Branchiooculofacial Syndrome

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)

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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.