Leber's congenital amaurosis is a tapetoretinal degeneration that has been diagnosed with increasing frequency in the last 10 years. The main findings include severe connatal or infantile blindness with abolished or minimal responses in the electroretinogram and other signs that are not always evident in the first few years of life, such as salt-and-pepper retinopathy, attenuated vessels, bone-corpuscle-like pigmentation in the fundus, optic atrophy, eyes sunken in the orbit, and the oculodigital sign (forceful digging of fingers into the orbit). An autosomal recessive pattern of inheritance and consanguinity of parents has been described in this entity.1-4 First reported by Leber1 in 1 869, it has since received many denominations: heredoretinopathia congenitalis monohybrida recessiva,2 hereditary retinal dysplasia,5 dysgenesis of the retinal neuroepithelium,6 retinal abiotrophy,' and hereditary retinal aplasia.7
Many other ocular and systemic problems have been reported in association with this syndrome. Cataract,2,8-10 keratoconus,2,8,9,11 strabismus,4 nystagmus,4,8 high myopia,1,2 photophobia, and keratoglobus2,6,8 are the most commonly associated ocularfindings. Systemic findings such as psychomotor and mental retardation,3-5,13,14 epilepsy,3,13 microcephaly,15 impairment of hearing,4,12,14,16 and EhlersDanlos syndrome also have been described. Loken5 and Senior18 in 1961 reported the association of Leber's congenital amaurosis with nephronophthisis, a special kidney dysplasia, first described by Fanconi19 in 1951. It was only in 1964 that a case with this association was studied in the USA,20 and since then only a limited number of cases of congenital amaurosis associated with nephronophthisis have appeared in the literature.9,18,21-25 This kidney disease causes a particular type of progressive uremia, with only a few abnormal laboratory findings such as increased blood urea nitrogen (BUN), isosthenuria, and negative response to Pitressin. Progressive polydipsia and polyuria are the first clinical signs and systemic hypertension is found only in the final stages of the disease. These patients die from uremia at adolescence or early adulthood. A history of consanguinity frequently is obtained in families with this renal problem and transmission seems to follow an autosomal recessive pattern.18,19,21,26,27 In the USA nephronophthisis also has been known as medullary cystic disease. This last classification is misleading because cysts are not an essential feature in this disease.28
We report a case with findings compatible with the diagnosis of Leber's congenital amaurosis with associated nephronophthisis.
The patient, a 15-year-old girl, was born in Bahia, Brazil. The pregnancy was uncomplicated and delivery was uneventful. The patient has been blind since birth. At age 4 years a cataract was noted OS, and when she was 6 years old she started to drink progressively larger volumes of water and to complain of general weakness. She reported waking up many times at nightto urinate. Abrother, whoalso was blind and who had the same problem of ingesting large volumes of water, died at the age of 1 1 years. Another brother, now at the age of 9 years, also is drinking large volumes of water, but has no visual problems according to his mother. The parents of the proband are first-degree cousins, and although the proband and the mother were the only ones available for examination, no other cases with similar problems apparently occurred in the family. The patient's primary complaint is of general weakness and a craving need for water (she drinks 4 liters of water per day).
Fig. 1. Right eye showing opacity in central portion of the cornea.
Fig. 2. Left eye showing complete cataract.
Fig. 3. Facial aspect of the patient.
Ocular examination revealed enophthalmos OU, poor light perception, intraocular pressure of 15 mmHg, sluggish direct and consensual pupillary responses, photophobia, and pendular nystagmus. Slit-lamp biomicroscopy revealed an advanced bilateral keratoconus, with many ruptures in Descemet's membrane and reduced corneal transparency at the apex of the keratoconus in both eyes (Figs. 1 -3). The anterior chamber was deep in the central portion OU, and gonioscopy was normal OU. The right eye had a posterior subcapsular cataract with spoke-like opacifications at the equator for 360°. The left eye showed complete opacification of the lens, and the anterior surface was irregular due to undergoing reabsorption. The fundus, more easily seen in OD, was typical of retinitis pigmentosa, with optic disc atrophy, attenuation of vessels, and bonecorpuscle-like pigmentation in the periphery. On physical examination, an approximate four-year retardation in physical development was found. Secondary sexual characteristics were not present. Her intelligence quotient was slightly diminished, due in part to her blindness. Her blood pressure, previously normal, has been 1 20/90 for the past one to two months.
Hemogram showed a moderate hypochromic, microcytic anemia, and eosinophilia (reverted to normal after treatment of ascaris and Trichuris trichiura). There was normal urinalysis, no hematuria, no glycosuria, no ketonuria, normal excretion of protein in 24-hour urine specimen, low urinary specific gravity, and normal urine cultures. BUN was increased from 56 to 101 mg/100 ml during the sixmonth period of follow-up; creatinine also increased from 1.7 to 8.1 in this period. Creatinine clearance was 41 ml/min. Normal fasting blood sugar, GTT, and insulinemia were found. Excretory urography showed poor concentration of contrast in both kidneys, with no other abnormalities. Renogram showed low isotope concentration in both kidneys and slow excretion. In the serum the level of calcium was low (8.8 mg%) and phosphorus was elevated (5.3 mg%); sodium and potassium levels were normal; alkaline reserve was low (17 mEg/1). Lipidie profile and Immunoelectrophoresis of serum proteins were within normal limits. Electrophoresis of serum protein showed a slight increase in a: and y globulin, with a decrease in ß globulin fraction. Spine x-ray showed diffuse osteoporosis. Audiogram was normal. Facilities for electroretinogram were not available. Due to corneal and lens opacities and searching nystagmus, fundus pictures were of poor quality. Kidney biopsy showed four glomeruli. One was totally and one partially hyalinized, and in the other two the glomerular tuft was normal, with normal basal membrane, patent capillaries, and normal cell ularity. One glomerulus showed fibrous proliferation of the parietal layer of Bowman's capsule. Atrophic and hypertrophic tubules were seen in the same field; fibrous proliferation and inflammatory infiltrate were seen in the interstitial space. Medullary vessels were preserved (Fig. 4). Pathology report described the findings as consistent with chronic glomerulonephritis.
Fig. 4. One glomerulus with fibrous proliferation of the parietal layer of Bowman's capsule iarrow). Atrophic and hypertrophic tubules are seen in the same field. Fibrous proliferation and inflammatory infiltrate is seen in the interstitial space (hematoxylin and eosin stain x 350.)
Even without electroretinography confirmation, the striking fundus appearance and the patient's poor light perception since birth made the diagnosis of Leber's congenital amaurosis highly likely. The electroretinographic results obtained by other authors in similar cases indicate either complete absence or greatly reduced photopic activity of the retina.3,4,14,18 With an increase in stimulus intensity and using a method of selective amplification of the flickering scotopic response, a definite response was obtained in about half of the cases previously considered to be extinguished.3
Other ocular abnormalities such as keratoconus,2,8,9,11 cataract,2,8-10 strabismus,4 nystagmus,4,8 and keratoglobus2,6,8 frequently have been found in association with Leber's amaurosis. This form of connatal or infantile blindness has been called heredoretinopathia congenitalis monohybrida recessiva autosomalis,2 hereditary retinal dysplasia; dysgenesis of the retinal neuroephithelium,6 retinal abiotrophy,3 and hereditary retinal aplasia.7 Its importance as one of the mostfrequent causes of blindness in children, at least in certain countries, was pointed out by Alstrom2 in 1 957. He found that 1 0% of children attending schools for the blind in Sweden had Leber's amaurosis. SchappertKimmijser3 found, in the same year, that Leber's amaurosis was responsible for 1 8% of known cases of blind children in Holland. There is still a controversy in the literature regarding the aplasie,7 dysplasic,6 or abiotrophic' nature of Leber's amaurosis. The fundus appearance changes with age. In the first months of life white spots, which are sometimes barely visible, are disseminated in the periphery together with fine (salt-and-pepper) pigmentary stippling. With time, the pigmentary abnormality is more evident, until it becomes a full-blown pigmentary retinopathy.6,7,13 Pathologic findings in the literature include an irregular pattern and sometimes a total absence of intact photoreceptors in the macula and periphery, with the outer granular layer reduced to a single sheet of cells at the posterior pole.5,7-9,12,18,22,24,29,30 The white fundus lesions correspond to subretinal deposits of undeveloped and degenerated elements from both the outer retinal layers and the retinal pigment epithelium.30
An autosomal recessive mode of inheritance is the rule in this condition, and frequently a history of consanguinity can be elicited.2,3,7 This is confirmed in the family of our patient.
Systemic problems that have been described in association with Leber's amaurosis include psychomotor and mental retardation, epilepsy, microcephaly, impaired hearing, and EhlersDanlos syndrome. In 1 961 Loken5 and Senior18 first reported the association of Leber's amaurosis with a kidney dysplasia, previously described by Fanconi,19 with the name familial juvenile nephronophthisis. In 1960 Ivemark3' published a detailed pathologic report on this kidney condition, implicating Henle's loop as the primary malfunctioning portion, secondarily affecting the glomeruli. The clinical course and laboratory data in patients with this disease have certain pecularities that make diagnosis possible even without the results of a kidney biopsy. In this patient the following findings indicated the diagnosis of nephronophthisis: absence of hematuria, proteinuria, pyuria, and glycosuria; low urinary density; normal lipidie profile; osteoporosis; absence of edema; insidious onset and slowly progressive course; polydipsia; and systemic hypertension only noticeable in the late stages of the disease. The kidney biopsy, although not diagnostic by itself, is compatible with nephronophthisis.
Even having a characteristic clinical course, this entity has been underdiagnosed for many years, and these cases have been included into the wide group of "chronic glomerulonephritis." Biopsy and pathologic findings in the literature have pointed consistently toward a primary tubular rather than a glomerular problem.18,21,26,27,31-33 The tubular apparatus, particularly Henle's loop, has been found to be severely atrophic, with focal areas of hyperplasia; and in advance cases widespread hyalinization has been seen in glomeruli. In the final stages, the glomeruli are affected secondarily. On a histologic basis, differentiating nephronophthisis from other chronic glomerulonephritis may be difficult. Frequently, as was seen in this case, there is a history of consanguinity. The heterozygous state often can be detected in relatives of an affected patient. They show a slightly reduced capability to concentrate urine.20,33-34
A decrease in polydipsia and polyuria with administration of high doses of potassium (4 gm/day) have been reported in the literature.20,35 The results of potassium therapy are interesting and remain unexplained at present. No chromosomic abnormality has been described. Genetic counseling should be provided to affected families.
The authors present a case of a 15-year-old girl with Leber's congenital amaurosis with associated nephronophthisis. The main findings in this case are: congenital blindness; enophthalmos; photophobia; nystagmus; keratoconus; cataracts; pigmentary degeneration in the fundus of both eyes; progressive uremia with absence of hematuria, proteinuria, pyuria, and glycosuria; low urinary density; normal lipidie profile; osteoporosis; absence of edema; polydipsia; polyuria; and a history of consanguinity between her parents. Transmission of this entity follows an autosomal recessive pattern.
This study was performed during the tenure of a Fight for Sight, Inc., New York City, postdoctoral fellowship. Mrs. Verona Pettyjohn provided editorial assistance.
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