Van der Woude syndrome

Autosomal dominant clefting syndrome with lower lip pits and cleft lip or palate

Van der Woude syndrome
Synonyms	Van der Woude syndrome 1, VWS, VDWS, lip-pit syndrome, cleft lip/palate with mucous cysts of the lower lip
Pronounce	N/A
Specialty	Medical genetics, Pediatrics, Oral and maxillofacial surgery, Plastic surgery, Dentistry
Symptoms	Lower lip pits, cleft lip, cleft palate, hypodontia, narrow arched palate, bifid uvula, submucous cleft palate
Complications	Feeding difficulty, speech problems, dental abnormalities, hearing problems, recurrent ear infections, psychosocial effects
Onset	Congenital
Duration	Lifelong
Types	N/A
Causes	Pathogenic variants in IRF6 or GRHL3
Risks	Family history of autosomal dominant orofacial clefting syndrome
Diagnosis	Clinical examination, family history, examination for lip pits, palate evaluation, dental evaluation, and genetic testing
Differential diagnosis	Popliteal pterygium syndrome, nonsyndromic cleft lip and palate, orofacial cleft, Pierre Robin sequence, cleft palate
Prevention	N/A
Treatment	Multidisciplinary cleft care, cleft repair, speech therapy, dental care, orthodontics, genetic counseling, lip pit excision when needed
Medication	N/A
Prognosis	Usually good with coordinated cleft and dental care
Frequency	Rare; estimated about 1 in 40,000 to 1 in 100,000 people
Deaths	N/A

Van der Woude syndrome is a rare inherited orofacial cleft syndrome characterized by lower lip pits, cleft lip with or without cleft palate, cleft palate alone, and sometimes hypodontia. It is usually inherited in an autosomal dominant manner and is most often caused by pathogenic variants in the IRF6 gene. A smaller proportion of clinically similar cases are caused by variants in GRHL3.IRF6-Related) Disorders([link). GeneReviews, National Center for Biotechnology Information.Van) der Woude syndrome([link). MedlinePlus Genetics. Van der Woude syndrome is considered the most common syndromic form of cleft lip and palate. It may resemble nonsyndromic clefting, but the presence of lower lip pits, a family history of mixed cleft types, or missing teeth can suggest the diagnosis."Van der Woude Syndrome: A Syndromic Form of Orofacial Clefting".Journal of Oral and Maxillofacial Pathology.2012;PMC:3908796.

Overview

Van der Woude syndrome affects development of the lip, palate, and related oral structures. The hallmark feature is one or more congenital pits or sinuses of the lower lip. These pits may be small depressions, openings, or mucous-secreting tracts. The syndrome is notable for variable expressivity. In the same family, one person may have only lower lip pits, another may have cleft lip and palate, and another may have cleft palate only. Some affected individuals may have very mild findings and remain undiagnosed until a child or relative is born with a cleft.

Signs and symptoms

Clinical features vary from very mild to more obvious craniofacial involvement.

Major features

• Lower lip pits - Small congenital depressions or sinuses on the lower lip, often bilateral and paramedian.
• Cleft lip - Separation or opening of the upper lip that may be unilateral or bilateral.
• Cleft palate - Opening in the roof of the mouth that may affect feeding, speech, and ear function.
• Cleft lip and palate - Combined cleft of the lip and palate.
• Submucous cleft palate - A cleft of the palatal muscles covered by intact mucosa, sometimes difficult to detect.
• Bifid uvula - A split uvula that may be a clue to submucous cleft palate.
• Hypodontia - Congenital absence of one or more teeth.

Lip pit findings

• Bilateral lower lip pits - The classic finding, usually located on both sides of the midline of the lower lip.
• Unilateral lower lip pit - A single lip pit, often representing incomplete expression.
• Median lower lip pit - A lip pit near the center of the lower lip.
• Commissural lip pit - A pit near the corner of the mouth, less typical than lower lip pits.
• Mucous discharge - Saliva or mucous may drain from a lip pit because the tract can connect with minor salivary glands.
• Lip swelling - May occur if the pit tract becomes inflamed or obstructed.

Dental and oral findings

• Hypodontia - Missing teeth, often involving premolars or incisors.
• Narrow palate - A high or narrow arched palate may occur.
• Malocclusion - Abnormal dental bite may develop because of clefting or missing teeth.
• Ankyloglossia - Tongue-tie has been reported in some affected individuals.
• Dental arch constriction - Narrowing of the dental arch may occur with cleft palate or missing teeth.
• Speech disorder - Speech difficulties may occur with cleft palate or velopharyngeal insufficiency.

Associated findings

• Hearing loss - May occur secondary to recurrent otitis media in children with cleft palate.
• Otitis media - Middle ear infections are more common in children with cleft palate.
• Feeding difficulty - Newborns with cleft palate may have difficulty feeding.
• Congenital heart disease - Reported in some individuals, though not a core diagnostic feature.
• Syndactyly - Fusion of fingers or toes has been reported rarely.
• Polythelia - Supernumerary nipples have been reported rarely.
• Cerebral abnormality - Rare brain findings have been described in some reports.

Causes

Van der Woude syndrome is caused by pathogenic variants affecting genes involved in craniofacial development.

• IRF6 - The most common gene associated with Van der Woude syndrome.
• GRHL3 - A less common gene associated with Van der Woude syndrome type 2 and clinically similar disease.
• Haploinsufficiency - A mechanism in which one working copy of a gene is not enough for normal development.
• Transcription factor - IRF6 and GRHL3 participate in gene regulation during development of the oral epithelium and palate.
• Orofacial development - The embryologic process disrupted in Van der Woude syndrome.

Most cases are caused by variants in IRF6, a gene on chromosome 1 that encodes interferon regulatory factor 6. IRF6 is important for formation and maturation of tissues in the face, lips, and palate.IRF6) gene([link). MedlinePlus Genetics. Some individuals with a Van der Woude phenotype and no identifiable IRF6 variant have pathogenic variants in GRHL3, which can produce a nearly identical orofacial clefting phenotype."Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development".American Journal of Human Genetics.2014;94(1)

23-32.doi:10.1016/j.ajhg.2013.11.009.PMID:24360809.PMC:3882735.

Inheritance

Van der Woude syndrome is usually inherited in an autosomal dominant pattern.

• Autosomal dominant inheritance - One altered copy of the disease-associated gene can cause the syndrome.
• High penetrance - Most people who inherit a pathogenic variant show some clinical feature.
• Variable expressivity - Features may range from isolated lower lip pits to cleft lip and palate.
• De novo mutation - A new pathogenic variant may occur in a child with no known family history.
• Familial clefting - Multiple relatives may have different cleft types or only lip pits.
• Genetic counseling - Recommended for affected individuals and families.

Each child of an affected person has a 50 percent chance of inheriting the pathogenic variant. The severity of clefting or lip-pit expression cannot be predicted reliably from the parent's features alone.

Pathophysiology

Normal development of the lip and palate requires coordinated growth and fusion of facial prominences during early embryonic life. IRF6 and GRHL3 are involved in epithelial differentiation and palatal development.

• Embryogenesis - Van der Woude syndrome features arise during early facial development.
• Mandibular process - Abnormal development of the lower lip region contributes to lower lip pits.
• Palatal shelf - Failure of proper elevation, fusion, or remodeling can contribute to cleft palate.
• Orofacial cleft - Results from incomplete fusion of developing facial structures.
• Minor salivary gland - Lip pit tracts may be surrounded by mucous glands.
• Orbicularis oris - Lip pits may extend into or near this lip muscle.

Lower lip pits are thought to result from persistent developmental grooves or sinus tracts in the lower lip. Cleft lip and palate arise from disrupted fusion of facial and palatal structures during embryonic development.

Diagnosis

Diagnosis is usually clinical and may be supported by genetic testing.

Clinical examination

• Lower lip examination - Careful inspection for bilateral, unilateral, or subtle lower lip pits.
• Cleft lip - Evaluation for complete or incomplete clefting.
• Cleft palate - Examination of the palate for overt clefting.
• Submucous cleft palate - Assessment for bifid uvula, zona pellucida, or abnormal palatal muscle function.
• Family history - Review for relatives with lip pits, cleft lip, cleft palate, missing teeth, or speech problems.
• Dental examination - Evaluation for hypodontia, malocclusion, and dental arch abnormalities.

Genetic testing

• IRF6 genetic testing - Testing can confirm many cases of Van der Woude syndrome.
• GRHL3 genetic testing - Considered when clinical features are suggestive and IRF6 testing is negative.
• Multigene panel - A clefting or craniofacial gene panel may be used when the diagnosis is uncertain.
• Exome sequencing - May be considered in complex or atypical cases.
• Cascade testing - Testing of relatives may identify mildly affected family members.

Additional evaluation

• Speech evaluation - Important for children with cleft palate or suspected velopharyngeal dysfunction.
• Audiology - Hearing testing is important in children with cleft palate or recurrent ear infections.
• Otolaryngology - Evaluation may be needed for ear disease and airway concerns.
• Dental radiography - Useful for identifying missing teeth or dental development problems.
• Cardiac evaluation - Considered when a murmur, cyanosis, or other signs of congenital heart disease are present.

Differential diagnosis

The differential diagnosis includes other clefting syndromes and nonsyndromic orofacial clefts.

• Popliteal pterygium syndrome - An IRF6-related disorder with clefting, lip pits, popliteal webbing, genital anomalies, and nail or limb findings.
• Nonsyndromic cleft lip and palate - Isolated clefting without lip pits or syndromic features.
• Nail-patella syndrome - A genetic condition with nail and skeletal findings that may rarely be confused in broad dysmorphology evaluation.
• Pierre Robin sequence - Micrognathia, glossoptosis, and cleft palate.
• Stickler syndrome - A connective tissue disorder associated with cleft palate, eye findings, hearing loss, and joint problems.
• 22q11.2 deletion syndrome - May include palatal abnormalities, heart defects, immune problems, and developmental issues.
• Ectodermal dysplasia - May include dental abnormalities and craniofacial findings.
• Orofaciodigital syndrome - A group of disorders affecting the mouth, face, and digits.

Management

Management is individualized and usually requires a multidisciplinary cleft and craniofacial team.

Cleft care

• Cleft lip repair - Surgical repair improves lip form and function.
• Cleft palate repair - Surgical repair improves feeding, speech development, and separation of oral and nasal cavities.
• Velopharyngeal insufficiency - May require speech therapy, surgery, or prosthetic management.
• Feeding support - Specialized bottles and feeding strategies may be needed in infancy.
• Craniofacial team - Coordinates surgery, speech, dentistry, orthodontics, hearing care, and psychosocial support.

Lip pit management

• Lip pit excision - Surgical removal may be done for cosmetic reasons, chronic drainage, inflammation, or recurrent infection.
• Mucocele - May develop if salivary tissue or the pit tract is incompletely removed.
• Wound healing - Careful surgical planning helps reduce scarring and lip muscle complications.
• Observation - Small asymptomatic pits may not require surgery.

Dental and orthodontic care

• Dental care - Regular dental follow-up is important because hypodontia and malocclusion are common.
• Orthodontics - May be needed for dental arch alignment and bite correction.
• Prosthodontics - May be helpful when teeth are missing.
• Hypodontia management - Treatment may include orthodontics, implants, bridges, or prosthetic replacement when appropriate.

Speech and hearing care

• Speech therapy - Helps with articulation, resonance, and speech development.
• Audiology - Hearing testing is recommended, especially in children with cleft palate.
• Tympanostomy tube - Ear tubes may be needed for recurrent otitis media or middle ear fluid.
• Otolaryngology - ENT care may be needed for hearing, middle ear disease, or airway issues.

Genetic counseling

• Genetic counseling - Explains autosomal dominant inheritance, variable expression, recurrence risk, and testing options.
• Prenatal testing - May be possible when the familial pathogenic variant is known.
• Preimplantation genetic testing - May be considered by some families using assisted reproduction.
• Family screening - Examination of relatives for subtle lip pits, clefting, or missing teeth may clarify inheritance.

 ==Prognosis==
 The prognosis is usually good with coordinated cleft, dental, speech, and surgical care.

• Normal life expectancy - Most affected individuals have normal lifespan.
• Speech outcome - Often improves with cleft repair and speech therapy.
• Dental outcome - Depends on the severity of hypodontia and malocclusion.
• Psychosocial health - Support may be helpful for visible facial differences, surgical care, and speech concerns.
• Recurrence risk - Offspring of an affected person have a 50 percent risk of inheriting the familial pathogenic variant.

Epidemiology

Van der Woude syndrome is rare, with estimated incidence generally reported between about 1 in 40,000 and 1 in 100,000 people. It is considered the most common syndromic cause of cleft lip and palate and may account for a small but important proportion of all cleft lip and palate cases. The condition affects males and females equally because it is autosomal, not sex-linked.

History

The association between lower lip pits and cleft lip or palate was described by Anne Van der Woude in 1954. Lower lip pits had been described earlier, but Van der Woude recognized their association with familial orofacial clefting.

• Anne Van der Woude - The physician associated with the syndrome's modern description.
• Lower lip pits - The feature that helped distinguish the syndrome from nonsyndromic clefting.
• Cleft lip and palate - The major associated craniofacial finding.
• IRF6 - The gene that later explained many families with the syndrome.

Patient education

Patients and families should know that Van der Woude syndrome is inherited and variable.

• Family history - Relatives may have only lip pits or missing teeth and no cleft.
• Cleft team care - Coordinated care improves feeding, speech, hearing, dental, and surgical outcomes.
• Dental follow-up - Missing teeth and orthodontic issues are common.
• Speech therapy - Important for children with cleft palate or velopharyngeal insufficiency.
• Genetic counseling - Important for recurrence risk and family planning.
• Psychosocial support - Helpful for children and adults affected by facial differences or repeated surgeries.

When to seek medical care

Medical evaluation is appropriate for infants, children, or adults with lip pits, clefting, or family history of clefting.

• Lower lip pits - Congenital pits or mucous-draining openings on the lower lip should be evaluated.
• Cleft lip - Any cleft lip should be assessed by a cleft or craniofacial team.
• Cleft palate - Feeding difficulty, nasal regurgitation, or abnormal palate findings require evaluation.
• Speech delay - Speech problems may indicate velopharyngeal dysfunction or submucous cleft palate.
• Hearing loss - Hearing concerns should be evaluated, especially in children with cleft palate.
• Missing teeth - Hypodontia may be a clue to Van der Woude syndrome.
• Family history - Relatives of an affected person may benefit from examination and genetic counseling.

See also

• Cleft lip
• Cleft palate
• Orofacial cleft
• Lower lip pits
• Hypodontia
• IRF6
• GRHL3
• Popliteal pterygium syndrome
• Autosomal dominant
• Genetic counseling
• Speech therapy
• Oral and maxillofacial surgery
• Plastic surgery
• Craniofacial surgery

External links

• [[1](https://www.ncbi.nlm.nih.gov/books/NBK1407/) GeneReviews - IRF6-Related Disorders]
• [[2](https://medlineplus.gov/genetics/condition/van-der-woude-syndrome/) MedlinePlus Genetics - Van der Woude syndrome]
• [[3](https://medlineplus.gov/genetics/gene/irf6/) MedlinePlus Genetics - IRF6 gene]
• [[4](https://rarediseases.org/rare-diseases/van-der-woude-syndrome/) NORD - Van der Woude syndrome]
• [[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC3882735/) Dominant Mutations in GRHL3 Cause Van der Woude Syndrome]

1. IRF6-Related Disorders - GeneReviews® - NCBI Bookshelf