Van der Woude syndrome is a condition that affects the development of the face. Many people with this disorder are born with either a cleft lip or a cleft palate (an opening in the upper lip or roof of the mouth), or both. Affected individuals usually have depressions (pits) near the center of the lower lip, which may appear moist due to the presence of salivary and mucous glands in the pits. Small mounds of tissue on the lower lip may also occur. In some cases, people with van der Woude syndrome have missing teeth.

People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. The average IQ of individuals with van der Woude syndrome is not significantly different from that of the general population.

Variations (also known as mutations) in the IRF6 gene cause most cases of van der Woude syndrome. The IRF6 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The IRF6 protein is active in cells that give rise to tissues in the head and face. It is also involved in the development of other parts of the body, including the skin and genitals.

Variants in the IRF6 gene that cause van der Woude syndrome prevent one copy of the gene in each cell from making any functional protein. A shortage of the IRF6 protein affects the development and maturation of tissues in the face, resulting in the signs and symptoms of van der Woude syndrome.

In about five percent of cases, van der Woude syndrome is caused by variants in the GRHL3 gene.

Normal Function

The IRF6 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The IRF6 protein is active in cells that give rise to tissues in the head and face. It is also involved in the development of other parts of the body, including the skin and genitals.

Health Conditions Related to Genetic Changes

Popliteal pterygium syndrome

Variants (also known as mutations) in the IRF6 gene cause popliteal pterygium syndrome. This condition affects the development of the face, skin, and genitals.

The IRF6 gene variants that cause this condition may change the transcription factor's effects on the activity of certain genes. This affects the development and maturation of tissues in the face, skin, and genitals, resulting in the facial and genital abnormalities, skin webbing, and fusion of the fingers or toes (syndactyly) seen in popliteal pterygium syndrome.

Van der Woude syndrome

Variants in the IRF6 gene cause van der Woude syndrome. This condition affects the development of the face and often causes cleft lip, cleft palate (an opening in the roof of the mouth, or both. IRF6 gene variants that cause this condition prevent one copy of the gene in each cell from making any functional protein. A shortage of the IRF6 protein affects the development and maturation of tissues in the skull and face. These abnormalities underlie the signs and symptoms of van der Woude syndrome.

Other disorders

Certain variations in the IRF6 gene have been associated with increased risk of cleft lip, cleft palate, or both. When these features appear without other signs or symptoms (such as in the conditions described above), the condition is called isolated cleft lip and/or palate. The IRF6 gene variations are believed to affect the function of the IRF6 protein in its role as a transcription factor, which may interfere with the normal development of the face.

Other Names for This Gene

• IRF6_HUMAN
• LPS
• OFC6
• PIT
• PPS
• VWS
• VWS1

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. Occasionally, an individual who has a copy of the altered gene does not show any signs or symptoms of the disorder.

Van der Woude syndrome should be considered in every child born with a cleft lip and/or palate. A clinical evaluation by a medical geneticist is generally performed to document all relevant clinical findings. In addition, the parents should be examined for isolated lip pits, cleft palate, and hypodontia (missing teeth). To make a clinical diagnosis of Van der Woude syndrome, at least one of the following findings must be present:

• Lip pits and cleft lip AND/OR palate (CLP). Lip pits must be paramedian on the lower lip, and can include mounds with a sinus tract leading from a mucous gland of the lip.
• Lip pits alone and a first-degree relative with CLP
• CLP and a first-degree relative with lip pits

Genetic testing for mutations in the IRF6 gene can also be used to diagnose this condition.

Van der Woude syndrome is believed to occur in 1 in 35,000 to 1 in 100,000 people, based on data from Europe, Asia, and Africa. Van der Woude syndrome is the most common cause of cleft lip and palate resulting from genetic variations.