Branch-Oculo-Facial Syndrome (BOFS)

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, slanted palpebral fissures
• Cleft lip or prominent philtrum 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)
• The 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)

Lab test

• Ocular sonography – using a 12 MHz probe revealed complex dysplasia and incomplete development of the anatomical structure of the left eyeball consistent with persistent primary vitreous hyperplasia. The axial length of the eyeball was smaller than normal, with an Anteroposterior of 11 mm, consistent with microphthalmia. At the age of 10 years, he underwent cataract surgery for the right eye. He also had nasolacrimal stenosis in the right eye.
• Magnetic resonance imaging –  left parietal-frontal cortical sulci, fissure, and basal cistern were prominent.
• Renal ultrasound – of the left kidney revealed multiple cystic lesions, indicating that the left kidney was nonfunctional. Urinary anomalies in the right kidney were not discovered at birth.
• Audiometric examinations – at the age of 1 year showed bilateral, severe-to-profound sensory neural hearing loss that the hearing levels were 75–80 dB.

Genetic Test

• 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, whereas those in whom the diagnosis of BOFS has not been considered are more likely to be diagnosed using genomic testing.
• 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 while limiting the 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.