What are the other Names for this Condition? (Also known as/Synonyms)

• IRF6 Related Disorders

What are IRF6-Related Disorders? (Definition/Background Information)

• IRF6-Related Disorders include two different disorders caused by abnormalities in the interferon regulatory factor 6 (IRF6) gene
  • Van der Woude syndrome (VWS) is at the mild end of the spectrum 
  • Popliteal pterygium syndrome (PPS) is at the severe end of the spectrum
• The symptoms of IRF6-Related Disorders vary greatly from case to case
  • People with VWS can have lip pits alone, cleft lip or cleft palate alone, or a combination of these anomalies
  • People with PPS have a thick web of skin (pterygium) on the backs of both legs (popliteal), extending from the hip (ischial tuberosity) to the heel (calcaneus) or in other locations, as well as other problems. A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in PPS
• Supportive/symptomatic treatment may include surgery, pediatric dentistry, orthodontia, speech therapy, feeding and hearing evaluation, physical therapy, and orthopedic care

(Source: IRF6-Related Disorders; Genetic and Rare Disease Information Center (GARD) of National Center for Advancing Translational Science (NCATS), USA.)

Who gets IRF6-Related Disorders? (Age and Sex Distribution)

• IRF6-Related Disorders is a rare congenital disorder. The presentation of symptoms may occur at birth
• The less severe Van der Woude syndrome occurs at an estimated incidence at birth between 1/35,000 and 1/100,000 in European and Asian populations 
• The prevalence of popliteal pterygium syndrome is estimated to be 1 in 300,000
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for IRF6-Related Disorders? (Predisposing Factors)

• A positive family history may be an important risk factor, since IRF6-Related Disorders can be inherited
• Currently, no other risk factors have been clearly identified for these disorders

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of IRF6-Related Disorders? (Etiology)

• IRF6-Related Disorders are caused by mutation(s) in the IRF-6 gene
• The causative IRF-6 mutations leading to either mild (Van der Woude syndrome) or severe (popliteal pterygium syndrome) signs and symptoms are inherited in an autosomal dominant manner

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of IRF6-Related Disorders?

The signs and symptoms of IRF-6-Related Disorders may vary in type and severity among affected individuals. The less severe form is known as Van der Woude syndrome, and the severe type of IRF6-Related Disorder is called popliteal pterygium syndrome.

The common signs and symptoms of Van der Woude Syndrome may include:

• Paramedian lower-lip pits (fistulae, usually bilateral), observed in over 80% of affected individuals 
• Small mounds with a sinus tract leading from a mucous gland of the lip
• Cleft lip; cleft palate 
• A combination of cleft lip and cleft palate
• Hypodontia (missing teeth)
• Dental hypoplasia

The non-classic signs of VWS may include 

• Single unilateral lip pits 
• Submucous cleft
• Bifid uvula 
• Ankyloglossia
• Limb abnormalities such as skin folds and syndactyly
• Sensorineural hearing loss

The signs and symptoms of popliteal pterygium syndrome:

• Cleft lip and/or cleft palate
• Lip depressions in the center of lips
• A moist appearance of lips due to presence of mucous and salivary glands in the lip pits
• Missing teeth
• Tissue connecting upper and lower eyelids and/or jaws
• Webbing of fingers and toes
• Thick skin (pterygium) on the back of legs (this may extend from hips to heel
• A cone shaped fold of skin on the nail of big toe
• Unusual genital folds in females
• Undescended testes in males
• Bifid scrotum (scrotum divided into two) in males

How are IRF6-Related Disorders Diagnosed?

IRF6-Related Disorders is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm IRF6 gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of IRF6-Related Disorders?

The complications of IRF6-Related Disorders may include:

• Dribbling and infection due to lip pits 
• Decreased food intake due to non-development of teeth
• Inadequate weight gain
• Impaired movement due to presence of skin folds behind legs
• Speech impediment
• Hearing problems
• Learning disabilities
• Low self-esteem owing to appearance

Complications may occur with or without treatment, and in some cases, due to treatment also.

How are IRF6-Related Disorders Treated?

There is no cure for IRF6-Related Disorders, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. This may include surgery to correct cleft lip, cleft palate and pterygium.

How can IRF6-Related Disorders be Prevented?

IRF6-Related Disorders may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of IRF6-Related Disorders? (Outcomes/Resolutions)

• The prognosis of IRF6-Related Disorders is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for IRF6-Related Disorders:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/