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, Melnick- Fraser Syndrome)) is an autosomal dominant genetic disorder involving the kidneys, ears, and neck. 90% of these are due to inheritance and in 10% cases it is acquired mutation. It is characterized by the presence of 1) brachial fistulae or cysts;  2) Ear malformations - including outer, middle or inner ear; 3) Renal malformations, which can range from renal hypoplasia to renal agenesis. 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. Sometimes they even consider them together as BOR/BO syndrome.

"Branchio-" means the second branchial arch, s structure that is usually present in the embryo that further gives rise to tissues on the front and the side of the neck. The abnormal development of this branchial arch leads to leads to the formation of neck masses called branchial cleft cysts which is most commonly seen in people with BO/BOR syndrome. Some people might have abnormal appearing pits or holes in the side of the neck called fistulae. They can form a connection with the mouth near the tonsil. Both branchial cleft cyst and fistulae can create problems later in life so they are usually removed during the early stages of childhood.

"Oto-" refer to the ear. It has been studied that most patients with BO/BOR syndrome usually have hearing abnormalities. It can be sensorineural, conductive, or mixed. Sensorineural hearing loss is usually seen in the patients with abnormalities in the inner ear: conductive hearing loss is due to the defects of bones in the middle ear; Mixed hearing loss is caused by both inner ear + middle ear abnormalities. Preauricular pits ( tiny holes) and tags (an extra bit of tissue) are the other anomalies associated with the ear anomalies.

"Renal" word means kidneys here; The major point to be noted here is that BO syndromes do not have real components. So BOR syndrome causes an alteration in kidney structure and function. The renal abnormalities range from mild to severe and may include one or both the kidneys. The most serious condition associated with kidneys is their inability to clear fluids and waste from the body which is usually given a name End-stage renal disease. The renal abnormalities may include the complete absence of kidneys in some cases while in others only mild hypoplasia is present

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.