NORD gratefully acknowledges Angela E. Lin, MD, FAAP, FACMG, Medical Genetics Unit, MassGeneral Hospital for Children, and Amanda Wong, NORD Editorial Intern from the Keck Graduate Institute, and for assistance in the preparation of this report.
Branchio-oculo-facial syndrome (BOFS) is a rare genetic disorder with defects of the head and neck that are apparent at birth (congenital) 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 world-wide.
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 defect.
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.
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.
The disorder is inherited in an autosomal dominant pattern and many parent/child families are known, even if not reported in medical articles.
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, may be moist, weep, or have atrophic skin. They vary in size from small defects as small as a “pit” to larger lesions which 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.
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.
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 are 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.
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.
BOFS is a very rare disorder that apparently affects males and females in equal numbers. Fertility does not appear to be affected since there are many affected parents and children. People vary within families and compared to other families.
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 branchio-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 branchio-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.
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.
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Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 7th ed. W. B. Saunders Co., Philadelphia, PA; 2013.
Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chenier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype–phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet Part A. 2011;155:22–32.
Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Med Genet. 2008;82(5):1171-1177. doi:10.1016/j.ajhg.2008.03.005.
Branchiooculofacial syndrome. Genetic and Rare Diseases Information Center (GARD). Available at: https://rarediseases.info.nih.gov/diseases/3212/branchiooculofacial-syndrome Last updated: 6/23/2011. Accessed November 6, 2018
Lin AE, Haldeman-Englert CR, Milunsky JM. Branchiooculofacial Syndrome. 2011 May 31 [Updated 2018 Mar 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK55063/ Accessed November 6, 2018.
McKusick VA, ed. Branchiooculofacial Syndrome. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Available at: https://www.omim.org/entry/113620?search=bofs&highlight=bofsMcKusick Last update: 07/09/2018. Accessed November 6, 2018.
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