Van der Woude syndrome: dentofacial features and implications for clinical practice

Authors


Professor Grant Townsend
School of Dentistry
The University of Adelaide
Adelaide SA 5005
Email: grant.townsend@adelaide.edu.au

Abstract

Background:  Van der Woude syndrome (VWS) is the most common clefting syndrome in humans. It is characterized by the association of congenital lower lip fistulae with cleft lip and/or cleft palate. VWS individuals have a high prevalence of hypodontia. Although caused by a single gene mutation, VWS has variable phenotypic expression. This study aimed to describe the range of clinical presentations in 22 individuals with VWS to facilitate its diagnosis.

Methods:  A retrospective study of 22 patients with a diagnosis of VWS was undertaken at the Australian Craniofacial Unit (ACFU) in Adelaide. Three extended families with affected members were included in the study cohort.

Results:  The overall prevalence of lip pits in this study cohort was 86%. Cleft phenotypes included bilateral cleft lip and palate (32%); unilateral cleft lip and palate (32%); submucous cleft palate (23%); and isolated cleft hard and soft palate (9%). Missing permanent teeth were reported in 86% of affected individuals.

Conclusions:  Submucous cleft palate in VWS may go undiagnosed if the lower lip pits are not detected. Associated hypodontia and resultant malocclusions will also require management by a dental team.

Abbreviations and acronyms
ACFU

Australian Craniofacial Unit

CL

cleft lip

CLP

cleft lip and palate

ICP

isolated cleft palate

IRF6

interferon regulatory factor six

MIH

molar incisor hypomineralization

SMCP

submucous cleft palate

VWS

Van der Woude syndrome

Introduction

Van der Woude syndrome (VWS; OMIM #119300) is characterized by the association of congenital lower lip fistulae with cleft lip and/or cleft palate.1 It is inherited as an autosomal dominant clefting syndrome that shows high penetrance but variable expressivity amongst carriers. The eponymously named VWS was first described by Anne Van der Woude who detailed the association between congenital pits of the lower lips and cleft lip and palate in 1954.2 She determined that the condition, later to be known as Van der Woude syndrome, was a complex inherited by a single gene that elicited variable expressivity ranging from lower lip pits with cleft lip and palate to no visible abnormalities. The reported incidence of Van der Woude syndrome varies in the literature from 1:100 000 to 1:40 000 births.3–6 VWS is present in approximately 2% of facial cleft patients and is often referred to in the literature as the most common clefting syndrome.7 VWS has been reported to show near complete penetrance and equal gender distribution.4,7

The defining characteristics of VWS are the congenital orofacial anomalies which include distinctive congenital lower lip pits.7,8 These are the principal manifestations of VWS and they occur in 88% of affected individuals. In 64% of cases they have been reported to be the only defect detected.4 Other cardinal signs of VWS include hypodontia in addition to orofacial clefting.4,9

Almost all cases of VWS have shown linkage to a region at chromosome 1q32-p41, known as VWS locus 1. However, some affected individuals have instead shown linkage to a second chromosomal locus (VWS locus 2), which is located at 1p34.10 More recently, a gene responsible for VWS has been identified. A mutation affecting the gene that encodes for interferon regulatory factor six (IRF6), which is located at the VWS critical region of 1q32–p41, underlies the majority of VWS cases.10 It is of great interest that a monogenic mutation can cause such a wide range of effects. Modifier loci have also been proposed to account for the highly variable expression of VWS.11

Diagnosis of VWS can be made clinically, based on the presence of congenital lip pits and other orofacial anomalies, which may occur together or exclusively. Most of the developmental anomalies are congenital and hence clinical diagnosis may occur soon after birth for the majority of cases. There is a varying degree of expressivity that must be accounted for when diagnosing patients. Genetic counselling is also vital in the definitive diagnosis and management of affected individuals.

The distribution of clinical phenotypes of VWS described in the literature varies greatly and for those cases that are not diagnosed around birth, dentists will be on the frontline in diagnosing the condition. Therefore, it is important that they have some understanding of the nature and extent of phenotypic variation in affected individuals. The aim of this study was to describe the range of clinical presentations in 22 individuals with VWS with a view to facilitating diagnosis of the syndrome.

Materials and methods

Study sample

This was a retrospective study of 22 patients with a diagnosis of Van der Woude syndrome, undertaken at the Australian Craniofacial Unit (ACFU) in the Women’s and Children’s Hospital in Adelaide, Australia. Management of cleft lip and palate children has been undertaken for over 30 years at the ACFU. Both South Australians and patients from other states have been treated by a multidisciplinary team and the ACFU has an extensive database of VWS patients. There were three extended families with affected members included in the study cohort. Ethical consent (WCH: 209A) was obtained to clinically examine these affected individuals, as well as evaluate their medical case notes.

The frequency of VWS amongst cleft patients at the ACFU and in the general Australian population was calculated. The mode of inheritance and penetrance rate of VWS were also determined. Penetrance rate was determined from the number of VWS patients with a clinical manifestation divided by the total numbers of carriers and patients expressing VWS phenotypes. Gene carriers without clinical phenotype were identified from pedigree analysis.

Genetics

Some case notes contained reports of genetic counselling that confirmed the presence of the syndrome in the affected individual or in one of their affected family members. Genetic testing for the mutation responsible for VWS is not yet available in Australia.

Clinical manifestations

Clinical manifestations were determined by medical case-note review and verified against archived clinical photographs. Oral examination of some patients was carried out by the authors and compared with documented findings. The presence, type and location of lip pits were recorded. The presence or absence of cleft lip and/or cleft palate was recorded. Information on affected family members, who could not be contacted or were deceased, was obtained from interviews with other relatives.

Dental anomalies

The prevalence of hypodontia and/or presence of any dental malocclusion was determined by clinical examination and review of relevant radiographs obtained at the ACFU.

Results

There was a total of 22 VWS affected patients on the ACFU database, including the members of three extended families. The prevalence of VWS among facial cleft patients was 1.5% (10 male and 12 female patients with VWS among a total of 1482 facial cleft patients on the ACFU database). The prevalence of VWS in the general Australian population is estimated to be 1 in 70 000. The gender distribution of affected individuals was almost even (45% male and 55% female).

There were 19 patients with lower lip pits or sinuses. Of those, 17 had bilateral symmetric lip pits. There was one report of asymmetry of the lip pits with one pit replaced by a nodule. There was also one report of a unilateral shallow lip pit. The overall prevalence of lip pits as a VWS phenotype in this study cohort was 86%. The lip pits were removed in early childhood prior to development of symptoms.

Cleft phenotypes displayed in ACFU patients included bifid uvula, submucous cleft palate, isolated cleft palate, incomplete and complete unilateral or bilateral cleft lip and palate (Table 1). Seven patients (32%) had bilateral cleft lip and palate, seven patients (32%) had unilateral cleft lip and palate, five patients (23%) had submucous cleft palate, and one more patient displayed a bifid uvula, which is a microform of the submucous clefting phenotype. Two patients (9%) had isolated cleft hard and soft palate. None of the patients had a cleft lip anomaly only.

Table 1.   Cleft phenotypes presenting in ACFU patients
Cleft phenotypeNo. of type/total (%)
Bilateral cleft lip and palate7/22 (32)
Unilateral cleft lip and palate7/22 (32)
Isolated cleft palate2/22 (9)
Submucous cleft palate6/22 (27)
Cleft lip0/22 (0)

Other anomalies that occurred in three of the VWS affected individuals included molar incisor hypomineralization (MIH), patent ductus arteriosus, and impaired neuropsychological development.

There were many cases of hypodontia in this study cohort. Nineteen of the 22 (86%) VWS affected individuals had reports of missing permanent teeth. The most common missing teeth were the permanent maxillary lateral incisors associated with the respective unilateral or bilateral clefting phenotype. Six of the 19 patients who were reported to have hypodontia had missing second premolars. All four different clefting phenotypes – unilateral cleft lip and palate, bilateral cleft lip and palate, isolated cleft palate and submucous cleft palate – were found to occur with hypodontia.

Analysis of family trees of the three extended families with affected members revealed an autosomal dominant mode of inheritance of VWS. VWS family 1 was shown to have an affected member in each generation as well as close to 100% penetrance (Fig 1). Family tree diagrams of the two other extended families in the study population were not included due to inadequate information on some affected individuals.

Figure 1.

 Family tree of Van der Woude family 1.

Discussion

Van der Woude syndrome has been determined to display an autosomal dominant mode of inheritance. This is reflected in the extended families who had multiple VWS affected members in each generation, as well as male-to-male transmission. The reported penetrance rate of VWS ranges from 80% to 100%. Our study population exhibited close to 100% penetrance, which agreed with the results of previous VWS epidemiological studies.4,7

The prevalence of VWS among cleft populations has been reported in the literature to range from 0.37% to 6%.12 A prevalence of 1.5% was noted amongst cleft patients from the ACFU. From the results of this study, the prevalence of VWS in the Australian population can be estimated to be around 1 in 70 000. This is similar to what has been previously reported: 1 in 60 000 to 1 in 100 000 live births for Caucasian populations.4,7 Therefore, it is likely that there are approximately 300 individuals affected by VWS living in Australia at the present time. It is reasonable to suggest that VWS individuals in Australia do not have an increased rate of mortality due to the availability of adequate health care to treat the congenital defects. There was no discernible difference in gender distribution of affected individuals, which was consistent with the results of previous studies.7,13

Patients in this study exhibited a full range of cleft phenotypic expression. Cleft types that were displayed included bifid uvula, submucous cleft palate, isolated cleft palate, and incomplete and complete unilateral or bilateral cleft lip and palate. This highlights the high degree of phenotypic variation in VWS. The cleft-type distribution differs among different studies (Table 2). According to previous studies, approximately two-thirds of cleft patients have cleft lip and palate, and the remaining one-third have cleft palate.11 In this series, approximately 64% displayed cleft lip and palate and approximately 36% had cleft palate only (including patients with submucous cleft palate only).

Table 2.   Comparison of distribution of cleft phenotypes between this study and other studies
 This studyHuang et al. (2007)Martelli-Junior et al. (2007)Onofre et al. (1997)Rintala and Ranta (1981)Shprintzen et al. (1980)
  1. CLP = cleft lip and palate; ICP = isolated cleft palate; SMCP = submucous cleft palate; CL = cleft lip.

CLP64%83%80%67%37%30%
ICP9%17%5%17%43%21%
SMCP27%0%0%0%8%13%
CL0%0%10%16%0%4%
No cleft0%0%5%0%13%34%
Total2264201337957
CountryAustraliaTaiwanBrazilBrazilFinlandUSA

In this study, no VWS patients were affected with cleft lip only (without cleft palate). This finding is similar to those of previous studies that have reported no cases or very low prevalence of the cleft lip only clinical phenotype.5,7,13 However, a study by Onofre et al.14 showed that over 16% of a South American VWS sample had a cleft lip anomaly.

In this series there was a high proportion of VWS patients who had submucous cleft palate. Twenty-seven per cent of the VWS cases had submucous cleft palate compared with 13% in a study by Shprintzen et al.7 and 8% in a study by Rintala and Ranta.5 All six cases of submucous cleft palate in this study occurred with bilateral lower lip pits or sinuses. This highlights the importance of diagnosis of VWS from the congenital lower lip pits or sinuses. Figure 2 shows a VWS based on female displaying characteristic bilateral lower lip pits. However, she also has a submucous cleft palate. The submucous cleft palate could not be diagnosed from an extra-oral examination alone and, hence, the presence of the lip pits should alert the physician or dentist to the possibility of a submucous cleft palate in this patient. If lip pits are not detected and VWS is not diagnosed, then a submucous cleft palate that may have occurred with the lip pits will most likely go undiagnosed until later in childhood when the effects of the submucous cleft palate become evident (e.g., hearing loss).

Figure 2.

 Affected female with very superficial congenital bilateral lower lip pits that were only detectable on probing. She also had submucous cleft palate. This highlights the importance and difficulty of diagnosis of VWS from lip pits alone.

Submucous cleft palate is clinically characterized by Calnan’s triad.15 The triad of intra-oral features are bifid uvula, notching of the hard palate and lucency of the mucosa at the midline of the palate (Fig 3). Although the overlying mucosa of the cleft is intact, the underlying muscles have lost their correct attachments and are incorrectly aligned (similar to a cleft palate). Not all these features need to be present to diagnose this condition.16 A submucous cleft palate can be easily mistaken at birth for a normal palate. Hence, dentists must be aware of the characteristic clinical features of this condition as they are often at the frontline of its diagnosis.

Figure 3.

 Affected male with submucous cleft palate. The soft palate cleft and bifid uvula are visible in this photograph. Also, note the translucent mucosal line along the midline of the hard palate which indicates a submucous cleft of the hard palate.

The main problems associated with submucous cleft palate are feeding difficulties at birth, impaired speech development, middle ear pathology and facial growth problems.15 However, only 10% of cases are symptomatic.17 The feeding problems during infancy often occur together with nasal regurgitation.15 Newborn infants should be examined intra-orally both visually and by palpation with a finger. Any feeding difficulties without an obvious cause should alert the physician or dentist to the possibility of submucous cleft palate.15

The definitive diagnosis of submucous cleft palate may be delayed until speech problems are identified, which is reported to be at two and half years of age when speech can be assessed accurately.17 Studies have shown that hypernasal speech and loss of labial sounds as a result of velopharyngeal incompetency are commonly associated with submucous cleft palate. Nasality is particularly noticeable on high vowels such as ee/i/ and oo/u/.18 Submucous cleft palate has also been shown to have a high frequency of association with middle ear disease (chronic otitis media) and hearing loss, which requires surgical intervention and insertion of ventilation tubes (ear grommets) to prevent infection and damage to the delicate middle ear structures.19

The strong association between hypodontia and VWS has been established previously.20 In this study, 60% of the study cohort were reported to have missing permanent teeth. This percentage may well have been higher if better dental records had been obtained from VWS family 1, but this was not possible. Twenty-seven per cent of this VWS cohort displayed missing second premolars. This is slightly higher than the 18% of cleft lip and palate patients who were reported by Shapira et al.21 to have missing second premolars. A study by Oberoi et al.22 also showed that congenital absence of the mandibular second premolars was more common in patients with VWS than in matched cleft controls. Interestingly, in this study, the severity of the clefting phenotype did not correspond with the frequency of hypodontia as had been reported by Oberoi et al.22 In fact, an affected female with bifid uvula had the greatest number of missing adult teeth. Bifid uvula is considered to be a microform of clefting, hence the least severe clefting phenotype corresponded with the highest frequency of hypodontia. An affected male with a submucous cleft of the hard palate from the same family had the next most severe expression of hypodontia with four missing adult teeth. All four affected individuals from this family were reported to have multiple teeth missing. This suggests that this family may have an additional genetic predisposition to hypodontia.

The occurrence of hypodontia in cleft patients may be attributed to multiple genetic and environmental factors, altered mesenchymal differentiation, and the direct effect of clefting on facial primordia.22,23 The high prevalence of hypodontia in VWS has direct clinical implications for dentists and early identification is vital for effective treatment planning. Congenital absence of teeth may contribute to constriction of the dental arches, especially in the maxilla, and this can result in dental malocclusion and skeletal discrepancies between the arches, which may necessitate orthodontic and/or orthopaedic intervention.

There was an isolated case of MIH that occurred in an affected male who had unilateral cleft lip and palate. There has been no previous report of this dental anomaly occurring in a VWS affected individual in the literature. However, in this case MIH is likely to be an isolated independent anomaly and not an associated feature of VWS.

The overall prevalence of characteristic lower lip pits in this study cohort was 86%. Hence, detection of the lower lip pits is vital for the correct diagnosis of VWS in the vast majority of affected individuals. Dentists are on the frontline in diagnosing VWS. However, diagnosis of lip pits can be difficult because of several different types of lip pits that can occur in VWS (Figs 4–7). These include bilateral symmetric, bilateral asymmetric, unilateral (which are considered incomplete expressions of the trait), median and microforms.9 The microforms of the lip pits occur as conical elevations, transverse mucosal ridges, or openings with no depth.14,24

Figure 4.

 Affected female with characteristic bilateral lower lip sinuses. She also has submucous cleft palate.

Figure 5.

 Affected female with characteristic bilateral lower lip sinuses and a bilateral cleft lip and palate.

Figure 6.

 Affected male with bilateral cleft lip and palate and characteristic congenital paramedian bilateral lower lip pits.

Figure 7.

 Affected female with unilateral cleft lip and palate and a unilateral lower lip nodule. This lower lip nodule is a microform of the characteristic lower lip pit.

In early childhood, the pits are often on the vermillion zone of the lower lip and are centered on top of conical elevations, but they progress to form simple depressions in adulthood, which can be asymptomatic.7 The sinus tract may enter the orbicularis oris muscle. Some fibres of this skeletal muscle have been found to be orientated in such a manner that, upon contraction, they induce a peristaltic ejection of mucous secretion. If the communicating ducts of the mucous acini are open then the fistulae may exude a mucin-like fluid.2 Chronic discomfort (due to inflammation as a result of the salivary excretions and/or bacterial penetration) and poor aesthetics are common reasons cited for surgical removal of lip pits.9

The critical significance of lip pits is that their expression is reported to be associated with increased severity of the cleft lip and/or cleft palate. Studies reported in the literature have described the types of cleft associated with different types of lower lip pits.3,5,14,24 These investigations have shown that the bilateral, unilateral or mixed-type lip pits are more likely to occur with cleft lip with or without cleft palate. This finding was also reflected in the ACFU patients with VWS. Fourteen of the 19 patients who had lower lip pits displayed either unilateral cleft lip and palate or bilateral cleft lip and palate.

Diagnosis of lip pits in cleft patients has further implications for genetic counselling because the probability of a cleft patient who also has lip pits having offspring with cleft lip with or without cleft palate, is reported to be 10 times greater than the probability of a cleft patient without the lip pits.2,3,7,25 All VWS-affected parents should be cautioned that they carry a risk of 50% of having a child with a cleft lip and/or cleft palate due to its autosomal dominant mode of transmission. Hence, genetic counselling is a critical stage in the management of a VWS patient and their family. A full family history and confirmed differential diagnosis of VWS from other overlapping syndromes (e.g., popliteal pterygium syndrome)10 is needed before counselling is given to family members. Information regarding the pattern of inheritance, the range of clinical manifestations, and the consequence of these phenotypes should be emphasized.

The sample size in this study is relatively small and may not be truly representative of VWS in Australia. However, this is the first study of VWS conducted in Australian families and it provides a foundation for further research based on larger numbers of families.

Conclusions

The highly variable phenotypic expression of VWS is demonstrated by the wide range of clefting phenotypes in this study cohort. The distribution of clefting phenotypes was not consistent with that reported in the literature, with a greater proportion of VWS individuals affected by submucous cleft palate. Under-diagnosis of VWS has been reported to be linked to lack of detection of the lower lip pits. As this study has shown, submucous cleft palate may go undetected if the lower lip pits are not detected and VWS is not diagnosed. Submucous cleft palate has been shown to result in feeding difficulties, speech and hearing impairment and facial growth problems. Hypodontia is also a significant phenotypic expression of VWS and will require management by a dental team. It is important that dentists appreciate the nature and extent of variation in clinical presentation of individuals with VWS and are proficient in its diagnosis. Families with an affected VWS member should undergo genetic counselling as part of their management to educate them on the clinical phenotypes and consequences, as well as, the risk of transmission to future offspring.

Acknowledgements

We would like to thank the Australian Craniofacial Unit staff for the use of their resources and patient base. We would also like to acknowledge that patients of Dr Mark Moore were part of the study cohort.

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