Clinical 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.

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:
  • Affected first-degree relative, independently diagnosed
  • Ectopic thymus (dermal)

Note: In bulleted findings listed below, those in bold are present in most affected individuals; findings in italics are not present in most affected individuals but are distinctive for BOFS.

Branchial (cutaneous) defects

• Cervical (90%) or infra- or supra-auricular (60%) 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
• Mildest defects may be unrecognized, heal spontaneously

Ocular anomalies

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

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 called “pseudocleft lip"), with or without cleft palate (99%), but no isolated cleft palate
• Upper lip pits
• Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial 7^th cranial nerve weakness)
• Inner ear and petrous bone anomalies (As in CHARGE syndrome and the branchiootorenal syndrome, there can be cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct.)
• Malformed and prominent pinnae
• Hearing loss (70%) (conductive, sensorineural, mixed)

Figure

Figure 1. Photo of a five-year-old boy 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") which was repaired; bilateral nasolacrimal (more...)

Immune system

• Thymic anomalies (ectopic, dermal)

Renal system

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

Ectodermal (hair, teeth, nails)

• Premature hair graying (poliosis) (35%)
• Hypoplastic teeth
• Dysplastic nails
• Cysts (often on the scalp; less commonly in the head and neck region)

Psychomotor development

• Visual and hearing handicaps (frequent)
• Psychomotor performance (usually normal)
• Autism spectrum disorder, intellectual disability (rare)

Growth

• Growth restriction: uncommon

Rare (<5 patients)

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

Molecular Genetic Testing

Gene. TFAP2A is the only gene in which mutations are known to cause branchiooculofacial syndrome.

Clinical testing

• Sequence analysis. More than 95% of individuals who meet the clinical diagnostic criteria for BOFS have TFAP2A sequence variants detectable by sequence analysis (i.e., small intragenic deletions/insertions and missense, nonsense, and splice site mutations) [Milunsky et al 2011].
• Deletion/duplication analysis. Whole-gene deletions of TFAP2A have been described [Milunsky et al 2008, Gestri et al 2009] and likely are present in fewer than 5% of persons with BOFS. Larger deletions of chromosome 6p24-p25 including TFAP2A are rare [Davies et al 1999, Misceo et al 2008]. No partial-gene or exonic deletions or duplications have been reported.

Table 1. Summary of Molecular Genetic Testing Used in Branchiooculofacial Syndrome

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Gene Sybolm	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
TFAP2A	Sequence analysis	Sequence variants 2	>95%	Clinical
	Deletion / duplication analysis 3	Whole-gene deletions	<5%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Clinical examination for the diagnostic features

2.

For those meeting clinical diagnostic criteria, sequence analysis of the seven coding exons and intron/exon boundaries of TFAP2A

3.

If a mutation is not detected on sequence analysis, deletion/duplication analysis

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in TFAP2A.

Natural History

Females and males are affected equally.

Newborns with clefts have the expected challenges to feeding, and possibly breathing.

Infants with clefts need support to feed properly, and do best when in the care of an established cleft palate team. Some of the smaller skin defects start to “heal” by secondary intention. Nasolacrimal duct stenosis or atresia lead to weeping eyes, and require the attention of a pediatric ophthalmologist.

In childhood, individuals with BOFS are coping with cosmetic, visual, hearing, and speech challenges. They may have strabismus; some have significant visual impairment. The most severely affected children have surgical, medical, cosmetic and learning needs similar to many other children with craniofacial disorders. However, mildly affected children may appear to need little support.

Adolescents may have issues with anxiety and social esteem. These appear to be more than the experience of living with a cleft lip and other craniofacial anomalies, but the number of affected individuals is small.

Most have normal intellect.

Adults with typical BOFS have usually been diagnosed in childhood. Individuals with very mild features may not be diagnosed until they give birth to a classically affected child. The observation that adults can be asymptomatic or minimally affected illustrates the variable expression of mutations in this gene.

Fertility does not appear to be affected.

Genotype-Phenotype Correlations

Genotype/phenotype correlations for mutations within TFAP2A are not well established.

A genotype-phenotype analysis of 41 individuals in 30 families was based on diagnostic criteria that were fulfilled in 87% [Milunsky et al 2011]. Significant inter- and intrafamilial variability were observed with the same mutations [Milunsky et al 2011]. Missense, frameshift, and splicing mutations along with more complex rearrangements [Tekin et al 2009, Milunsky et al 2011] throughout the gene result in similar phenotypes.

The absence of overt clefting is noted in the few individuals who have whole-gene deletions [Milunsky et al 2008, Gestri et al 2009] and larger chromosomal deletions that include TFAP2A [Davies et al 1999, Misceo et al 2008]. All individuals with a deletion appear to have an abnormally prominent philtrum that may be on the spectrum of microform cleft lip [Lin et al 2009]. Otherwise the marked inter- and intrafamilial variability appear similar to that observed with intragenic mutations.

To date information is insufficient to make generalizations about the presence of autistic features and severe intellectual disability in BOFS since only two instances have been noted.

• Patient SP2 reported by Reiber et al [2010], who had the mutation c.806T>C, had both severe intellectual disability and autism.
• Patient 3 reported by Gestri et al [2009], who had a whole-gene deletion, had autistic features.

Penetrance

BOFS has shown almost complete penetrance. Careful examination of individuals identified in a family with BOFS with a TFAP2A mutation 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.

Anticipation

Not enough data have been reported to assess whether anticipation may occur in BOFS. This is especially difficult because of the marked clinical variability in this disorder. Five of six families with BOFS with no mosaicism identified had apparently more “severe” findings in subsequent generations [Milunsky et al 2011]. Further study is necessary.

Nomenclature

The term “branchiooculofacial syndrome” was suggested by Fujimoto et al [1987]. No other name has been used for this distinctive syndrome.

Prevalence

BOFS is rare, with fewer than 100 well-described cases with molecular genetic analysis. The prevalence is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the branchiooculofacial syndrome (BOFS), the following studies are recommended:

• CT imaging of the temporal bone to anticipate optimal hearing correction [Raveh et al 2000, Tekin et al 2009, Stoetzel et al 2009]
• Echocardiogram if there is a murmur or cardiac symptoms
• Renal ultrasonography

The following consultations are recommended:

• 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
• Formal evaluation of cleft lip/palate and other possible facial abnormalities by a cleft lip/palate team, which often includes a medical geneticist, pediatric plastic surgeon, otorhinolaryngologist, speech and language therapist, dental and orthodontic specialist, and ophthalmologist
• 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
• Referral to a nephrologist if renal abnormalities are identified
• Referral to an audiologist
• For those with a cleft, assessment by a speech therapist
• Development assessment particularly for children with visual and/or hearing problems
• Monitoring for depression, attention dysregulation

Note: Motor delays are not part of BOFS, and thus, physical and occupational therapy is not anticipated.

Treatment of Manifestations

Milunsky et al [2011] provided management guidelines. See .

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 III].

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. In addition 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 should be treated like a moist “wound” by a plastic surgeon, but generally do not 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, which should be sent for histopathologic examination.

Obstruction from nasolacrimal duct stenosis or atresia must be relieved and 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 Deafness and Hereditary Hearing Loss Overview).

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 make recommendations that more severely affected individuals require more psychologic support.

Surveillance

Monitor for changes related to the major findings over time.

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

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• A significant proportion (~40%-50%) of individuals diagnosed with BOFS have an affected parent [Milunsky et al 2011].
• A proband with BOFS may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations approximates 50%-60% [Milunsky et al 2011].
• It is recommended that parents of a proband have molecular genetic testing for the family-specific mutation to facilitate accurate recurrence risk counseling. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until molecular testing has been completed.

Note: (1) Although ~40%-50% of individuals diagnosed with BOFS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the manifestation of symptoms (e.g., premature graying). (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation 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.
• If a parent of the proband is affected and/or has a TFAP2A mutation, the risk to the sibs of inheriting the mutation is 50%.
• When the parents are clinically unaffected (after careful examination), the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for BOFS because of the possibility of variable expressivity and/or germline mosaicism in a parent.

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

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

To determine if a parent, child, or other family member could be affected, a careful physical examination is the most important “test.”

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, the variable expressivity of BOFS warrants molecular testing of parents for more accurate recurrence risk counseling. 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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.

Ultrasound examination. A systematic review of the prenatal features of BOFS has not been conducted. It is possible that prenatal detection of cleft lip/palate in a fetus at increased risk for BOFS would allow the syndrome to be diagnosed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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].

Normal allelic variants. TFAP2A contains seven coding exons (reference sequence NM_003220.2)

Pathologic allelic variants. Mutations 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 mutations in simplex cases (i.e., a single occurrence in the family) that resulted in BOFS. Additional mutations and another familial deletion have now been described [Gestri et al 2009, Stoetzel et al 2009, Tekin et al 2009, Reiber et al 2010].

Although the mutations occur throughout the gene, a hotspot region in exons 4 and 5 that harbors missense mutations in about 90% of probands/families with BOFS has been identified [Milunsky et al 2011]. Recurrent mutations are now well recognized (Table 2).

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 mutations (28/30; 93%), one frameshift mutation, 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.

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 4 and 5) 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 mutations 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]. Gestri et al [2009] studied the role of TFAP2A mutations in zebrafish eye morphogenesis that revealed an association with a multitude of ocular pathologies. In addition, the mutations compromised the gene function thereby sensitizing the developing eye to deleterious mutations in 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 mutant Tcfap2a mice have craniofacial anomalies, abnormal middle ear development, and defects in pigmentation.

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Author Notes

As of January, 2011, 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

• 31 May 2011 (me) Review posted live
• 11 January 2011 (al) Original submission