Juvenile nephronophtisis,1 also called medullary cystic disease2 is an inherited renal condition which may manifest its presence not only through the kidney symptoms of polydipsia, polyuria, and early renal failure, but also through various extrarenal symptomatology.1-5 One of the most common eye involvements in this disease is a retinal degeneration of the pigmentosa type.5 Increasing awareness to such an association of renal and retinal involvements enable us to detect the kidney disorder earlier and provide additional opportunity to explain the possible mode of origin and inheritance of this special clinical entity.
The study reported here describes a family where two children with congenital Leber amaurosis developed, after a few years, a typical picture of juvenile nephronophtisis. Laboratory studies failed to reveal any special causative factors, but the early appearance of an impaired urinary concentrating ability gave initial hints to the existence of this serious renal involvement.
Patient No. 1 (II 2)
This 1 7-year-old female is under a chronic hemodialysis program. She isthe second child in herfamily (Fig. 1), and is a product of a normal gestation and delivery. From birth the mother noted that the child did not exhibit following eye movements. A general examination in the neonatal period revealed no physical or neurological defects. On ophthalmologic examination a pendulant horizontal nystagmus was found, No pupillary reflexes were obtained, but the pupils dilated well. Funduscopic examination showed no special retinal lesions but a grayish peripheral retinal appearance.
A tentative diagnosis of congenital Leber amaurosis was confirmed by an unrecordable electroretinogram. The child was re-examined several times and in the fundus a typical attenuation of the retinal vessels with hypopigmentation of the choroid was found. As congenital Leber amaurosis may be a symptom of a serious disorder affecting other systems, an extensive laboratory investigation was carried out at the age of three years. Chromatographic analysis of the amino acids in the serum and urine showed no abnormalities and Immunoelectrophoresis of serum and cerebrospinal fluid revealed nothing remarkable. Values for total lipids, cholesterol, lypoproteins, alkaline phosphatase, bilirubin, and total proteins were normal. Serum calcium, inorganic phosphorus, and blood sugar also presented normal values.
At this time enuresis, polydipsia, and polyuria were observed. These caused the suspicion of a concomitant kidney involvement. Urinalysis was free of any pathological findings. The only functional abnormality was a diminished urinary concentrating ability. In the following years a severe normochromic normocytic anemia developed with progressive deterioration of the kidney functions. No hypertension was present. An audiogram showed normal hearing function. A percutaneous kidney biopsy showed some small cysts in the medulla, extensive glomerular destruction with interstitial fibrosis and hyalinization. These findings confirmed the clinical diagnosis of juvenile nephronophtisis. Because of end stage renal failure a chronic hemodialysis program was started. At the last examination she had typical keratoconus in both eyes. In the fundus the disks were pale, the retinal vessels very narrow and an irregular patch of retinal exudate was present near the optic disk (Fig. 2). Slight pigmentation was found at the equatorial region. No other systemic involvements were found.
Fig. 1: Family pedigree.
Patient No. 2 (II 3)
This male child was born in 1 964 and had a history of normal gestation and delivery. He was the third child in his family (Fig. 1) and from birth appeared blind. The pupillary reflexes were absent and he didn't exhibit following eye movements. A gross nystagmus with a quick component toward the central position was observed. In the fundi the optic disks were small, pale, and surrounded bya pink halo. The disks were separated by a thin collar of tissue on their lateral side from a depigmented area which occupied the macular region. The retinal blood vessels were very narrow and the choroidal vasculature was particularly conspicuous. Around the equatorial region of the fundus, small patches of punctate pigment were seen. As the electrical retinal responses were abolished a congenital Leber amaurosis was diagnosed.
An extensive laboratory investigation like that done in his older sister revealed nothing remarkable except for a lack in the concentrating ability of the kidney. During the later growth his developmental process was poor and the child was found to be also severely mentally retarded. Even though he developed a severe uremia, the parents refused any intervention or treatment and the child died at the age of 10years. From the necropsy it was clear that he also had suffered from typical juvenile nephronophtisis.
Fig. 2: The funduscopic appearance of the left eye of Patient No. 1 (II 2). Note the patch of exudate in the ini 'erotemporal side with the twisting course of the retinal vessel.
Because of the need to avoid arousing needless suspicions, in the remaining child (II 1) the renal investigation was limited to kidney functions, but the eye examination included electrophysiological evaluations. All the results were normal.
The parents of the children were not consanguineously related and were healthy without any renal or ocular symptomatology. The functional evaluation of the visual system and of the kidneys presented normal results. An inquiry among the family members of the parents revealed that no others had showed any ocular or renal symptoms.
Both cases in our family exhibited a remarkable uniformity in the mode and age of onset, clinical presentation, course, and final outcome. The findings of grossly defective vision from birth suggested a genetic defect and the absent electroretinograms confirmed the diagnosis of congenital Leber amaurosis. Even though the nephronophtisis appeared clinically later in childhood there is little doubt that the renal disease may have an etiological association with the ocular condition. Keratoconus has been observed in congenital Leber amaurosis7 and mental subnormality with onset in middle childhood is a possible association in this disease.
A few remarks must be made concerning the mode of inheritance of this condition in the present family. Both parents are apparently normal and they have one healthy and two affected offsprings. The affected children appeared to be of both sexes and the relatives of the parents did not display any of the described anomalies. An autosomal recessive inheritance was assumed in spite of the absence of consanguinity in the parents. In previously reported pedigrees consanguinity between parents was shown/"8
We do not consider this difference significant as both conditions, the juvenile nephronophthisis and the congenital Leber amaurosis, are known to be inherited as a recessive trait in other families. The appearance of the disease without traces backwards or forwards makes such a recessive pattern of transmission highly probable. In both cases the disease followed a peculiarly similar time course in each member lending credence to the hypothesis that genetic factors also control the temporal evolution of the retinal and renal involvement. The unaffected sibling was told that as long as he did not marry a relative, the risk of having a diseased child would be negligible.
As most recessively inherited diseases tend to result from enzyme defects9 the possibility that familial juvenile nephronophtisis represent an inborn error of metabolism could not be excluded. Such a hypothesis fits well with the assumption that all hereditary diseases should finally be explainable in biochemical terms.10 Some theories concerning the pathogenesis of renal cystic diseases indict tubular abnormalities probably resulting from metabolic injury. A variety of metabolites have been shown to be capable of inducing cystic kidneys in newborn animals." Even though that such an estimate is to be accepted with caution in humans, the possibility of a metabolic disturbance at a specific gestational stage leading to the renal and the retinal dysgenesis can be taken into account. The validity of such a conclusion may be questioned since no evidence of such a metabolic abnormality was found in our cases before significant renal damage had developed.
The difficulty to explain such a metabolic error stems primarily from the complexity of the system involved and from the limitations in determining where to look for the possible biochemical defect in this disorder. The lack of sufficiently sophisticated methods for the detection of such biochemical abnormalities or the improper examination of the specific metabolic pathway seems to lead generally to the common failure. An extensive work-up in our cases could not reveal any causative factor for the congenital Leber amaurosis and juvenile nephronophtisis. It is possible that the abberant biochemical basis for this complex association of renal and ocular disorders appear only transiently during embryonic development and any postnatal attempt to identify it was unsuccessful.
In drawing this conclusion to a close itseems that more extensive studies are necessary before we can emerge from the present stage of theories and speculation regarding the pathogenesis of this clinical entity. The highly specific chemical abnormality presumably underlying this genetical condition will continue to be a challenge to researchers.
Two siblings suffering from congenital Leber amaurosis were found to be affected also by juvenile nephronophtisis. Keratoconus in one child and mental retardation in the other developed during their later growth. An extensive laboratory study showed normal results but revealed an impaired urinary concentrating ability. The hereditary pattern operating in this complex disease was found to be consistent with an autosomal recessive trait.
The authors wish to acknowledge Zvi Friedman for the figures.
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