End-stage renal failure associated with congenital deafness.

Introduction

The commonest cause of hereditary deafness associated with renal failure is the Alport syndrome, but it is important to be aware of other possible diagnoses. We report a patient presenting, at end-stage renal failure, with a family history of sensori-neural deafness, in whom the diagnosis was branchio-oto-renal (BOR) syndrome; resequencing the EYA1 gene revealed a novel mutation.

Case history

A 26-year-old male was referred as an emergency to the renal service with a plasma creatinine of 1235 μmol/L. He had attended his general practitioner with a 3-week history of oral thrush, nausea, weight loss, nocturia and pruritus. He did not complain of visual problems, rash or arthralgia and was not taking any medications. His hearing had been impaired since birth, to the point that he required hearing aids from the age of 11. His mother, maternal grandfather, maternal aunt and uncle, and a brother were also deaf (Figure 1). The maternal aunt was known to have a moderate renal impairment. On examination, the blood pressure was 168/97, the chest was clear and abdominal examination unremarkable. Urinalysis showed proteinuria 4+ and haematuria 3+; urine protein/creatinine ratio was 560 mg/mmol. Blood tests showed a haemoglobin of 7.2 g/dL, MCV 90.6 fL, platelets 243 × 109 g/L, potassium 5.9 mmol/L, urea 47.4 mmol/L and creatinine 1235 μmol/L. His serum albumin was 40 g/L, serum calcium 1.97 mmol/L, phosphate 1.96 mmol/L and parathyroid hormone level 64.0 pmol/L. Haematinic levels were normal. His autoimmune screen showed no abnormality. Abdominal ultrasound demonstrated that both kidneys were <8 cm in bipolar length.

Fig. 1

The family tree of the patient. Shown for each of the 18 members is the presence or absence of the four main features of the BOR syndrome: preauricular pits, hearing loss, branchial fistulae and renal abnormalities.

A diagnosis of the Alport syndrome was considered, and a skin biopsy was performed to examine the expression of type IV collagen α-chains; immunohistochemistry showed normal α-I and α-V in the basement membrane. Direct ophthalmoscopy was normal and did not demonstrate anterior lenticonus. In addition, the pattern of inheritance in the kindred was not consistent with X-linked Alport syndrome, since there was evidence of father-to-son transmission. Further examination of the patient revealed preauricular pits bilaterally (Figure 2). The same finding was identified in his mother and brother. The combination of preauricular pits, deafness and renal disease suggested a diagnosis of BOR syndrome.

Fig. 2

(i) Preauricular pits and (ii) branchial fistulae in the patient.

The patient has been successfully treated with dialysis and a cadaveric renal transplant. He and his fiancée were planning to have children. Genetic counselling was provided, and resequencing of the EYA1 gene was performed that revealed a c.1376 + 2T > C mutation in intron 13, which alters the consensus splice donor site and is presumed to be the cause of disease in this patient (Figure 3). Genetic counselling of the couple addressed several issues, including the one in two risk that he would transmit the mutant EYA1 allele each time they conceived. Review of his family history reinforced his understanding that there is substantial variability in the expression of the condition, even amongst carriers of the same mutation. Consequently, the value of conventional prenatal diagnosis would be limited, as demonstration of the presence of the EYA1 gene mutation would not yield clear prognostic information concerning the risk of significant renal disease. The couple was advised that a potential option is preimplantation genetic diagnosis. While this technique has not yet been applied to BOR syndrome in the United Kingdom, it is now practicable to perform preimplantation genetic haplotyping, which would allow selective implantation of embryos that do not carry the mutation.

Fig. 3

Sequence analysis of exon 13 of the EYA1 gene in the patient. The first (uppermost) trace is from the patient. The second trace is a normal control. The c.1376+2T>C mutation occurs 2 base pairs into intron 13 and affects the splice donor site. This mutation is predicted to result in aberrant splicing of exon 13 to exon 14.

Discussion

Cases of familial deafness associated with renal dysfunction are not infrequently mislabelled as the Alport syndrome, without further investigation [1]. The differential diagnosis for patients presenting with deafness and renal dysfunction is wide—a search of the Online Mendelian Inheritance in Man database (OMIM) for sensorineural deafness and renal disease yields 80 disorders. The commoner diagnoses that nephrologists should be aware of are summarized in Table 1.

Table 1

Inherited deafness and renal disease [16]

Disease	Main clinical features	Inheritance	Gene implicated
Alport syndrome	Glomerular disease	X-linked	COL4A5
	Sensorineural deafness	(Autosomal dominant & recessive forms recognized)
	Anterior Lenticonus
Epstein syndrome and Fechtner syndromea	Glomerular disease	Autosomal dominant	MYH9
	Sensorineural deafness
	Macrothrombocytopaenia
	Leukocyte inclusions—Fechtner
	Cataracts—Fechtner
Branchio-oto-renal syndrome	Renal anomalies	Autosomal dominant	EYA1
	Deafness (sensorineural or conductive)		SIX 1
	Preauricular pits		SIX5
	Branchial fistulae
Familial hypo-/hyper-parathyroidism,	Renal anomalies	Autosomal dominant	GATA3
deafness and renal disease (HDR)	Sensorineural deafness		CaSR
	Hypo-/hyper-parathyroidism

aEpstein and Fechtner syndromes are considered variable expressions of a single illness: ‘MYH9-related disease’.

Other causes of deafness and renal disease include Muckle–Wells syndrome, Cockayne syndrome, Refsum's disease, Charcot-Marie-Tooth disease, familial spastic paraplegia, diabetes mellitus, photomyoclonus, mitochondrial cytopathies, ataxia hyperuricaemia and Bartter's syndrome.

An accurate diagnosis may provide useful prognostic information for the patient and family. Furthermore, it may assist with selection of suitable living donors among relatives of those at end-stage renal failure.

This report illustrates a case of BOR syndrome (OMIM 113650) [2] presenting in adulthood, in whom renal anomalies had not previously been identified, and a nephrological opinion never previously sought.

BOR is an autosomal dominant disorder characterized by the association of branchial cysts or fistulae, external ear malformation and/or preauricular pits, hearing loss and renal anomalies [3]. Although an association between hearing impairment, preauricular pits and branchial fistulae was recognized in the mid-19th century, BOR was first precisely defined by Melnick and Fraser in the 1970s [4,5]. The estimated incidence of BOR is 1:40 000 and may be the underlying diagnosis in ∼2% of profoundly deaf children [6].

There is both phenotypic and genetic heterogeneity within BOR. Reported frequencies of specific features include hearing loss (93%), preauricular pits or tags (82%), renal anomalies (67%), branchial fistulae (49%), pinnae deformity (36%) and external auditory canal stenosis (29%) [7]. These have been subsequently classified into major and minor anomalies occurring in >20% or ≤20%, respectively [7] (Table 2). Renal abnormalities occur in around 66% of affected individuals and include bilateral hypodysplasia, unilateral renal agenesis, which may be associated with contralateral hypodysplasia, and hydronephrosis caused by pelvi-ureteric obstruction or vesico-ureteric reflux. Patients with ocular and branchial features of BOR in the absence of renal involvement have in the past been described as having branchiootic syndrome, BOS (OMIM 602588 [8], 120502 [9] and 608389 [10]). Other minor anomalies, including haematuria and proteinuria, have also been reported [7,11]. End-stage renal failure affects ∼6% of patients, although the prevalence may be higher where other family members are similarly affected [1,12]. Progression to end-stage renal failure more commonly occurs during childhood, and presentation in adulthood remains under-recognized [7].

Table 2

Phenotypic features in BOR syndrome [7]

Major anomalies,	Minor anomalies,
occurring > 20%	occurring ≤ 20%
Hearing loss	Preauricular tag
Preauricular pits	Lacrimal duct aplasia
Renal anomalies	Short palate
Branchial fistulae	Retrognathia
Pinnae deformities	Benign intracranial tumour
External auditory	Cleft palate
canal stenosis	Congenital hip dysplasia
	Euthyroid goitre
	Facial nerve paresis
	Gustatory lacrimation
	Non-rotation of the gastrointestinal tract
	Pancreatic duplication cyst
	Temporoparietal linear naevus

Genetic studies have shown that BOS and BOR are not genetically distinct as had been thought, since two BOS loci map to genes that are mutated in BOR. The commonest two underlying genes act in a regulatory network: EYA1 (implicated in BOR1/BOS1) and SIX1 (BOS3). These are predicted orthologues of genes involved in Drosophila eye development: eyes absent gene (eya) and sine oculis (so), respectively. EYA1, a transcriptional co-activator, has a conserved, 271-amino-acid C-terminal known as the eya domain (ED). Mutations in EYA1 account for ∼40% of BOR syndrome patients [3]. SIX1 has two highly conserved domains, a homeodomain (HD) and a specific six domain (SD) [3]. Recent evidence has also implicated another member of the SIX gene family in BOR, transcription factor SIX5 (BOR2), which also forms a regulatory complex with EYA1 [13]. The underlying gene at a third BOS locus (BOS2 on the long arm of chromosome 1) has not yet been identified.

An important aspect of this case is that patients with branchial abnormalities or preauricular pits and deafness should be screened for renal disease. It has been proposed that all family members of patients with BOR should be screened at least with a renal ultrasound scan [14], and that patients who meet specified criteria should be screened for EYA1 mutations [15] (Table 3).

Table 3

Phenotypic criteria for EYA1 testing in BOR syndrome [15]

Major criteria	Minor criteria
Branchial anomalies	External ear anomalies
Deafness	Middle ear anomalies
Preauricular pits	Inner ear anomalies
Renal anomalies	Preauricular tags
	Other: facial asymmetry, palate abnormalities
	Screening for EYA1 mutations is appropriate
	in those with:
	1. At least three major findings
	2. Two major findings and at least two
	minor findings
	3. At least one major finding and an affected
	first-degree relative with BOR syndrome

Conclusions

There are several causes of deafness and renal disease. This report highlights the importance of considering broader differential diagnoses when faced with an apparently familiar clinical picture.

Teaching points

This case highlights the following important teaching points:

Renal dysfunction associated with deafness has a broader differential diagnosis than Alport syndrome alone.

BOR syndrome is a common cause of hereditary deafness. Renal anomalies and consequent dysfunction are common in this group. Even within families, the disease is phenotypically heterogeneous due to incomplete penetrance.

Patients diagnosed with BOR syndrome should have a full nephrological work-up including ultrasonography, urinalysis and plasma creatinine. Early identification of renal disease may allow intervention to slow decline and enables timely planning of appropriate renal replacement therapy.

Resequencing of EYA1 will identify a causative mutation in ∼40% of BOR cases. This confirms the diagnosis and would permit preimplantation genetic diagnosis.