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A rare otomandibular dysplasia syndrome characterized by branchial arch anomalies (branchial clefts, fistulae, cysts), malformations of the ear associated with hearing impairment (malformations of the auricle with pre-auricular pits, conductive or sensorineural hearing impairment), and renal malformations (urinary tree malformation, renal hypoplasia or agenesis, renal dysplasia, renal cysts).
ORPHA:107Classification level: Disorder
- Branchiootic syndrome
- Branchiootorenal spectrum disorder
- Branchiootorenal syndrome
- Melnick-Fraser syndrome
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant
- Age of onset: Neonatal, Infancy, Childhood
- ICD-10: Q87.8
- OMIM: 113650 610896
- UMLS: C0265234
- MeSH: D019280
- GARD: 10147
- MedDRA: 10071135
Worldwide, the prevalence of Branchiootorenal (BOR) syndrome in the general population is unknown; however, in the pediatric population it is estimated to be 1/40,000.
The expression of the disease varies widely from one family to another and among individuals of the same family. Some individuals do not present with renal abnormalities or a urinary tract malformation.
The causative gene, EYA1, is located on the long arm of chromosome 8. Point mutations and deletions in EYA1 have been identified in approximately 40-75% of affected individuals. In a smaller proportion of patients, mutations in the SIX1 and SIX5 genes have been identified, the products of which interact with EYA1 to form transcription factor complexes.
The diagnosis of BOR syndrome might be suspected clinically in an individual with second branchial arch anomalies, auricular malformations, preauricular pits or tags, deafness and/or renal anomalies. Especially if there are other affected family members. By genetic testing, the diagnosis can be validated in around half of the patients.
The main differential diagnosis is branchio-oculo-facial syndrome (BOFS), caused by TFAP2A variants, which is characterized by branchial defects, highly variable ocular defects and characteristic craniofacial features which can include ear anomalies. Moreover, renal anomalies can occur in patients with BOFS. Other differential diagnosis include hypoparathyroidism-sensorineural deafness-renal disease (HDR) syndrome, due to GATA3 variants, which is distinguished by the presence of hypoparathyroidism in the majority of patients; and otofaciocervical syndrome. Moreover, hearing loss is a common symptom in many genetic disorders.
Prenatal diagnosis is possible if the pathogenic variant has previously been identified in a family member. Although, the variable expressivity of the syndrome makes it impossible to predict the severity of the disease in the fetus.
The disorder is inherited in an autosomal dominant manner; most patients have an affected parent whilst some cases occur sporadically. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The penetrance is thought to be complete while there is a great intrafamilial and interfamilial variability in the presence, severity and type of anomalies.
Management and treatment
Management of affected patients includes excision of branchial fistulae or cysts, hearing aids and education programs appropriate for the hearing impaired, and follow-up by a nephrologist. Dialysis or renal transplantation may be required.
Most patients with BOR syndrome receiving appropriate treatment are able to lead normal, active lives. The prognosis of BOR syndrome patients primarily depends on the severity of the renal involvement. Pregnancies where the fetus has severe renal impairment can end in a miscarriage. Later in life, the renal disease might progress to end-stage renal disease.
A summary on this disease is available in Deutsch (2007) Español (2022) Français (2022) Nederlands (2022) Italiano (2007)
- Article for general public
- Svenska (2015) - Socialstyrelsen
Disease review articles
- Clinical genetics review
- English (2018) - GeneReviews
: produced/endorsed by FSMR(s)