Late onset of renal disease in nephronophthisis with features of Joubert syndrome type B

Theofanis Apostolou, Nikoletta Nikolopoulou, Marios Theodoridis, Vassilios Koumoustiotis, Ekaterini Pavlopoulou, Dimitrios Chondros1 and Antonis Billis

Department of Nephrology and 1 Department of Computerised Tomography, ‘Evangelismos’ General Hospital, Athens, Greece

Keywords: cerebellar vermis hypoplasia; chronic interstitial nephritis; extra-renal manifestations; Joubert syndrome; juvenile nephronophthisis; medullary cystic disease; nystagmus



   Introduction
 Top
 Introduction
 Cases
 Discussion
 References
 
The familial juvenile nephronophthisis (NPH)–medullary cystic disease (MCD) complex is a heterogeneous group of hereditary tubulointerstitial nephropathies with remarkable clinical differences [1]. The complex is characterized histologically by the development of a chronic sclerosing tubulointerstitial nephropathy with tubular atrophy and dilatation. This process leads to end-stage renal disease [1]. Macroscopically, it results in bilateral formation of cysts usually at the corticomedullary junction of the kidneys.

NPH is the most common variant and the most common genetic cause of end-stage renal disease in the first two decades of life. It is an autosomal recessive interstitial nephritis frequently associated with extra-renal manifestations, mainly ocular disorders (Leber amaurosis, Senior–Loken syndrome), skeletal defects, hepatic fibrosis, and central nervous system abnormalities [1]. Joubert syndrome type B (JSB) represents a developmental disorder of the NPH complex with multiple organ involvement including aplasia of the cerebral vermis and retinal dystrophy [2]. MCD is a less common variant, with a dominant mode of inheritance that appears later in life usually without extra-renal associations [1].

Two siblings, male and female, presented to our department with a disease that had the typical course of a congenital chronic interstitial nephritis resembling that of NPH, with extra-renal manifestations similar to those of JSB without any linkage to chromosome 2 (2q12-q13), with features of MCD nephropathy. We report these cases because of their rarity, and genetic interest.



   Cases
 Top
 Introduction
 Cases
 Discussion
 References
 
Case 1
A male patient was referred to our department on August 1999 because of severe renal impairment, which was discovered after an episode of acute gouty arthritis of his left toe.

He was 33 years old with mild mental retardation, a childish but good sense of humour, ataxic gait, pendular nystagmus, kyphoscoliosis to the right, severe visual impairment, and normal blood pressure.

He was the second child of his family, the first being a 36-year-old female who also had congenital nystagmus. The 73-year-old father and 62-year-old mother were healthy with normal renal function (creatinine 1.3 and 0.95 mg %, respectively), a normal renal ultrasound scan and with no family history of consanguinity or congenital ocular disorders on ophthalmologic examination. The son was delivered normally without any respiratory abnormality, and from his first months of life had pendular nystagmus. As time went by the parents noticed that the child was not following objects' movements and that he had a delayed mental development for his age. He was referred to a reputable ophthalmologic department abroad where the electroretinogram (ERG) was silent but with present visual evoked potentials. The electroencephalogram (ECG) was normal. He was discharged with advice to follow a specifically tailored educational programme, which was sufficiently successful that by the age of 22 he was employed as a telephone operator in a state bank. There was no other remarkable change in his life until his presentation to our department. He denied having polyuria in the past, but his mother said that he was very fond of drinking abundant quantities of water, with episodes of occasional and intermittent weakness.

On examination he was noted to have nystagmus and an ataxic gait but there were no other abnormal findings. He was not obese and had normal secondary sexual characteristics. The laboratory investigation revealed severe end-stage renal disease (BUN 221 mg %, creatinine 7.5 mg %), high serum parathyroid hormone levels (578 pg/ml), and uric acid (11 mg %), with anaemia (Ht 32%). Urine analysis revealed a low specific gravity (1008) in the absence of sediment abnormalities or proteinuria. Liver enzymology, CT, and MRI of the upper abdomen gave no evidence of liver dysfunction. The ophthalmologic examination showed nystagmus, difficulty in nocturnal vision with severe visual impairment (1/10 of normal vision). Fundoscopy revealed pallor of the optic disc, severe attenuation of the retinal vessels, and the presence of pigment in the periphery. Audiogram was normal. A renal ultrasound revealed two small kidneys with increased echogenicity and multiple bilateral cysts measuring 1–3 cm in diameter, distributed throughout the cortex and in the corticomedullary junction. MRI scan of the kidneys confirmed the above findings while CT and MRI scan of the brain showed hypoplasia of the cerebellar vermis and dilatation of the fourth ventricle (case 1, Figures 1Go and 2Go). Roentgenogram of the hands was normal.



View larger version (125K):
[in this window]
[in a new window]
 
Fig. 1. MRI image. Severe hypoplasia of the cerebellar vermis.

 


View larger version (123K):
[in this window]
[in a new window]
 
Fig. 2. MRI scans, axial section. Normal sized kidneys with cysts in the cortex and in the corticomedullary junction.

 

Case 2
The sister of the above patient, a 36-year-old woman, was also born with pendular nystagmus and mild visual impairment, and during childhood she developed a mildly ataxic gait. Ophthalmic examination performed at an early age, revealed the same findings as in case 1 except for the visual impairment, which was less prominent. Her mental development was satisfactory, although she had the behaviour of a girl younger than her age. On questioning she revealed that she was very fond of salty food and had had many episodes of hypotension, which she self-treated with excess salt intake. Initially, emotionally influenced by her brother's condition, she refused any investigations except simple laboratory tests that revealed mild renal insufficiency (serum creatinine 1.5 mg %, with upper normal value 1.4 mg %) without any other significant abnormal laboratory finding. Later in the course of her brother's follow-up, she was persuaded to have a CT and MRI scan of the brain and upper abdomen. The scans revealed the same hypoplasia of the cerebellar vermis and the dilatation of the forth ventricle in the brain, but two normal kidneys and a normal liver. Repeat ophthalmologic examination showed nystagmus and difficulty in nocturnal vision with visual impairment (5/10 of the normal vision). Fundoscopy revealed drusen of the optic disc with depigmentation, severe stenosis of the retinal vessels and the presence of pigment in the periphery.

The analysis of the genomic DNA of the two siblings (samples were sent to Prof. F. Hildebrandt, University Children Hospital, Freiburg, Germany) gave no evidence for a homozygous deletion of the NPH p1 gene.



   Discussion
 Top
 Introduction
 Cases
 Discussion
 References
 
The NPH–MCD complex is an autosomal recessive renal disease of unknown aetiology. It includes renal diseases with various clinical features, and different patterns of inheritance [16]. Familial juvenile NPH represents a more homogeneous entity. Genetic analysis has demonstrated an NPH locus on chromosome 2q12-q13 [2,3]. It is rare in the general population, but accounts for 10–15% of children with end-stage renal disease reported in the EDTA registry [7]. The main clinical symptom is progressive renal failure, which is relentless, insidious, and often undetected until end-stage, which usually occurs during the second decade of life. This progression is accompanied by the typical chronic course of a tubulointerstitial disease, i.e. reduced concentrating ability, polyuria, polydipsia, and sometimes excessive sodium loss with dramatic hyponatraemic dehydration.

Several disorders have been described in association with familial juvenile NPH. The most frequent association involves the eyes. Leber amaurosis (early blindness, extinct electroretinogram) in infants or Senior–Loken syndrome (blindness or milder ocular manifestations plus retinitis pigmentosa) in children is the most common extra-renal manifestation, although other eye anomalies have been reported [8]. Other extra-renal manifestations of NPH include cerebral involvement, particularly mental retardation and cerebellar dysfunction. In 1969, Joubert et al. [9] described five children with an autosomal recessive condition characterized by jerky eye movements, episodic tachypnea and apnoea, profound developmental delay, and cerebellar hypoplasia. The condition was referred to as Joubert syndrome. It is clear now that this syndrome is also associated with NPH, although genetic analysis did not reveal the homozygous deletions typically seen in NPH1 [4,7].

Saraiva and Baraitser [2] propose a classification of patients with this diagnosis, dividing them into those with retinal dystrophy and those without (JSB and JSA, respectively). In JSB (patients with retinal dystrophy), the presence of renal cysts is very common while renal impairment accompanies some of these cases. Retinal dystrophy is defined as the association of a non-recordable or significantly attenuated electroretinogram with flash and pattern visual evoked potentials present (unlike Leber congenital amaurosis or Senior–Loken syndrome) and possible retinal pigment disorders.

MCD is a less common condition with an autosomal dominant mode of inheritance but unknown frequency. It appears later in life, usually in the third decade, and leads to end-stage renal failure at the age of 40–50 years. Associated extra-renal manifestations are not common [17]. The main association is with gout and hyperuricaemia, which probably represents a distinct entity [12]. Genetic analysis of MCD families has so far excluded an MCD gene on chromosome 2. Recently, two different loci responsible for MCD were mapped on chromosomes 1 and 16 [5,6].

In this report, the male siblings, progression to end-stage renal failure was insidious, with defective concentrating ability, polydipsia, and probable sodium depletion (weakness). His sister suffered from the same symptoms with episodes of hypotension, but with only mild renal impairment. It is of note that their progression to chronic renal failure was not parallel or even similar and it occurred in adult life, a finding not consistent with NPH variant. There was no evidence of vertical transmission of the condition (both parents were healthy) and no similar cases in the family's history, excluding the dominant mode of inheritance and consequently the MCD dominant variant.

Retrieving our patients' ophthalmologic examinations performed in childhood, we found out that both had nystagmus, visual impairment, and a silent electroretinogram but with present visual evoked potentials. There was no reference to retinal pigmentation, which was a finding of the recent examinations. These associations can occur in Senior–Loken syndrome, but the age of the patients, the delayed onset of renal failure, nystagmus, cerebellar disorders, and the presence of evoked visual potentials with impairment of vision and no blindness, make this diagnosis less likely.

Both our patients had mental retardation, which was sufficiently mild to allow them to participate in normal social life, although with an infantile and innocent way of thinking. CT and MRI scan of the brain of both cases revealed cerebellar hypoplasia and dilatation of the forth ventricle (case 1, Figures 1Go and 2Go), findings typical of JSB. Liver enzymes were normal. The finding of kyphoscoliosis of the male sibling may be partly attributed to long-term renal osteodystrophy but the roentgenogram of the hands of both patients were normal, excluding polydactyly and the cone-shaped epiphyses seen in other cases of NPH with extra-renal involvement.

The onset of end-stage renal disease in the brother and the impairment of renal function in the sister occurred at a late stage in their lives, resembling the usual MCD pattern. Another interesting association is the brother's hyperuricaemia and gout. Although the occurrence of these findings has been reported in some families with MCD nephropathy, the significance of this association is not well established. It is not clear whether this represents a single genetic nosological entity or is simply a consequence of the end-stage renal disease. Our patient's hyperuricaemia is probably more severe than that of end-stage renal disease alone, and even after many months on dialysis he still has unusually high levels of uric acid.

Extra-renal genetic manifestations usually occur in NPH variants. If one accepts that our patients suffered from this condition with delayed onset, the relatively mild clinical course might possibly point to an environmental factor playing a beneficial role in delaying the progression to end-stage renal disease. The intra-familial variability that exists between the two siblings for the rate of progression to end-stage renal disease might support the hypothesis of the action of non-genetic influence on the development of end-stage renal disease in this entity or may indicate an effect of modifier genes, as some authors have suggested [11]. The genomic analysis did not demonstrate an association with the NPH locus, a finding that could be in accordance with observations that NPH with extra-renal manifestations do not map on chromosome 2 [4,7,11].

In summary, these cases suggest that there are variable patterns and clinical heterogeneity of these congenital diseases, possibly resulting from genomic variations and/or environmental influences. Studies of larger families with long-term follow up, together with the conclusion of the analysis of the human genome, may shed further light on these important inherited disorders.



   Acknowledgments
 
We wish to express our acknowledgements to Professor F. Hildebrandt, University Children Hospital, Freiburg, Germany for his kind contribution for the analysis of the genomic DNA of the two siblings and his significant comments on the reported cases. We also wish to express our thanks to Dr Alastair J. Hutchison, Consultant at the Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, UK who very kindly accepted to have a substantial look at our final revision.



   Notes
 
Correspondence and offprint requests to: Theofanis Apostolou MD, Nephrology Department, Evangelismos General Hospital, 10676 Athens, Greece. Email: tapostolou{at}ath.forthnet.gr Back



   References
 Top
 Introduction
 Cases
 Discussion
 References
 

  1. Broyer M, Kleinknecht C. Structural tubulointerstitial disease: nephronophthisis. In: Morgan SH, Grunfeld JP, eds. Inherited Disorders of the Kidney. Oxford University Press, Oxford, 1998; 340–348
  2. Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet1992; 43: 726–731[ISI][Medline]
  3. Antignac C, Arduy CH, Beckmann JS et al. A gene for familial juvenile nephronophthisis (recessive medullary cystic disease) maps to chromosome 2p. Nature Genet1993; 3: 342–345[ISI][Medline]
  4. Hildebrandt F, Singh-Sawhney I, Schnieders B et al. Mapping of a gene for familial juvenile nephronophthisis: refining the map and defining flanking markers on chromosome 2. Am J Hum Genet1993; 53: 1256–1261[Medline]
  5. Christodoulou K, Tsingis M, Stavrou C et al. Chromosome I localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet1998; 7: 905–911[Abstract/Free Full Text]
  6. Scolari F, Viola BF, Amoroso A et al. Identification of a new locus for medullary cystic disease on chromosome 16. Nephrol Dial Transplant1999; 14: Abstract A48[Abstract]
  7. Hildebrandt F, Jungers Grunfeld JP. Medullary cystic and medullary sponge renal disorders. In: Schrier WB, Gottschalk C, eds. Diseases of the Kidney. Little, Brown and Co, Boston, 1996; 499–500
  8. Dufier JL, Orsaud D, Dhermy P et al. Ocular changes in some progressive hereditary nephropathies. Pediatr Nephrol1987; 1: 525–530[ISI][Medline]
  9. Joubert M, Eisenring J, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis: a syndrome of episodic hyperpnoea, abnormal eye movements, ataxia and retardation. Neurology1969; 19: 813–825[ISI][Medline]
  10. Verloes A, Lambotte C. Further delineation of a syndrome of cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. Am J Med Genet1989; 32: 227–232[ISI][Medline]
  11. Hildebrandt F, Sraham B, Nothwang HG et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: Rate of progression to renal failure. Kidney Int1997; 51: 261–269[ISI][Medline]
Received for publication: 15. 5.00
Revision received 27. 7.01.