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Branchiooculofacial Syndrome

Synonym: BOF Syndrome

, MD, FAAP, FACMG, , MD, and , MD, FACMG.

Author Information

Initial Posting: ; Last Update: March 29, 2018.

Summary

Clinical characteristics.

The branchiooculofacial syndrome (BOFS) is characterized by: branchial (cervical or infra- or supra-auricular) 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.

Diagnosis/testing.

The diagnosis is based on clinical findings and confirmed with the identification of a heterozygous pathogenic variant in TFAP2A.

Management.

Treatment of manifestations: In general, children with BOFS should be managed by a multispecialty team including, for example, craniofacial specialists, plastic surgeons, otolaryngologists, and speech therapists. Small, linear or superficial branchial skin defects may heal spontaneously; however, some require surgical intervention. Anophthalmia or severe microphthalmia may require a conformer (a structure, usually plastic, inserted into the eye socket to encourage its growth); nasolacrimal duct stenosis or atresia often requires surgery. It is recommended that cleft lip be repaired by an experienced pediatric plastic surgeon. Lesser forms of cleft lip ("pseudocleft") may need surgical correction.

Surveillance: Monitor for changes related to the major findings over time as directed by the team of specialists.

Genetic counseling.

BOFS is inherited in an autosomal dominant manner. De novo pathogenic variants are observed in 50%-60% of affected individuals. Each child of an individual with BOFS has a 50% chance of inheriting the pathogenic variant. Once the TFAP2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

The branchiooculofacial syndrome (BOFS) is diagnosed clinically. There are no formal diagnostic guidelines developed by consensus panels, algorithms using a hierarchy of clinical findings, or evidence-based test standards.

Diagnostic criteria had been used informally based on the hallmark defects (B, O, F) and were proposed formally in 2011 incorporating the importance of thymic anomalies and independently diagnosed first-degree relatives [Milunsky et al 2011] (Table I).

Note: Of the original three features that comprise the mnemonic BOF, the "B" (cutaneous skin defect) is the most distinctive when it is bilateral and anterior cervical in location.

Suggestive Findings

Branchiooculofacial syndrome (BOFS) should be suspected in individuals with findings in two or three of the following categories:

Branchial (cutaneous) defects. Cervical or infra- or supra-auricular skin defects:

  • Vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions;
  • Differ from the punctuate sinus tracts of the branchiootorenal (BOR) syndrome
  • If very mild, may be unrecognized and heal spontaneously, but tend to "weep"

Ocular anomalies

  • Microphthalmia, anophthalmia
  • Coloboma
  • Cataract
  • Ptosis
  • Nasolacrimal duct stenosis/atresia
  • Strabismus

Facial anomalies

  • Characteristic appearance with dolichocephaly, hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures (Figure 1)
  • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate, but no isolated cleft palate
  • Upper lip pits
  • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial 7th cranial nerve weakness)
  • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct
  • Malformed and prominent pinnae
  • Hearing loss (conductive, sensorineural, mixed)
Figure 1. . Photo of a boy age five years with the BOF syndrome.

Figure 1.

Photo of a boy age five years with the BOF syndrome. Details of the molecular findings are reported in Milunsky et al [2008] (patient 3, age 2 years). He has a right-sided cervical cutaneous defect ("B") that was repaired; bilateral nasolacrimal duct (more...)

Establishing the Diagnosis

The diagnosis of BOFS is established in a proband who meets the following clinical diagnostic criteria and confirmed by identification of a heterozygous pathogenic variant in TFAP2A on molecular genetic testing (see Table 1). Diagnostic criteria:

  • All three of the main features are present:
    • Branchial (cutaneous) skin defect
    • Ocular anomaly
    • Facial anomalies (characteristic facial appearance)
    OR
  • Two of the three main features plus one of the following are present:

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of BOFS is broad, individuals with the distinctive features described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of BOFS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of BOFS molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of TFAP2A detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A multigene panel that includes TFAP2A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of BOFS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic.

Table 1.

Molecular Genetic Testing Used in Branchiooculofacial Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
TFAP2ASequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 5<5% 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Clinical Characteristics

Clinical Description

Most individuals with branchiooculofacial syndrome (BOFS) can be diagnosed in infancy on the basis of their clinical features. Females and males are affected equally.

Classic BOF Findings

Branchial (cutaneous) defects occur in a cervical (90%) or infra- or supra-auricular (60%) location.

  • Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions.
  • Mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract which may appear to "weep," revealing the patency.

Ocular anomalies include the following:

  • Structural eye malformations such as
    • Microphthalmia, anophthalmia
    • Coloboma
    • Cataract
  • Periorbital abnormalities such as
    • Ptosis
    • Nasolacrimal duct stenosis/atresia leading to weeping eyes
  • Visual concerns such as
    • Strabismus
    • Significant visual impairment

Facial anomalies. Characteristic appearance includes dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures (see Figure 1). Other findings may include:

  • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"])
    • Occurring with or without cleft palate (99%)
    • No instances of isolated cleft palate reported
  • Upper lip pits
  • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial 7th cranial nerve weakness)
  • Ear anomalies
    • Malformed and prominent pinnae
    • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct
    • Hearing loss (70%) (conductive, sensorineural, mixed)
  • Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip

Additional Findings Observed in BOFS

Immune system. Thymic anomalies (ectopic, dermal) (~35%), typically bilateral with normal thymic function

Renal system

  • Structural anomalies (35%) (e.g., dysplastic, absent, multicystic)
  • Vesicoureteral reflux

Ectodermal (hair, teeth, nails)

  • Premature hair graying, poliosis (forelock or patchy) (35%)
  • Hypoplastic teeth
  • Dysplastic nails
  • Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly in the head and neck region)

Psychomotor development (typically normal)

  • Visual and hearing handicaps (frequent)
  • Autism spectrum disorder, intellectual disability (rare)

Growth restriction. Uncommon

Miscellaneous and rare (<5 individuals each)

  • Heterochromia irides
  • Congenital heart defect (atrial septal defect, tetralogy of Fallot)
  • Polydactyly (bilateral, usually postaxial)
  • Medulloblastoma (described once [Milunsky et al 2008])

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation exists.

Significant inter- and intrafamilial variability were observed with the same pathogenic variants [Milunsky et al 2011]. Missense, frameshift, and splicing variants along with more complex rearrangements [Tekin et al 2009, Milunsky et al 2011] throughout the gene result in similar phenotypes.

The majority of individuals with a deletion involving TFAP2A appear to have an abnormally prominent philtrum that may be on the spectrum of microform cleft lip [Lin et al 2009]. LeBlanc et al [2013] described an infant and mother with a 593-kb deletion including TFAP2A and five additional genes. Neither is reported to have any type of cleft or abnormal philtrum. Otherwise the marked inter- and intrafamilial variability appear similar to that observed with intragenic pathogenic variants.

Penetrance

BOFS has shown almost complete penetrance. Careful examination of individuals identified in a family with BOFS with a TFAP2A pathogenic variant is necessary to reveal subtle findings including premature graying (individuals may have dyed their hair), faint hair on the neck, or heterochromia of the irides.

Prevalence

The prevalence of BOFS is not known. It is a rare condition, with fewer than 150 individuals having a well-described clinical and/or molecular diagnosis. An informal survey of clinical geneticists who attended a 2017 dysmorphology conference identified an additional 27 unpublished individuals (18 with a clinical diagnosis and 9 with a molecular diagnosis). While these numbers are insufficient to calculate a population-based prevalence, they support the impression that BOFS remains a rare disorder.

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of BOFS

DisorderGene(s)MOIClinical Features
OverlappingDistinguishing
Branchiootorenal (BOR) spectrum disordersEYA1
SIX5
SIX1
AD
  • Ear abnormalities
  • Branchial abnormalities
  • Renal abnormalities
In BOR spectrum disorders:
  • No BOFS facial features
  • Branchial pits (vs draining sinuses w/overlying skin defects in BOFS)
CHARGE syndromeCHD7AD
  • Eye abnormalities
  • Ear abnormalities
  • Orofacial cleft
In CHARGE syndrome:
  • No skin defects
  • No premature grey hair
  • No BOFS facial features
  • Frequent posterior segment coloboma & choanal atresia
22q11.2 deletion syndrome (DS)22q11.2 deletionAD
  • Eye abnormalities
  • Ear abnormalities
  • Branchial abnormalities
  • Renal abnormalities
  • Orofacial cleft
In 22q11.2DS:
  • No BOFS facial features
  • Cardiac defects common
Waardenburg syndrome (WS)
(see WS1)
PAX3
MITF
EDNRB
EDN3
SNAI1
SNAI2
SOX10
AD
AR
  • Premature greying of hair
  • Telecanthus
  • Hearing loss
In WS:
  • No renal abnormalities
  • No BOFS facial features
EEC3
(see TP63-Related Disorders)
TP63AD
  • Orofacial cleft
  • Ectodermal abnormalities
In EEC3:
  • Ectrodactyly
  • No BOFS facial features

BOFS = branchiooculofacial syndrome

BOR = branchiootorenal syndrome

EEC3 = ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the branchiooculofacial syndrome (BOFS), the following evaluations are recommended if they have not already been completed:

  • Examination of the skin defects by a pediatric plastic surgeon to delineate the extent of the lesion(s), to determine if there is a sinus and, most importantly, to determine if a thymic remnant could be present
  • Complete eye examination by a pediatric ophthalmologist to assess for visual limitations, strabismus, and nasolacrimal duct obstruction
  • Referral of those with anophthalmia and/or severe microphthalmia to support services for the visually impaired
  • Formal evaluation of cleft lip/palate and other possible facial abnormalities by a cleft lip/palate team, which often includes a clinical geneticist, pediatric plastic surgeon, otorhinolaryngologist, audiologist, speech and language therapist, and dental and orthodontic specialist
  • Hearing evaluation
  • CT imaging of the temporal bone to anticipate optimal hearing correction [Raveh et al 2000, Stoetzel et al 2009, Tekin et al 2009]
  • Renal ultrasonography with referral to a nephrologist if renal abnormalities are identified
  • Development assessment particularly for children with visual and/or hearing problems
  • Monitoring for depression, attention dysregulation, autism, intellectual disability
  • Echocardiogram if there is a murmur or cardiac symptoms
  • Consultation with a clinical geneticist and/or genetic counselor

Note: (1) Motor delays are not part of BOFS; thus, physical and occupational therapy is not anticipated. (2) The role of cancer surveillance is not established.

Treatment of Manifestations

Milunsky et al [2011] provided management guidelines which remain clinically useful and have not been updated.

In general, children with BOFS and multiple anomalies should be followed in a setting in which multispecialty care can be provided by a team including, for example, craniofacial specialists, plastic surgeons, otolaryngologists, and speech therapists (adapted from Milunsky et al [2011], Table IV).

Ideally, multispecialty evaluations and surgery should be performed within a craniofacial clinic.

  • Surgical treatment should be done only by a pediatric plastic surgeon experienced in treating cleft lip. Lesser forms of cleft lip (formerly known as "pseudocleft") may need surgical correction [Lin et al 2009].
  • In addition to the nasal tip flattening or asymmetry that may be associated with cleft lip, a characteristic full, flat nasal tip may need a corrective procedure.
  • Affected individuals may need reconstruction of malformed protruding pinnae. If diagnosed in early infancy, auricular molding may be indicated.
  • When branchial or supra-auricular skin defects are small, linear, or superficial, they may heal spontaneously.
  • The larger skin defects may resemble a moist "wound" and often need surgical intervention. They should not be cauterized. Most larger skin defects require surgical excision.
  • Importantly, a sinus tract must be dissected by an experienced pediatric plastic surgeon.
    • Exploration for a thymic remnant may be necessary; such tissue should be sent for histopathologic examination.
    • If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of the ectopic thymus.

Ophthalmic concerns are best addressed by a pediatric ophthalmologist.

  • Obstruction from nasolacrimal duct stenosis or atresia must be relieved and individuals monitored for restenosis.
  • Severe microphthalmia or anophthalmia may be managed by inserting a conformer into the eye socket to encourage its growth.

Hearing loss is treated routinely (see Hereditary Hearing Loss and Deafness Overview).

Renal and cardiac abnormalities are managed in a standard manner.

The teeth should be monitored for size and number, caries, and malocclusion.

Sensory, psychologic, and developmental challenges should be treated with supportive therapies. Currently, data are insufficient to recommend requiring more psychologic support for more severely affected individuals.

Surveillance

Monitor for changes over time related to the major findings as directed by the team of specialists.

Monitor older children as they enter adolescence for signs of low self-esteem and other psychologic issues.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known
  • A careful physical examination to look for subtle physical findings of BOFS if the pathogenic variant in the family is not known

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

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

Branchiooculofacial syndrome (BOFS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • ~40%-50% of individuals diagnosed with BOFS have an affected parent [Milunsky et al 2011].
  • ~50%-60% of individuals diagnosed with BOFS have the disorder as the result of a de novo TFAP2A pathogenic variant [Milunsky et al 2011].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
  • The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members, milder phenotypic presentation, or early death of the parent before the onset of symptoms (e.g., premature graying). Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has 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 mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with BOFS has a 50% chance of inheriting the TFAP2A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TFAP2A pathogenic variant, his or her family members may be 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 identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, 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.

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 Diagnosis

Once the TFAP2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • AmeriFace: The Cleft/Craniofacial Advocates
    PO Box 751112
    Las Vegas NV 89136
    Phone: 888-486-1209 (toll-free 24 hours); 702-769-9264
    Fax: 702-341-5351
    Email: info@ameriface.org

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.

Branchiooculofacial Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TFAP2A6p24​.3Transcription factor AP-2-alphaTFAP2A databaseTFAP2ATFAP2A

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 Branchiooculofacial Syndrome (View All in OMIM)

107580TRANSCRIPTION FACTOR AP2-ALPHA; TFAP2A
113620BRANCHIOOCULOFACIAL SYNDROME; BOFS

Molecular Genetic Pathogenesis

TFAP2A is a retinoic acid-responsive member of the AP-2 family of transcription factors that regulate gene expression during embryogenesis of the eye, ear, face, body wall, limbs, and neural tube [Schorle et al 1996, Zhang et al 1996, Ahituv et al 2004, Nelson & Williams 2004].

Gene structure. TFAP2A contains eight coding exons (reference sequence NM_003220.2, NM_001042425.1, NM_001032280.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants within TFAP2A or deletion of the entire gene result in the branchiooculofacial (BOF) syndrome. Milunsky et al [2008] described a familial whole-gene deletion and four de novo missense variants in simplex cases (i.e., a single occurrence in the family) that resulted in BOFS. Additional pathogenic variants and familial deletions have now been described [Gestri et al 2009, Stoetzel et al 2009, Tekin et al 2009, Reiber et al 2010, Aliferis et al 2011, Frascari et al 2012, Galliani et al 2012, LeBlanc et al 2013, Murray et al 2013, Günes et al 2014, Meshcheryakova et al 2015, Titheradge et al 2015, Xiong et al 2015, Yi et al 2016].

Although the pathogenic variants occur throughout the gene, a hot spot region in exons 6 and 7 that harbors missense variants in about 90% of probands/families with BOFS has been identified [Milunsky et al 2011].

Mosaicism has been detected in one family [Milunsky et al 2011].

The molecular spectrum in 30 families with 41 affected individuals with BOFS included heterozygous missense variants (28/30; 93%), one frameshift variant, and one whole-gene deletion [Milunsky et al 2011]. Tekin et al [2009] reported a complex TFAP2A allele (deletion of 18 and insertion of 6 nucleotides) between amino acids 276 and 281 in an individual with BOFS. More than 30 missense/nonsense pathogenic variants have now been described along with several small deletions/insertions and fewer than five whole-gene deletions.

Normal gene product. TFAP2A protein comprises 437 amino acids. It has a central basic DNA binding region, a carboxy terminus helix-span-helix motif that mediates dimerization, and an amino terminus that contains a transactivation domain [Eckert et al 2005]. The amino acids in the basic region of the DNA binding domain (exons 6 and 7) show high evolutionary conservation from Homo sapiens through Ciona intestinalis (transparent sea squirt) [Milunsky et al 2008].

In addition to its role in regulating gene expression during embryogenesis, TFAP2A is also involved in tumorigenesis with protein expression levels affecting cell transformation, tumor growth, metastasis, and survival [Jean et al 1998, Heimberger et al 2005, Orso et al 2007]. Numerous gene interactions likely underlie the variability in phenotype resulting from molecular defects involving TFAP2A. TFAP2A is known to be expressed in premigratory and migratory neural crest cells [Hilger-Eversheim et al 2000, Li & Cornell 2007] and is required for early morphogenesis of the lens [Gestri et al 2009].

Abnormal gene product. In humans, the described anomalies in BOFS appear to be related to pathogenic variants or deletions of TFAP2A leading to dysfunctional regulation especially during embryogenesis.

Loss or alteration of function of TFAP2A protein orthologs in zebrafish or mice result in facial clefting, limb anomalies, and defects of the eye, ear, body wall, neural tube, and heart outflow tract [Schorle et al 1996, Zhang et al 1996, Nottoli et al 1998, West-Mays et al 1999, Brewer et al 2002, Holzschuh et al 2003, Knight et al 2003, Ahituv et al 2004, Brewer et al 2004, Nelson & Williams 2004, Feng et al 2008].

A study by Gestri et al [2009] of the role of TFAP2A pathogenic variants in zebrafish eye morphogenesis revealed an association with a multitude of ocular pathologies. In addition, the pathogenic variants compromised the gene function, thereby sensitizing the developing eye to deleterious pathogenic variants of other genes including bmp4 and tcf711a [Gestri et al 2009].

Damberg [2005] found that the AP-2 family may be involved in the regulation of the monoaminergic systems in the adult brain, resulting in neuropsychiatric disorders.

Brewer et al [2004] noted that surviving mutated Tcfap2a mice have craniofacial anomalies, abnormal middle ear development, and defects in pigmentation.

Li et al [2013] demonstrated that several pathogenic variants in the DNA binding domain can have dominant-negative activity on wild type AP-2α protein. Hence, differences in activity due to null, hypomorphic, or antimorphic alleles may lead to the phenotypic variability characteristic of BOFS

References

Published Guidelines / Consensus Statements

  • Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A. 2011;155A:22–32. [PubMed: 21204207]

Literature Cited

  • Ahituv N, Erven A, Fuchs H, Guy K, Ashery-Padan R, Williams T, de Angelis MH, Avraham KB, Steel KP. An ENU-induced mutation in AP-2alpha leads to middle ear and ocular defects in Doarad mice. Mamm Genome. 2004;15:424–32. [PubMed: 15181535]
  • Aliferis K, Stoetzel C, Pelletier V, Hellé S, Angioï-Duprez K, Vigneron J, Leheup B, Marion V, Dollfus H. A novel TFAP2A mutation in familial branchio-oculo-facial syndrome with predominant ocular phenotype. Ophthalmic Genet. 2011;32:250–5. [PubMed: 21728810]
  • Brewer S, Feng W, Huang J, Sullivan S, Williams T. Wnt1-Cre-mediated deletion of AP-2alpha causes multiple neural crest-related defects. Dev Biol. 2004;267:135–52. [PubMed: 14975722]
  • Brewer S, Jiang X, Donaldson S, Williams T, Sucov HM. Requirement for AP-2alpha in cardiac outflow tract morphogenesis. Mech Dev. 2002;110:139–49. [PubMed: 11744375]
  • Damberg M. Transcription factor AP-2 and monoaminergic functions in the central nervous system. J Neural Transm. 2005;112:1281–96. [PubMed: 15959839]
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Chapter Notes

Author Notes

As of January 2018, there is no disease advocacy organization ("support group") for BOFS. Through Dr Lin, several parents of children with BOFS have reached out to the families of newly diagnosed individuals.

Acknowledgments

We thank the many families and international colleagues who have supported our research.

Revision History

  • 29 March 2018 (ha) Comprehensive update posted live
  • 31 May 2011 (me) Review posted live
  • 11 January 2011 (al) Original submission
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