Branch-oculo-facial syndrome (BOFS) is a rare genetic autosomal dominant multiple-malformation congenital disorder with defects of the head and neck facies, growth retardation, imperforate nasolacrimal duct, and premature aging that are apparent at birth (congenital) and 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, microphthalmia or anophthalmia, coloboma, and cataract and nasolacrimal duct stenosis/atresia; and facial anomalies that can include ocular hypertelorism or telecanthus, aplastic or hemangiomatous cervical skin lesions with or without branchial sinuses; malformed,broad nasal tip, up slanted palpebral fissures, cleft lip or prominent philtrum 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 the inner ear and/or petrous bone anomalies are common and usually diagnosed in childhood. As of 2018, fewer than 100 cases have been reported in the medical literature, although additional patients are probably followed worldwide.
Another name
- BOFS
- Branchial clefts with characteristic facies, growth retardation, imperforate nasolacrimal duct, and premature aging
- Hemangiomatous branchial clefts-lip pseudocleft syndrome
- Lip pseudocleft-hamartomatous branchial cyst syndrome
Symptoms
Symptoms may vary from mild to severe forms. The sole pathogenic gene is TFAP2A. Although molecular genetic testing is useful to confirm the clinical diagnosis, the classic phenotype should not be confused with other syndromes.
Infants with BOFS may have a low birth weight and may continue to experience abnormally slow growth after birth (postnatal growth retardation).
“B” refers to “branchial” skin defects, although a more accurate term is pharyngeal. The skin defects are not true hemangiomas, but unfortunately, the description as hemangiomatous has persisted. They are usually dark pink or red, maybe moist, weep, or have atrophic skin. They vary in size from small defects as small as a “pit” to larger lesions that require resection and reconstructive surgery. They should not be treated with simple cauterization. Many are linear along both sides of the neck. Less commonly, they occur below or behind the ear.
“O” refers to various ocular (eye) anomalies especially microphthalmia (small eyes), ptosis, strabismus, and cataracts. Blockage of the tear ducts (lacrimal duct obstruction) is common. The eyes are typically widely spaced.
“F” refers to individual facial defects, which together create the impression of a recognizable facial appearance. The oral cleft can be incomplete or partial, the so-called pseudocleft lip. The philtrum is unusually wide and a ridge gives the impression it had been surgically repaired, or “healed” in utero. There is often a severe bilateral cleft lip and palate. Teeth can be small, absent, or malformed. The nose is malformed with a broad bridge and flattened tip. The ears are malformed, typically low-set, and posteriorly rotated. Hair may be prematurely grey. Facial asymmetry due to lower facial nerve weakness can be present.
Additional features include low birth weight, growth delay, learning challenges, intellectual disability, and mental health issues. However, detailed studies of the neuropsychologic issues have not been performed to determine a reliable frequency.
Classic BOF Findings Symptoms
Branchial (cutaneous) defects occur in a cervical (90%) or infra- or supra-auricular (60%) location.
- Defects vary from barely perceptible thin skin or hair patch to erythematous “hemangiomatous” lesions to large weeping erosions.
- Mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract which may appear to “weep,” revealing the patency.
Ocular anomalies include the following:
- Structural eye malformations such as
- Microphthalmia, anophthalmia
- Coloboma
- Cataract
- Periorbital abnormalities such as
- Ptosis
- Nasolacrimal duct stenosis/atresia leading to weeping eyes
- Visual concerns such as
- Strabismus
- Significant visual impairment
Facial anomalies. Characteristic appearance includes dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures. Other findings may include:
- Cleft lip or prominent philtrum pillars (technically known as a lesser-form cleft lip [formerly “pseudocleft lip”])
- Occurring with or without cleft palate (99%)
- No instances of isolated cleft palate reported
- Upper lip pits
- Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial 7th cranial nerve weakness)
- Ear anomalies
- Malformed and prominent pinnae
- The inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct
- Hearing loss (70%) (conductive, sensorineural, mixed)
- Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip
Additional Findings Observed in BOFS
Immune system. Thymic anomalies (ectopic, dermal) (~35%), typically bilateral with normal thymic function
Renal system
- Structural anomalies (35%) (e.g., dysplastic, absent, multicystic)
- Vesicoureteral reflux
Ectodermal (hair, teeth, nails)
- Premature hair graying, poliosis (forelock or patchy) (35%)
- Hypoplastic teeth
- Dysplastic nails
- Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly in the head and neck region)
Psychomotor development (typically normal)
- Visual and hearing handicaps (frequent)
- Autism spectrum disorder, intellectual disability (rare)
Growth restriction. Uncommon
Miscellaneous and rare (<5 individuals each)
- Heterochromia irides
- Congenital heart defect (atrial septal defect, tetralogy of Fallot)
- Polydactyly (bilateral, usually postaxial)
- Medulloblastoma (described once
Anomalies of the thymus, ranging from absence to atypical position, occur. Skin features include subcutaneous cysts of the scalp and elsewhere. In addition to the structural differences, there can be visual impairment, hearing loss, and speech disabilities. Autism spectrum disorder, congenital heart defects, and polydactyly are rare. Although cognitive ability is usually normal, there is no large study of subtler learning and behavior challenges.
Causes
BOFS is caused by mutations in the TFAP2A gene and follows an autosomal dominant pattern of inheritance.
Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Branchio-oculo-facial syndrome is caused by mutations in the TFAP2A gene. This gene provides instructions for making a protein called transcription factor AP-2 alpha (AP-2α). As its name suggests, this protein is a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Transcription factor AP-2α regulates genes that are involved in several cellular processes, such as cell division and the self-destruction of cells that are no longer needed (apoptosis). This protein is critical during development before birth, particularly of the branchial arches, which form the structures of the face and neck.
Most TFAP2A gene mutations that cause branchio-oculo-facial syndrome change single protein building blocks (amino acids) in the transcription factor AP-2α protein. These changes tend to occur in a region of the protein that allows it to bind to DNA. Without this function, transcription factor AP-2α cannot control the activity of genes during development, which disrupts the development of the eyes, ears, and face and causes the features of the branchio-oculo-facial syndrome.
In 50-60% of individuals with BOFS, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. In some families, the parent who has very mild features is diagnosed after the child is recognized to have BOFS.
There is no correlation between the type of gene mutation and the appearance of the person. However, patients who have a chromosome deletion involving TFAP2A have a slightly different appearance.
Diagnosis
The diagnostic criteria have been based on the hallmark features that include a branchial skin defect, ocular anomaly, and facial anomalies (B, O, F). If all three of the hallmark abnormalities are present, it would be characterized as a branches-oculo-facial syndrome. If two of the three hallmark defects are present, plus thymus tissue found in an abnormal location (ectopic thymus) or if a parent or child is affected, it would be characterized as a branches-oculo-facial syndrome.
TFAP2A is currently the only gene associated with BOFS. Molecular genetic testing for mutations in the TFAP2A gene is available to confirm the diagnosis.
Physical Exam
The diagnosis of BOFS is based on recognition of the distinctive craniofacial features. “B” refers to branchial skin defects, although a more accurate term is pharyngeal. “O” refers to various ocular (eye) anomalies. “F” refers to the various facial differences including cleft lip/palate, unusual nose, malformed nose, and small teeth. Problems outside of the head and neck region include kidney defects and congenital heart defects.
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 diagnosis: Differential diagnosis is a list of possible conditions that may explain symptoms. সহজ বাংলা: একই লক্ষণের সম্ভাব্য রোগের তালিকা।" data-rx-term="differential diagnosis" data-rx-definition="Differential diagnosis is a list of possible conditions that may explain symptoms. সহজ বাংলা: একই লক্ষণের সম্ভাব্য রোগের তালিকা।">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.
Treatment
The care and management of people with BOFS are aimed at the specific signs and symptoms and should be carried out by a multi-specialty team who are skilled in craniofacial disorders. A medical geneticist usually makes the clinical diagnosis, which is confirmed with molecular testing. Reconstructive surgery is needed to repair facial deformities and obstructed nasal ducts. Importantly, skin defects should not be treated with simple cauterization. Strabismus (“crossed eyes”) may be corrected by surgery.
In addition, people with BOFS should be managed by an ophthalmologist, otolaryngologist, dentist, and speech therapist. Depending on the person’s issues, there may be a need for a neuropsychologic or developmental evaluation and mental health support.
Genetic counseling is recommended for the patients and their families for reproductive health.
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