The Penetrance and Variable Expression of the Van Der Woude Syndrome: Implications for Genetic Counseling

The Penetrance and Variable Expression of The Van der Woude Syndrome: Implications for Genetic Counseling

ROBERT J. SHPRINTZEN, Ph.D. ROSALIE B. GOLDBERG, M.S. EUGENE J. SIDOTI, M.D. Bronx, New York 10467

The presence of congenital fistulae in the lower lip in combination with cleft lip, cleft palate, or both is diagnostic of the Van der Woude syndrome. This autosomal dominant syndrome had been reported to have a penetrance of 80% with variable expression. An analysis of eleven families with 67 affected individuals showed variable expression of clefting and lower lip pits However, penetrance was found to be close to 100%. An approach to counseling advocates advising a 50% chance of inheriting the gene for Van der Woude syndrome.

Van der Woude syndrome (Van der syndrome, to explore its variability as a hu- Woude, 1954) is a reportedly rare autosomal man model for clefting, and to raise questions dominant congenital malformation syn- concerning genetic counseling and embryol- drome. The features are limited to pits in the ogy. lower lip, cleft lip, and cleft palate. With the exception of the lip pits, the syndrome is Clinical Materials phenotypically identical to isolated cleft lip- Eleven families with at least one member cleft palate in all of its variations. The expres- affected with Van der Woude syndrome were sion of Van der Woude syndrome is highly taken from the case load at the Center for variable. Individuals have been reported with Craniofacial Disorders (CCFD) of Montefiore lip pits only, with clefts only, and with lip pits Hospital and Medical Center. Seven of these in combination with clefts. Clefts associated families had at least two affected members; with Van der Woude syndrome run the full | five had at least four affected members; and range of expression and include unilateral, two had over ten affected members including bilateral, or incomplete cleft lips, complete one family with 32 cases. In total, CCFD was unilateral or bilateral or incomplete cleft pal- able to document 67 cases of Van der Woude ates, submucous cleft palates, etc. syndrome from eleven pedigrees. Twenty-two The syndrome was studied in depth and patients and 16 unaffected individuals from reported in 1967 by Cervenka, et al. The their families were examined by the authors. variable expression of the syndrome was as- In addition, 30 cases from the largest pedigree certained from the analysis of 38 pedigrees, 23 were examined by other specialists who were seen by the authors and 15 provided by other consulted by the authors. specialists. The purpose of this report is to help further delineate the Van der Woude Results of Examinations Significant variability of expression of Van Dr. Shprintzen is Director of the Center for Cranio- facial Disorders (CCFD) at Montefiore Hospital and der Woude syndrome was ascertained both Medical Center, New York, and Associate Professor of from pedigrees and patient examinations. Ta- Plastic Surgery and Otolaryngology, Albert Einstein Col- ble 1 summarizes the distribution of 57 cases lege of Medicine (AECOM). Mrs. Goldberg is Clinical (probands were excluded) according to cleft Coordinator and Genetic Counselor, CCFD, and Associ- type, the presence or absence of lip pits, and ate in Plastic Surgery, AECOM. Dr. Sidoti is Medical Coordinator and Pediatrician, CCFD, and Associate sex. Table 1 also compares the distribution of Clinical Professor of Pediatrics, AECOM. the patients at CCFD to Cervenka's sample. 52 Shprintzen et al., van peR woubE syNDROME 53

TABLE 1. Distribution According to Expression of Van der Woude Syndrome for CCFD Sample (57 Subjects) and Cervenka's Sample (125 Subjects), Excluding Probands.

Male Female CCFD, 1979 Total Pits No Pits Pits No Pits

Cleft Lip 0 (0%) 1 (2%) 0 (0%) 1 (2%) 2 (4%) Cleft Lip-Palate 9 (16%) 0 (0%) 8 (14%) 0 (0%) 17 (30%) Cleft Palate 7 (12%) 2 (4%) 3 (5%) 0 (0%) 12 (21%) Submucous Cleft 2 (4%) 0 (0%) 5 (9%) 0 (0%) 7 (13%) No Cleft 7 (12%) 0 (0%) 10 (18%) 2? (4%) _19 (34%) 57 Cervenka, 1967 Cleft Lip 0 (0%) 5 (4%) 3 (2%) 0 (0%) 8 (6%) Cleft Lip-Palate 6 (5%) 2 (2%) 8 (6%) 1 (1%) 17 (14%) Cleft Palate 8 (6%) 4 (3%) 7 (7%) 1 (1%) 20 (17%) No Cleft 23 (18%) 11 (9%) 32 (25%) 14 (11%) _80 (63%) 125

A Chi square analysis was performed to determine the goodness of fit of the CCFD sample to that of Cervenka, et al. (1967). The Chi square value showed significant differences between the distributions of the two samples at the .001 level of confidence. In our sample, phenotypic expression ranged from complete bilateral cleft lip-cleft palate with lip pits (Figure 1) to lip pits with submucous cleft palate (Figure 2). Submucous cleft palate was defined as morphologic abnormalities in both the oral and nasal surfaces of the velum as described by Croft, et al. (1978). There was variable phenotypic expression of lip pits as well as of cleft type. The classic description of symmetrically placed paramedian sinuses, or fistulae in the lower lip, was not found in all cases (Figure 3). Frequently, there were paramedian mounds on the lower lip, which, on palpation, ex- FIGURE 1. Infant with bilateral cleft lip-cleft palate truded saliva (Figure 4). Pits or fistulae in the and lower lip pits. gingival surfaces of the lower lip were also found in several cases and were often asym- including cleft palate or cleft lip. The referrals metrical (Figure 5). which yielded our Van der Woude sample were patients referred for presumed isolated Discussion clefts or those referred with hypernasal speech Our data on 11 pedigrees with 67 individ- of previously unknown origin. These referrals uals affected with Van der Woude syndrome, numbered 291, including 17 of the Van der 20 of whom we have examined, have raised Woude patients who were registered at some important questions concerning this re- CCFD, or 6% of our registered cleft palate portedly rare syndrome. First, these 11 pedi- and submucous cleft palate population during grees were obtained over a four-year period at that time. It is of further interest to note that, CCFD (1975-1978). In those four years, we between 1959 and 1974, over 600 patients have registered 752 new patients. Of these, with clefts were registered. None were re- many had known craniofacial syndromes or ported to have lower lip pits We attribute unique multiple malformation syndromes not this to the following factors:

54 Cleft Palate Journal, January 1980, Vol. 17 No. 1

FIGURE 2. Adolescent female with submucous cleft FIGURE 4. Paramedian lower lip mounds (arrows). palate and bifid uvula (arrow) and lower lip mounds (arrow heads).

FIGURE 5. Asymmetric lower lip pits (arrows). Note the buccal placement of the pit on the right.

dismissed as not important. The increase in FIGURE 3. Paramedian lower lip pits (arrows) with the number of diagnosed cases of Van der saliva extruding on the left. Woude syndrome has been accompanied by an increase in the identification of other con- 1. The syndrome, while known as a diagnostic genital malformation syndromes, as well. It entity in the 1950's, has become better delin- should also be noted that lower lip pits are eated only since Cervenka, et al. (1967) pub- usually totally asymtomatic (Cervenka, et al., lished their data. 1967). Without careful scrutiny of the lower 2. CCFD added genetic counseling as a specific lip, they may go unnoticed by both the pa- discipline to its routine evaluation in 1975. As tient and clinic personnel. Certainly, in pa- a result, patient examination became far more tients with clefts, the upper lip and palate thorough, especially for minor anomalies deserve the majority of attention from exam- which might have gone unnoticed or been ining specialists with the lower lip being of

Shprintzen et al., vAN DER wOUDE SYNDROME 55

lesser importance to patient management, un- to have lip pits and a submucous cleft palate less, for example, an Abbe flap is contem- with the classic triad of bifid uvula, muscular plated. diastasis, and notching of the hard palate Comparing the breakdown of our sample (Figure 6). He was totally asymptomatic. His to that of Cervenka, et al. (1967), marked speech was normal and the lip pits had been differences are seen (Table 1). The majority surgically removed early in life. This type of of Cervenka's cases had no clefts (63%), in- case can easily be overlooked, especially in cluding 20% obligate gene carriers who were pedigree analysis, and points out the need for nonpenetrant. In our sample excluding pro- careful examination of as many relatives of bands, three categories each contained 30% of affected individuals as possible. the subjects: cleft palate with lip pits (includ- Another major difference between the sam- ing submucous clefts), cleft lip-cleft palate ple at CCFD and Cervenka's were the number with lip pits, and lip pits with no cleft. When of nonpenetrant cases. Cervenka reported that probands were included, the largest category 20% of his obligate gene carriers were nonpe- was cleft lip-cleft palate with lip pits (32%). netrant. In our sample, there were only two In our sample, 68% of the patients (excluding reportedly nonpenetrant cases ascertained probands) had clefts. Thus, perhaps the big- from pedigree analysis. Both of these cases gest difference between our sample and Cer- came from the same pedigree with poor doc- venka's is the lower number of noncleft pa- umentation. In all of our personal examina- tients in our series. Part of this difference may tions, we have found no nonpenetrant cases. be related to the number of cases we identified However, it should be pointed out that not with submucous cleft palate, a category not every family member was personally exam- present in Cervenka's series. Of special interest ined and any study of this type is, of necessity, was one family which had a female child with limited by the family knowledge available to bilateral cleft lip-cleft palate. Upon examin- those interviewed. ing the family members, the father was found The difference between our sample and

FIGURE 6. Broad, minimally bifid uvula (arrow) in an adult male with lower lip pits. Speech was normal. There was muscular diastasis and notching of the hard palate upon palpation. His daughter had bilateral cleft lip-cleft palate and lower lip pits. 56 Cleft Palate Journal, January 1980, Vol. 17 No. 1

Cervenka's points out some difficulties with (1967) at 80%. Based on histories available, the counseling approach recommended by the penetrance in our population would be Cervenka, et al. (1967). Recurrence risk fig- 97%. None of the reportedly nonpenetrant ures (Table 2) were based upon: patients were available for examination, and, in fact, were distant relatives of the proband 1. the frequency of clefting with or without lip from a single pedigree. A mild expression of pits, Van der Woude syndrome could not be ruled 2. the incidence of clefts for various types in out by the historians. In the examined indi- offspring of parents with pits only versus pits viduals, penetrance was 100%. In our largest and clefts, 3. a presumed penetrance of 80%. vedigree, there were no instances of nonpe- netrance (Figure 7). Also, our sample included For example, the recurrence risk for clefting individuals with lip pits and submucous cleft when only one parent has lip pits with no palate. The diagnoses in three of these indi- cleft, is 22%. This is based on a penetrance of viduals were made at 7, 14, and 31 years of 80% and the empiric observations from Cer- age upon referral to CCFD for hypernasal venka's sample of how many cleft children speech. It is conceivable that individuals such resulted from mating between nonaffected in- as these could be regarded as nonpenetrant dividuals and individuals with lip pits only. on histories available from distant relatives. We believe that these recurrence risks are Phenotypic variability in our sample was misleading. First, these risks computed from quite extensive. Van der Woude syndrome our sample population would be different. presents a good opportunity to study a human Secondly, Van der Woude syndrome has been model of clefting. For example, anomalies of well established as an autosomal dominant the maxillary lateral incisors and chronic ser- trait, as is, for example, Crouzon syndrome or ous otitis media are well known abnormalities Treacher Collins syndrome. Counseling an in individuals with cleft lip-cleft palate, cleft individual with Van der Woude syndrome for palate, or submucous cleft palate (Smith, the likelihood of clefting in offspring is exactly 1976). Upon examination and from history, analogous to counseling for the risk of ex- we found several first degree relatives of pro- ophthalmus in Crouzon syndrome or for the bands with histories of chronic serous otitis or risk of severe microtia in Treacher Collins duplication or hypoplasia of the lateral inci- syndrome. In other words, once the dominant sors. Since both of these minor anomalies also gene for Van der Woude syndrome is inher- occur frequently in the general population, it ited, the trait with any of its possible expres- becomes difficult to determine if the presence sions is inherited, and any of those expressions of dental and middle ear anomalies in first is possible. This probably means that we can degree relatives of probands represents a min- best counsel for gene inheritance but not for imal expression of the gene for Van der gene effect. Therefore, our own preference in Woude. This quandry points out the need for counseling is to discuss the likelihood of in- careful examination of as many relatives as heriting the gene (50%), the possible ways it possible when a diagnosis of Van der Woude may be expressed, and its penetrance. This syndrome is made. Certain visible parameters approach does not include information on related to middle ear disease may be found in recurrence risk for any single feature. otherwise normal relatives, such as Eusta- Penetrance was reported by Cervenka et al. chian tube hypoplasia or minor palatal anomalies (Croft, et al., 1978). TABLE 2. Recurrence Risk of Clefting in Children of EmpBrvorocicat ConsIpERATIONS. Cleft lip Affected Parents from Cervenka, et al., 1967. and cleft palate are classically regarded as two

separate embryologic events (Fraser, 1971). Parental Defect o 101,513: g”. id However, as can be seen in our largest pedi-

gree (Figure 7), cleft palate and cleft lip-cleft Parent with Pits Only 22% palate are found in the same family, and, in Parent with Pits and Cleft 39% fact, are found in the same sibship on three Parent with Cleft Only But 30% occasions. We are at a loss to explain this Having Parent or Sib with phenomenon, but two hypotheses can be put Pits forward: Shprintzen et al., VAN DER WOUDE SYNDROME 57 VAN DER WOUDE SYNDROME

FIGURE 7. Pedigree in a family with 32 affected individuals. Note the variability of cleft type within sibships and between parents and offspring.

1. Modifying genes may be present (Cervenka, and that, when dominant inheritance is pos- et al., 1967). In other words, individuals who sible based on pedigree analysis, counseling carry the gene for Van der Woude syndrome should involve mentioning the possible diag- are also subject to any polygenic influences nosis of the syndrome. While it is true that contributing to clefting. This may result in an there are other multiple malformation syn- additive process for clefting of the lip, palate, dromes with clefting, none of them mimics or both. isolated cleft lip/cleft palate as closely as the 2. Influences which are not genetic may alter or add to the process of clefting. These would Van der Woude syndrome. include teratogens, hyperthermia, etc. This Acknowledgement: This study was supported would make Van der Woude syndrome dom- by a grant from the Max and Victoria Dreyfus. inant with multifactorial influence. Foundation. The study was presented in part at the annual meeting of the American Cleft Support for either of these hypotheses, or Palate Association, San Diego, February, both (they are not mutually exclusive), is 1979. , found in a report of apparently monozygotic Reprints: Dr. Robert J. Shprintzen twins with Van der Woude syndrome (both Center for Craniofacial Disorders had lip pits) discordant for clefts (Cervenka, et al., 1967). Montefiore Hospital & Medical Center 111 East 210 Street CounseELinNc. A final quandry is presented for Bronx, N.Y. 10467 counseling families where a parent and one child have clefts but no lip pits. It may be that the child simply fell into the 4-7% recur- References rence risk typically given for isolated clefting CiERVENKA, J., Gorm, R. J., and Anperson, V. E., The (depending on cleft type, sex, etc.). However, syndrome of pits of the lower lip and cleft lip and/or since we know that one form of expression of palate, Genetic considerations, Amer. J. Hum. Genet., 19, Van der Woude syndrome is clefting with no 416-432, 1967. pits, might this be an example of dominant Crort, C. B., SuprinTzEN, R. J., DantttErR®, A. I., and Lewin, M. L., The occult submucous cleft palate and inheritance of the syndrome? Do we counsel the musculus uvulae, Cleft Palate J., 215, 150-154, 1978. on a presumed multifactorial model with an FrasER, F. C., Etiology of cleft lip and palate, Chapter in even higher risk (12%, for example), or should Cleft Lip and Palate, Grabb, Rosenstein, and Bzoch, eds. the risk be given as 12 to 50% based on the Boston: Little, Brown and Co., 1971. possibility that this may be an example of SmITH, D. W., Recognizable Patterns of Human Malformation, ed. 2. Philadelphia: W B Saunders Co., 1976. Van der Woude syndrome with no lip pits? Van per Woupr, A., Fistula labii inferioris congenita Our feeling is that the frequency of Ven der and its association with cleft lip and palate, Amer. ]. Woude syndrome has been underestimated Hum. Genet., 6, 244-256, 1954.