Branchiooculofacial Syndrome

A number sign (#) is used with this entry because of evidence that branchiooculofacial syndrome (BOFS) is caused by heterozygous mutation in the TFAP2A gene (107580) on chromosome 6p24.

Description

Branchiooculofacial syndrome (BOFS) is characterized by branchial cleft sinus defects, ocular anomalies such as microphthalmia and lacrimal duct obstruction, a dysmorphic facial appearance including cleft or pseudocleft lip/palate, and autosomal dominant inheritance. Although anomalies of the external and middle ear frequently cause conductive hearing loss in BOFS, severe to profound sensorineural hearing loss due to inner ear anomalies has rarely been reported (summary by Tekin et al., 2009).

See also chromosome 6pter-p24 deletion syndrome (612582) for a similar phenotype. The deletion region lies telomeric to the TFAP2A gene.

Clinical Features

Lee et al. (1982) described a 38-year-old woman and her 8-year-old son who had low birth weight for dates and retarded postnatal growth, bilateral branchial cleft sinuses, congenital strabismus, obstructed nasolacrimal ducts, broad nasal bridge, protruding upper lip, and carp mouth. Graying of the mother's hair occurred at age 18. Intelligence was normal. The same disorder may have been reported by Hall et al. (1983) and Fujimoto et al. (1987). Hall et al. (1983) described 2 unrelated children (1 male, 1 female) with hemangiomatous branchial clefts and pseudocleft of the upper lip (resembling a surgically repaired cleft or a fused cleft). They found reports of 2 additional patients who, they suspected, also represented sporadic cases of this syndrome. In several persons in 3 families, Fujimoto et al. (1987) observed an autosomal dominant disorder of abnormal upper lip, which resembled a poorly repaired median cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears, and branchial cleft sinuses and/or linear skin lesions behind the ears. In each of the 3 families an affected parent had at least 1 affected child, and father-to-son transmission was observed in 1. Other anomalies included coloboma, microphthalmia, auricular pits, lip pits, highly arched palate, dental anomalies, and subcutaneous cysts of the scalp. Premature graying of hair occurred in affected adults. The abnormality of the upper lip might be described as an unusually broad and prominent philtrum.

Mazzone et al. (1992) reported a patient who, in addition to typical features of BOFS, had partial agenesis of the cerebellar vermis. Lin et al. (1992) concluded that the father and son reported by Legius et al. (1990) had the BOF syndrome and that this additional finding of male-to-male transmission confirmed autosomal dominant inheritance. Fielding and Fryer (1992) described 2 sibs with this syndrome, each of whom also had orbital hemangiomatous cysts. Both parents were clinically normal and unrelated. Thus this may have represented an autosomal recessive form of the disorder or germline mosaicism for the dominant gene. Schmerler et al. (1992) reviewed the development of an affected child over a 12-year period of observation. Normal intelligence, regular class placement, hypernasal speech, and continued growth along the 3rd centile were noted. The infant had been referred at the age of 5 months for evaluation of his facial appearance and 'burn-like' lesions behind both ears. McCool and Weaver (1994) observed the BOF syndrome in a mother and her son who lacked the ocular and branchial abnormalities but had bilateral supraauricular sinuses and hearing loss. The son had bilateral cleft lip and right alveolar cleft; the mother had asymmetric nostrils and upper lip. The supraauricular sinuses were thought to represent persistence of the otic vesicle sinus tract.

Lin et al. (1995) described 15 new cases of the BOF syndrome and reviewed previously reported cases (28 with typical and 5 with atypical manifestations) in detail. Postauricular cervical branchial defects were found in 40 of 43 patients, and supraauricular defects were found in 6. Pathologic findings of the excised branchial defects showed thymic remnants in several cases. Colobomata were found in 16 of 35 patients, cataracts in 8 of 33, deafness in 14 of 38, scalp cysts in 4 of 38, and premature graying of hair in 9 of 38. Pseudoclefts were observed in 23 patients, and cleft lip and/or palate in 20. Urologic examination of 19 patients revealed kidney abnormalities (agenesis, cysts, hydronephrosis) in 7. Autosomal dominant inheritance of the BOF syndrome is supported by a 3-generation German family, 2 instances of father-to-son transmission, and 7 other parent-offspring families (Fujimoto et al., 1987; Lin et al., 1995).

Richardson et al. (1996) described a boy with cleft lip and palate, microphthalmos, colobomata of optic nerves and irides, and cystic dysplasia of the left kidney. His mother had similar ocular abnormalities (plus polycoria), obstruction of nasolacrimal ducts, bifid nasal tip, abnormal philtrum, hypodontia, and premature graying of the hair. His maternal grandmother had the same facial defects and nasolacrimal duct obstruction, but normal eyes. The spectrum of abnormalities in this family fits the BOF syndrome, although cervical hemangiomata or branchial sinuses were not found in affected persons in this family.

McGaughran (2001) described a 1-year-old male with BOF syndrome together with preaxial polydactyly and a white forelock at birth. The author stated that this was only the second case in which preaxial polydactyly had been described in the branchiooculofacial syndrome.

Demirci et al. (2005) reported the ocular manifestations of BOF syndrome in a 10-year-old girl who had undergone excision of an orbital dermoid cyst and branchial cleft fistula at age 4 years. At age 10, she had sinus tracts on each side of the nose, connecting the lacrimal sac to the skin. In addition, she had an iris pigment epithelial cyst in one eye and a combined hamartoma of the retina and retinal pigment epithelium in the other.

Although BOF syndrome and branchiootorenal (BOR) syndrome (113650) are sufficiently distinctive that they should not be confused, both can be associated with nasolacrimal duct stenosis, deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, Legius et al. (1990) reported father and son with features of both conditions. In light of these issues, Lin et al. (2000) performed a mutation search of the EYA1 gene in 5 BOF syndrome patients and found no EYA1 mutations, suggesting that BOF syndrome is not allelic to the BOR syndrome. Lin et al. (2000) emphasized that the unusual areas of thin, erythematous wrinkled skin of the neck or infra/supraauricular region of BOF syndrome differ from the discrete cervical pits, cysts, and fistulas of the BOR syndrome.

Tekin et al. (2009) reported a 4-year-old Turkish girl who was diagnosed with bilateral profound sensorineural hearing loss at 1 year of age, in whom temporal bone CT scan revealed bilateral cochlear dysplasia, enlarged vestibule, and enlarged vestibular aqueduct; she underwent cochlear implantation. In addition, she was diagnosed with right multicystic dysplastic kidney and underwent unilateral nephrectomy. At 4 years of age, she had dolichocephaly, broad nasal bridge, upslanting palpebral fissures, bilateral pseudoclefts on philtrum, low-set posteriorly rotated ears, bilateral scars from skin defects in the supraauricular region, 2 pits in the suprasternal notch, and bilateral accessory nipples. Ophthalmologic examination was normal.

Stoetzel et al. (2009) studied a 3-generation family in which the proband, his father, and his paternal grandmother had BOFS and a heterozygous missense mutation in the TFAP2A gene. CT scan of the temporal bone in the affected individuals showed consistent stenosis of the round window, stenosis of the oval window, malformations of the stapes, hypoplasia of the long process of the incus, normal cochlea, and normal internal auditory meatus. Stoetzel et al. (2009) noted that major differences on CT scan between BOFS and BOR syndrome, particularly of the cochlea and internal auditory meatus canals, which are generally normal in BOFS but always abnormal in BOR syndrome, could help distinguish the 2 phenotypes.

Titheradge et al. (2015) described a 3-generation family in which 4 members, the proband and her brother, mother, and daughter, displayed variable severity of BOFS. The proband and her mother had typical features of the disorder, but the proband also had preaxial polydactyly, sensorineural hearing loss, and dental anomalies. Her 2-year-old daughter was mildly affected with only typical facies, right-sided cleft lip and left-sided pseudocleft lip. All 3 were found to have a heterozygous mutation in the TFAP2A gene. The proband's brother, who was not sequenced, died at 6 hours of life. He had multiple congenital anomalies including contractures of the hands, large low-set ears, left anophthalmia, and left-sided cleft lip. Autopsy revealed agenesis of the right kidney and ureter, dysplastic left kidney with narrowing of the left ureter, and secondary lung hypoplasia.

Cytogenetics

Davies et al. (1999) reported a child with microphthalmia and corneal clouding and a number of other dysmorphic features, including hypertelorism, micrognathia, dysplastic ears, thin limbs, and congenital cardiac defects. This child had an interstitial deletion of chromosome 6p25-p24 that did not include the FOXC1 gene (601090) but did include the TFAP2A gene. Davies et al. (1999) suggested that there is an additional locus within chromosome 6p25-p24 involved in anterior eye chamber development and that AP2-alpha is a candidate gene.

Molecular Genetics

Milunsky et al. (2008) performed genomewide microarray analysis in a mother and son with BOF syndrome and detected a 3.2-Mb deletion at chromosome 6p24.3. Sequencing of candidate genes in that region in 4 additional unrelated BOFS patients, 2 of whom had previously been studied by Lin et al. (2000), revealed 4 different de novo missense mutations in a conserved region of the TFAP2A gene (see, e.g., 107580.0001 and 107580.0002) that were not found in more than 300 controls. Milunsky et al. (2008) noted that although the affected mother and son did not have overt cleft lip and palate, the boy did have an abnormally short philtrum and bilaterally notched vermilion-mucosa border, which are on the spectrum of microform cleft lip in BOFS. The authors stated that their 'patient 5' was the first BOFS patient to be reported with medulloblastoma.

Gestri et al. (2009) sequenced the TFAP2A gene in 37 patients with developmental eye defects plus variable defects associated with BOFS and identified 2 heterozygous mutations in 2 patients (107580.0003 and 107580.0004, respectively). In addition, multiplex ligation-dependent probe amplification (MPLA) revealed a heterozygous deletion on chromosome 6p24.3, encompassing TFAP2A and an adjacent predicted gene, C6ORF218, in 2 sibs and their father from the family previously reported by Fielding and Fryer (1992). The father, who was originally described as unaffected, was found to exhibit mild, classic features of BOFS, including prominent philtrum, bilateral 2/3 partial syndactyly of the toes, bilateral malformed pinnae, and premature aging changes. He also showed subtle ocular changes, with normal anterior segments bilaterally but a dysplastic right optic disc with an unusual vessel pattern and mild dysplasia of the left disc.

In a 4-year-old Turkish girl with profound bilateral sensorineural hearing loss and features of BOFS, Tekin et al. (2009) identified a heterozygous deletion/insertion mutation in the TFAP2A gene (107580.0005).

In 2 families with BOFS, 1 of which was originally reported by Lin et al. (1995), and 3 sporadic patients with BOFS, Reiber et al. (2010) identified heterozygous mutations in the TFAP2A gene (see, e.g., 107580.0001 and 107580.0006-107580.0007). Reiber et al. (2010) stated that 1 of the sporadic patients studied by Reiber et al. (2010) designated patient 'SP2,' had been previously reported by Bennaceur et al. (1998) as 'patient 2.' Patient SP2 was not blind and did not have severe deafness, but did display severe mental retardation. Reiber et al. (2010) suggested that her developmental disability, which was not due to a dual sensory handicap of blindness and deafness, might be part of the spectrum of BOFS.