van der Woude Syndrome

Updated: Mar 21, 2023
  • Author: Gregory P Conners, MD, MPH, MBA, FAAP, FACEP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Overview

Practice Essentials

van der Woude syndrome is an autosomal dominant syndrome characterized by a cleft lip or cleft palate, distinctive pits of the lower lip, 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 d 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 in 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 Intraoral view of cleft lip and cleft palate in an infant with van der Woude syndrome. (Photo courtesy of Mary J. Hauk, DDS.)

Signs and symptoms of van der Woude syndrome

van der Woude syndrome is characterized by cleft lip and/or cleft palate and distinctive lower lip pits.

Hypernasal voice and cleft or bifid uvula may be present. Hypodontia may be observed and most commonly presents as missing maxillary or mandibular second premolars or maxillary lateral incisors.

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 are rare but include limb anomalies, popliteal webs, and brain abnormalities.

Accessory nipples, congenital heart defects, and Hirschsprung disease have been reported.

Workup in van der Woude syndrome

Although diagnosis of van der Woude syndrome is primarily clinical, chromosomal analysis may be appropriate.

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

Management of van der Woude syndrome

Surgical repair of cleft lip and cleft palate or other anomalies may be required. Reconstruction of the lower lip may involve dermal allograft reconstruction. [1]

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). [2]

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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 a mutation in the interferon regulatory factor-6 (IRF6) gene can be helpful when distinguishing between uncomplicated cleft lip and/or cleft palate and van der Woude syndrome. [3] A wide variety of chromosomal mutations that cause van der Woude syndrome and are associated with IRF6 gene mutations have been described. [4] A potential modifying gene has been identified at 17p11.2-p11.1.

A study by Manjegowda et al found copy number variations affecting IRF6 in members of an Indian family with van der Woude syndrome, suggesting that such variations are involved in the development of the syndrome in the Indian population. [5]

In a study on monozygotic twins with van der Woude syndrome, Petrin et al found evidence that differences in DNA methylation can produce variations in phenotype even in persons with the same mutation for the syndrome. The DNA methylation levels significantly differed between twins at sites in or near the TP63 gene, which works with IRF6 in the palatal fusion process. [6]

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Epidemiology

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 findings, 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. [7]

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