrofacial dysostoses. Isolated clefts of the lower lip are exceedingly rare and presumably caused by incomplete midline merging of the two lateral mandibular processes. These most often occur as nonsyndromic abnormalities and generally have a good developmental outcome.
While there are less obvious structural differences among CPs compared to CL/Ps, the morphology of CPs may be important in separating them into broad groups with differing risks for associated abnormalities or syndromes. While a clear distinction is often not possible, most isolated nonsyndromic CPs tend to have a narrower, V-shaped appearance with relatively normal development of the mandible in relationship to maxilla. However, CPs with a broader, more U-shaped appearance and associated hypoplasia of the mandible and glossoptosis are referred to as Robin sequence-type clefts and carry a much higher risk of being part an associated genetic or chromosomal syndrome. Bifid uvula and submucosal CP represent mild phenotypic expression of CP and should be looked for in family members of individuals with overt CP. Thus, subtle physical distinctions on the craniofacial examination can help to raise or lower the suspicion of a syndromic association.
The history and physical examination of individuals with many of the OC syndromes characteristically show major malformations, growth and developmental delays, and minor dysmorphic features all thought to be due to a single unifying etiology (Jones, 1997). However, approximately 40% of patients with OCs have one or more associated malformations but do not have a recognizable syndrome (Jones, 1993). These individuals appear to represent a heterogeneous group, with some having a good neurodevelopmental outcome and low recurrence risk and others having a more guarded prognosis.
Future recurrence risk counseling includes not just interpretation of recurrence risk figures but also compassionate communication of those risks and reproductive options to the family and affected individual. This is an important task and should be performed by a specialized genetic counselor, clinical geneticist, or other knowledgeable professional. Therefore, the medical and family history, a detailed physical and craniofacial examination, and parental examinations are central to distinguishing those individuals with nonsyndromic OCs from those with associated malformations or an OC syndrome.
References
Cervenka, J, Gorlin, RJ, Anderson, VE (1967). The syndrome of pits of the lower lip and cleft and/or palate: genetic considerations. Am J Hum Genet 19: 416–432.
DeMyer, W (1975). Median facial malformations and their implications for brain malformations. Birth Defects Original Article Series XI: 155.
Eppley, BL, David, L, Li, M, et al. (1998). Amniotic band facies. J Craniofac Surg 9: 360–365.
Jones, KL (1997). Introduction including dysmorphology approach and classification. In: Smith's Recognizable Patterns of Human Malformation, edited by KL Jones. Philadelphia: Saunders, pp. 1–7.
Jones, MC (1993). Facial clefting: etiology and developmental pathogenesis. Clin Plast Surg 20: 599–606.
Jones, MC (2000). Cleft lip with or without cleft palate and cleft palate alone: a clinic based population revisited to determine the frequency of multiple malformation syndromes within the population and to define subgroups among individuals with isolated clefts. Presented at the David W. Smith Workshop on Malformation and Morphogenesis, San Diego, CA, August 2-4, 2000.
Lettieri, J (1993). Lips and oral cavity. In: Human Malformations and Related Anomalies, vol. 2, edited by RE Stevenson, JG Hall, and RM Goodman. New York: Oxford University Press, pp. 367–381.
Milerad, J, Larson, O, Hagberg, C, Ideberg, M (1997). Associated malformations in infants with cleft lip and palate: a prospective, population-based study. Pediatrics 100: 180–186.
Stoll, C, Alembik, Y, Dott, B, Roth, MP (2000). Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37: 41–47.