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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 5  |  Page : 1165-1168
Branchio-oto-renal syndrome presenting with syndrome of hyporeninemic hypoaldosteronism

Division of Pediatric Nephrology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, Maharashtra, India

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Date of Web Publication21-Sep-2017


Branchio-oto-renal (BOR) syndrome is an autosomal dominant, clinically heterogeneous disorder characterized by branchial arch anomalies, hearing impairment, and renal malformations. We report the case of a 10-year-old boy with BOR syndrome who presented with hyperkalemic hyperchloremic metabolic acidosis due to hyporeninemic hypoaldosteronism. The child also had mental retardation and spastic diplegia which have hitherto not been described in BOR syndrome.

How to cite this article:
David JJ, Shanbag P. Branchio-oto-renal syndrome presenting with syndrome of hyporeninemic hypoaldosteronism. Saudi J Kidney Dis Transpl 2017;28:1165-8

How to cite this URL:
David JJ, Shanbag P. Branchio-oto-renal syndrome presenting with syndrome of hyporeninemic hypoaldosteronism. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2022 Nov 27];28:1165-8. Available from: https://www.sjkdt.org/text.asp?2017/28/5/1165/215129

   Introduction Top

Branchio-oto-renal (BOR) syndrome, also known as Melnick–Fraser syndrome, is a clinically heterogeneous, rare autosomal dominant disorder characterized by branchial arch abnormalities, hearing impairment, and renal anomalies.[1],[2] The incidence of BOR syndrome is 1 in 40,000 population and has been reported to occur in 2% of profoundly deaf children.[3] Syndrome of hyporeninemic hypoaldostero-nism (SHH) is characterized by hyperkalemic hyperchloremic metabolic acidosis usually associated with mild-to-moderate renal insuf-ficiency.[4] We report the case of a 10-year-old boy with BOR syndrome who presented with hyperkalemic hyperchloremic metabolic aci-dosis due to SHH. In addition, the child had mild mental retardation and spastic diplegia which so far have not been described with BOR syndrome.

   Case Report Top

A 10-year-old boy presented to the plastic surgery department for release of bilateral tendo-achilles contractures. He had received a hearing aid at two years of age for bilateral sensorineural deafness following evaluation for delayed speech. The child also had mild mental retardation (intelligence quotient: 70) and spastic diplegia and was a known thalasse-mia trait. During pre-anesthetic evaluation, he was found to have hemoglobin of 8.2 g/dL and serum potassium of 8.4 mEq/L. An urgent electrocardiogram was found to be normal, and the patient was referred to us for further investigation. There was neither a history of polyuria or polydipsia nor a history suggestive of febrile urinary tract infections in the patient. There was no history of the child receiving drugs such as nonsteroidal anti-inflammatory agents, co-trimoxazole, cyclosporine, or tacro-limus.

This was the second child born to non-consanguineous parents. The father had a left preauricular pit but was otherwise asymptomatic. Family history revealed sensorineural deafness in his brother aged 13 years and in a paternal aunt. A first cousin with sensorineural deafness had died at 18 years of age of endstage renal disease (ESRD).

On examination, mild pallor was present. Pulse was 82/min, respiratory rate was 22/min, and blood pressure was 90/60 mm Hg. The weight and height were 17.8 kg and 121 cm, respectively, both below the third percentile for age and sex. There was a left preauricular pit. Central nervous system examination revealed increased tone in both lower limbs with bilateral tendo-achilles contractures. Other systems were essentially normal.

Investigations revealed hemoglobin of 8.2 g/dL with mean corpuscular volume of 54.7 fL and red blood cell count of 5.83 × 1012/L. Urinalysis was normal. Arterial blood gases showed pH of 7.29 with bicarbonate of 12.8 mEq/L, serum potassium of 8.4 mEq/L, serum sodium of 138 mEq/L, and serum chloride of 118 mEq/L (serum anion gap: 15.6). Blood urea nitrogen was 23 mg/dL, serum creatinine was 1.2 mg/dL, serum inorganic phosphorus was 5.0 mg/dL, and serum calcium was 9.6 mg/dL. Urine pH was 5.1 with urine electrolytes showing potassium of 15.6 mEq/L, sodium of 32 mEq/L, and chloride of 22 mEq/ L (urinary anion gap: 25). Plasma and urine osmolality were 285 and 204 mosmol/kg, respectively. The calculated transtubular potassium gradient (TTKG) was 2.6. Estimated glomerular filtration rate (eGFR) by the Schwartz formula was 55.5 mL/min/1.73 m2, i.e. stage-3 chronic kidney disease (CKD). Abdominal ultrasonography showed bilateral small kidneys with Grade-1 echogenicity (right kidney: 5.5 cm × 3.1 cm, left kidney: 6.4 cm × 3.1 cm). Renal function and ultrasonography of the kidneys in the older brother and parents were normal. Genetic analysis could not be done due to financial constraints.

Repeat TTKG after administration of fludro-cortisone was 9.2, suggesting hypoaldoste-ronism and not renal tubular insensitivity to aldosterone. Basal plasma renin activity (sitting) was 0.81 ng/mL/h (reference values: 1.4–2.6 ng/mL/h). Plasma aldosterone was undetectable. A diagnosis of BOR syndrome with hyperkalemic hyperchloremic metabolic aci-dosis due to hyporeninemic hypoaldostero-nism was made. The child was started on oral iron, oral furosemide 1 mg/kg/day in two divided doses, and oral sodium bicarbonate 3 mEq/kg/day. Repeat parameters after a month revealed normal arterial blood gases and serum potassium. Follow-up at six months showed an increase in height of 3 cm. The child has been followed up for the past five years. He remains normotensive and normokalemic with normal acid–base balance on oral furosemide and sodium bicarbonate. His height at 15 years is 156 cm, serum creatinine is 1.8 mg/dL, and eGFR is 48.9 mL/min/1.73 m2 (stage-3 CKD). Urinalysis shows no proteinuria.

   Discussion Top

The BOR spectrum disorders include BOR syndrome and branchio-otic syndrome (BOS).[5] BOR syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae, and cystic and renal malformations.[5] BOS has the same features as BOR syndrome but without renal involvement. The BOR spectrum disorders occur due to mutations in the EYA 1, SIX 5, and SIX 1 genes.[5]

Chang et al[6] proposed criteria for the diagnosis of BOR syndrome [Table 1]. Our patient had three major criteria, namely, preauricular pit, sensorineural deafness, and renal hypo-plasia. Extreme variability is observed among patients in the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormalities. Variability from the right side to the left side in an affected individual, and also among individuals within the same family, has also been described. BOR and BOS may be seen in the same family.[5] Our patient had otologic and renal abnormalities whereas his brother had only sensorineural deafness.
Table 1: Criteria for diagnosis of branchio-otorenal syndrome.

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Renal defects are severe in approximately 6% of patients and include collecting system duplication, renal hypoplasia, cystic dysplasia, and renal agenesis. Ultrasound of the kidneys may show decreased renal volume and loss of normal corticomedullary differentiation and hyperechogenecity of the renal cortex. Some affected individuals progress to ESRD in later life.[3],[7] A first cousin of our patient with a similar presentation had died at 18 years of age of ESRD.

SHH is characterized by hyperkalemic hyper-chloremic metabolic acidosis and is usually associated with a mild-to-moderate decrease in renal function.[4] Metabolic acidosis and hyper-kalemia are complications of CKD, but usually appear when the GFR falls below 25 mL/ min/1.73 m2.[8] In SHH, hyperkalemia and metabolic acidosis are out of proportion to the degree of renal dysfunction, and plasma renin and aldosterone levels are inappropriately low. Electrocardiographic changes have been described in SHH, but many patients are asymp-tomatic.[8] Our patient had hyperkalemic hyper-chloremic metabolic acidosis with an estimated GFR of 55.5 mL/min/1.73 m2, i.e., stage-3 CKD, or moderate decrease in renal function. Despite a serum potassium level of 8.4 mEq/L, the child was asymptomatic and had no electrocardiographic changes of hyperkalemia.

The child has had fairly stable renal function, remaining in stage-3 CKD over the past five years (a slight decrease in eGFR from 55.5 to 48.9 mL/min/1.73 m2). Renin-angiotensin-aldosterone system (RAAS) suppression using angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers has been recommended as the first-line therapy to prevent progression of CKD.[9] This was not done in this patient due to the possibility of hyper-kalemia. Lee et al[10] described a patient with nephronophthisis-medullary cystic kidney disease who presented with SHH at eight months of age and had stable renal function over a follow-up period of 16 years. They postulated that a constitutionally suppressed RAAS in SHH could be a renoprotective mechanism against the progression of CKD.

SHH is not infrequent in adults with CKD but is seen less commonly in children.[11] Transient SHH has been described in children with acute glomerulonephritis, lupus nephritis, and with the use of indomethacin.[12],[13],[14] This is the first report of an association of BOR syndrome with SHH. In addition, our patient had mild mental retardation with spastic diplegia (these were also present in his cousin who died of ESRD), which have hitherto not been described with BOR syndrome.

   Conclusion Top

It is important that patients with branchial arch or ear anomalies and hearing loss be screened for renal anomalies so that treatable and/or possibly progressive lesions are identified on time.

   Acknowledgment Top

We would like to thank Dr. M. E. Yeolekar, dean, of our institution for permitting us to send this manuscript for publication.

Conflict of interest: None declared.

   References Top

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 1976;9:25-34.  Back to cited text no. 1
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 1978;2:241-52.  Back to cited text no. 2
Fraser FC, Sproule Jr., Halal F. Frequency of the branchio-oto-renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet 1980;7:341-9.  Back to cited text no. 3
Weidmann P, Reinhart R, Maxwell MH, et al. Syndrome of hyporeninemic hypoaldostero-nism and hyperkalemia in renal disease. J Clin Endocrinol Metab 1973;36:965-77.  Back to cited text no. 4
Smith RJ. Branchiootorenal spectrum disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993-2015. 19 March, 1999. Available from: http://www.ncbi.nlm. nih.gov/books/NBK1380/[Last updated on 2013 Jun 20].  Back to cited text no. 5
Chang EH, Menezes M, Meyer NC, et al. Branchio-oto-renal syndrome: The mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat 2004;23:582-9.  Back to cited text no. 6
König R, Fuchs S, Dukiet C. Branchio-oto-renal (BOR) syndrome: Variable expressivity in a five-generation pedigree. Eur J Pediatr 1994;153:446-50.  Back to cited text no. 7
Kraut JA, Kurtz I. Metabolic acidosis of CKD: Diagnosis, clinical characteristics, and treatment. Am J Kidney Dis 2005;45:978-93.  Back to cited text no. 8
Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004;43:S1-290.  Back to cited text no. 9
Lee BH, Kang HG, Choi Y. Hyporeninemic hypoaldosteronism in a child with chronic kidney disease – Is this condition reno-protective? Pediatr Nephrol 2009;24:1771-2.  Back to cited text no. 10
Rodríguez-Soriano J, Vallo A, Sanjurjo P, Castillo G, Oliveros R. Hyporeninemic hypoaldosteronism in children with chronic renal failure. J Pediatr 1986;109:476-82.  Back to cited text no. 11
Don BR, Schambelan M. Hyperkalemia in acute glomerulonephritis due to transient hyporeni-nemic hypoaldosteronism. Kidney Int 1990;38: 1159-63.  Back to cited text no. 12
Kozeny GA, Hurley RM, Fresco R, et al. Systemic lupus erythematosus presenting with hyporeninemic hypoaldosteronism in a 10-year-old girl. Am J Nephrol 1986;6:321-4.  Back to cited text no. 13
Kutyrina IM, Androsova SO, Tareyeva IE. Indomethacin-induced hyporeninaemic hypo-aldosteronism. Lancet 1979;1:785.  Back to cited text no. 14

Correspondence Address:
Preeti Shanbag
Division of Pediatric Nephrology, Lokmanya Tilak Municipal Medical College, General Hospital, Sion, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

PMID: 28937080

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