Journal of Pediatric Ophthalmology and Strabismus

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Tapeto-Retinal Degeneration and Familial Juvenile Nephronophthisis (FJN)

A Th M van Balen, MD; J J M van Collenburg, MD

Abstract

The number of syndromes in which tapeto- reti na I degeneration is a part, is ever increasing. Apart from the obvious secondary tapeto-retinal degenerations due to syphilis, rubella, measles, or vaccination, and the possibly secondary metabolically induced tapeto-retinal degenerations in the Laurence-MoonBiedl-Bardet syndrome, the Cockayne syndrome, and the Bassen-Kornzweig syndrome, we have hereditary syndromes like that of Usher, Refsum, Sjogren and Pierre Marie II, in which the tapeto-retinal degeneration is assumed to be one of the manifestations of a pleiotropic gene.

In 1960 Contreras and Espinoza,1 and in 1961 Senior, Friedmann and Braudo2 described the combination of tapeto-retinal degeneration and juvenile familial nephropathy of the kind that was given the name of nephronophthisis by Fanconi et al in 1951 .3 Senior and coworkers ventured the subtitle: "a new oculorenal dystrophy" and a limited number of publications appeared in the following years that claimed the presentation of new cases of this syndrome.

The typical clinical picture4 is that of a child, usually aged four to ten years with a history of polydipsia and polyuria, often with return of nocturnal enuresis and a history of pallor and growth retardation. The child usually has normal blood pressure, though hypertension may intervene as the disease progresses. Anemia and azotemia always develop in the course of the disease, while hyponatremia and even hypokalemia may be present Hematuria is uncommon, and proteinuria, if it occurs, is very mild. The urine is always of low specific gravity and high sodium content and contains no bacteria. The creatinine clearance is always diminished. In the course of the disease osteodystrophy usually develops; signs of osteodystrophy itself are not specific for the diagnosis. The disease progresses steadily to death from renal failure unless haemodia lysis and/ or renal transplantation are performed.

The typical histologic findings5 of the kidney are macroscopically a diffuse but slight contraction of both kidneys, which are finely granular; in most cases there are grossly apparent but irregularly scattered cysts of variable size in the medulla. By light microscopy the lesions are diffuse but mainly tubular and interstitial. Glomeruli which are either obsolescent or surrounded by a periglomerular fibrosis seem only secondarily affected. Most tubules are atrophic with considerable thickening of the basement membranes, but the surviving nephrons are often hypertroph ied.

In the interstitium there is a diffuse fibrosis with variable cellular infiltration. Vessel walls are often thickened. The cysts, when present, predominate at the corticomedullary junction or within the medulla and are lined by flat, frequently atrophic epithelium. Microdissection studies have shown that tubules are distorted by numerous diverticula and that cysts are localized in distal convoluted tubules and collecting ducts. Sometimes the thickened tubular basement membrane is also split and surrounded by an eosinophilic hyaline material.4

The retinal disease in the family reported by Senior and coworkers2 was called by them: "a retinal dystrophy undistlnguishable from Leber's tapeto retinal degeneration." This was based on the histopathological study of the retina of one of their patients done by Ashton: "A primary hereditary retinal degeneration, but the picture differs from the classical retinitis pigmentosa in that the migrating pigment is scattered, confined to the outer nuciear layers and shows no attempt at a perivascular distribution, nor is there any glial replacement of the visual cells. The clinical picture has been: normal disos and retinal vessels, fine pigment clumping in the equatorial region."

Mainzer et al9 found typical retinitis pigmentosa in a sister (14 years) and a brother (10 years). Meier and Hess,7 Sarles and coworkers,' Schimke ß and Abraham et a/10 all found retinitis pigmentosa- 1 ike pictures in funduscopy. Dekaban11 describes the abnormalities in the…

The number of syndromes in which tapeto- reti na I degeneration is a part, is ever increasing. Apart from the obvious secondary tapeto-retinal degenerations due to syphilis, rubella, measles, or vaccination, and the possibly secondary metabolically induced tapeto-retinal degenerations in the Laurence-MoonBiedl-Bardet syndrome, the Cockayne syndrome, and the Bassen-Kornzweig syndrome, we have hereditary syndromes like that of Usher, Refsum, Sjogren and Pierre Marie II, in which the tapeto-retinal degeneration is assumed to be one of the manifestations of a pleiotropic gene.

In 1960 Contreras and Espinoza,1 and in 1961 Senior, Friedmann and Braudo2 described the combination of tapeto-retinal degeneration and juvenile familial nephropathy of the kind that was given the name of nephronophthisis by Fanconi et al in 1951 .3 Senior and coworkers ventured the subtitle: "a new oculorenal dystrophy" and a limited number of publications appeared in the following years that claimed the presentation of new cases of this syndrome.

The typical clinical picture4 is that of a child, usually aged four to ten years with a history of polydipsia and polyuria, often with return of nocturnal enuresis and a history of pallor and growth retardation. The child usually has normal blood pressure, though hypertension may intervene as the disease progresses. Anemia and azotemia always develop in the course of the disease, while hyponatremia and even hypokalemia may be present Hematuria is uncommon, and proteinuria, if it occurs, is very mild. The urine is always of low specific gravity and high sodium content and contains no bacteria. The creatinine clearance is always diminished. In the course of the disease osteodystrophy usually develops; signs of osteodystrophy itself are not specific for the diagnosis. The disease progresses steadily to death from renal failure unless haemodia lysis and/ or renal transplantation are performed.

The typical histologic findings5 of the kidney are macroscopically a diffuse but slight contraction of both kidneys, which are finely granular; in most cases there are grossly apparent but irregularly scattered cysts of variable size in the medulla. By light microscopy the lesions are diffuse but mainly tubular and interstitial. Glomeruli which are either obsolescent or surrounded by a periglomerular fibrosis seem only secondarily affected. Most tubules are atrophic with considerable thickening of the basement membranes, but the surviving nephrons are often hypertroph ied.

In the interstitium there is a diffuse fibrosis with variable cellular infiltration. Vessel walls are often thickened. The cysts, when present, predominate at the corticomedullary junction or within the medulla and are lined by flat, frequently atrophic epithelium. Microdissection studies have shown that tubules are distorted by numerous diverticula and that cysts are localized in distal convoluted tubules and collecting ducts. Sometimes the thickened tubular basement membrane is also split and surrounded by an eosinophilic hyaline material.4

The retinal disease in the family reported by Senior and coworkers2 was called by them: "a retinal dystrophy undistlnguishable from Leber's tapeto retinal degeneration." This was based on the histopathological study of the retina of one of their patients done by Ashton: "A primary hereditary retinal degeneration, but the picture differs from the classical retinitis pigmentosa in that the migrating pigment is scattered, confined to the outer nuciear layers and shows no attempt at a perivascular distribution, nor is there any glial replacement of the visual cells. The clinical picture has been: normal disos and retinal vessels, fine pigment clumping in the equatorial region."

Mainzer et al9 found typical retinitis pigmentosa in a sister (14 years) and a brother (10 years). Meier and Hess,7 Sarles and coworkers,' Schimke ß and Abraham et a/10 all found retinitis pigmentosa- 1 ike pictures in funduscopy. Dekaban11 describes the abnormalities in the retina of his case as of developmental origin.

Our patients were found in a family of Turkish origin of which the father and mother were related probably in the second degree. The anamnesis and the examination were difficult because of a language barrier.

METHODS

The patients had a full clinical and laboratory examination regarding their renal function. The normal ophthalmological examination and an extensive electro-ophthalmological examination were performed. EOGs and ERGs have been made both in the patients and the other members of the family. As to the EOG, the ratio between the light peak and dark trough were measured according to Arden's method; the lower limit of the normal range being 1.85.

The ERG examination was carried out in two different ways: the steady state responses representing the activity of the rod system and of the cone system were measured separately; the former by giving blue lightf lashes in the dark adapted state, the latter by white lightflashes superimposed on a bright blue background.12 The lower limit of the normal range for the ERGs of the rod system is 200 µ V in our set-up, that of the cone system is 100¿uV. In the parents, established carriers of the disease, the steady state ERGs were normal. We therefore followed the suggestion of Abraham et al 10 to register the dynamic ERG. ERGs triggered by red lightflashes have been recorded during dark adaptation after a five-minute preadaptation to a white background (of 5.000 asb). In normal subjects, the transition from the photopic to the scotopic dominated ERG was at about seven minutes.

CASE HISTORIES

Patient No. 1

Z.A., female, Karyotype 46, XX, no chromosome abnormalities, born in 1965, was first seen in our eye clinic in 1972 when she was seven years old (Fig. 1). At that time she had been ill for several years. When she was nearly three years old, she started having visual problems and was seen by a Turkish ophthalmologist. At the same age she started having polyuria, polydipsia and growth retardation and from the age of five to six she also had difficulties with walking. In 1971, the fami ly moved to the Netherlands. I ? 1972, she was examined again and found to have tapeto- reti nal degeneratioa Several months later she was seen by a pediatrician and found to have severe anemia and severe azotemia; she was admitted to a hospital for evaluation of renal insufficiency in February 1973.

Physical examination revealed a pale, small child with height as well as weight below the 3rd percentile. Her normal blood pressure was (105/70). She had no further abnormalities.

Laboratory data revealed severe anemia (Hgb 4,4 mmol/ 1), severe azotemia (urea 35 mmol/ 1), high serum creatinine (400 µ mol/ 1), severe hypocalcemia (1.65 mmol/l) with normal phosphate (1.42 mmol/l), and a high alkaline phosphatase (4008U/1). There was a high urine output with very low sg of the urine (1.005), just a trace or no proteinuria and no hematuria Urine cultures were negative.

Roentgenologic examination revealed no abnormalities on chest x-ray and abdominal flat plate; an IVP showed no concentration of dye; cystography showed a normal bladder without vesico ureteral reflux. Bone x-rays showed signs of severe demineralization and rickets.

Renographic examination showed no function of either kidney.

Renal biopsy (Fig. 2), revealed many totally nyalinized glomeruli and obvious perigiomerular fibrosis; some glomeruli had "a very obvious" juxtaglomerular apparatus; there were marked tubular atrophy + dilatation with thickening and sometimes splitting of the tubular basement membrane and diffuse interstitial and cellular infiltration (Fig. 3). No cysts were seen. Immunofluorescence of the kidney tissue was negative.

Fig. 1. The girl ZA. at the age of 10 years.

Fig. 1. The girl ZA. at the age of 10 years.

The diagnosis was familial juvenile nephronophthisis (FJN). The child was treated with a protein restricted diet, extra vitamin D and blood transfusions.

From 1973 until the beginning of 1975, the child was readmitted three times in the same hospital because of increasing renal insufficiency and rickets leading to a heavily handicapped condition.

She also developed severe hyponatremia Na 117 mmol/ 1). She was then referred to our hospital in January 1975 for further evaluation and possible treatment with hemodialysis and renal transplantation.

On admission the girl had signs of severe rickets, and was moving around in a wheelchair because she was unable to walk. Her blood pressure was normal (110/70). There was anemia (Hgb 6,1 mmol/l), azotemia (urea 17,0 mmol/l), a very low serum Ca (1.33 mmol/l), and a markedly increased alkatine phosphatase (3T10 U/l). There was also an elevated parathormonlevel (0.82 ng/ml; N ≥ 0.2), and a slightly elevated periterai plasma renin activity (15,0 ng/ml/hr; ? 0.6-4.9). With extra sodium chloride serum Na was normal. Bone x-rays showed severe generalized rickets and demineralization (Fig. 4).

Fig. 2. Biopsy of renal cortex of Z.A. (original magnification x 85).

Fig. 2. Biopsy of renal cortex of Z.A. (original magnification x 85).

Fig. 3. Detail of renal biopsy of Z.A. (original magnification ? 530).

Fig. 3. Detail of renal biopsy of Z.A. (original magnification ? 530).

The girl was treated with a protein restricted diet, extra fluid and sodium chloride, very high doses of oral calcium and dihydrotachysterol, oral iron and vitamins. She also received physiotherapy.

Her condition improved in such a way that after four months she was again able to walk and could be discharged. However, her kidney function deteriorated further and she was readmitted in November 1975 to start treatment with intermittent hemodialysis. She is presently waiting for a kidney transplant*

Ophthalmologicat examination: visual acuity RE 5/12; LE 5/12 (Ftooks symbol test), Strabismus divergens alternane. Nystagmus horizontal second degree. Funduscopy: normal discs, slightly attenuated vessels. Pigment dusting circularily around the macula The periphery of the fundus: atrophic spots and coarse pigment (Fig. 5). In 1975, the fundus showed atrophy of the pigmentations. Retinoscopy refraction: RE S+3 - c - 1x20°; LE S+3 = c - 1,5x180°. Eiectro-ophthalmological examination: 1972 (examination under general anesthesia). ERG: no photopic or scotopic responses. VECP: hardly any response. EOG: a very low standing potential and no lightrise. ERG 1974: no photopic responses; very reduced scotopic responses of 1.7 µ V for the RE and 3.12 /¿V for the LE. VECP: good responses; both for the RE and the LE 17 µ\?. EOG: not done (not possible without anesthesia).

Fig. 4. X-ray of hand and wrist of Z.A.

Fig. 4. X-ray of hand and wrist of Z.A.

Patient No. 2

Patient No 1's younger brother, R.A., Karotype 46, XY, no chromosomal abnormalities, born in 1966, has the same syndrome (Fig. 6). He developed eye abnormalities and symptoms of polyuria and polydipsia at the age of three. He was seen in our eye clinic in 1972, where he was diagnosed having tapeto- reti nal degeneration with poor vision.

Fig. 5. Fundus of left eye of ZA.

Fig. 5. Fundus of left eye of ZA.

On pediatric examination in 1973, no anemia, no azotemia (urea 5.4 mmol/l), and a slightly elevated serum creatinine level (107/*mol/l) was found.

In January 1975 he was seen again; at that time his serum creatinine had risen to 225 µ mol/ 1 and he was azotemic (urea 19 mmol/l). He was then referred to our hospital, where he was admitted in February 1975.

Physical examination revealed no abnormalities except poor vision; his blood pressure was normal (110/70). His urine production exceeded 2000 mis per 24 hours.

Laboratory data revealed moderate anemia (Hgb 6.2 mmol/l), normal serum electrolytes, slight acidosis (PH 7.33; BE-10 meo/ 1), urea 12,6 mmol/l, creatinine 213 µ mol/ 1, Ca 1.85 mmol/l, ? 1.33 mmol/l alkaline phosphatase 615 U/l; parathormon 0,6 ng/ml (Ns= 0.2 mg/ml); normal liver function tests. Urinalysis: no abnormalities, low osmolality of the urine (200 mosm/l); creatinine clearance diminished (23 ml/min/1.7 mp 2).

Roentgenologic examination: an IVP showed very poor concentration of dye, small kidneys were seen. Bone x-rays showed signs of deminerafization, no rickets. The boy was treated with a protein restricted diet, sodium bicarbonate, oral calcium and dihydrotachysterol.

Ophthalmological examination: Visual acuity RE 0,3; LE 0,4. Retinoscopy refraction: S+4,5; S+4. Funduscopy: normal discs, attenuated vessels. Periphery many atrophic spots and pigment spots in the shape of bone-corpuscles (Fig. 7). Electroophthalmologics! examination: 1972 examination under general anesthesia). ERG: no photopic or scotopic responses. VECP: hardly any responses. EOG: a very low standing potential and no lightrise. ERG 1974: no photopic or scotopic responses. VECP: reasonable responses; for the RE 7 µ? and the LE 10 µ?. EOG: not done (not possible without anesthesia). His condition until now has remained stable.

Fig. 6. The boy RA. at the age of nine years.

Fig. 6. The boy RA. at the age of nine years.

Patient No. 3

U.A., female, born in 1969, was first seen in 1974 at the age of five years. She had normal renal functioa Visual acuity was RE 5/10; LE 7/10; funduscopy: discs and vessels normal. In the periphery white and atrophic spots.

Etectro-ophthalmological examination. ERG 1974: both scotopic and photopic responses normal. VECP: high responses; both for the RE and the LE 45 µ V. ERG 1975: both scotopic and photopic responses normal, respectively 330 µ? and 170 µ?. EOG: shows a lightrise.

Patient No. 4

G.A., male, born in 1971 , was first seen in 1975 at the age of four years. He had normal renal function. Visual acuity was not measurable but apparently normal; funduscopy: discs and vessels normal with rather coarse pigmentation in the periphery.

Electro-ophthalmological examination. ERG 1974: not carried out VECP: high responses. ERG 1975: scotopic responses a bit too low, photopic responses good for both the RE and the LE. The ERG was recorded using stick-on electrodes under the eyes instead of a contact lens, and is therefore, not quite accurate.

Fig. 7. Peripheral fundus of right eye of RA.

Fig. 7. Peripheral fundus of right eye of RA.

The father, C.A., born in 1937, was examined in August 1975. He had normal renal function Visual acuity was RE 1.1; LE 1.1. Media and fundi normal. Electro-ophthalmological examination. ERG 1975: both scotopic and photopic responses normal values on 280 µ V and 130 µ V resp. EOG: shows a normal lightrise. Dynamic ERG: (recorded according to the method of Abraham et al*) is normal (Fig. 8). Dark adaptation (Goldmann-Weekers) is normal.

The mother, H.A., born in 1946, was examined in September 1975. She had normal renal functioa Visual acuity was RE 1.1; LE 1.1. Media normal. Fundi normal. Electro-ophthalmological examination. ERG 1975: both scotopic and photopic normal responses. EOG shows a normal lightrise. Dynamic ERG (recorded according to the method of Abraham et al*) is normal.

DISCUSSION

The clinical and laboratory data of both patients fit the typical picture of nephrophthisis, as first described by Fanconi er al 3 in 1951. Also the histologic findings of Z.A. are consistent with those reported in the literature.13"15

Since 1961, several authors mentioned the combined oculorenal disease and different names have been used.2,7,e,10,ie,,r For instance:

- hereditary renal-retinal dysplasia 9

- familial renal-retinal dystrophy17

-familial nephropathy with retinitis pigmentosa 7

- association de nephropathie tubulointerstitielle chronique et de dégénérescence tape'to-re'tinienne.19

Despite all these different names, all the described cases seem to have the same renal abnormalities - those of FJN. In the majority of the reported families, the parents were consanguineous and also in our family this is probably the case. No parents had the disease.17

This pattern is compatible with an autosomal recessive mode of inheritance. As renal dysplasia is no hereditary abnormality and the name retinal dysplasia refers to a totally different abnormality, the name hereditary renal-retinal dysplasia seems to be confusing.

Pathogenesis of FJN is still unknown; of several hypotheses the most likely is an inherited nephrotoxic metabolic abnormality,18'1' which leads to localized thickening of the tubular basement membrane, produces partial obstruction of the urine flow in a nephron with a well functioning glomerulus, and results in cystic dilatation of its tubules.1' Thus, medullary cysts of FJN seem to be acquired lesions.15

Although the name, used by Royer 1ß is probably the best descriptive sort of name, that one used by Abraham and coworkers 10 is undoubtedly the most original one.

It is not yet known whether retinal lesions are a regular feature of FJN when survival is long enough to allow their development, or whether there are at least two genetic forms of FJN, in only one of which ocular lesions are present. However, the observations10 of sibs concordant for nephronophthisis but discordant for retinitis pigmentosa, only the older sibs having the ocular lesions, suggest that the absence of retinitis pigmentosa in a patient does not mean that it will not eventually develop. The fundus picture is differently described by several authors. The only patho-histological description2 gives the diagnosis of Leber's amaurosis congenita. Clinically this diagnosis is improbable because the children in our cases were not blind or nearly blind at birth.

The question whether Leber's amaurosis is a dysplasia and not an abiotrophy like the tapeto-retinal degeneration of pigmentosa type is still open. Histopathological examinations are too scarce to solve the problem and it could well be that the histopathological differences that are described are mere stages of the same process.

Fig. 8. Dynamic ERG of C.A. Note the equal amplitude of b, and b, at seven minutes of dark adaptation.

Fig. 8. Dynamic ERG of C.A. Note the equal amplitude of b, and b, at seven minutes of dark adaptation.

Our patients did not have very typical symptoms of retinitis pigmentosa. The optic discs were not atrophic and the retinal vessels not very thin, despite very low electroretinographic activity. This leads us to the diagnosis secondary tapetoretinal degeneration. Together with the hypothesis that the medullary cysts of FJN are acquired lesions on basis of an inherited nephrotoxic metabolic abnormality, we propose to enlist tapetoretinal degeneration in this syndrome in the group of probably secondary tapetoretinal degeneration.

The electroretinographic signs of heterozygoty by Abraham ef a/,10 that were a strong argument for a pleiotropic gen could not be found by us.

SUMMARY

Two children born from a consanguineous marriage have a syndrome consisting of TRD and FJN. Arguments are given to assume that the TRD is possibly secondary like in the Laurence-Moon-Biedl-Bardet syndrome and the Bässen Kornzweig syndrome. No ERG signs of heterozygoty were found in the parents in contrast to the findings of Abraham et a/.10

ACKNOWLEDGMENTS

We wish to express our gratitude to Dr. G.G. Wolvius for letting us examine the patients; to Dr. J.A.J. Spaas for examining the renal biopsy; to Dr. G.H.M. van Lith for doing the electroophthalmological examinations; and to Dr. J.W. Delleman for his advice.

REFERENCES

1. Contreras BC, Espinoza SJ: Discussion clinica y anatomopatologica de enfermos que presentaron un problema diagnostica Pediatr (Santiago) 3:271 , 1960.

2. Senior ?, Friedman Al, Braudo JL: Juvenile familial nephropathy with tapeto-retinal degene rati on. A new oculorenal dystrophy. Amer J Ophthal 52:625. 1961.

3. Fanconi G et al: Die familiare juvenile Nephronophthise. Helvet Paediat Acta 6:1, 1951.

4. Gibson AAM, Arnell GC: Nephronophthisis. A report of eight cases In Britain. Arch Dis Child 47:84, 1972.

5. Habib R: Pediatric nephrology, vol. 1. Ed. by J. Strauss. New York, Strattoa

6. Mainzer F et al: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Amer J Med 49:556, 1970.

7. Meier DA, Hess JW: Familial nephropathy with retinitis pigmentosa. A new oculorenal syndrome in adults. Amer J Med 39:58, 1965.

8. Sarles HE et al: Hereditary nephritis, retinitis pigmentosa and chromosomal abnormalities. Amer J Med 45:312, 1968.

9. Schimke RN: Hereditary renalretinal dysplasia. Ann Int Med 70:735, 1969.

10. Abraham FA et al: Nephronophthisis and tapetoretinal dystrophy. Amer J Ophthal 78:591, 1974.

11. Dekaban AS: Hereditary syndrome of congenital retinal blindness (Leber), polycystic kidneys and maldevelopment of the brain. Amer J Ophthal 68:1029, 1969.

12. Lith GHM van, Meininger J, Marie GW van: Electrophysiological equipment for total and local retinal stimulation. Docum Ophthal Proc Ser 2:213, 1973.

13. Pedreira FA, M armer EL, Bergstrom WH: Familial juvenile nephronophthisis and medullary cystic disease. J of Pediat 73:77, 1968.

14. Betts PR, Forrest-Hay I: Juvenile nephronophthisis. Lancet 2:475, 1973.

15. Bernstein J, Kissane JM: Hereditary disorders of the kidney; medullary cysts. Perspect Pediatr Pathol 1:137, 1973.

16. Price JDE, Pratt-Johnson JA: Medullary cystic disease with degeneration CMA J 102:165, 1970.

17. Senior B: Familial renaV-retinal dystrophy. Amer J Dis Child 125:442, 1973.

18. Giselson ? et al: Renal medullary cystic disease or familial juvenile nephronophthisis. A renal tubular disease. Amer J Med 48:174, 1970.

19. Royer P et al: Les nephropathies tubulointerstitiel les chroniques idiopathiques de l'enfant Sem Hop (Am Pediat) 39:620, 1963.

10.3928/0191-3913-19761101-05

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