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A rare, dominantly inherited multiple congenital anomalies syndrome characterized by highly variable clinical phenotype involving the three main affected systems: branchial (cutaneous) defects, ophthalmic malformations and facial anomalies. Additional features can be present.
ORPHA:1297Classification level: Disorder
The prevalence of branchio-oculo-facial syndrome (BOFS) is unknown but fewer than 150 individuals with a well-described clinical and/or molecular diagnosis have been reported in the literature so far.
The branchial defects include cervical or infra- and/or supra-auricular skin defects that vary in size and shape but are typically characterized as thinned erythematous cutaneous defects. Ocular features are highly variably expressed including microphthalmia, anophthalmia, coloboma, cataract, ptosis, nasolacrimal duct obstruction, strabismus and significant visual impairment. The characteristic craniofacial features include dolichocephaly, hypertelorism, telecanthus, upslanted palpebral fissures, broad nose with full nasal tip, pre-auricular and upper lip pits, external ear anomalies (malformed and prominent pinnae), inner ear and petrous bone anomalies (such as cochlear dysplasia, Mondini dysplasia and enlarged vestibular aqueduct), cleft lip (including lesser forms, such as microform, ''pseudocleft'' or abnormal philtrum) with or without cleft palate, and lower facial nerve and/or muscle hypoplasia (partial 7th cranial nerve weakness). Patients have conductive/sensorineural/mixed hearing loss. Additional findings include ectopic dermal thymus, renal anomalies (dysplastic, multisystem or absent kidneys, vesicoureteral reflux) and ectodermal anomalies (premature hair graying, hypoplastic teeth, dysplastic nails and subcutaneous dermoid-like cysts, often on the scalp). Psychomotor development is typically normal. Autism spectrum disorder, intellectual disability, growth restriction, congenital heart defects and polydactyly are rare.
BOFS is caused by mutations involving the gene TFAP2A (6p24.3) that encodes the transcription factor AP-2 alpha that regulate gene expression during embryogenesis (of the eye, ear, face, body wall, limbs and neural tube).
The clinical diagnosis of BOFS is established if all three of the main features (branchial, ocular and craniofacial) are present or if two of the three main features are present in addition to either ectopic thymus or a positive family history in a first-degree relative. Diagnosis may be confirmed with molecular testing.
The most important differential diagnosis of BOFS is the branchio-oto-renal syndrome (BOR syndrome).
Prenatal diagnosis and preimplantation genetic testing are possible where the pathogenic variant has previously been identified in a family member.
BOFS has shown almost complete penetrance and a significant inter- and intrafamilial variability. No clear genotype-phenotype correlation exists. Transmission is autosomal dominant and an affected individual has a 50% chance of having an affected child at each pregnancy. About 50-60% of the diagnosed individuals have a de novo pathogenic variant.
Management and treatment
Multidisciplinary care is required, including craniofacial specialists, plastic surgeons, ophthalmologists, otolaryngologists, dentists and genetic counseling for affected families. Renal and cardiac abnormalities should be excluded and when necessary supportive therapies should be considered.
Prognosis is generally good but depends on the severity of associated manifestations.
A summary on this disease is available in Italiano (2009) Deutsch (2004) Español (2021) Français (2021) Nederlands (2021)
- Article for general public
- Svenska (2015) - Socialstyrelsen
Disease review articles
- Clinical genetics review
- English (2018) - GeneReviews
: produced/endorsed by FSMR(s)