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: Branchiootorenal dysplasia; Melnick-Fraser syndrome; Branchio oto renal syndrome; BOR syndrome Branchio Oto Renal Syndrome; Melnick Fraser Syndrome; Branchio-Otorenal Syndrome; Dysplasia, Branchiootorenal; BOR Syndrome; Branchio-Otorenal Dysplasia; Branchiootorenal Syndrome 2; Branchiootorenal Syndrome 1; Branchio-Oculo-Facial Syndrome; Branchio Oculo Facial Syndrome; Branchial Clefts with Characteristic Facies, Growth Retardation, Imperforate Nasolacrimal Duct, and Premature Aging; Lip Pseudocleft-Hemangiomatous Branchial Cyst Syndrome; Lip Pseudocleft Hemangiomatous Branchial Cyst Syndrome; Hemangiomatous Branchial Clefts-Lip Pseudocleft Syndrome; Hemangiomatous Branchial Clefts Lip Pseudocleft Syndrome; Lee Root Fenske Syndrome; BOF Syndrome; Syndrome, BOF; Branchiooculofacial Syndrome

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 renal abnormalities include the complete absence of kidneys in some cases while in others only mild hypoplasia is present. 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(ESRD).

History and Epidemology

• Heusinger(1864) first recognized an association between fistulae, preauricular pits, and hearing impairment defects.
• Melnick et al. and Fraser et al. in 1975 defined BOR syndrome as a specific entity having an autosomal dominant inheritance pattern with maximum penetrance.
• The incidence rate for BOR syndrome is around 1 in 40,000 people.
• Males and females are equally affected by this disorder.

Pathophysiology

BOR results from the mutation of the EYA1 gene.

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

90% of BOR syndromes result from inheritance and 10% of the cases are thought to be the result of acquired mutations. Branciootorenal syndrome has an Autosomal dominant inheritance pattern with variable expressivity as a result of which the same family members express the different levels of severity of the disease. It also shows a 100% penetrance. The mutations in the genes - SIX1, EYA1, and SIX5 play a major role in the causation of BOR syndrome. Out of these, EYA1 gene mutations play a major role (40%) followed by the SIX1 gene, and SIX5 gene mutation is only found in a small number of people suffering from BOR syndrome.

• EYA1 gene mutations(BOR1, BOS2)
  • About 40% of people are having EYA1 mutation.
  • This usually encodes for transcription factors in the metanephric mesenchyme.

• SIX1 Gene mutation (BOR3, BOS3)
  • Found in less than 5% of the cases
  • This gene mainly encodes the transcription factors that control the expression of PAX@ and GDNF.
  • The renal malformation is not associated with this mutation

• SIX5 Gene mutation (BOR2)
  • It is seen in 2-3 percent of cases with BOR syndrome.
  • Hearing is not impaired with this mutation.

The proteins produced from these genes play a major role in the development before birth. Interaction of EYA1 protein with SIX5 and SIX1 modulates the genes involved in embryonic development. These interactions also play a major role in the development of the ear, kidneys, and second branchial arch. The latter organs are mainly involved in the Branciootorenal syndrome.

Differentiating Branchio-oto-renal syndrome from other Diseases

The symptoms of the following disorders can be overlapping with symptoms of Branchio-renal syndrome. comparison is important to make the relevant differential diagnosis:

• The oculo-auriculo-vertebral spectrum
  • Characterized by physical features involving Jaw, mouth, ears, eyes, and bones of the spinal column
  • One side of the body is more affected as compared to the other side of the body
• Branchio-oculofacial syndrome
  • Rare autosomal dominant disorder
  • Most commonly - growth delay, abnormal sinuses, unusual facial appearance, and/or premature aging
  • less commonly - graying of hair, high arched palate, abnormal teeth, and cyst under the skin of the scalp can be found
• Towns Brocks syndrome
  • Rare genetic disorder
  • Deafness or hearing loss
  • Associated ear, hand, and foot anomalies
  • No anal opening
• Treacher Collins syndrome
  • Characterized by abnormalities in the facial area and head due to the maldevelopment of the skull

Diagnosis

History and Symptoms

The most common presenting symptoms in patients with BOR syndrome is:

Otologic manifestations

• With more than 90% of patients have at least one of the following in addition to that:
  • Deafness- It can be sensorineural, conductive, or mixed ranging from mild hearing difficulties to marked hearing loss.
    • Around 90% of the patients have underlying hearing loss.
    • Among these hearing losses, approximately 50% of the people present with mixed hearing loss, 30% with conductive hearing loss, and 20% with sensorineural hearing loss.
  • Preauricular tags
  • Preauricular pits
  • Middle ear malformations: ossicular hypoplasia or displacement
  • Inner ear anomalies: with dysplasia in semicircular canals, cochlear hypoplasia, enlargement of aqueducts ( Both cochlear and vestibular)
  • External auditory canal stenosis or malformation
  • Lop-ear deformity

Branchial Arch menifestations

• Branchial cleft cyst, fistulae, sinus tract.

Renal malformations

• Renal Hypoplasia or agenesis in some cases
• ureteropelvic junction obstruction
• Vesicoureteral reflux

Miscellaneous Findings

• Lacrimal duct aplasia/Hypoplasia
• Facial nerve palsy
• Retrognathia
• MVP
• Cleft lip/palate

Diagnotic criteria

• Positive family history of branchial, oto, renal abnormalities is strongly suggestive of BOR syndrome.

• If no evidence of family history then clinical criteria should be used to make the diagnosis
  • Either 3 major criteria
  • 2 major plus 2 minor criteria

Diagnostic criteria for BOR Syndrome ( 2 major /or 2 major + 2 minor)

MAJOR CRITERIA	MINOR CRITERIA
Hearing loss	Middle ear anomalies
Renal anomlies	Inner ear anomalies
2nd Branchial arch anomlies	Euthyroid goiter
Pinnae malformation	Preauricular tags
Preauricular pits	Lacrimal duct aplasia
External auditory canal anomlies	Facial asymmetry/palate abnormalities

Gene Studies Currently, there are three known gene mutations which result in BOR syndrome. If a clinical diagnosis of BOR syndrome is made, confirmation should be attempted via sequence analysis for EYA1. If an EYA1 mutation is not found with sequence analysis, one should utilize duplication/deletion analysis for EYA1 and sequence analysis for SIX 1 and SIX 5. EYA1 mutation About 40% of people with BOR syndrome will have an EYA1 mutation. EYA1 encodes for a transcription cofactor that is expressed in the metanephric mesenchyme during development of the kidneys. SIX1 mutation The SIX1 mutation is estimated to be found in 2% of BOR syndrome cases. It encodes transcription factors that control expression of GDNF and PAX2. The majority of patients with this mutation do not demonstrate renal malformation. SIX5 mutation The SIX5 mutation is present in about 2.5% of BOR syndrome cases. Hearing may be normal in these patients.

For making diagnosis 2 out of 5 following features should be present The diagnosis of BOR/BOS syndrome is made when at least two of five features (branchial defects, hearing loss, preauricular pits, abnormalities of the part of the ear that projects from the head (pinna), and renal malformations) are present in an individual with two or more affected family members, or three features are present in an individual with no affected family members. Evaluation of hearing function (audiological assessment), and imaging (CT or computerized tomography) of the temporal bone to identify the middle and inner ear defects, should be performed. Renal abnormality is investigated by urinalysis, renal function tests, and imaging studies such as renal ultrasonography and CT. Molecular genetic testing for mutations in the EYA1(BOR1, BOS2), SIX5 (BOR2), and SIX1 (BOR3, BOS3) genes is available to confirm a clinical diagnosis of BOR/BOS syndrome. EYA1 mutations are to be found in about 40% of people with BOR/BOS syndrome. A SIX1 mutation is estimated to be found in 4% of people with BOR/BOS syndrome and a SIX5 mutation is present in about 5% of people with BOR/BOS syndrome. 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.