- Email: [email protected]
Renal failure and deafness: Branchio-oto-renal syndrome
Renal Failure and Deafness: Branchio-Oto-Renal Syndrome Madhukar Misra, MD, MRCP, and Karl D. Nolph, MD, FACP, FRCP ● Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant condition that may present with hearing loss, branchial cysts, and renal failure. The characteristic phenotypic expression of the full syndrome may be partial or complete, and a whole range of renal abnormalities may be present. Its similarity to Alport’s syndrome may lead to misdiagnosis. We report here a case of adult-onset renal failure in a 44-year-old white man previously believed to have Alport’s syndrome and a review the relevant literature. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: BOR syndrome; renal failure.
T
HE CONSTELLATION of symptoms and signs seen in branchio-oto-renal (BOR) syndrome include renal disease, hearing loss, and branchial cysts. This syndrome is often confused with Alport’s syndrome. BOR syndrome was first described by Melnick et al.1 However, the association of ear malformations and renal disease was first recognized by Hilson2 as early as 1957. After the description of Melnick et al of BOR syndrome, Fitch and Srolovitz3 described severe renal disease in two members of a family with auricular pits and renal dysplasia in 1976. After these first reports, the combination of ear deformities, hearing loss, preauricular pits, and/or cervical fistulae with renal anomalies has been reported mainly in the pediatric or genetic literature.4-7 We report a case of renal failure in an adult man with deafness and presumed Alport’s syndrome who was referred to us for a second opinion. We believe it is important that the existence of this syndrome is recognized as a cause of renal failure in the adult nephrology community and is distinguished from Alport’s syndrome. CASE REPORT A 44-year-old man was referred to the nephrology clinic for evaluation of new onset proteinuria, microhematuria,
From the Division of Nephrology, University of Missouri Health Sciences Center; and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO. Received October 7, 1997; accepted in revised form March 3, 1998. Address reprint requests to Madhukar Misra, MD, MRCP (UK), Division of Nephrology, Department of Internal Medicine, University of Missouri-Columbia, MA436 Health Sciences Center, Columbia, MO 65212. E-mail: karl_nolph@ muccmail.missouri.edu
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3202-0023$3.00/0 334
hypertension, and renal failure. Earlier that year, a routine annual physical had shown an elevated serum creatinine level of 1.6 mg/dL, dipstick-positive proteinuria, and microhematuria. One year earlier, he had been noted to be hypertensive (blood pressure, 146/96 mm Hg) and hyperlipidemic (total serum cholesterol level, 337 mg/dL; triglyceride level, 366 mg/dL) and had been started on fluvastatin, 40 mg daily, and lisinopril, 10 mg/d. His past medical history included an apparently normal childhood with a tonsillectomy at the age of 9 years and a history of chronic ear discharge. He had two surgeries to his left ear at 27 and 33 years of age, when it was noted that his middle ear bones were misshapen, with disruption of the ossicular chains. He subsequently underwent a radical tympanomastoidectomy with facial nerve decompression. His hearing loss was believed to be congenital, and he was prescribed hearing aids. By the age of 19 years, deafness had worsened significantly, and a diagnosis of bilateral moderately severe mixed hearing loss was made. He also gave a history of the diagnosis of branchial cysts that drained intermittently from both sides of his neck. They were noted at the time of ear surgery but were not operated on. There was no history of their being infected. The patient has two brothers and three sisters. Two of the sisters and one brother also have hearing loss. His brother, who is 52 years old, has hypertension, hearing loss, branchial cysts, and ear pits, and so does his only son. His five grandchildren, however, are unaffected. One of his sisters with hearing loss has two children who are unaffected. The other sister with hearing loss has no children. There is no history of abortions, early neonatal deaths, or stillbirths in relevant members of the family. The patient has one son and a daughter who are unaffected by the disease. His son, however, has an attention deficit disorder. The patient’s father, a diabetic, died at the age of 62 years after a heart attack. His paternal uncle and aunt have no hearing loss but have diabetes. Cousins on the paternal side of the family have no history of hearing loss or renal disease. His mother is aged 74 years, and has insulin-dependent diabetes and hearing loss. She has four sisters and a brother, all of whom are alive. There is no other known history of hearing loss, renal disease, branchial cysts, or ear pits on the maternal side of the family. The maternal grandparents are both dead. Clinical examination showed a pleasant gentleman, with a height of 173 cm and weight of 68.5 kg. He had bilateral hearing aids in his ear. There was a single posterior parietal hair whorl. The right eye had poor visual acuity. There were two preauricular pits on the left ear and on the right ear, there
American Journal of Kidney Diseases, Vol 32, No 2 (August), 1998: pp 334-337
RENAL FAILURE AND DEAFNESS: BOR SYNDROME
335
left kidney to be 8.4 cm in size, with no evidence of hydronephrosis and normal echogenicity. An intravenous urogram was considered but later deferred, owing to the presence of renal failure. The patient declined a renal biopsy.
DISCUSSION
Fig 1. Right ear showing a pit at the base of anterior helix and a hearing aid.
was a preauricular pit at the base of his superior helix (Fig 1) that drained greenish fluid. Both earlobes had horizontal deep creases. He had a high but intact palate. The uvula was midline. There was mild micrognathia. The neck had full range of motion. There were bilateral single branchial cysts with clear drainage (Fig 2A and B). Chest examination showed a slightly smaller left pectoralis major compared with the right with a pectus excavatum. There was no evidence of scoliosis. Cardiovascular examination showed a regular rate and rhythm without murmurs. Blood pressure in the right arm in the supine posture was 134/70 mm Hg. The abdomen was soft, nontender, and nondistended, with no hepatosplenomegaly. Genitalia were normal, with bilaterally descended testes. Extremities had a full range of motion. Neurological examination was entirely intact, other than hearing. Deep tendon reflexes were 2⫹ and equal bilaterally. Laboratory values were as follows: complete blood count, normal; blood urea nitrogen, 36 mg/dL; serum creatinine, 1.9 mg/dL; total serum cholesterol, 216 mg/dL; and serum triglycerides, 209 mg/dL. The rest of the serum chemistries were normal. A 24-hour urine collection showed proteinuria of 1.1 g/1,650 mL (total volume) and a creatinine clearance of 40 mL/min. Microscopic urinalysis showed 5 to 7 red blood cells per high-power field without casts. Renal ultrasound showed the right kidney to be 7.9 cm in size and the
BOR syndrome is an autosomal dominant condition with variable expression that occurs with a frequency of about 1 in 40,000 births. The gene is localized to chromosome 8. Mitochondrial mutations are known to be involved in hearing loss syndromes. Recently, a candidate gene for this syndrome has been identified involving a mitochondrial protein of the respiratory electron chain.8 Approximately 2% of all individuals with deafness have this condition. Not all the individuals with this syndrome have all of these features, although the patient described here did show all of the features. It also appeared that his brother has all the features noted with this condition, whereas his two sisters who are affected may only have the hearing loss with no preauricular pits or branchial cysts. Other common facial abnormalities include a long narrow face, a deep overbite, and facial paralysis. Lacrimal duct abnormalities have also been described.7 Preauricular pits are small cul de sac–like sinuses. They are usually situated at or near the anterior limb of the ascending helix. They are unilateral in 75% of patients and may occur in 5.2% of blacks and less than 1% of whites, being inherited in an autosomal dominant fashion with variable penetrance.9 Renal abnormalities are present in approximately 66% of affected individuals. About 6% of individuals with the condition progress to renal
Fig 2. (A) Right lateral view of neck showing branchial cyst becoming more prominent on swallowing. (B) Close-up view of right branchial cyst expressing fluid on massaging the surrounding tissues.
336
failure. The renal abnormalities in BOR syndrome consist of distorted calyceal systems, hydronephrosis, nephronophthisis, hypoplastic/ dysplastic kidneys, ureteropelvic obstruction, unilateral or bilateral renal agenesis, and vesicoureteral reflux.10 BOR syndrome is an important cause of bilateral renal agenesis in liveborn offspring of affected parents.11-13 This may be the cause of excessive unexplained fetal deaths in these families, suggesting a higher recurrence rate in children of parents with a previously affected child. Histologically, cases with renal insufficiency may show glomerular hyalinization, mesangial proliferation, and basement membrane splitting.14 The hyalinization may be focal and segmental in less advanced cases. Dense deposits have been reported in the mesangium and inner basement membrane on electron microscopy. On immunofluorescence microscopy, various amounts of immunoglobulin G (IgG), IgM, C3, and even IgA in the mesangium have been reported. No activation of the complement system has been reported.14 Autopsy reports of patients with BOR syndrome report the presence of dilated tubules with microcalcification,3 as well as the presence of teratoid tissue in the kidney.7 A high incidence of renal dysplasia has been described in patients undergoing urologic evaluation in the series described by Fraser et al.5 Careful evaluation by the investigators showed a high incidence of urologic anomalies in the IVUs of individuals with BOR syndrome that had routinely been read as normal (three of four patients). The investigators commented that it was wrong to assume that renal anomalies were not there unless they had been specifically looked for in cases with BOR syndrome. The likely pathogenesis of renal anomalies during embryogenesis can be explained as an aberrant inductive interaction between the ureteric bud and the metanephrogenic mesenchymal mass.15 It is not clear why there is an association between renal malformation and abnormalities of the ear. The kidney and cochlea may share a common antigen.16 Autopsy reports of a dysplastic stria vascularis17 in addition to renal dysplasia3 suggest a common embryogenetic defect.7 Dysplastic kidneys in association with ear anomalies formed the basis of one of the earliest reports
MISRA AND NOLPH
in the literature in which Hilson2 described dysmorphic pinna-polycystic kidney syndrome and dysmorphic pinna-hypospadias-renal dysplasia syndrome. Unlike these two syndromes that are autosomal dominant in inheritance, the oto-renal genital syndrome18 is an autosomal recessive disorder. The recognition of this syndrome is important for the detection and treatment of any renal involvement, the severity of which may vary from renal agenesis to the absence of renal disease. In the presence of severe reflux, significant renal damage may occur silently until frank renal failure ensues. Once BOR syndrome is recognized in a patient, it is prudent to thoroughly examine all family members for the presence of the syndrome. This is true even if there are minimal stigmata of the disease in the family members. REFERENCES 1. Melnick M, Bixler D, Silk K, Yune H, Nance WE: Autosomal dominant branchio-oto-renal dysplasia. Birth Defects. Orig Article Series 11:121-128, 1975 2. Hilson D: Malformation of ears as sign of malformation of genito urinary tract. Br Med J 2:785-789, 1957 3. Fitch N, Srolovitz H: Severe renal dysgenesis produced by a dominant gene. Am J Dis Child 130:1356-1357, 1976 4. Fraser FC, Ling D, Clogg D, Nogrady B: Genetic aspects of the BOR syndrome—Branchial fistulas, ear pits, hearing loss and renal anomalies. Am J Med Genet 2:241252, 1978 5. Fraser FC, Sproule JR, Halal F: Frequency of the branchio oto renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet 7:341-349, 1980 6. Melnick M, Bixler D, Nance WE, Silk K, Yune H: Familial branchio-oto-renal dysplasia: A new addition to the branchial arch syndromes. Clin Genet 9:25-34, 1976 7. Melnick M, Hodes ME, Nance WE, Yune H, Sweeney A: Branchio-oto-renal dysplasia and brachio oto dysplasia: Two distinct autosomal dominant disorders. Clin Genet 13:425-442, 1978 8. Gu JZ, Lin X, Wells DE: The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndrome. Genomics 35:6-10, 1996 9. Bergsma D: Birth Defects Compendium. (ed 2). New York, NY, Liss, 1979, p 377 10. Chen A, Francis M, Ni Li, Cremers Cor WRJ, Kimberling WJ, Sato Y, Phelps PD, Bellman SC, Wagner MJ, Pembrey M, Smith RJH: Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet 58:365-370, 1995
RENAL FAILURE AND DEAFNESS: BOR SYNDROME
11. Carmi R, Binshtock M, Abeliovich D, Bar-Ziv J: The branchio oto renal (BOR) syndrome: Report of bilateral renal agenesis in three sibs. Am J Med Genet 14:625-627, 1983 12. Cremers CWRJ, Fikkers-Van Noord M: The earpitsdeafness syndrome. Clinical and genetic aspects. Int J Pediatr Otorhinolaryngol 2:309-322, 1980 13. Chitayat D, Hodgkinson KA, Chen MF, Haber GD, Nakishima S, Sando T: Branchio-oto-renal syndrome: Further delineation of an underdiagnosed syndrome. Am J Med Genet 43:970-975, 1992 14. Dumas R, Uziel A, Baldet P, Segond A: Glomerular lesions in the branchio-oto-renal (BOR) syndrome. Int J Pediatr Nephrol 3:67-70, 1982
337
15. Gluecksohn-Waelsch S: Genetic control of mammalian differentiation, in Geerts SJ (ed): Genetics Today, vol 2. Proceedings of the XIth International Congress of Genetics. The Hague, Netherlands, Pergamon, 1963, pp 209-219 16. Quick CA, Fish A, Brown C: The relationship between cochlea and kidney. Laryngoscope (St Louis) 83:14691482, 1973 17. Arnold W, Weidauer H, Seelig HP: Experimenteller Beweis einer gemeinsamen Antigenizitat zwischen Innenohr und Nieve. Arch-Oto-Rhino-Lar 212:99-117, 1976 18. Winter JS, Kohn G, Mellman WJ, Wagner S: A familial syndrome of renal, genital and middle ear anomalies. J Pediatr 72:88-93, 1968
T
HE CONSTELLATION of symptoms and signs seen in branchio-oto-renal (BOR) syndrome include renal disease, hearing loss, and branchial cysts. This syndrome is often confused with Alport’s syndrome. BOR syndrome was first described by Melnick et al.1 However, the association of ear malformations and renal disease was first recognized by Hilson2 as early as 1957. After the description of Melnick et al of BOR syndrome, Fitch and Srolovitz3 described severe renal disease in two members of a family with auricular pits and renal dysplasia in 1976. After these first reports, the combination of ear deformities, hearing loss, preauricular pits, and/or cervical fistulae with renal anomalies has been reported mainly in the pediatric or genetic literature.4-7 We report a case of renal failure in an adult man with deafness and presumed Alport’s syndrome who was referred to us for a second opinion. We believe it is important that the existence of this syndrome is recognized as a cause of renal failure in the adult nephrology community and is distinguished from Alport’s syndrome. CASE REPORT A 44-year-old man was referred to the nephrology clinic for evaluation of new onset proteinuria, microhematuria,
From the Division of Nephrology, University of Missouri Health Sciences Center; and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO. Received October 7, 1997; accepted in revised form March 3, 1998. Address reprint requests to Madhukar Misra, MD, MRCP (UK), Division of Nephrology, Department of Internal Medicine, University of Missouri-Columbia, MA436 Health Sciences Center, Columbia, MO 65212. E-mail: karl_nolph@ muccmail.missouri.edu
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3202-0023$3.00/0 334
hypertension, and renal failure. Earlier that year, a routine annual physical had shown an elevated serum creatinine level of 1.6 mg/dL, dipstick-positive proteinuria, and microhematuria. One year earlier, he had been noted to be hypertensive (blood pressure, 146/96 mm Hg) and hyperlipidemic (total serum cholesterol level, 337 mg/dL; triglyceride level, 366 mg/dL) and had been started on fluvastatin, 40 mg daily, and lisinopril, 10 mg/d. His past medical history included an apparently normal childhood with a tonsillectomy at the age of 9 years and a history of chronic ear discharge. He had two surgeries to his left ear at 27 and 33 years of age, when it was noted that his middle ear bones were misshapen, with disruption of the ossicular chains. He subsequently underwent a radical tympanomastoidectomy with facial nerve decompression. His hearing loss was believed to be congenital, and he was prescribed hearing aids. By the age of 19 years, deafness had worsened significantly, and a diagnosis of bilateral moderately severe mixed hearing loss was made. He also gave a history of the diagnosis of branchial cysts that drained intermittently from both sides of his neck. They were noted at the time of ear surgery but were not operated on. There was no history of their being infected. The patient has two brothers and three sisters. Two of the sisters and one brother also have hearing loss. His brother, who is 52 years old, has hypertension, hearing loss, branchial cysts, and ear pits, and so does his only son. His five grandchildren, however, are unaffected. One of his sisters with hearing loss has two children who are unaffected. The other sister with hearing loss has no children. There is no history of abortions, early neonatal deaths, or stillbirths in relevant members of the family. The patient has one son and a daughter who are unaffected by the disease. His son, however, has an attention deficit disorder. The patient’s father, a diabetic, died at the age of 62 years after a heart attack. His paternal uncle and aunt have no hearing loss but have diabetes. Cousins on the paternal side of the family have no history of hearing loss or renal disease. His mother is aged 74 years, and has insulin-dependent diabetes and hearing loss. She has four sisters and a brother, all of whom are alive. There is no other known history of hearing loss, renal disease, branchial cysts, or ear pits on the maternal side of the family. The maternal grandparents are both dead. Clinical examination showed a pleasant gentleman, with a height of 173 cm and weight of 68.5 kg. He had bilateral hearing aids in his ear. There was a single posterior parietal hair whorl. The right eye had poor visual acuity. There were two preauricular pits on the left ear and on the right ear, there
American Journal of Kidney Diseases, Vol 32, No 2 (August), 1998: pp 334-337
RENAL FAILURE AND DEAFNESS: BOR SYNDROME
335
left kidney to be 8.4 cm in size, with no evidence of hydronephrosis and normal echogenicity. An intravenous urogram was considered but later deferred, owing to the presence of renal failure. The patient declined a renal biopsy.
DISCUSSION
Fig 1. Right ear showing a pit at the base of anterior helix and a hearing aid.
was a preauricular pit at the base of his superior helix (Fig 1) that drained greenish fluid. Both earlobes had horizontal deep creases. He had a high but intact palate. The uvula was midline. There was mild micrognathia. The neck had full range of motion. There were bilateral single branchial cysts with clear drainage (Fig 2A and B). Chest examination showed a slightly smaller left pectoralis major compared with the right with a pectus excavatum. There was no evidence of scoliosis. Cardiovascular examination showed a regular rate and rhythm without murmurs. Blood pressure in the right arm in the supine posture was 134/70 mm Hg. The abdomen was soft, nontender, and nondistended, with no hepatosplenomegaly. Genitalia were normal, with bilaterally descended testes. Extremities had a full range of motion. Neurological examination was entirely intact, other than hearing. Deep tendon reflexes were 2⫹ and equal bilaterally. Laboratory values were as follows: complete blood count, normal; blood urea nitrogen, 36 mg/dL; serum creatinine, 1.9 mg/dL; total serum cholesterol, 216 mg/dL; and serum triglycerides, 209 mg/dL. The rest of the serum chemistries were normal. A 24-hour urine collection showed proteinuria of 1.1 g/1,650 mL (total volume) and a creatinine clearance of 40 mL/min. Microscopic urinalysis showed 5 to 7 red blood cells per high-power field without casts. Renal ultrasound showed the right kidney to be 7.9 cm in size and the
BOR syndrome is an autosomal dominant condition with variable expression that occurs with a frequency of about 1 in 40,000 births. The gene is localized to chromosome 8. Mitochondrial mutations are known to be involved in hearing loss syndromes. Recently, a candidate gene for this syndrome has been identified involving a mitochondrial protein of the respiratory electron chain.8 Approximately 2% of all individuals with deafness have this condition. Not all the individuals with this syndrome have all of these features, although the patient described here did show all of the features. It also appeared that his brother has all the features noted with this condition, whereas his two sisters who are affected may only have the hearing loss with no preauricular pits or branchial cysts. Other common facial abnormalities include a long narrow face, a deep overbite, and facial paralysis. Lacrimal duct abnormalities have also been described.7 Preauricular pits are small cul de sac–like sinuses. They are usually situated at or near the anterior limb of the ascending helix. They are unilateral in 75% of patients and may occur in 5.2% of blacks and less than 1% of whites, being inherited in an autosomal dominant fashion with variable penetrance.9 Renal abnormalities are present in approximately 66% of affected individuals. About 6% of individuals with the condition progress to renal
Fig 2. (A) Right lateral view of neck showing branchial cyst becoming more prominent on swallowing. (B) Close-up view of right branchial cyst expressing fluid on massaging the surrounding tissues.
336
failure. The renal abnormalities in BOR syndrome consist of distorted calyceal systems, hydronephrosis, nephronophthisis, hypoplastic/ dysplastic kidneys, ureteropelvic obstruction, unilateral or bilateral renal agenesis, and vesicoureteral reflux.10 BOR syndrome is an important cause of bilateral renal agenesis in liveborn offspring of affected parents.11-13 This may be the cause of excessive unexplained fetal deaths in these families, suggesting a higher recurrence rate in children of parents with a previously affected child. Histologically, cases with renal insufficiency may show glomerular hyalinization, mesangial proliferation, and basement membrane splitting.14 The hyalinization may be focal and segmental in less advanced cases. Dense deposits have been reported in the mesangium and inner basement membrane on electron microscopy. On immunofluorescence microscopy, various amounts of immunoglobulin G (IgG), IgM, C3, and even IgA in the mesangium have been reported. No activation of the complement system has been reported.14 Autopsy reports of patients with BOR syndrome report the presence of dilated tubules with microcalcification,3 as well as the presence of teratoid tissue in the kidney.7 A high incidence of renal dysplasia has been described in patients undergoing urologic evaluation in the series described by Fraser et al.5 Careful evaluation by the investigators showed a high incidence of urologic anomalies in the IVUs of individuals with BOR syndrome that had routinely been read as normal (three of four patients). The investigators commented that it was wrong to assume that renal anomalies were not there unless they had been specifically looked for in cases with BOR syndrome. The likely pathogenesis of renal anomalies during embryogenesis can be explained as an aberrant inductive interaction between the ureteric bud and the metanephrogenic mesenchymal mass.15 It is not clear why there is an association between renal malformation and abnormalities of the ear. The kidney and cochlea may share a common antigen.16 Autopsy reports of a dysplastic stria vascularis17 in addition to renal dysplasia3 suggest a common embryogenetic defect.7 Dysplastic kidneys in association with ear anomalies formed the basis of one of the earliest reports
MISRA AND NOLPH
in the literature in which Hilson2 described dysmorphic pinna-polycystic kidney syndrome and dysmorphic pinna-hypospadias-renal dysplasia syndrome. Unlike these two syndromes that are autosomal dominant in inheritance, the oto-renal genital syndrome18 is an autosomal recessive disorder. The recognition of this syndrome is important for the detection and treatment of any renal involvement, the severity of which may vary from renal agenesis to the absence of renal disease. In the presence of severe reflux, significant renal damage may occur silently until frank renal failure ensues. Once BOR syndrome is recognized in a patient, it is prudent to thoroughly examine all family members for the presence of the syndrome. This is true even if there are minimal stigmata of the disease in the family members. REFERENCES 1. Melnick M, Bixler D, Silk K, Yune H, Nance WE: Autosomal dominant branchio-oto-renal dysplasia. Birth Defects. Orig Article Series 11:121-128, 1975 2. Hilson D: Malformation of ears as sign of malformation of genito urinary tract. Br Med J 2:785-789, 1957 3. Fitch N, Srolovitz H: Severe renal dysgenesis produced by a dominant gene. Am J Dis Child 130:1356-1357, 1976 4. Fraser FC, Ling D, Clogg D, Nogrady B: Genetic aspects of the BOR syndrome—Branchial fistulas, ear pits, hearing loss and renal anomalies. Am J Med Genet 2:241252, 1978 5. Fraser FC, Sproule JR, Halal F: Frequency of the branchio oto renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet 7:341-349, 1980 6. Melnick M, Bixler D, Nance WE, Silk K, Yune H: Familial branchio-oto-renal dysplasia: A new addition to the branchial arch syndromes. Clin Genet 9:25-34, 1976 7. Melnick M, Hodes ME, Nance WE, Yune H, Sweeney A: Branchio-oto-renal dysplasia and brachio oto dysplasia: Two distinct autosomal dominant disorders. Clin Genet 13:425-442, 1978 8. Gu JZ, Lin X, Wells DE: The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndrome. Genomics 35:6-10, 1996 9. Bergsma D: Birth Defects Compendium. (ed 2). New York, NY, Liss, 1979, p 377 10. Chen A, Francis M, Ni Li, Cremers Cor WRJ, Kimberling WJ, Sato Y, Phelps PD, Bellman SC, Wagner MJ, Pembrey M, Smith RJH: Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet 58:365-370, 1995
RENAL FAILURE AND DEAFNESS: BOR SYNDROME
11. Carmi R, Binshtock M, Abeliovich D, Bar-Ziv J: The branchio oto renal (BOR) syndrome: Report of bilateral renal agenesis in three sibs. Am J Med Genet 14:625-627, 1983 12. Cremers CWRJ, Fikkers-Van Noord M: The earpitsdeafness syndrome. Clinical and genetic aspects. Int J Pediatr Otorhinolaryngol 2:309-322, 1980 13. Chitayat D, Hodgkinson KA, Chen MF, Haber GD, Nakishima S, Sando T: Branchio-oto-renal syndrome: Further delineation of an underdiagnosed syndrome. Am J Med Genet 43:970-975, 1992 14. Dumas R, Uziel A, Baldet P, Segond A: Glomerular lesions in the branchio-oto-renal (BOR) syndrome. Int J Pediatr Nephrol 3:67-70, 1982
337
15. Gluecksohn-Waelsch S: Genetic control of mammalian differentiation, in Geerts SJ (ed): Genetics Today, vol 2. Proceedings of the XIth International Congress of Genetics. The Hague, Netherlands, Pergamon, 1963, pp 209-219 16. Quick CA, Fish A, Brown C: The relationship between cochlea and kidney. Laryngoscope (St Louis) 83:14691482, 1973 17. Arnold W, Weidauer H, Seelig HP: Experimenteller Beweis einer gemeinsamen Antigenizitat zwischen Innenohr und Nieve. Arch-Oto-Rhino-Lar 212:99-117, 1976 18. Winter JS, Kohn G, Mellman WJ, Wagner S: A familial syndrome of renal, genital and middle ear anomalies. J Pediatr 72:88-93, 1968