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.

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

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).

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.

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.

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 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

• ~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, the parent 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:

• If a parent of the proband is affected, the risk to the sibs of inheriting the pathogenic variant is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [Milunsky et al 2011].
• If the TFAP2A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• The sibs of a proband with clinically unaffected parents are still at increased risk for BOFS because of the possibility of a milder phenotypic presentation in a heterozygous parent or the theoretic possibility of parental germline 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.

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/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).

Prenatal Testing and Preimplantation Genetic Testing

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

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

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]

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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