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 ... 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, which lies telomeric to the TFAP2A gene.
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, ... 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 third 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 dolicocephaly, 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.
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 ... 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.
Background. The branchiooculofacial syndrome (BOFS) is a distinctive craniofacial syndrome first characterized by Lee et al [1982], Hall et al [1983], and Fujimoto et al [1987]. Lin et al [1995] published a large review of the clinical findings. The associated gene (TFAP2A) was discovered in 2008 using array comparative genomic hybridization [Milunsky et al 2008], followed by a large genotype-phenotype analysis [Milunsky et al 2011]....
DiagnosisBackground. The branchiooculofacial syndrome (BOFS) is a distinctive craniofacial syndrome first characterized by Lee et al [1982], Hall et al [1983], and Fujimoto et al [1987]. Lin et al [1995] published a large review of the clinical findings. The associated gene (TFAP2A) was discovered in 2008 using array comparative genomic hybridization [Milunsky et al 2008], followed by a large genotype-phenotype analysis [Milunsky et al 2011].Clinical Diagnosis The branchiooculofacial syndrome (BOFS) is diagnosed clinically. There are no formal diagnostic guidelines developed by consensus panels, algorithms using a hierarchy of clinical findings, or evidence-based test standards. Diagnostic criteria had been used informally based on the hallmark defects (B, O, F) and were proposed formally in 2011 incorporating the importance of thymic anomalies and independently diagnosed first-degree relatives [Milunsky et al 2011 Table I)]. Note: Of the original three features that comprise the mnemonic BOF, the “B” (cutaneous skin defect) is the most distinctive when it is bilateral and anterior cervical in location. Diagnostic criteria:All three of the main features are present:Branchial (cutaneous) skin defectOcular anomalyFacial anomalies (characteristic facial appearance) ORTwo of the three main features plus one of the following are present:Affected first-degree relative, independently diagnosedEctopic thymus (dermal)Note: In bulleted findings listed below, those in bold are present in most affected individuals; findings in italics are not present in most affected individuals but are distinctive for BOFS.Branchial (cutaneous) defectsCervical (90%) or infra- or supra-auricular (60%) skin defectsVary from barely perceptible thin skin or hair patch to erythematous “hemangiomatous” lesions to large weeping erosionsDiffer from the punctuate sinus tracts of the branchiootorenal (BOR) syndromeMildest defects may be unrecognized, heal spontaneouslyOcular anomaliesMicrophthalmia, anophthalmiaColobomaStrabismusPtosisNasolacrimal duct stenosis/atresiaCataractFacial anomaliesCharacteristic 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 called “pseudocleft lip"), with or without cleft palate (99%), but no isolated cleft palate Upper lip pitsLower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial 7th cranial nerve weakness) Inner ear and petrous bone anomalies (As in CHARGE syndrome and the branchiootorenal syndrome, there can be cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct.)Malformed and prominent pinnaeHearing loss (70%) (conductive, sensorineural, mixed)FigureFigure 1. Photo of a five-year-old boy 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") which was repaired; bilateral nasolacrimal (more...)Immune systemThymic anomalies (ectopic, dermal)Renal systemStructural anomalies (35%) (dysplastic, absent, multicystic, etc.)Vesicoureteral refluxEctodermal (hair, teeth, nails)Premature hair graying (poliosis) (35%)Hypoplastic teethDysplastic nailsCysts (often on the scalp; less commonly in the head and neck region) Psychomotor developmentVisual and hearing handicaps (frequent)Psychomotor performance (usually normal) Autism spectrum disorder, intellectual disability (rare) GrowthGrowth restriction: uncommonRare (<5 patients)Heterochromia iridesCongenital heart defect (atrial septal defect, tetralogy of Fallot)Polydactyly (bilateral, usually post-axial)Medulloblastoma (described once [Milunsky et al 2008])Molecular Genetic Testing Gene. TFAP2A is the only gene in which mutations are known to cause branchiooculofacial syndrome.Clinical testingSequence analysis. More than 95% of individuals who meet the clinical diagnostic criteria for BOFS have TFAP2A sequence variants detectable by sequence analysis (i.e., small intragenic deletions/insertions and missense, nonsense, and splice site mutations) [Milunsky et al 2011].Deletion/duplication analysis. Whole-gene deletions of TFAP2A have been described [Milunsky et al 2008, Gestri et al 2009] and likely are present in fewer than 5% of persons with BOFS. Larger deletions of chromosome 6p24-p25 including TFAP2A are rare [Davies et al 1999, Misceo et al 2008]. No partial-gene or exonic deletions or duplications have been reported. Table 1. Summary of Molecular Genetic Testing Used in Branchiooculofacial SyndromeView in own windowGene SybolmTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTFAP2ASequence analysisSequence variants 2>95%ClinicalDeletion / duplication analysis 3Whole-gene deletions<5%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband1.Clinical examination for the diagnostic features2.For those meeting clinical diagnostic criteria, sequence analysis of the seven coding exons and intron/exon boundaries of TFAP2A3.If a mutation is not detected on sequence analysis, deletion/duplication analysisPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in TFAP2A.
Natural History Females and males are affected equally.Newborns with clefts have the expected challenges to feeding, and possibly breathing. Infants with clefts need support to feed properly, and do best when in the care of an established cleft palate team. Some of the smaller skin defects start to “heal” by secondary intention. Nasolacrimal duct stenosis or atresia lead to weeping eyes, and require the attention of a pediatric ophthalmologist. In childhood, individuals with BOFS are coping with cosmetic, visual, hearing, and speech challenges. They may have strabismus; some have significant visual impairment. The most severely affected children have surgical, medical, cosmetic and learning needs similar to many other children with craniofacial disorders. However, mildly affected children may appear to need little support. Adolescents may have issues with anxiety and social esteem. These appear to be more than the experience of living with a cleft lip and other craniofacial anomalies, but the number of affected individuals is small. Most have normal intellect. Adults with typical BOFS have usually been diagnosed in childhood. Individuals with very mild features may not be diagnosed until they give birth to a classically affected child. The observation that adults can be asymptomatic or minimally affected illustrates the variable expression of mutations in this gene. Fertility does not appear to be affected.
Genotype/phenotype correlations for mutations within TFAP2A are not well established. ...
Genotype-Phenotype Correlations Genotype/phenotype correlations for mutations within TFAP2A are not well established. A genotype-phenotype analysis of 41 individuals in 30 families was based on diagnostic criteria that were fulfilled in 87% [Milunsky et al 2011]. Significant inter- and intrafamilial variability were observed with the same mutations [Milunsky et al 2011]. Missense, frameshift, and splicing mutations along with more complex rearrangements [Tekin et al 2009, Milunsky et al 2011] throughout the gene result in similar phenotypes.The absence of overt clefting is noted in the few individuals who have whole-gene deletions [Milunsky et al 2008, Gestri et al 2009] and larger chromosomal deletions that include TFAP2A [Davies et al 1999, Misceo et al 2008]. All individuals with a deletion appear to have an abnormally prominent philtrum that may be on the spectrum of microform cleft lip [Lin et al 2009]. Otherwise the marked inter- and intrafamilial variability appear similar to that observed with intragenic mutations.To date information is insufficient to make generalizations about the presence of autistic features and severe intellectual disability in BOFS since only two instances have been noted. Patient SP2 reported by Reiber et al [2010], who had the mutation c.806T>C, had both severe intellectual disability and autism.Patient 3 reported by Gestri et al [2009], who had a whole-gene deletion, had autistic features.
Phenotypic overlap with the branchiootorenal (BOR) syndrome has been suggested, but BOFS has more distinctive craniofacial anomalies, and the two should not be confused....
Differential DiagnosisPhenotypic overlap with the branchiootorenal (BOR) syndrome has been suggested, but BOFS has more distinctive craniofacial anomalies, and the two should not be confused.Although there may appear to be superficial overlap in some of the findings, there should be no confusion in differentiating BOFS from CHARGE syndrome since the latter does not have skin defects, and BOFS does not have choanal atresia. The abnormal pinna and inner ear anomalies differ.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with the branchiooculofacial syndrome (BOFS), the following studies are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with the branchiooculofacial syndrome (BOFS), the following studies are recommended:CT imaging of the temporal bone to anticipate optimal hearing correction [Raveh et al 2000, Tekin et al 2009, Stoetzel et al 2009]Echocardiogram if there is a murmur or cardiac symptoms Renal ultrasonographyThe following consultations are recommended: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 presentFormal evaluation of cleft lip/palate and other possible facial abnormalities by a cleft lip/palate team, which often includes a medical geneticist, pediatric plastic surgeon, otorhinolaryngologist, speech and language therapist, dental and orthodontic specialist, and ophthalmologist Complete eye examination by a pediatric ophthalmologist to assess for visual limitations, strabismus, and nasolacrimal duct obstructionReferral of those with anophthalmia and/or severe microphthalmia to support services for the visually impairedReferral to a nephrologist if renal abnormalities are identifiedReferral to an audiologistFor those with a cleft, assessment by a speech therapistDevelopment assessment particularly for children with visual and/or hearing problemsMonitoring for depression, attention dysregulationNote: Motor delays are not part of BOFS, and thus, physical and occupational therapy is not anticipated.Treatment of ManifestationsMilunsky et al [2011] provided management guidelines. See .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 III].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. In addition 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 should be treated like a moist “wound” by a plastic surgeon, but generally do not 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, which should be sent for histopathologic examination.Obstruction from nasolacrimal duct stenosis or atresia must be relieved and 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 Deafness and Hereditary Hearing Loss Overview). 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 make recommendations that more severely affected individuals require more psychologic support.SurveillanceMonitor for changes related to the major findings over time.Monitor older children as they enter adolescence for signs of low self-esteem and other psychologic issues. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Branchiooculofacial Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTFAP2A6p24.3Transcription factor AP-2 alphaTFAP2A homepage - Mendelian genesTFAP2AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Branchiooculofacial Syndrome (View All in OMIM) View in own window 107580TRANSCRIPTION FACTOR AP2-ALPHA; TFAP2A 113620BRANCHIOOCULOFACIAL SYNDROME; BOFSMolecular Genetic 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].Normal allelic variants. TFAP2A contains seven coding exons (reference sequence NM_003220.2) Pathologic allelic variants. Mutations 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 mutations in simplex cases (i.e., a single occurrence in the family) that resulted in BOFS. Additional mutations and another familial deletion have now been described [Gestri et al 2009, Stoetzel et al 2009, Tekin et al 2009, Reiber et al 2010]. Although the mutations occur throughout the gene, a hotspot region in exons 4 and 5 that harbors missense mutations in about 90% of probands/families with BOFS has been identified [Milunsky et al 2011]. Recurrent mutations are now well recognized (Table 2). 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 mutations (28/30; 93%), one frameshift mutation, 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.Table 2. Recurrent Pathologic TFAP2A Allelic Variants Revealing a Mutational Hotspot View in own windowExonDNA Nucleotide Change Protein Amino Acid Change Reference Sequences4c.709C>Gp.Arg237GlyNM_003220.2 NP_003211.14c.710G>Cp.Arg237Pro4c.724G>Ap.Glu242Lys4c.752G>Ap.Gly251Glu4c.760A>Gp.Arg254Gly4c.760A>Tp.Arg254Trp4c.761G>Cp.Arg254Pro4c.763A>Gp.Arg255Gly5c.767C>Tp.Ala256ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Table adapted from Table III in Milunsky et al [2011]. 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 4 and 5) 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 mutations 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]. Gestri et al [2009] studied the role of TFAP2A mutations in zebrafish eye morphogenesis that revealed an association with a multitude of ocular pathologies. In addition, the mutations compromised the gene function thereby sensitizing the developing eye to deleterious mutations in 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 mutant Tcfap2a mice have craniofacial anomalies, abnormal middle ear development, and defects in pigmentation.