eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

van der Woude Syndrome

Gregory P Conners, MD, MPH, MBA, Professor of Emergency Medicine and Pediatrics, Departments of Emergency Medicine and Pediatrics, University of Rochester School of Medicine and Dentistry

Updated: Apr 16, 2009

Introduction

Background

van der Woude syndrome is an autosomal dominant syndrome characterized by a cleft lip or cleft palate, distinctive pits of the lower lips, or both. It is the most common syndrome associated with cleft lip or cleft palate. The degree to which individuals who carry the gene are affected widely varies, even within families. These variable manifestations include lower lip pits alone, absent teeth, or isolated cleft lip and cleft palate of varying severity. Hypodontia (absent teeth) has been increasingly recognized as a frequently associated anomaly. Many other associated anomalies have also been described.

Cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)

Closer view of cleft lip and cleft palate in an infant with van der Woude syndrome, showing raised pits of lower lip. (Photo courtesy of Mary J. Hauk, DDS.)

Intraoral view of cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)

Pathophysiology

The most prominent and consistent features of van der Woude syndrome are orofacial anomalies caused by an abnormal fusion of the palate and lips at 30-50 days postconception. Most cases of van der Woude syndrome have been linked to a deletion in chromosome 1q32-q41; however, a second chromosomal locus at 1p34 has also been identified. The responsible mutation has been identified in the interferon regulatory factor-6 (IRF -6) gene, but the exact mechanism of this mutation on craniofacial development is uncertain.

Demonstrating the presence or absence of an IRF-6 mutation can be helpful when distinguishing between uncomplicated cleft lip and/or cleft palate and van der Woude syndrome. A wide variety of chromosomal mutations that cause van der Woude syndrome and are associated with IRF-6 gene mutations have been described. A potential modifying gene has been identified at 17p11.2-p11.1. 

Frequency

International

In general, van der Woude syndrome affects about 1 in 100,000-200,000 individuals. About 1-2% of patients with cleft lip or cleft palate have van der Woude syndrome.

Mortality/Morbidity

The severity of van der Woude syndrome widely varies, even within families. Approximately 25% of individuals with van der Woude syndrome are asymptomatic or have minimal symptoms, such as absent teeth or trivial indentations in the lower lips. Others have severe clefting in the lip or palate. Lip pits are often associated with accessory salivary glands that empty into the pits, which occasionally leads to embarrassing visible discharge. Hypodontia is present in 10-81% of affected individuals. Most upper and/or lower second premolars are frequently absent.

Race

Differences among races have not been described.

Sex

van der Woude syndrome equally affects both sexes. A single, small study has suggested that males with the syndrome may have poorer cognitive function than females.¹

Clinical

History

• Because of its variability, obtaining a detailed family history is important in diagnosing van der Woude syndrome. However, approximately 30-50% of all cases of van der Woude syndrome arise as a de novo mutation.
• The pedigree should suggest an autosomal dominant inheritance pattern, unless the phenotype is the result of a de novo mutation in the affected individual. Expressivity also widely varies, and careful clinical examination of parents and relatives may be necessary.
• Physical examination of relatives, close examination of family photos, or interviews of older relatives may be necessary to identify minimally affected family members.

Physical

• Orofacial manifestations
  • van der Woude syndrome is characterized by cleft lip and/or cleft palate and distinctive lower lip pits. This combination is present in approximately 70% of overtly affected individuals but is present in less than one half of those who carry the gene.
  • Severity may widely vary, even in members of the same family.
    
• Cleft lip and cleft palate
  • The cleft lip and cleft palate may be isolated.
  • The severity of these symptoms widely varies and may be unilateral or bilateral.
  • Submucous cleft palate is common and may be easily missed during physical examination.
  • Hypernasal voice and cleft or bifid uvula may be present. A bifid uvula is also a possible isolated finding in certain individuals with van der Woude syndrome.
• Lip pits
  • Lower lip pits are fairly distinctive. The pits are usually medial, often (but not always) on the vermilion portion of the lower lip. They tend to be centered on small elevations in infancy but become simple depressions by adulthood; however, the presentation varies. They are usually bilateral but are occasionally median or paramedian or unilateral and are most often found on the left side.
  • Visible or expressible saliva may be present in the lip pits because of an association with the accessory salivary glands. Pits may lead to tracts that are surprisingly long, making surgical removal challenging.
  • Lip pits may be the only symptom.
• Teeth: Hypodontia may be observed and most commonly presents as missing maxillary or mandibular second premolars or maxillary lateral incisors. This may be the only symptom. An association of van der Woude syndrome and taurodontism (teeth with greatly enlarged pulp chambers) has been reported.²
• Other oral manifestations: Although infrequently reported, other symptoms include syngnathia (congenital adhesion of the jaws); narrow, high, arched palate; and ankyloglossia (short glossal frenulum or tongue-tie).
• Extraoral manifestations  
  • Extraoral manifestations are rare but include limb anomalies, popliteal webs, and brain abnormalities.
  • Accessory nipples, congenital heart defects, and Hirschsprung disease have been reported.
  • Extraoral manifestations may be unassociated additional anomalies or infrequently expressed aspects of van der Woude syndrome.
  • Symptoms of van der Woude syndrome have been seen in individuals with popliteal pterygium syndrome, which has also been linked to mutations in the same gene. These 2 entities are believed to be allelic variants of the same condition.

Causes

• van der Woude syndrome is transmitted in autosomal dominant fashion.
  
• Penetrance has been reported to be 75% but is likely closer to 100% if supposedly unaffected carriers are closely examined for minor expressions of the syndrome.
  
• The gene for van der Woude syndrome has been localized to chromosome 1q32-q41. Intriguing linkage studies have suggested that a second modifying gene mapped to chromosome 17p11.2-p11.1 may influence the degree of phenotypic expression of a gene defect at this locus. A second chromosome locus for van der Woude syndrome has been mapped to 1p34.
• The interferon regulatory factor-6 (IRF-6) gene has been tentatively identified as the specific gene responsible for van der Woude syndrome; this gene has been shown to regulate fetal craniofacial development in mice.

Differential Diagnoses

Cleft Lip and Palate

Other Problems to Be Considered

Commissural lip pits
Orodigitofacial dysostosis
Popliteal pterygium syndrome

Workup

Laboratory Studies

• Although diagnosis of van der Woude syndrome is primarily clinical, chromosomal analysis may be appropriate. This technology is rapidly improving and may be noninvasively performed using tissue that is easily obtained, transported, and stored, such as a piece of fingernail.

Imaging Studies

• When planning surgical intervention, imaging studies of affected areas, such as CT scanning of the oropharynx, may be appropriate. Fistulography of lip pits may help to determine their depth and course.

Other Tests

• Intelligence and cognitive testing may demonstrate abnormalities; these have been shown in one study to affect males more than females.¹

Treatment

Medical Care

• Along with a thorough orofacial examination, a thorough general physical examination helps to determine if other associated anomalies of the cardiovascular system, genitourinary system, limbs, or other organ systems are present.
• Examination and genetic counseling by a pediatric geneticist (dysmorphologist) is suggested for families that may be affected by van der Woude syndrome. This should include an examination of as many potentially affected family members as possible.
• The American Academy of Pediatric Dentistry have released guidelines for the treatment of persons with special health care needs.³

Surgical Care

• Surgical repair of cleft lip and cleft palate or other anomalies may be required.
• Reconstruction of the lower lip may involve dermal allograft reconstruction.⁴
• Even in less severely affected individuals, surgical excision of lip pits is often performed, either to alleviate discomfort or for cosmetic reasons (eg, improving the appearance of lip pits or reducing mucous discharge). Surgical removal of salivary tracts associated with lip pits may be challenging because they may be quite long, extending into other oral structures.⁵

Consultations

• Treatment of children with cleft palate is often best undertaken by a multidisciplinary team of pediatric plastic surgeons; dentists; otolaryngologists; geneticists; genetic counselors; social workers; and occupational, speech, and physical therapists.

Medication

• Drug therapy currently is not a component of the standard of care for van der Woude syndrome. See Treatment.

Follow-up

Deterrence/Prevention

• Although van der Woude syndrome is transmitted by an autosomal dominant inheritance pattern, the degree of expression in affected families widely varies.
  
• Because the expressivity of the phenotype varies, the potential effects on unborn children are difficult to predict and may be of particular concern to parents. High-resolution ultrasonography and fetal echocardiography may be of some use in prenatally characterizing the severity of the phenotype.
• Genetic counseling is recommended.
  
• As genetic diagnostic and therapeutic methods advance, the principal syndromic form involving cleft lip and cleft palate may prove amenable to early detection and even preventive therapy.

Complications

• Cleft palate may be associated with feeding difficulties, voice disorders, frequent otitis media, and hearing loss.
• Lip pits may be associated with other disorders, including popliteal pterygium syndrome and orodigitofacial dysostosis.

Miscellaneous

Special Concerns

• Although lip pits are suggestive of van der Woude syndrome, not all children with lip pits have the syndrome. In fact, commissural pits not associated with van der Woude syndrome are present in approximately 2% of neonates and may be associated with preauricular sinuses.
• Midline pits are unusual and are often sporadic, as are pits in the upper lip.
• Children with cleft lip and cleft palate, lip pits, and complex congenital heart disease who did not have family histories suggestive of van der Woude syndrome have been reported. This may be a variant (30-50% of individuals with van der Woude syndrome do not have a family history of the disorder and most likely have de novo mutations in the disease gene) or a similar but different entity.

Multimedia

Media file 1: Cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)

Media file 2: Closer view of cleft lip and cleft palate in an infant with van der Woude syndrome, showing raised pits of lower lip. (Photo courtesy of Mary J. Hauk, DDS.)

Media file 3: Intraoral view of cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)

References

1. Nopoulos P, Richman L, Andreasen N, Murray JC, Schutte B. Cognitive dysfunction in adults with Van der Woude syndrome. Genet Med. Apr 2007;9(4):213-8. [Medline].

2. Nawa H, Oberoi S, Vargervik K. Taurodontism and Van der Woude syndrome. Is there an association?. Angle Orthod. Sep 2008;78(5):832-7. [Medline].

3. American Academy of Pediatric Dentistry. Clinical guideline on management of persons with special health care needs. Chicago, IL: American Academy of Pediatric Dentistry; 2004.

4. Bozkurt M, Kulahci Y, Zor F, Kapi E, Yucetas A. Reconstruction of the lower lip in Van der Woude syndrome. Ann Plast Surg. Apr 2009;62(4):451-5. [Medline].

5. Krauel L, Parri FJ, Munoz E, Sancho AM, Gean E, Morales L. Van der Woude Syndrome and lower lip pits treatment. J Oral Maxillofac Surg. Mar 2008;66(3):589-92. [Medline].

6. Cobourne MT. The complex genetics of cleft lip and palate. Eur J Orthod. Feb 2004;26(1):7-16. [Medline].

7. Du X, Tang W, Tian W, et al. Novel IRF6 mutations in Chinese patients with Van der Woude syndrome. J Dent Res. Oct 2006;85(10):937-40. [Medline].

8. Ghassibe M, Bayet B, Revencu N, et al. Orofacial clefting: update on the role of genetics. B-ENT. 2006;2 Suppl 4:20-4. [Medline].

9. Janku P, Robinow M, Kelly T, et al. The van der Woude syndrome in a large kindred: variability, penetrance, genetic risks. Am J Med Genet. 1980;5(2):117-23. [Medline].

10. Lacombe D, Pedespan JM, Fontan D, Chateil JF, Verloes A. Phenotypic variability in van der Woude syndrome. Genet Couns. 1995;6(3):221-6. [Medline].

11. Matsuzawa N, Shimozato K, Natsume N, Niikawa N, Yoshiura K. A novel missense mutation in Van der Woude syndrome: usefulness of fingernail DNA for genetic analysis. J Dent Res. Dec 2006;85(12):1143-6. [Medline].

12. Menko FH, Koedijk PH, Baart JA, Kwee ML. Van der Woude syndrome--recognition of lesser expressions: case report. Cleft Palate J. Jul 1988;25(3):318-21. [Medline].

13. Oberoi S, Vargervik K. Hypoplasia and hypodontia in Van der Woude syndrome. Cleft Palate Craniofac J. Sep 2005;42(5):459-66. [Medline].

14. Onofre MA, Brosco HB, Taga R. Relationship between lower-lip fistulae and cleft lip and/or palate in Von der Woude syndrome. Cleft Palate Craniofac J. May 1997;34(3):261-5. [Medline].

15. Pauli RM, Hall JG. Lip pits, cleft lip and/or palate, and congenital heart disease. Am J Dis Child. Mar 1980;134(3):293-5. [Medline].

16. Puvabanditsin S, Garrow E, Sitburana O, et al. Syngnathia and Van der Woude syndrome: a case report and literature review. Cleft Palate Craniofac J. Jan 2003;40(1):104-6. [Medline].

17. Rizos M, Spyropoulos MN. Van der Woude syndrome: a review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counselling and treatment. Eur J Orthod. Feb 2004;26(1):17-24. [Medline].

18. Sertie AL, Sousa AV, Steman S, et al. Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1. Am J Hum Genet. Aug 1999;65(2):433-40. [Medline].

19. Shprintzen RJ, Goldberg RB, Sidoti EJ. The penetrance and variable expression of the Van der Woude syndrome: implications for genetic counseling. Cleft Palate J. Jan 1980;17(1):52-7. [Medline].

20. Tomlinson JK, Liem NT, Savarirayan R, Meara JG. Isolated and syndromic syngnathism: management, implications, and genetics. Ann Plast Surg. Aug 2006;57(2):231-5. [Medline].

21. Van der Woude A. Fistula labii inferioris congenita and its association with cleft lip and palate. Am J Hum Genet. Jun 1954;6(2):244-56. [Medline].

22. Velez A, Alamillos FJ, Dean A, Ruiz-Masera JJ. Congenital lower lip pits (Van der Woude syndrome). J Am Acad Dermatol. Mar 1995;32(3):520-1. [Medline].

23. Vignale R, Araujo J, Pascal G, et al. Van der Woude syndrome. A case report. Pediatr Dermatol. Nov-Dec 1998;15(6):459-63. [Medline].

Keywords

van der Woude syndrome, VWS, VDWS, cleft lip syndrome, lip pit syndrome, cleft palate, dimpled papillae of the lip, cleft lip, lip pits, hypodontia, hypernasal voice, cleft uvula, bifid uvula, syngnathia, ankyloglossia, congenital heart defect, Hirschsprung disease, popliteal pterygium syndrome, congenital heart defects

Contributor Information and Disclosures

Author

Gregory P Conners, MD, MPH, MBA, Professor of Emergency Medicine and Pediatrics, Departments of Emergency Medicine and Pediatrics, University of Rochester School of Medicine and Dentistry
Gregory P Conners, MD, MPH, MBA is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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