Branchio-oculo-facial syndrome (BOFS) is a disease that arises from a mutation in the

TFAP2A Transcription factor AP-2 alpha (Activating enhancer binding Protein 2 alpha), also known as TFAP2A, is a protein that in humans is encoded by the ''TFAP2A'' gene. Function Transcription factor AP-2 alpha is a 52-kD sequence-specific DNA-bindi ...

gene. It is a rare

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder that starts to affect a child's development before birth. Symptoms of this condition include skin abnormalities on the neck, deformities of the ears and eyes, and other distinctive facial features such a cleft lip along with slow growth, mental retardation and premature graying of hair.

Signs and symptoms

"Branchio" refers to the branchial arches, also known as the pharyngeal arches, of the affected individual. The branchial arches are structures in the developing

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

that give rise to certain tissues in the neck and facial area. In individuals affected by this condition, the branchial arches fail to develop properly. This leads to some of the physical conditions of this syndrome, which include abnormal patches of skin on the neck and face region and can be abnormally hairy, thin or red and with a high number of blood vessels. "Oculo" refers to the eyes. Individuals have

vision impairment Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...

due to several malformations in the eyes such as small eyeballs, blockage in the tear ducts or lacking eyes completely. "Facial" refers to the face; those affected can have several abnormalities in that region. These abnormalities include a cleft lip, a

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

which is an opening in the roof of the mouth, widely spaced eyes ( hypertelorism), sharp corners of the mouth that point upward, a broad nose that can include a flattened tip, along with several deformations of both the external and middle ear structures. This syndrome is restricted to the face, but it can also cause underdeveloped or malformed kidneys.

Pathophysiology

The disease is genetically inherited and stems from a mutation that deletes the

gene. This gene is important because it provides the blueprint for the arrangement of 437

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s that make up the protein

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

known as AP-2 alpha. This protein transcription factor binds to a carboxy terminus helix-span-helix motif and an amino terminus portion of DNA that affects the activity of numerous cellular activities such as

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ...

and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

. AP-2 alpha is especially important during the embryos development principally in the development of the branchial arches. Currently there are also four other proteins that are affected by the deletion of TFAP2A gene as well. One is L249P, this protein changes to cause a conformational space change with a substituted

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

. Furthermore, a change in the R254W and R255G proteins results in a replacement of a charged polar side chain by a nonpolar side chain, and lastly, an alteration in the G262E protein results in a nonpolar side chain being replaced by a charged polar side chain.

Diagnosis

Branchio-oculo-facial syndrome is difficult to diagnose because it has

incomplete penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...

. It is often misdiagnosed as

branchio-oto-renal syndrome Branchio-oto-renal syndrome (BOR) is an autosomal dominant genetic disorder involving the kidneys, ears, and neck. It often has also been described as Melnick-Fraser syndrome. Signs and symptoms The signs and symptoms of branchio-oto-renal syndro ...

because of their similarities in symptoms.

Management

The care and management of people with BOFS is 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, the 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.

Epidemiology

It was estimated that only 100 cases of BOFS have been documented in the medical literature .

References

External links

{{Medical resources , DiseasesDB = , ICD10 = Q18.8 , ICD9 = , ICDO = , OMIM = 113620 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 1297 , SNOMED CT = 449821007 Genetic diseases and disorders Transcription factor deficiencies Rare syndromes Syndromes with intellectual disability Syndromes with cleft lip and/or palate