Branchiooculofacial Syndrome

Clinical characteristics.

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, cataract, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include dolichocephaly, 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 weakness of cranial nerve VII). 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 of BOFS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in TFAP2A identified by molecular genetic testing.

Management.

Treatment of manifestations: In general, children with BOFS should be managed by a multispecialty team including craniofacial specialists, plastic surgeons, otolaryngologists, and speech-language therapists. Small, linear, or superficial branchial skin defects may heal spontaneously; however, some require surgical intervention. Treatment of ophthalmic manifestations is per pediatric ophthalmologist. Nasolacrimal duct stenosis or atresia often requires surgery. Anophthalmia or severe microphthalmia may require a conformer (a structure, usually plastic, inserted into the eye socket to encourage its growth). It is recommended that cleft lip be repaired by an experienced pediatric plastic surgeon. Nasal tip abnormalities, lesser forms of cleft lip ("pseudocleft"), and malformed pinnae may need surgical correction. Standard treatments for hearing loss, renal malformations, dental manifestations, and congenital heart defects. Treatment of sensory, psychologic, and developmental challenges with supportive therapies.

Surveillance: Ophthalmology examination and vision assessment as recommended by ophthalmologist; audiology evaluation as recommended by otolaryngologist and/or audiologist; at each visit assess for a recurrent urinary tract infection suggestive of vesicoureteral reflux, assess teeth for size, number, carries, and malocclusion, and assess for new cysts; developmental and behavioral assessment annually or as needed; monitor for signs of low self-esteem and other psychological issues at each visit in older children as they enter adolescence.

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 and preimplantation genetic testing are possible.

Suggestive Findings

BOFS should be suspected in probands 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;
• Are most distinctive when they are bilateral and anterior cervical in location, and may be described as "cutis aplasia" [Wurfbain et al 2023];
• 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, and upslanted palpebral fissures (See Figure 1.)
• Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate (Isolated cleft palate has not been reported.)
• Upper lip pits
• Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII)
• 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 branchiooculofacial syndrome syndrome (BOFS). Details of the molecular findings are reported in Milunsky et al [2008] (patient 3, age two years). He has a right-sided cervical cutaneous defect ("B") that was repaired; (more...)

Establishing the Diagnosis

The clinical diagnosis of BOFS can be established in a proband based on proposed clinical diagnostic criteria [Milunsky et al 2011], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in TFAP2A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous TFAP2A variant of uncertain significance does not establish or exclude the diagnosis.

Molecular Diagnosis

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

• Single-gene testing. Sequence analysis of TFAP2A is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes TFAP2A and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition 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 are likely to change 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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; 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.

Table 1.

Molecular Genetic Testing Used in Branchiooculofacial Syndrome

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. Although the facial features are generally recognizable, some individuals may have subtle differences [Authors, personal observation].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation exists.

Significant inter- and intrafamilial variability have been 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 nine 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with branchiooculofacial syndrome (BOFS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Branchiooculofacial Syndrome: Recommended Evaluations Following Initial Diagnosis

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 that 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-language therapists (see Table 4). Ideally, multispecialty evaluations and surgery should be performed within a craniofacial clinic.

Table 4.

Branchiooculofacial Syndrome: Treatment of Manifestations

Surveillance

To monitor existing manifestations and the individual's response to supportive care, the evaluations summarized in Table 5 are recommended.

Table 5.

Branchiooculofacial Syndrome: Recommended Surveillance

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 surveillance and treatment of hearing, vision, renal, and other manifestations. 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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Approximately 40%-50% of individuals diagnosed with BOFS have an affected parent [Milunsky et al 2011].
• Approximately 50%-60% of individuals diagnosed with BOFS have the disorder as the result of a de novo TFAP2A pathogenic variant [Milunsky et al 2011].
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a TFAP2A pathogenic variant may be mildly/minimally affected [Milunsky et al 2011].
• The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband.

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 is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [Milunsky et al 2011].
• If the proband has a known TFAP2A pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [Milunsky et al 2011].
• If the parents appear to be clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a milder phenotypic presentation in a heterozygous parent and the possibility of parental mosaicism.

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, the parent's 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the TFAP2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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]. 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].

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

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.

Mechanism of disease causation. Loss of function

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

• 28 September 2023 (sw) Comprehensive update posted live
• 29 March 2018 (ha) Comprehensive update posted live
• 31 May 2011 (me) Review posted live
• 11 January 2011 (al) Original submission

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]

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