Branchiooculofacial syndrome

Other Names: BOFS syndrome; Branchial clefts with characteristic facies growth retardation imperforate nasolacrimal duct and premature aging; Hemangiomatous branchial clefts-lip pseudocleft syndrome; Lip pseudocleft-hemangiomatous branchial cyst syndrome

Branchio-oculo-facial syndrome is a condition that affects development before birth, particularly of structures in the face and neck. Its characteristic features include skin anomalies on the neck, malformations of the eyes and ears, and distinctive facial features.

"Branchio-" refers to the branchial arches, which are structures in the developing embryo that give rise to tissues in the face and neck. In people with branchio-oculo-facial syndrome, the first and second branchial arches do not develop properly, leading to abnormal patches of skin, typically on the neck or near the ears. These patches can be unusually thin, hairy, or red and densely packed with blood vessels (hemangiomatous). In a small number of individuals, tissue from a gland called the thymus is abnormally located on the skin of the neck (dermal thymus). Problems with branchial arch development underlie many of the other features of branchio-oculo-facial syndrome.

"Oculo-" refers to the eyes. Many people with branchio-oculo-facial syndrome have malformations of the eyes that can lead to vision impairment. These abnormalities include unusually small eyeballs (microphthalmia), no eyeballs (anophthalmia), a gap or split in structures that make up the eyes (coloboma), or blockage of the tear ducts (nasolacrimal duct stenosis).

Problems with development of the face lead to distinctive facial features in people with branchio-oculo-facial syndrome.

Epidemiology

Branchio-oculo-facial syndrome is a rare condition, although the prevalence is unknown.

Cause

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 branchio-oculo-facial syndrome.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Branchio-oculo-facial syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In about half of cases, an affected person inherits the mutation from one affected parent. The remaining cases occur in people whose parents do not have a mutation in the TFAP2A gene. In these situations, the mutation likely occurs as a random event during the formation of reproductive cells (eggs and sperm) in a parent or in early fetal development of the affected individual.

Signs and symptoms

The characteristic signs and symptoms of BOFS include skin defects, eye abnormalities, and distinctive facial features. These features vary among affected individuals. The skin defects include proliferation of blood vessels (hemangiomatous) in the lower neck or upper chest; lumps in the area of the neck or collarbone (branchial cleft sinuses); and linear skin lesions behind the ears. Eye abnormalities can include microphthalmia, coloboma, and strabismus. The distinctive facial features can include widely spaced eyes; the presence of a pseudocleft of the upper lip resembling a poorly repaired cleft lip; a malformed nose with a broad bridge and flattened tip; blockage of the tear ducts (lacrimal duct obstruction); and malformed ears. Often, affected individuals may have burn-like lesions behind the ears. Other features can include delayed growth, thymic and kidney abnormalities, dental abnormalities, and hearing loss. Intellect is usually normal.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the pinna(Abnormally shaped ears)
• Atypical scarring of skin(Atypical scarring)
• Conductive hearing impairment(Conductive deafness)
• Deep philtrum
• Everted lower lip vermilion(Drooping lower lip)
• Hemangioma(Strawberry mark)
• Low-set, posteriorly rotated ears
• Postauricular pit(Pit behind the ear)
• Preauricular pit(Pit in front of the ear)
• Supraauricular pit(Pit above the ear)

30%-79% of people have these symptoms

• Broad nasal tip(Broad tip of nose)
• Dolichocephaly(Long, narrow head)
• Fingernail dysplasia(Abnormal fingernail development)
• High palate(Elevated palate)
• Intrauterine growth retardation(Prenatal growth retardation)
• Iris coloboma(Cat eye)
• Microdontia(Decreased width of tooth)
• Nasal speech(Nasal voice)
• Nasolacrimal duct obstruction(Blocked tear duct)
• Neurological speech impairment(Speech disorder)
• Non-midline cleft lip
• Premature graying of hair(Early graying)
• Reduced number of teeth(Decreased tooth count)
• Short stature(Decreased body height)
• Upslanted palpebral fissure(Upward slanting of the opening between the eyelids)
• Wide nasal bridge(Broad nasal bridge)

Diagnosis

Branchiooculofacial syndrome (BOFS) should be suspected in individuals with findings in two or three of the following categories:

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, upslanted palpebral fissures .
• Cleft lip or prominent philtral 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)
• 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)

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. Once the TFAP2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Treatment

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. 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.
• 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 may resemble a moist "wound" and often 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; such tissue should be sent for histopathologic examination.
• If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of the ectopic thymus.
• Ophthalmic concerns are best addressed by a pediatric ophthalmologist.
• Obstruction from nasolacrimal duct stenosis or atresia must be relieved and individuals 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 Hereditary Hearing Loss and Deafness Overview).
• Renal and cardiac abnormalities are managed in a standard manner.
• 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 recommend requiring more psychologic support for more severely affected individuals.

NIH genetic and rare disease info

• NIH info on Branchiooculofacial syndrome

Branchiooculofacial syndrome is a rare disease.

Branchiooculofacial syndrome Resources
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