ocular abnormalities in patients with alport's syndrome

Nephrol Dial Transplant (1996) 11: 2355-2358

Continuing Nephrological Education (CNE)

IMephrologyDialysis

Transplantation

Ocular abnormalities in patients with Alport's syndrome

A.Vanderschueren1,1. Stalmans1, R. Lombaerts2 and A. Leys1

Departments of 'Ophthalmology and 2Paediatrics, University Hospital of Leuven, Belgium

Key words: Alport; cornea; lens; lenticonus; ocular;macula

Case reports

Family 1

A boy called PF was known to have nephritis fromthe age of 2 years, and underwent extensive screening(including renal biopsy and familial screening) at theage of 14 because of renal failure and hypertension.The diagnosis of Alport's syndrome was made.Ophthalmoscopy revealed bilateral, whitish, macularflecks with an abnormal macular reflex (Figures 1,2).Pigment epithelial alterations were detected in theperipheral retina. Cornea and lens appeared normal.Sensorineural hearing loss had been diagnosed byaudiometry at primary school and was confirmedduring follow-up. At the age of 15, PF underwent arenal transplantation. One month later, he had feverand biopsy-proven signs of a minor acute rejection.Within 1 month he developed a fulminating lympho-proliferative disorder with infiltration of the kidneysand the bone-marrow. A transplantectomy was per-formed, but unfortunately the patient died 2 monthsafter the transplantation. The eyes were not obtainedfor examination.

RE, the mother of this boy, had proteinuria, whichwas considered to have occurred after an angina pulta-cea at 20 years of age. The familial screening carriedout 9 years later to prove the diagnosis of her son'sdisease revealed the presence of nephritis with haemat-uria and proteinuria. She was less severely affectedthan her son and did not develop renal failure.Audiometry was normal. Ophthalmological examina-tion at the age of 42 years revealed a visual acuity of20/20, and no ocular abnormalities could be detected(Figure 3).

Correspondence and offprint requests to: Prof. Dr A. Leys, DienstOftalmologie, U. Z. Sint Rafael, Kapucijnenvoer 33, 3000 Leuven,Belgium.

Family 2

The second family consists of five sisters and ninebrothers. Four of the women are healthy, but oneamongst them has an affected son. The fifth womanhas a mild form of nephritis. The history of the fiveaffected brothers will be discussed here.

A perceptive high-tone hearing loss was detected inCW at the age of 7 years. The renal problems pro-gressed from proteinuria at the age of 11 to chronicrenal insufficiency, for which he required haemodialysisfrom the age of 29. He also suffered from hypertensionwhich, in combination with an excessive fluid intakebetween the dialysis sessions, caused headaches andpapilloedema with a normal CT scan (pseudo-tumorcerebri). Therefore corticosteroids were administered,and later a lumboperitoneal drainage was performed.At the age of 34, he received a kidney allograft. Hishearing decreased further to a loss of 70 dB right and80 dB left in the high tones.

The ophthalmological follow-up started at the ageof 11. At that time no abnormalities were discovered.Two years later, however, macular white spots andabsence of the foveolar reflex were observed. At theage of 30, both optic discs were swollen, and in theright eye a few haemorrhages and papillomacularyellow exudates were seen. The diagnosis of bilateralpapilloedema, characteristic Alport-related macularchanges with superficial flecks, and an anterior len-ticonus was made (Fig. 4). Since the physiological disccup remained present, no dilated epipapillary vesselswere discovered on fluorescein angiography and thepatient had not noticed any sight eclipses, congenitalpapillary drusen had to be excluded. This is anautosomal dominant condition and the associationwith Alport's syndrome has been described. Therefore,five of his brothers (the 4 other affected ones and 1healthy one) underwent an ophthalmological examina-tion. None of them had papillary drusen. The furtherevolution permitted us to make the diagnosis of benignintracranial hypertension in CW: the papilloedemadisappeared in the following months. The vision was20/30 on both sides (with correction of myopia andastigmatism). At the age of 36 an uncomplicatedbilateral cataract extraction with lens implantation wasperformed.

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2356 A. Vanderschueren et al.

Fig. 1. Fig. 3.

Fig. 2. Fig. 4.

Since the clinical findings in the four other affectedbrothers are quite similar, their history will be discussedmore briefly.

In CJ-M, the diagnosis of (terminal) Alport nephritiswas made when he was 19 years old. He underwentdialysis up to the age of 27, when he received a firstrenal allograft. A second allograft transplantation wasperformed when he was 34. His audiogram showed aperceptive hearing loss of the high tones. The firstophthalmological examination was carried out at theage of 31. Besides the typical Alport-related maculo-pathy and lenticonus, this patient also had corneal

opacities and arcus-like stromal changes. A bilateralextracapsular cataract extraction with lens implant-ation was performed at the age of 32. There were nocomplications at the right side, but during the insertionof the intra-ocular lens in the lens bag of the left eye,the posterior capsule ruptured and an anterior chamberlens had to be inserted.

Nephritis was discovered in C Ju when he was 12years old. Two years later, the diagnosis of Alportnephritis was confirmed. At the age of 20, renal dialysiswas started, and 10 years later he underwent a kidneyallograft transplantation. The first ophthalmological


Ocular abnormalities in patients with Alport's syndrome

document was obtained when he was 33 years old. Hehad maculopathy, anterior lenticonus, and corneal andlenticular opacities. He underwent a bilateral uncom-plicated extracapsular cataract extraction with lensimplantation at the age of 36.

The diagnosis of Alport nephritis was made in CFrat the age of 17. He needed dialysis at the age of 25and he received a donor kidney 12 years later. At thattime he was checked ophthalmologically. He had lostthe sight in one eye due to a traumatic rupture of thelens capsule and a retinal detachment. Besides thetypical Alport-related maculopathy, retinal pigmentepithelium alterations were seen. In the anterior seg-ment of the non-traumatized eye, an anterior lenticonusand corneal as well as lens opacities were present. Anaudiogram was also carried out and showed abnormal-ities compatible with Alport's syndrome.

Ophthalmological examination of CJo at the age of23 revealed typical macular changes, retinal pigmentepithelium alterations, discrete anterior lenticonus andprominent corneal as well as lenticular opacities.

In summary, all of the patients in this family weremen and developed nephritis in the first or seconddecade, requiring dialysis in the second or third decade,and they all underwent an allograft transplantation.Hearing loss was diagnosed at primary school age.The audiograms showed perceptive deafness with cle-arly abnormal hearing limits in the high tones. In allfive brothers, typical Alport-related macular fleckswere observed and retinal pigment epithelium defectswere seen in two patients. In one sibling with terminalrenal insufficiency, intracranial hypertension caused atransient papilloedema. In the anterior segment wefound in all cases an anterior lenticonus, which seemsto be predisposing to capsular rupture. Other featureswere posterior capsular lens opacities, corneal lesions(either polymorphous dystrophy or discrete subendo-thelial or subepithelial abnormalities) and arcus-likestromal changes.

Discussion

The classical Alport's syndrome is an inherited disordercharacterized by progressive nephritis, sensorineuralhigh-tone hearing loss, and ocular lesions.

The clinical course is more predictable in males thanin females. In males there is often haematuria veryearly in childhood. Renal failure develops at the endof the first decade, the second decade, or the beginningof the third decade. Females have a more variablecourse. Some are as severely affected as males butothers have very mild symptoms or stay asymptomatic.

Ocular lesions are an additional feature of theAlport's syndrome. Pathognomonic features areanterior lenticonus, retinal flecks and corneal posteriorpolymorphous dystrophy. Anterior lenticonus is a loc-alized, well-defined protrusion of the lens in theanterior chamber (Fig. 4 arrow). It is bilateral and farmore common in affected males than in females. Anoil droplet retinoscopy reflex is an early clinical sign

2357

[5]. Visual dysfunction and progressive myopizationappear later on [6,7]. The lenticonus is never presentat birth but develops progressively.Electronmicroscopic examination and immunohistol-ogical studies confirm the theory of abnormal basementmembranes in the anterior lens capsule. An attenuationof this capsule with an unusual fibrillar structure andvacuoles is visualized microscopically.Immunohistological studies demonstrate the possibleabsence of the alpha 3, 4 and 5 chains of collagen IV[8]. Probably these chains form a network in somebasement membranes that is distinct from the networkformed by the alpha 1 and 2 of collagen IV [8,9]. Thegenes encoding the alpha 3 and 4 chains have beenmapped to chromosome 2, these of the alpha 1 and 2chains to chromosome 13.

There are two major types of retinal flecks: the morecommon macular and the rare peripheral flecks. Themacular flecks appear as bilateral, faint, denselypacked, whitish, dot-like lesions in the perifoveal area.They do not cause visual dysfunction and electro-physiological and fluoroangiographic evaluations arenormal [10]. If electrophysiological abnormalities dooccur, they can be explained by renal dysfunction,dialysis or renal transplantation in nearly all cases[11]. These flecks carry a poor prognosis with respectto renal outcome: renal failure develops at early age[3,4]. Most authors accept a superficial position of themacular flecks in the internal limiting membrane, butrecently a dissemination in various levels of the retinahas been suggested [12]. The Miiller cells are proposedas the progenitors [10,12]. The midperipheral retinalflecks are also a specific feature of the Alport's syn-drome. They appear associated with the pigmentepithelium and Bruch's membrane, which is con-firmed by the early, mild hyperfluorescence withfluoroangiographic.

Another specific ocular feature is corneal posteriorpolymorphous dystrophy, which consists of endothelialvesicles and can be associated with subepithelial opacit-ies [13]. A fragile corneal epithelium can cause recur-rent erosions and a painful eye [14]. An arcus juvenilis,spherophakia, anterior polar, cortical and posteriorcapsular cataract, posterior lenticonus, and lens co-loboma have been described. Other retinal changesreported in patients with Alport's syndrome are anabnormal macular reflex, pigment dispersion syn-drome, a macular hole, and optic driisen.

Patients with familial nephritis without deafness(variant of Alport's syndrome) usually do not haveocular abnormalities.

In summary, the ocular manifestations of Alport'ssydrome consist of anterior as well as posterior segmentabnormalities.

The anterior segment lesions are responsible for thesubjective complaints of the patient. Troubled mediadue to corneal and/or lenticular opacities cause visualdysfunction. Progressive myopization and refractiondifficulties, as well as a higher risk of lens capsulerupture are caused by anterior lenticonus. Cornealerosions may cause a painful eye.


2358 A. Vanderschueren et al.

The macular flecks do not cause visual dysfunction,but contain important information for the nephrolo-gist, since they reflect a more severe affection ofthe kidneys.

References

1. Cugh KS, Sakhuja V, Agarwal A et al: Hereditary nephritis(Alport's syndrome), clinical profile and inheritance in 28 kind-reds. Nephrol Dial Transplant 1993; 8: 690-695

2. Jacobs M, Jeffrey B, Kriss A et al. Ophthalmologic assessmentof young patients with Alport's syndrome. Ophthalmology 1992;99: 1039-1044

3. McCartney PJ. Alport's syndrome and the eye. Aust. NZ.J. Ophthalmol 1989; 17: 165-168

4. Thompson SM, Deady JP et al. Ocular signs in Alport'ssyndrome. Eye 1987; 1: 146-153

5. Leys A. Alport's syndrome. In: Tasman W, Jaeger EA, eds.Duane's Clinical Ophthalmology. 1994; Ch. 31, 9-10

6. Rajarshi B, Kumar A, Pakrasi S. Alport's syndrome : ocular

manifestations and unusual features. Ada Ophthalmol 1990;68: 347-349

7. Singh DS, Bisht DB, Kapoor S et al. Lenticonus in Alport'ssyndrome, a family study. Ada Ophthalmol 1977; 77: 164-170

8. Cheong HI, Kashtan CE et al. Immunohistologic studies of typeVI collagen in anterior lens capsules of patients with Alport'ssyndrome. Lab Invest 1994; 4: 553-557

9. Kashtan CE, Michael AF. Alport's syndrome : from bedside togenome to bedside. Am J Kidney Dis 1993; 22: 627-640

10. Gehrs KM, Pollock SC, Zilkha G. Clinical features and patho-genesis of Alport retinopathy. Retina 1995; 15: 305-311

11. Jeffrey B, Jacobs M et al. An electrophysiological study onchildren and young adults with Alport's syndrome. BrJ Ophthalmol 1994; 78: 44-48

12. Govan JA. Ocular manifestations of Alport's syndrome : ahereditary disorder of basement membranes? Br J Ophthalmol1983; 67: 493-503

13. Teekhasaenee C, Nimmanit S et al. Posterior polymorphousdystrophy and Alport's syndrome. Ophthalmology 1991; 98:1207-1215

14. Burke JP, Claerkin LG, Talbot JF. Recurrent corneal epithelialerosions in Alport's syndrome. Ada Ophthalmol 1991; 69:555-557


ocular abnormalities in patients with alport's syndrome

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