Van Der Woude Syndrome: Symptoms, Types, Causes and Treatment

Van der Woude Syndrome (VWS) is the most common syndromic form of orofacial clefting, characterized primarily by lower lip pits and cleft lip and/or palate. While rare, VWS is a striking example of how genetic changes can lead to recognizable patterns of craniofacial anomalies. In this comprehensive guide, we’ll explore the key symptoms, clinical types, underlying causes, and the latest approaches to management and treatment, synthesizing the best available research for a clear and human-centered overview.

Symptoms of Van Der Woude Syndrome

Van der Woude Syndrome presents with a distinctive set of features that set it apart from other craniofacial conditions. Most notably, individuals may have lower lip pits, cleft lip, cleft palate, or a combination of these. However, the symptoms may vary widely among affected individuals—even within the same family.

Symptom	Frequency/Details	Additional Notes	Source
Lip pits	~88% of cases	Bilateral, paramedian, often moist	1 2 3 4 8 13
Cleft lip/palate	21–70% (varies by study)	May occur alone or with lip pits	1 2 3 4 8 9 13
Missing teeth	Occasional	Hypodontia, mainly upper jaw	2 8
Minor features	Variable	Mild depressions, small mounds, fistulas	1 4 13

Table 1: Key Symptoms

Lower Lip Pits

Lower lip pits are the hallmark of Van der Woude Syndrome. These typically appear as symmetrical, small depressions or fistulas on either side of the midline of the lower lip (paramedian location). The pits may be moist due to the presence of salivary glands, sometimes excreting small amounts of saliva. They can vary from shallow dimples to deep tracts extending into the underlying tissue. In some cases, instead of typical pits, small mounds or minor depressions may be present, which can be subtle and easily overlooked during a routine examination 1 2 3 4.

Orofacial Clefts

Cleft lip, cleft palate, or both are present in a significant proportion of VWS cases. These clefts may occur with or without the presence of lip pits. VWS accounts for approximately 2% of all orofacial cleft cases, making it the most common syndromic form of this birth defect. The distribution of clefts varies, with some individuals presenting only with cleft palate, others with cleft lip, and some with both. The severity and type of cleft are highly variable and may even differ among family members with the same genetic mutation 1 2 3 7 8 9.

Dental and Other Features

Some individuals with VWS may have missing teeth (hypodontia), particularly in the upper jaw. Other minor features can include small mounds of tissue on the lower lip, minor depressions, and, rarely, hypotonia (reduced muscle tone) of the lower lip. These features contribute to the facial asymmetry sometimes reported in VWS 2 4 8 15.

Variability and Penetrance

VWS is notable for its high penetrance (up to 96.7%), meaning most people with the causative mutation will show some features of the disease. However, there is considerable variability in expression—even within the same family—ranging from subtle lip pits to more severe clefting 1 4 7 9.

Types of Van Der Woude Syndrome

Though VWS is defined by its cardinal features, the syndrome’s clinical expression can be highly variable. Understanding its types helps in diagnosis, genetic counseling, and management.

Type	Defining Features	Notes on Inheritance/Overlap	Source
Classic VWS	Lip pits with/without cleft lip/palate	Autosomal dominant, high penetrance	1 3 4 7 8 13
VWS without cleft	Lip pits only	Still carries genetic risk	1 4 13
VWS without lip pits	Cleft lip/palate only	Harder to distinguish clinically	1 7 8 13
Overlap syndromes	VWS + Popliteal Pterygium Syndrome (PPS)	PPS includes limb/genital anomalies	7

Table 2: Types and Clinical Variants

Classic Van der Woude Syndrome

The classic form is defined by the presence of lower lip pits along with cleft lip, cleft palate, or both. This combination is the most recognizable and typically prompts a diagnosis of VWS, especially when there’s a family history 1 3 4 8 13.

VWS without Clefts

Some individuals exhibit only the characteristic lower lip pits without any clefting. This “mild” form may go unrecognized, but these individuals can still transmit the syndrome to their children, who may display more severe features. Lip pits alone, particularly when familial, should prompt further evaluation 1 4 13.

VWS without Lip Pits

Conversely, some affected individuals may have only a cleft lip and/or palate without visible lip pits. This presentation makes diagnosis more challenging, as it can be mistaken for non-syndromic clefting. However, a careful family history and examination of relatives may reveal subtle features or affected family members 1 7 8 13.

Overlap with Popliteal Pterygium Syndrome

Rarely, VWS overlaps with Popliteal Pterygium Syndrome (PPS), a related condition caused by mutations in the same gene (IRF6). PPS includes all the features of VWS plus webbing of the popliteal region (behind the knee), genital anomalies, and digital abnormalities. The distinction is important for prognosis and genetic counseling 7.

Causes of Van Der Woude Syndrome

Van der Woude Syndrome is a genetic disorder with a well-established molecular basis. Understanding its causes is vital for diagnosis, counseling, and future research.

Cause	Genetic Mechanism	Prevalence/Details	Source
IRF6 mutations	Haploinsufficiency, missense	~70% of cases	3 5 6 10 11 12
GRHL3 mutations	Dominant-negative effect	Minority of cases (~17%)	5 6
Chromosome 1 deletions	Microdeletions at 1q32-41	Involve IRF6 and/or GRHL3	10 11
Inheritance	Autosomal dominant	High penetrance, variable expressivity	1 3 4 7 8 13

Table 3: Genetic Causes

IRF6 Gene Mutations

The majority of VWS cases are caused by mutations in the interferon regulatory factor 6 (IRF6) gene, located on chromosome 1q32-q41. IRF6 plays a crucial role in the development of orofacial structures. Most mutations lead to “haploinsufficiency,” meaning a single functional copy of the gene is insufficient for normal development. Mutations may include missense, nonsense, or frameshift variants, and microdeletions involving the IRF6 locus have also been documented 3 5 10 11 12.

GRHL3 Gene Mutations

In a subset of families without IRF6 mutations, pathogenic changes in the GRHL3 (grainyhead-like 3) gene—also on chromosome 1—have been identified. GRHL3 mutations disrupt the development of the oral periderm, a critical epithelial layer during palate formation, resulting in a phenotype nearly indistinguishable from classic VWS. These mutations act through a dominant-negative effect 5 6.

Chromosome 1 Microdeletions

Microdeletions encompassing the IRF6 and/or GRHL3 genes on chromosome 1q32.2–q41 can also cause VWS. These deletions may be inherited or arise de novo and typically result in the core features of VWS without significant additional anomalies 10 11.

Inheritance Patterns

VWS follows an autosomal dominant inheritance pattern with high penetrance (96–99%), but variable expressivity. This means that while most individuals with the mutation will show symptoms, the severity and combination of features can differ—even among close relatives 1 3 4 7 8 13.

Variable Expression and Modifying Factors

The syndrome’s wide variability suggests there may be additional genetic or environmental factors that modify the expression of the main IRF6 or GRHL3 mutation. Cases have even been reported where identical twins, carrying the same mutation, display different features 5.

Treatment of Van Der Woude Syndrome

Managing Van der Woude Syndrome requires a multidisciplinary approach, with the goal of restoring function, appearance, and quality of life. Treatment is tailored to each individual's symptoms and preferences.

Treatment	Main Purpose	Notes on Approach/Outcome	Source
Surgical excision (lip pits)	Cosmetic, functional	Vertical wedge/inverted-T/muscle repair preferred	4 14 15
Cleft repair	Restore speech/feeding	Standard cleft surgery protocols	4 17
Dental management	Address missing/extra teeth	Prosthodontics, orthodontics	2 8
Genetic counseling	Family planning, risk info	Essential due to inheritance	1 4 13 16

Table 4: Treatment Modalities

Surgical Management of Lip Pits

Lip pits, while often asymptomatic, may cause cosmetic concerns or intermittent saliva leakage. Surgical removal is usually requested for aesthetic reasons or if the pits are deep or symptomatic. Several surgical techniques have been described:

• Vertical Wedge Excision: Removes the pit and associated tract with a wedge of tissue, minimizing recurrence and scarring.
• Inverted-T Lip Reduction: Particularly beneficial for deeper pits or associated hypotonia.
• Mutaf-Goldstein Technique: Offers good aesthetic and functional results, especially in cases with lip muscle involvement 4 14 15.

Simple excision alone may be insufficient and can result in recurrence or complications such as mucocele formation. Deep muscle repair may be required to restore symmetry and tone to the lower lip 4 14 15.

Cleft Lip and Palate Repair

Clefts are repaired using standard surgical protocols, typically in infancy or early childhood. The timing and type of surgery depend on the nature and severity of the cleft. Early intervention is vital for feeding, speech development, and facial growth. Repeat procedures or revisions may be necessary as the child grows 4 17.

Dental and Orthodontic Care

Missing teeth (hypodontia) are addressed with prosthetic replacements, bridges, or orthodontic treatments. Early dental assessment is important for planning long-term oral rehabilitation 2 8.

Genetic Counseling

Given the autosomal dominant inheritance and high penetrance of VWS, genetic counseling is an essential aspect of care. Affected individuals and their families should be informed of the risk of transmission (50% chance per child) and the variability of expression. Physical examination of relatives, including subtle features, is crucial for accurate counseling 1 4 13 16.

Multidisciplinary Approach

Optimal outcomes require coordination between plastic surgeons, oral and maxillofacial surgeons, geneticists, pediatricians, speech therapists, and dental specialists. Psychosocial support may also be beneficial for patients and families coping with visible facial differences or functional challenges 4 17.

Conclusion

Van der Woude Syndrome is a rare but important genetic craniofacial disorder with distinct clinical and molecular features. Early recognition, comprehensive evaluation, and multidisciplinary care are key to optimal outcomes.

Key Points:

• Van der Woude Syndrome is characterized by lower lip pits and cleft lip and/or palate, with variable features even within families 1 2 3 4 8.
• The majority of cases are caused by mutations in the IRF6 gene; some involve GRHL3 or microdeletions of chromosome 1 3 5 6 10 11.
• Inheritance is autosomal dominant with high penetrance but variable expressivity 1 4 7 8 13.
• Treatment is individualized, typically involving surgical correction of lip pits and clefts, dental rehabilitation, and genetic counseling 4 14 15 17.
• Early identification and a multidisciplinary approach are essential for managing the physical and psychosocial aspects of the syndrome 4 17.

Understanding Van der Woude Syndrome not only guides clinical care but also provides insight into the genetic and developmental processes that shape the human face.