Branchiootorenal syndrome

Other Names: Branchiootorenal dysplasia; Melnick-Fraser syndrome; Branchio oto renal syndrome; BOR syndrome

Branchiootorenal syndrome is characterized by birth defects or anomalies of tissues in the neck, malformations of the external ear, hearing loss, and kidney malformations. Branchiootic (BO) syndrome includes many of the same features as BOR syndrome, but affected individuals do not have kidney abnormalities. The two conditions are otherwise so similar that researchers often consider them together (BOR/BO syndrome or branchiootorenal spectrum disorders).

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Epidemiology

The epidemiology of branchio-oto-renal syndrome has it with a prevalence of 1/40,000 in Western countries.

Cause

Mutations in the genes, EYA1, SIX1, and SIX5, are known to cause branchiootorenal syndrome. About 40 percent of people with this condition have a mutation in the EYA1 gene. SIX1 and SIX5 mutations are much less common causes of the disorder. There are likely other genes that have not yet been identified that when mutated can cause this syndrome as well. The proteins produced from the EYA1, SIX1, and SIX5 genes play important roles in development before birth. The EYA1 protein interacts with several other proteins, including SIX1 and SIX5, to regulate the activity of genes involved in many aspects of embryonic development. Research suggests that these protein interactions are essential for the normal formation of many organs and tissues, including the second branchial arch, ears, and kidneys. Mutations in the EYA1, SIX1, or SIX5 gene may disrupt the proteins' ability to interact with one another and regulate gene activity. The resulting genetic changes affect the development of organs and tissues before birth, which leads to the characteristic features of BOR syndrome.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Branchiootorenal syndrome may be inherited or occur sporadically. The inheritance pattern of branchiootorenal syndrome is autosomal dominant. Autosomal dominant inheritance is when one mutated copy of the gene that causes a disorder in each cell is needed for a person to be affected. Autosomal dominant conditions may occur for the first time in a person in a family due to a spontaneous gene mutation, or these conditions may be inherited from an affected parent. When a person with an autosomal dominant disorder has a child, there is a 50% chance that their child will inherit the condition.

Signs and symptoms

Signs and symptoms of branchiootorenal syndrome can vary greatly from person to person and even between people within the same family. Hearing loss is the most common symptom and is shared by approximately 90% of people with this syndrome. Hearing loss may be conductive, sensorineural, or a combination of both. Other common signs and symptoms include branchial cleft cysts, branchial fistulae, outer, middle, and inner ear malformations, and kidney malformations. Specifically mutations in the EYA1 or SIX1 genes can be associated with kidney malformations.

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
• Hearing impairment(Deafness)

30%-79% of people have these symptoms

• Abnormality of the middle ear ossicles
• Atresia of the external auditory canal(Absent ear canal)
• Branchial cyst
• Enlarged cochlear aqueduct
• External ear malformation
• Hypoplasia of the cochlea
• Preauricular skin tag
• Renal hypoplasia/aplasia(Absent/small kidney)
• Stenosis of the external auditory canal(Narrowing of passageway from outer ear to middle ear)

5%-29% of people have these symptoms

• Abnormal lacrimal duct morphology
• Cleft palate(Cleft roof of mouth)
• Facial palsy(Bell's palsy)
• Hydronephrosis
• Multicystic kidney dysplasia
• Renal insufficiency(Renal failure)
• [[Retrognathia](Receding chin)
• Ureteropelvic junction obstruction
• Vesicoureteral reflux

1%-4% of people have these symptoms

• Cupped ear(Cup-shaped ears)
• Lacrimal duct aplasia(Absent tear duct)
• Lacrimal duct stenosis(Narrowing of the tear duct)
• Microtia(Small ears)
• Mixed hearing impairment(Hearing loss, mixed)
• Preauricular pit(Pit in front of the ear)

Diagnosis

The diagnosis of branchiootorenal spectrum disorder is based on clinical signs and symptoms. The diagnosis is established in a proband with the clinical features and/or heterozygous pathogenic variants in EYA1, SIX1, or SIX5 identified on molecular genetic testing.

Treatment

Hereditary hearing loss conditions, in general, tend to be managed by a team that includes an otolaryngologist, an audiologist, a clinical geneticist, a pediatrician, sometimes an educator of the Deaf, a neurologist, and in case of branchiootorenal syndrome, a nephrologist (kidney doctor).

Treatment of hearing loss may include determining which aids would be most helpful, for example hearing aids or vibrotactile devices; cochlear implantation may be considered in children over age 12 months with severe-to-profound hearing loss. Early hearing intervention through amplification, surgery, or cochlear implantation may be recommended for children who are at risk to lose their hearing before they learn to speak.

People with hereditary hearing loss often require regular follow-up with a hearing specialist such as an audiologist to monitor stability or progression of the hearing loss.

Treatment of branchial fistulae or cysts may require surgery. For people with branchiootorenal syndrome and severe kidney malformations or complications, dialysis or kidney transplant may be required.

Branchiootorenal syndrome Resources
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NIH genetic and rare disease info

• NIH info on Branchiootorenal syndrome

Branchiootorenal syndrome is a rare disease.