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IRF6-Related Disorders

, PhD, , MD, FACMG, , MD, FACS, FAAP, and , PhD.

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Initial Posting: ; Last Update: July 3, 2014.

Estimated reading time: 30 minutes


Clinical characteristics.

IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end.

Individuals with VWS show one or more of the following anomalies:

  • Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip
  • Cleft lip (CL)
  • Cleft palate (CP)
    Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only.
  • Submucous cleft palate (SMCP)

The PPS phenotype includes the following:

  • CL±P
  • Fistulae of the lower lip
  • Webbing of the skin extending from the ischial tuberosities to the heels
  • In males: bifid scrotum and cryptorchidism
  • In females: hypoplasia of the labia majora
  • Syndactyly of fingers and/or toes
  • Anomalies of the skin around the nails
  • A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic)
  • In some non-classic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon)

In both VWS and PPS, growth and intelligence are normal.


Diagnosis of VWS and PPS is based on clinical findings. Detection of a heterozygous pathogenic variant in IRF6 confirms the diagnosis in approximately 72% of individuals with the Van der Woude syndrome phenotype and approximately 97% of individuals with the popliteal pterygium syndrome phenotype.


Treatment of manifestations: Supportive/symptomatic treatment may include surgery, pediatric dentistry, orthodontia, speech therapy, feeding and hearing evaluation, physical therapy, and orthopedic care.

Prevention of secondary complications: Timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss; evaluations by a speech-language pathologist can aid in determining if speech therapy or other interventions are appropriate for a child with secondary hearing loss.

Surveillance: Parameters for surveillance for cleft lip and/or cleft palate have been published by the American Cleft Palate-Craniofacial Association.

Genetic counseling.

IRF6-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an IRF6-related disorder have an affected parent; however, penetrance is incomplete and de novo mutation has been reported. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected or has an IRF6 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Prenatal diagnosis for pregnancies at increased risk is possible using molecular genetic testing if the pathogenic variant has been identified in an affected family member. Prenatal ultrasound examination may detect a cleft lip with/without cleft palate in some fetuses later in the second trimester, but it is much less likely to detect an isolated cleft palate or lip pits.

GeneReview Scope

IRF6-Related Disorders: Included Phenotypes
  • Van der Woude syndrome
  • Popliteal pterygium syndrome

For synonyms and outdated names see Nomenclature.


IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end.

Van der Woude syndrome. To make the diagnosis of Van der Woude syndrome, at least one of the following three findings must be present:

  • Lip pits* in combination with one of the following:
    • Cleft lip with or without cleft palate (CL±P)
    • Cleft palate (CP)
    • Submucous cleft palate (SMCP)
  • Lip pits* alone and a first-degree relative with CL±P, CP, or SMCP
  • CL±P, CP, or SMCP and a first-degree relative with lip pits*

* 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.


(1) In families in which lip pits are present in at least one family member, molecular genetic testing of IRF6 is appropriate.

(2) Presence of cleft lip (CL) or cleft lip and palate (CL+P) together with cleft palate only (CP) in the same family should also suggest VWS and should prompt a close search for lip pits and consideration of molecular genetic testing even if lip pits are not found; see (3).

(3) Since lip pits are not present in 15% of persons with VWS, it is possible that some individuals with a de novo IRF6 pathogenic variant will not have lip pits or a family member with lip pits.

(4) Most individuals with Van der Woude syndrome have normal psychomotor development. Presence of psychomotor disabilities may be seen in rare individuals with Van der Woude syndrome or popliteal pterygium syndrome. However, psychomotor delay (observed in multiple family members in only one of >350 reported families studied) may be the result of an unrelated cause [Sander et al 1994].

Popliteal pterygium syndrome. To make the diagnosis of popliteal pterygium syndrome, an individual must have (1) the lip and/or palate anomalies listed for Van der Woude syndrome and (2) one or more of the following:

  • Popliteal pterygia
  • Syndactyly
  • Abnormal external genitalia
  • Ankyloblepharon
  • Pyramidal skin on the hallux
  • A spectrum of intraoral adhesions, the most severe of which is complete syngnathia

Confirming the Diagnosis

The diagnosis of an IRF6-related disorder is confirmed by detection of a heterozygous pathogenic variant in IRF6 (Table 1).

One genetic testing strategy is to perform sequential molecular genetic testing.


Sequence analysis of exons 1 through 8 and the coding region of exon 9 of IRF6 should be performed first.


If sequence analysis of IRF6 does not yield a pathogenic variant, deletion/duplication analysis of IRF6 can be considered.


If molecular genetic testing of IRF6 does not yield a pathogenic variant, sequence analysis followed by deletion/duplication analysis of GRHL3 should be considered (see Differential Diagnosis).


If no pathogenic variant is identified in IRF6 or GRHL3, sequence analysis of MCS9.7, the enhancer element located 9.7 kb upstream of the transcriptional start site of IRF6 [Fakhouri et al 2014] can be considered.

An alternative genetic testing strategy is use of a multigene panel that includes IRF6 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Summary of Molecular Genetic Testing Used in IRF6-Related Disorders

Gene 1PhenotypeMethodProportion of Probands with a Pathogenic Variant Detectable by Method
IRF6VWSSequence analysis 2~72% 3
Deletion/duplication analysis 4<2% (7/448) 5
PPSSequence analysis 2~97% 6
Deletion/duplication analysis 4Unknown 7

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Sequence analysis of IRF6 (exons 1-9) detects pathogenic variants in approximately 68% of individuals with VWS [de Lima et al 2009]. Pathogenic variants in exons 3, 4, 7, and 9 account for 80% of known VWS-causing variants (N=307) [de Lima et al 2009].


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Whole- and partial-gene deletions have been found in fewer than 2% (7/448) of families with VWS [Sander et al 1994, Schutte et al 1999, Kayano et al 2003, Osoegawa et al 2008, Tan et al 2008, de Lima et al 2009]. The frequency of deletions smaller than 10 kb is unknown.


Sequence analysis of exon 4 of the IRF6 coding region detects pathogenic variants in approximately 72% of individuals with PPS [de Lima et al 2009]. Additional sequencing of the entire coding region of IRF6 detects pathogenic variants in approximately 97% of individuals with PPS (N=37) [de Lima et al 2009].


Unknown, but likely rare, pathogenic variants were identified on sequence analysis in 36 of 37 individuals with PPS [de Lima et al 2009].

Clinical Characteristics

Clinical Description

The craniofacial features of Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) form a continuum such that it is often difficult to distinguish between mildly affected individuals with PPS and those with VWS [Bixler et al 1973, Soekarman et al 1995, Lees et al 1999, Kondo et al 2002].

Van der Woude Syndrome

Individuals with VWS show one or more of the following anomalies: congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip; cleft lip (CL); cleft palate (CP); or submucous cleft palate (SMCP) [Van der Woude 1954].

Van der Woude [1954] observed that 27% of the offspring of affected parents had lip fistulae alone and 21% had fistulae associated with CL and/or CP. Burdick et al [1985] gathered information on 864 affected individuals from 164 families. In this population, 44% had lip pits only, 37% had cleft lip (with/without lip pits and with/without cleft palate), 16% had cleft palate only (with/without lip pits), and 3% had no apparent phenotype. Overall, lip pits were observed in 86% of affected individuals.

The ratio of cleft lip with or without cleft palate (CL±P) to "CP only" is about two to one in individuals with VWS [Burdick et al 1985]. Of note, this is the same relative proportion as in the general population.

The IRF6-related disorders are especially interesting as there are very few single-gene disorders or genetic syndromes in which individuals from the same family have both types of clefting (i.e., one family member having cleft palate alone and another having cleft lip and palate). This type of mixed clefting can also occur with mutation of MSX1 [van den Boogaard et al 2000], TP63, and FGFR1 and can be seen in individuals with 22q11.2 deletion syndrome, fetal alcohol syndrome, Kabuki syndrome, and CHARGE syndrome (see Differential Diagnosis).

The sex ratio is nearly equal in VWS for CP and CL±P, as well as for the presence of lip pits. It was also noted that CL±P and CP co-occur both vertically and horizontally in pedigrees. Forty percent of families with at least three affected individuals have both forms of clefting; in those, 75% have both forms of clefting in sibs.

Non-classic forms of the VWS phenotype have been described [Soricelli et al 1966, Ranta & Rintala 1983, Ranta et al 1983, Schinzel & Klausler 1986, Burdick et al 1987, Gorlin et al 1990, Kantaputra et al 2002]; features include:

  • Conical elevations (CE) of the lip
  • Single unilateral lip pits
  • Bulges located below the vermilion border
  • Hypodontia
  • Submucous cleft
  • Bifid uvula
  • Ankyloglossia
  • Limb abnormalities
  • Hirschsprung disease
  • Hearing loss

Growth and intelligence are normal. An exception is a family in which affected individuals had developmental disabilities and a large contiguous gene deletion that spans IRF6 [Sander et al 1994]. Rarely developmental delay may be presumed to be unrelated in a family that also segregates VWS [Zechi-Ceide et al 2007]. In two other families, individuals with large deletions had normal intelligence [Schutte et al 1999, Kayano et al 2003]. In one of the latter cases, the deletion was even larger than that described by Sander et al [1994], suggesting that developmental delay in the family of Sander et al [1994] is not related to deletion of IRF6.

In another small study, Jones et al [2010] found that following surgery for their clefts, eight (47%) of 17 individuals with VWS had wound complications compared to 13 (19%) of 68 individuals with nonsyndromic cleft lip and/palate (NSCLP).

Popliteal Pterygium Syndrome

The PPS phenotype includes cleft lip and/or palate (91%-97% of individuals); fistulae of the lower lip (45.6% [Froster-Iskenius 1990]); webbing of the skin extending from the ischial tuberosities to the heels, bifid scrotum and cryptorchidism in males, hypoplasia of the labia majora in females, syndactyly of fingers and/or toes, and anomalies of the skin around the nails [Lewis 1948, Rintala et al 1970]. A characteristic pyramidal fold of skin overlying the nail of the hallux is almost pathognomonic.

Growth and intelligence are normal.

Non-classic forms of the PPS phenotype have been described [Leck & Aird 1984, Froster-Iskenius 1990, Puvabanditsin et al 2003, Matsuzawa et al 2010]. These include:

  • Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon);
  • Spina bifida occulta.

Genotype-Phenotype Correlations

Van der Woude syndrome. Whole-gene deletions and nearly all protein truncation variants cause a VWS phenotype. Missense variants that cause VWS are evenly divided between the two protein domains encoded in exons 3, 4, and 7-9. Two pathogenic missense variants at arginine 84, p.Arg84Gly [Item et al 2005] and p.Arg84Pro [de Lima et al 2009], are found only in individuals with VWS, suggesting that p.Arg84Gly and p.Arg84Pro affect IRF6 function differently from p.Arg84His and p.Arg84Cys, which are seen most commonly in PPS.

Popliteal pterygium syndrome. Most missense variants that cause PPS are located in exon 4.

It appears likely that certain pathogenic variants (p.Arg84His, p.Arg84Cys) are more apt to cause PPS than VWS. A cluster of pathogenic missense variants in the DNA binding domain that are predicted to directly contact the DNA are more commonly seen in families with PPS (p<0.01); these include p.Trp60, p.Lys66, p.Gln82, p.Arg84, and p.Lys89. However, families may include individuals with features of only VWS and other members with the additional features of PPS.


IRF6-related disorders have high, but incomplete, penetrance.

Van der Woude syndrome. Additional studies have supported Van der Woude's observation of dominant inheritance with variable expressivity and high, but incomplete, penetrance [Cervenka et al 1967, Janku et al 1980, Shprintzen et al 1980, Burdick et al 1985]. In the most current and extensive literature review of VWS [Burdick et al 1985], a citation list search and manual search of Index Medicus starting from 1965 revealed data on 864 affected individuals in 164 families reported since Demarquay [1845] first observed VWS. Based on these data, penetrance was estimated at 92% [Burdick et al 1985].

Lip pit phenotype. The penetrance of the lip pit phenotype is estimated at 86%.


The following terms were used in the original description of Van der Woude syndrome by Anne Van der Woude [1954], but are no longer used:

  • Congenital pits of the lower lip
  • Fistula labii inferioris congenital
  • Congenital fistulae of the lower lip

Current nomenclature is "lip pits," "lip eminences," or more inclusively "lip abnormalities."


Van der Woude syndrome. VWS represents the most common single-gene cause of cleft lip and cleft palate, accounting for about 2% of all individuals with CL+P [Cohen & Bankier 1991, Murray et al 1997] or roughly one in 35,000 to one in 100,000 in the European and Asian populations [Cervenka et al 1967, Rintala & Ranta 1981, Burdick 1986].

Popliteal pterygium syndrome. A prevalence of approximately one in 300,000 has been suggested [Froster-Iskenius 1990].

Differential Diagnosis

Pits of the lower lip similar to those seen in VWS also occur in the following disorders:

  • VWS2 (Van der Woude syndrome, locus 2) (OMIM 606713) is defined as VWS caused by a heterozygous pathogenic variant in GRHL3. Wong et al [2001] described a Finnish family in which ten of 11 affected family members had cleft palate (CP) and one had cleft lip and palate (CLP); only one of the 11 affected individuals clinically examined had lip pits. Two of the affected individuals had a "wave-like" lower lip in addition to CP. Although the authors suggested that this could be a novel finding of VWS, linkage to IRF6 at 1q32-q41 was excluded (multipoint LOD scores < -13.0 for markers across this region). The locus was subsequently mapped to a 30-cM region on the short arm of chromosome 1 in 1p32-p36 [Koillinen et al 2001]. Peyrard-Janvid et al [2014] identified a heterozygous pathogenic variant in GRHL3 in this Finnish family. Subsequently, they sequenced 44 more individuals with clinical features of VWS who lacked a pathogenic variant in IRF6 and found a pathogenic variant in seven of these families. Thus, pathogenic variants in GRHL3 appear to account for 17% of individuals with clinical features of VWS who lack a pathogenic variant in IRF6 and approximately 5% of all cases of VWS. In these eight families with VWS2, Peyrard-Janvid et al [2014] observed the full range of VWS-associated orofacial clefts and lip pits. However, affected individuals were more likely to have cleft palate, less likely to have cleft lip, and less likely to have lip pits.
  • Bartsocas-Pappas syndrome (BPS) (also known as popliteal pterygium syndrome, lethal type) (OMIM 263650) is characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, genital hypoplasia, ankyloblepharon, syngnathia, and ectodermal defects including alopecia, absent eyelashes and eyebrows, and brittle nails. The diagnosis is based on clinical findings. BPS is autosomal recessive and caused by pathogenic variants in RIPK4 [Kalay et al 2012, Mitchell et al 2012].
  • Kabuki syndrome (KS) (also known as Kabuki make-up syndrome or Niikawa syndrome) is characterized by typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild to moderate intellectual disability, and postnatal growth deficiency. Forty percent of individuals with Kabuki syndrome have a high-arched or cleft palate [Burke & Jones 1995]. Several individuals with KS who have lower-lip pits have been identified [Matsumura et al 1992, Franceschini et al 1993, Kokitsu-Nakata et al 1999, Makita et al 1999]. In particular, Makita et al [1999] reported a five-year-old Japanese girl with both the KS and VWS clinical phenotypes. No microdeletions or single nucleotide variants involving IRF6 were observed [Makita et al 1999, Kondo et al 2002]. The diagnosis is primarily established by clinical findings. KS is caused by pathogenic variants in KMT2D (formerly MLL2) or KDM6A.
  • Branchiooculofacial syndrome (BOFS) is characterized by: branchial (cervical [90%] or infra- or supra-auricular [60%]) skin defects that range from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; ocular anomalies that can include microphthalmia, anophthalmia, coloboma, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include ocular hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures, cleft lip or prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip") with or without cleft palate, upper lip pits and lower facial weakness (asymmetric crying face or partial 7th cranial nerve weakness). Malformed and prominent pinnae and hearing loss from inner ear and/or petrous bone anomalies are common. Intellect is usually normal. The diagnosis is based on clinical findings. TFAP2A is the only gene in which pathogenic variants are currently known to cause BOFS.
  • Isolated CLP. Ranta & Rintala [1983] examined the lower lips of 397 children with CP, 518 with CL+P, and 1000 with no cleft phenotype. In addition to lip pits in these groups, 39.3% of CP, 0.8% of CL+P, and 0.7% of noncleft cases had conical elevations (CE) of the lower lip [Ranta & Rintala 1983]. The finding was interesting in that the familial occurrence of clefts among those in the CP group with CE (30%) was statistically higher than in those without them (20.7%). In addition, the incidence of hypodontia was significantly higher among 251 children with CP and CE (40%) than in those without them (25%) [Ranta et al 1983]. In all, 56% of children with CP had an associated hypodontia or CE phenotype. It is unknown how many of these may represent an IRF6-related disorder.
  • Mixed clefting (cleft lip with or without cleft palate (CL±P) and CP only). The mixed clefting seen in IFR6-related disorders can also occur in MSX1-related disorders [van den Boogaard et al 2000], TP63-related disorders (e.g., ankyloblepharon-ectodermal defects-cleft lip/palate syndrome), FGFR1-related disorders (e.g., isolated gonadotropin-releasing hormone deficiency), 22q11.2 deletion syndrome, fetal alcohol syndrome [Shaw & Lammer 1999], and CHARGE syndrome.
    Although lip pits are absent in these disorders, they lack sufficient additional features to exclude VWS without lip pits [van den Boogaard et al 2000, Dodé et al 2003, Jezewski et al 2003]. Thus, these disorders should be considered in evaluating any family in which multiple members have orofacial clefts.
  • Ankyloblepharon (or eyelid synechiae) present at birth is seen occasionally in PPS. These may also be seen in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Rapp-Hodgkin syndrome (OMIM 129400), ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 1 (OMIM 129900), curly hair-ankyloblepharon-nail dysplasia syndrome (OMIM 214350), and trisomy 18.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an IRF6-related disorder, the following evaluations are recommended if they have not already been completed:

  • In individuals diagnosed with VWS: evaluation for the characteristic features of PPS: knee contractures with webbing behind the knee, genital anomalies, syndactyly of the toes, and the pyramidal skin-fold on the nail of the hallux. Based on the findings referral to the following specialists may be considered:
    • Orthopedic surgery
    • Urology
    • Plastic surgery
  • Feeding and hearing evaluation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Individuals with a cleft lip and/or palate should be evaluated and treated by a multidisciplinary team of specialists. The American Cleft Palate-Craniofacial Association [2009] has published parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies that can guide treatment of these patients. Click here for full text.

Management is supportive/symptomatic.

  • Cleft lip. Management is surgical, dental, and orthodontic.
  • Cleft palate. In addition to surgery, dentistry, and orthodontics, speech therapy and audiologic evaluation are usually needed. Otolaryngology evaluation is needed for management of middle ear effusions.
  • Lip pits. Surgery may be indicated for cosmetic purposes or for lip function. The lip pits may be connected to mucous-secreting glands and may be excised for this.
  • Eyelid and oral synechiae (ankyloblepharon and syngnathia, respectively) may require surgical excision.
    • Syngnathia often requires emergent release due to feeding and respiratory concerns and may require tracheotomy.
  • Popliteal pterygium. Management involves physical therapy and surgical and orthopedic intervention, as necessary.
  • Syndactyly may require surgery.
  • Abnormal genitalia may require surgery especially in the presence of cryptorchidism. The genital anomalies may result in infertility.

Prevention of Secondary Complications

Timely treatment of otitis media secondary to eustachian tube dysfunction related to cleft palate is indicated to prevent secondary hearing loss. Some individuals may have pressure-equalizing tubes placed.

Evaluations by a speech-language pathologist can aid in determining if speech therapy or other interventions are appropriate for a child with secondary hearing loss.


The following surveillance guidelines are adapted from the American Cleft Palate-Craniofacial Association [2009] parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. Click here for full text.

Neonatal period and infancy

  • Weekly assessment of nutritional intake and weight gain during the first month of life
  • Otolaryngologic evaluation
  • Audiologic evaluation
  • Assessment of prelinguistic speech-language development
  • Dental evaluation
  • Consultation with other specialists as applicable

Longitudinal evaluation and treatment

  • Audiologic evaluation as soon as possible in a neonate and again at the time of an infant's first visit to a cleft clinic. The timing and frequency of follow-up evaluations should be based on the individual's history of ear disease or hearing loss. Evaluations should be carried out routinely through adolescence.
  • Dental evaluation at an infant's first visit to the cleft clinic and within six months of the first tooth erupting, no later than age 12 months. Routine dental evaluation should continue throughout life.
  • Otolaryngologic evaluation at an infant's first visit to the cleft clinic and within the first six months of life. These evaluations should continue throughout adolescence.
  • Speech-language pathology evaluation at an infant's first visit to the cleft clinic to provide parents with information about speech and language development. By age six months, infants should be seen for assessment of prelinguistic speech-language development. During the first two years of life, children should be evaluated at least twice, and then at least annually until age six years. After age six years, evaluations should be at least annually until after adenoid involution, and then at least every two years until dental and skeletal maturity.
  • Consultation with other specialists as applicable

Evaluation of Relatives at Risk

Offspring and/or sibs of an affected individual should be clinically examined for evidence of cleft palate including submucous cleft, lip abnormalities (pits or mounds), and the pyramidal skin-fold on the nail of the hallux, given the variable expressivity and incomplete penetrance of VWS and PPS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

IRF6-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with an IRF6-related disorder have an affected parent. However, penetrance is incomplete.
  • A proband with an IRF6-related disorder may have the disorder as the result of a de novo pathogenic variant.
  • The family history of some individuals diagnosed with an IRF6-related disorder may appear to be negative because of failure to recognize the disorder in family members or incomplete penetrance. Therefore, an apparently negative family history cannot be confirmed unless physical examination of both parents (with special attention to evaluation for lip pits and/or clefts, especially submucous clefts that may be asymptomatic) and molecular genetic testing (if the family-specific pathogenic variant is known) have been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic or germline mosaicism for the variant and may be unaffected or mildly affected. (Although no instances of somatic or germline mosaicism have been reported, it remains a theoretic possibility.)

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has an IRF6 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Approximately 92% of individuals with an IRF6 pathogenic variant have clinical signs of an IRF6-related disorder [Burdick et al 1985]. About 70% of individuals with a pathogenic variant have an orofacial cleft requiring surgical intervention [Murray, personal communication]. However, the clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the sibs.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but the possibility of incomplete penetrance in a parent or of germline mosaicism needs to be considered.
  • If a pathogenic variant found in the proband cannot be detected in the DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.

Offspring of a proband. Each child of an individual with an IRF6 pathogenic variant has a 50% chance of inheriting the pathogenic variant. The clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the offspring.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has an IRF6 pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of transmitting the disorder.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the IRF6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Ultrasound examination. Prenatal ultrasound examination may detect a cleft lip with/without cleft palate in some fetuses later in the second trimester, but it is much less likely to detect an isolated cleft palate or lip pits. A level 2 targeted ultrasound examination at a center that routinely performs such procedures is most accurate.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. Prenatal testing may provide the benefit of preparing the parents and family for a child with a facial difference or disability. However, the clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the offspring.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
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Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

IRF6-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
IRF61q32​.2Interferon regulatory factor 6IRF6 databaseIRF6IRF6

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for IRF6-Related Disorders (View All in OMIM)


Molecular Pathogenesis

Further functional analyses to identify downstream target genes and interacting proteins is important to the understanding of the role of IRF6 in palatal development, especially given the overlap of murine Irf6 expression at the medial edge of the palatal shelves immediately before and during fusion with that of murine Tgfb3 and the proposed role of the SMIR domain of IRF6 in mediating interactions between IRFs and Smads, a family of transcription factors known to transduce TGF-beta signals [Fitzpatrick et al 1990, Brivanlou & Darnell 2002].

Gene structure. IRF6 comprises nine exons and eight introns. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Two common SNPs were found in the coding sequence for IRF6: c.459G>T (p.Ser153Ser) and c.820G>A (p.Val274Ile). Rare variants found in unaffected controls include c.9C>T (p.Leu3Leu), c.55G>A (p.Asp19Asn), c.181C>G (p.Ala61Pro), c.339G>T (Val113Val), c.671C>T (p.Thr224Ser), c.726C>T (p.Thr242Thr), and c.1153T>C (p.Leu385Leu) [de Lima et al 2009].

Pathogenic variants. Protein truncation (nonsense and frameshift) variants, missense variants, and whole-gene deletions are known to cause disease. Pathogenic variants have now been identified in at least 335 of 448 families with VWS and PPS, representing 229 different alleles [Sander et al 1994, Schutte et al 1999, Kondo et al 2002, Kayano et al 2003, Kim et al 2003, Shotelersuk et al 2003, Wang et al 2003, Gatta et al 2004, Ghassibé et al 2004, Kantaputra et al 2004, Matsuzawa et al 2004, Item et al 2005, Mostowska et al 2005, Peyrard-Janvid et al 2005, Wang et al 2005, Ye et al 2005, Du et al 2006, Brosch et al 2007, Birnbaum et al 2008, de Medeiros et al 2008, Osoegawa et al 2008, Tan et al 2008, de Lima et al 2009, Jehee et al 2009, Yeetong et al 2009, Desmyter et al 2010, Ferrero et al 2010, Matsuzawa et al 2010]. A summary of these variants and additional pathogenic variants are described in Leslie et al [2013].

  • Sander et al [1994] identified a microdeletion in 1q32-q41 in an individual with VWS and developmental delay.
  • Of 37 individuals with VWS, one was found to have a deletion [Schutte et al 1999]. In the same study, testing of seven persons with PPS, 76 persons with mixed syndromic forms of clefting, and 178 persons with nonsyndromic clefting found no deletions.
  • A 17,162-bp deletion, including exons 4-9, was identified in a Japanese individual with VWS [Kayano et al 2003].
  • Using chromosome microarray analysis (CMA), Osoegawa et al [2008] determined that five of 18 individuals with VWS had microdeletions at chromosome band 1q32.2, ranging in size from 100 kb to 1 Mb. All five individuals had a positive family history for VWS, and two of the cases were previously identified but used as blinded controls.
  • Tang et al [2009] identified a de novo deletion that was estimated at 1.7 to 3 Mb.

Table 2.

Selected IRF6 Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein Change
(Alias 12
Reference Sequences
Benignc.820G>Ap.Val274Ile 3NM_006147​.2
Pathogenicc.250C>Gp.Arg84Gly 4
c.251G>Cp.Arg84Pro 5
c.251G>Ap.Arg84His 5
c.250C>Tp.Arg84Cys 5

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


p.= indicates that protein has not been analyzed, but no change is expected.


Some evidence suggests an association with isolated CLP.


Seen only in individuals with VWS


Most commonly seen in individuals with PPS

Normal gene product. The function of the normal gene product of IRF6 is currently unknown. However, IRF6 protein belongs to the interferon regulatory factor family of transcription factors. This protein family shares a highly conserved helix-loop-helix DNA binding domain (amino acids 13-113) and a less well-conserved protein binding domain (amino acids 226-394). The DNA binding domain contains a unique penta-tryptophan motif. The IRFs form homo- and heterodimers through the protein binding domain, called IRF association domain (IAD). This domain is also called the SMIR (SMAD/IRF) domain because the secondary structure of this protein binding domain is shared in the two families [Eroshkin & Mushegian 1999]. Most IRFs, including IRF6, are broadly, but not ubiquitously, expressed. The expression of IRF4 and IRF8 is restricted to hematopoietic cells.

The IRFs are best known to regulate the expression of interferon-alpha and interferon-beta after viral infection [Taniguchi et al 2001]. Following a viral infection, the latent IRF proteins in the cytoplasm are activated by multiple phosphorylation events at serine residues in the C terminus. They form homo- and heterodimers, accumulate in the nucleus, bind to the promoters of the interferon and interferon-stimulated genes, and are active in transcription [Lin et al 1998].

Mouse knockout studies support the role for Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8, and Irf9 in the immune response, and none of these mutated strains has embryologic abnormalities [Matsuyama et al 1993, Holtschke et al 1996, Kimura et al 1996, Mittrücker et al 1997, Sato et al 2000, Honda et al 2005, Takaoka et al 2005]. However, IRF1, IRF2, IRF3, IRF4, and IRF7 also regulate cell growth or arrest [Iida et al 1997, Harada et al 1998, Heylbroeck et al 2000, Zhang & Pagano 2002]. Although IRF6 was identified as a homolog of IRF4, which is required for B- and T-cell development and homeostasis [Mittrücker et al 1997], its function in immune response remains unknown.

Mice deficient for Irf6 have abnormal skin, limb, and craniofacial development [Ingraham et al 2006, Richardson et al 2006]. Murine embryos that are heterozygous for the null allele [Ingraham et al 2006] or the PPS-associated Arg84Cys allele [Richardson et al 2006] have oral epithelial adhesions. The extent and severity of the oral adhesions is greater in the Arg84Cys mice than in the mice with the null allele, providing further evidence that the Arg84Cys allele has a dominant-negative effect. Molecular and histologic analyses showed that Irf6 mutated embryos lack periderm cells at the sites of oral adhesions [Richardson et al 2009]. In the absence of periderm the underlying basal epithelial cells express E-cadherin on their surface, which provides a mechanism for aberrant interactions between adjacent tissues. These aberrant interactions could prevent timely elevation and apposition of the palatal shelves, leading to cleft palate. Peyrard-Janvid et al [2014] also observed similar oral epithelial adhesions and absence of periderm in murine embryos that were heterozygous for a mutated allele of Grhl3. These observations support the role of proper periderm development during palatogenesis.

Abnormal gene product. The pathogenic variants in individuals with VWS are consistent with haploinsufficiency. The missense pathogenic variants that cause VWS localize to the regions encoding the DNA binding domains (exons 3 and 4) and the protein binding domain (exons 7, 8, and 9) and most likely result in loss of function.

The pathogenic variants found in many individuals with PPS are highly localized to amino acid residues in the DNA binding domain (exons 3 and 4). Based on structural similarity to IRF1 [Escalante et al 1998], these residues (including p.Trp60, p.Lys66, p.Gln82, p.Arg84, p.Lys89) are predicted to directly contact the DNA target. Pathogenic missense variants at these positions abrogate DNA binding in IRF1 [Escalante et al 1998] but do not affect protein binding. Consequently, these pathogenic variants are predicted to have a dominant-negative effect on IRF function and may explain the broader phenotype observed in PPS [Kondo et al 2002, de Lima et al 2009]. Not all pathogenic missense variants at p.Arg84 are highly associated with PPS; p.Arg84Gly and p.Arg84Pro are found only in individuals with VWS, suggesting a different effect on IRF6 function for these variants.


Published Guidelines / Consensus Statements

  • American Cleft Palate-Craniofacial Association. Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies (pdf). Available online. 2009. Accessed 6-29-20.

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Chapter Notes

Author History

Bryan Cary Bjork, PhD; Harvard Medical School (2003-2011)
Kate M Durda, MS; University of Iowa (2011-2014)
Steven Goudy, MD, FACS, FAAP (2014-present)
Katherine Nash Krahn, MS; University of Iowa (2003-2011)
Elizabeth Leslie, PhD (2014-present)
Jeffrey C Murray, MD; University of Iowa (2003-2014)
Howard M Saal, MD, FACMG (2014-present)
Brian C Schutte, PhD (2003-present)

Revision History

  • 3 July 2014 (me) Comprehensive update posted live
  • 1 March 2011 (me) Comprehensive update posted live
  • 15 May 2006 (me) Comprehensive update posted live
  • 30 October 2003 (me) Review posted live
  • 27 May 2003 (jcm) Original submission
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