Branchio-oto-renal syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shivam Singla, M.D.[2]

Synonyms and keywords:

Overview

Branchio-oto-renal syndrome (also known as branciootorenal syndrome, BOR syndrome or BOR) is an autosomal dominant genetic disorder involving the kidneys, ears, and neck. In ears, it is associated with a wide number of defects ranging from sensorineural, conductive, or mixed hearing loss to structural defects of the inner ear, middle ear and outer ear along with branchial fistulas or cyst. Renal abnormalities include the complete absence of kidneys in some cases while in others only mild hypoplasia is present. The most important differential studied is Branchiootic syndrome (BO) which has exactly the same features as BOR syndrome but the affected individuals do not have the kidneys abnormalities like in BOR syndrome. The two condition similarities some times create a hard time for researchers and sometimes they even consider them together as BOR/BO syndrome.

"Branchio-" refers to the second branchial arch, which is a structure in the developing embryo that gives rise to tissues in the front and side of the neck. In people with BOR/BO syndrome, abnormal development of the second branchial arch can result in the formation of masses in the neck called branchial cleft cysts. Some affected people have abnormal holes or pits called fistulae in the side of the neck just above the collarbone. Fistulae can form tunnels into the neck, exiting in the mouth near the tonsil. Branchial cleft cysts and fistulae can cause health problems if they become infected, so they are often removed surgically. "Oto-" and "-otic" refer to the ear; most people with BOR/BO syndrome have hearing loss and other ear abnormalities. The hearing loss can be sensorineural, meaning it is caused by abnormalities in the inner ear; conductive, meaning it results from changes in the small bones in the middle ear; or mixed, meaning it is caused by a combination of the inner ear and middle ear abnormalities. Some affected people have tiny holes in the skin or extra bits of tissue just in front of the ear. These are called preauricular pits and preauricular tags, respectively. "Renal" refers to the kidneys; BOR syndrome (but not BO syndrome) causes abnormalities of kidney structure and function. These abnormalities range from mild to severe and can affect one or both kidneys. In some cases, end-stage renal disease (ESRD) develops later in life. This serious condition occurs when the kidneys become unable to filter fluids and waste products from the body effectively.

Pathophysiology

BOR results from the mutation of the EYA1 gene.

Branchio-oto-renal syndrome has an autosomal dominant pattern of inheritance.

causes Mutations in genes, SIX1, EYA1, and SIX5, are found in people with BOR/BO syndrome. Nearly 40 percent of the people with this disease found the mutation in the EYA1 gene. SIX1 gene much less common cause of the disorder as compared to other genes. SIX5 gene mutation is only found in a small number of people suffering from BOR syndrome. Some of the people reported to have this mutation early in the diagnostic workup also found EYA1 gene mutations as well later in the disease course. Some of the researchers even believe that EYA1 gene mutation is the actual cause in these patients. Still, more studies are required in this field. The proteins produced from these three genes have major roles in development before birth. The EYA1 protein interacts with numerous other proteins, including SIX5, and SIX1 to control and regulate the genes involved in embryonic development. Various research also suggests that these protein interactions play an important role in the formation of other organs and tissues like ear, kidneys, and second branchial arch. So the mutations in these genes( EYA1, SIX1, or SIX5) disrupts the ablility of proteins interaction and in turn, affect the gene activity as well. These changes in gene activity further lead to the effect on the organ development and tissues before the birth and resulting in the maldevelopment in ears, kidneys, and neck which are the characteristic features of BOR/BO syndrome.

Diagnosis

History and Symptoms

Individuals with BOR may have underdeveloped (hypoplastic) or absent kidneys with resultant renal insufficiency or renal failure.

Ear anomalies include extra openings in front of the ears (preauricular pits), extra pieces of skin in front of the ears (preauricular tags), or further malformation or absence of the outer ear (pinna). Malformation or absence of the middle ear is also possible. Individuals can have mild to profound hearing loss, which can either be sensorineural, conductive, or mixed. People with BOR may also have cysts or fistulae along the sides of their neck corresponding to the location of the embryologic brancial clefts.