Posterior Polymorphous Dystrophy and Alport Syndrome CHAIWAT TEEKHASAENEE, MD,t SUMALEE NIMMANIT, MD/ SOROT WUTTHIPHAN, MD,· KRIENGSAK VAREESANGTHIP, MD,2 TAWEE LAOHAPAND, MD,3 PRIDA MALASITR, MD, MRCP,2 ROBERT RITCH, MD4
Abstract: Seventeen Thai patients from nine families with Alport syndrome underwent complete ocular examination and specular microscopy. Fourteen (82.3%) patients had ocular changes. Eleven (64.7%) had endothelial vesicles compatible with posterior polymorphous dystrophy. Four of these also had subepithelial opacities, a previously undescribed phenomenon. Other ocular changes included lenticonus and macular and midperipheral retinal flecks. A second group of 18 consecutive patients from 14 families with posterior polymorphous dystrophy detected during routine ocular examination underwent renal evaluation. Five had hematuria, four of whom had sensorineural hearing loss. Two of the four patients also had characteristic renal biopsy findings. Another had sensorineural hearing loss without hematuria, and renal biopsy showed a thin glomerular basement membrane. Posterior polymorphous dystrophy is a common but frequently overlooked finding in Alport syndrome. The frequent association of these two hereditary conditions suggests a common defect in basement membrane formation. Patients with posterior polymorphous dystrophy should be examined for renal abnormalities and hearing loss. Ophthalmology 1991; 98: 1207-1215
Alport syndrome is a basement membrane disorder characterized clinically by hereditary nephritis and sensorineural hearing loss. Up to 43% of patients have ocular findings (Table 1).'-3 Anterior lenticonus and retinal flecks Originally received: October 26, 1990. Revision accepted: March 29, 1991. Department Department 3 Department 4 Department New York. 1
2
of Ophthalmology, Ramathibodi Hospital, Bangkok. of Medicine, Siriraj Hospital, Mahidol University, Bangkok. of Pathology, Siriraj Hospital, Mahidol University, Bangkok. of Ophthalmology, The New York Eye and Ear Infirmary,
Presented in part as a poster at the American Academy of Ophthalmology, Annual Meeting, Atlanta, Oct/Nov 1990. Supported in part by The Glaucoma Foundation, New York, New York and the Sang Thai Medical Foundation, Bangkok, Thailand. Reprint requests to Chaiwat Teekhasaenee, MD, Department of Ophthalmology, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
are the most frequently described findings. 4 - 9 A few patients with corneal changes similar to posterior polymorphous dystrophy have been reported. 10.1 1 Posterior polymorphous dystrophy also has basement membrane (Descemet's) abnormalities, but a definite association between these two hereditary disorders has not been established. We performed complete ocular examinations, including specular microscopy, on a sequential series of patients with Alport syndrome. In addition, we examined another series of patients with posterior polymorphous dystrophy for renal and hearing abnormalities.
PATIENTS AND METHODS All patients were of Thai origin. Group 1 consisted of 17 patients (13 men and 4 women) from 9 families known to have typical Alport syndrome (Table 2). Their ages ranged from 8 to 58 years (mean, 26.6 years). Alport syn1207
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merular basement membrane changes. Three patients, two of whom had systemic hypertension, had chronic renal failure with an increase in serum creatinine more than 2 mg/percent. One had advanced renal failure requiring continuous ambulatory peritoneal dialysis. Complete family and medical histories were recorded. Ocular examination included refraction, slit-lamp biomicroscopy, applanation tonometry, gonioscopy, and dilated ophthalmoscopy. Specular microscopy was performed on all patients with a Haag-Streit Endoset (Liebefeld-Berne, Switzerland). The endothelium was photographed with a CooperVision (Rochester, NY) PRO CEM-4 standard field corneal endothelial microscope. Slit-lamp and fundus photography were performed in all patients. Group 2 consisted of 18 patients (10 men and 8 women) from 14 families with typical posterior polymorphous dystrophy detected on routine ocular examination (Table 3). Their ages ranged from 12 to 67 years (mean, 41.6 years). One patient had bilateral secondary angle-closure glaucoma and corneal arcus. One patient had retinal flecks and another had bilateral bullous keratopathy with a transparent membrane on the iris surface and ectropion uveae. The others had endothelial vesicles without evidence of more extensive abnormal endothelial cells. None had anterior lenticonus or subepithelial opacification. The disorder had been diagnosed in these patients before the onset of this study, so that the patients in this group did not have merely very subtle findings that might have been evident only on careful searching. None of them had a history of chronic renal disease or had had a previous renal evaluation. Urinalysis and audiometry were performed on all 18 patients. A complete renal evaluation including renal biopsy was performed in those who had either hematuria or sensorineural hearing loss.
Table 1. Reported Ocular Findings in Alport Syndrome Lens Lenticonus 4.7 Cataract 1.5.9.11.51.52 Capsular rupture 53 Spherophakia 51 Myopia54 Iris Iris atrophy and pigment dispersion syndrome 55 Iris atrophy and heterochromia 7.56 Pupil Anisocoria 5 Cornea Arcus juvenilis50 Superficial white deposits5 Fine punctate changes 57 Thickening of the anterior layers52 Lattice-type dystrophy19 Posterior polymorphous dystrophy10.11 Retina Abnormal macular reflex2.7·8.56 Macular and mid-peripheral retinal flecks2.5.6.8-11.58 Pigment epithelium dystrophy55 Vascular tortuosity and teleangiectasis 58 .59
drome was diagnosed clinically by the presence of hematuria with or without sensorineural hearing loss confirmed by audiometry. At least one member of each family had a typical renal biopsy appearance by electron microscopy showing widespread lamellation of the glomerular basement membrane lamina densa (Fig 1). All patients in Group 1 had hematuria and 8 had sensorineural hearing loss by audiometry. Ten patients had undergone renal biopsy and had had characteristic glo-
Table 2. Group 1: Patients with Alport Syndrome Patient No.
Sex
Age (yrs)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
F M F M M M M M M M M M M F M M F
20 58 35 14 8 27 22 14 27 30 33 17 19 42 20 50 17
13M,4F 26.6 (mean)
Total NP
1208
=
not performed; AC
=
High Posterior Subepithelial Polymorphous Renal Blood Renal Hearing Retinal Dystrophy Lenticonus Cataract Flecks Hematuria Biopsy Pressure Failure Loss Arcus Opacification +
+ + + + + + + + + + + + + + + + +
+ NP + + + NP NP + + NP NP + NP + + '+ NP
+
17
10
2
+
+
+
+ + + + +
anterior cortical; N = nuclear.
+
+ +
3
8
+ +
+
+ +
+
+ + + + +
+
+ + + +
4
11
+
+
+ + + +
+ + +
+AC +N
+ + +
+
+AC
+
8
3
6
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endothelial changes identical to those in posterior polymorphous dystrophy. The lesions appeared as clear vesicles on the endothelial surface, either isolated or in groups, surrounded by a gray halo or thickening at the level of Descemet's membrane (Figs 2A, B). None had band-like figures on the posterior corneal surface, corneal decompensation, ectropion uveae, or secondary glaucoma. Results of specular microscopy showed focal annular dystrophic lesions surrounded by normal endothelium (Fig 3). Four patients (23.5%) had bilateral anterior corneal opacities located immediately beneath an intact epithelium. The lesions appeared either as patchy opacification with irregular borders or as a round opacity in the upper third of the cornea (Figs 4A, B, C). The overlying epithelium was smooth and did not stain with fluorescein. There was no associated pannus or vascularization. Only one patient had bilateral arcus senilis. Eight patients (47.1 %) had bilateral anterior lenticonus with a typical oil droplet appearance when retroilluminated (Figs SA, B). One of these had spontaneous anterior lens capsule rupture resulting in cataract formation (Figs 6A, B). One patient had nuclear cataracts and another had anterior subcapsular cataracts. Another had an annular pigmented lesion on the apex of the lenticonus (Figs 7A, B). All patients had open angles. None had peripheral anterior synechia formation. Six patients had midperipheral retinal flecks, three of whom also had macular involvement. The lesions ap-
Fig 1. Electron microscopy of the glomerular basement membrane in a patient with Alport syndrome shows typical thickening and splitting of the lamina densa into interwoven lamellae (arrow) with small dense particles (arrowhead) in between (original magnification, X33,OOO). GBM = glomerular basement membrane; E = endothelial cytoplasm; FP = epithelial foot processes; L = glomerular capillary lumen; M = mesangial cells.
RESULTS GROUP 1
Fourteen patients (82.3%) had bilateral ocular abnormalities (Table 2). Eleven patients (64.7%) had bilateral
Table 3. Group 2: Patients with Posterior Polymorphous Dystrophy Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
17
18
Total
Sex
Age (yrs)
M F F F M F M M M F F M M M F M M F
42 67 14 63 31 49 46 48 32 51 46 51 23 12 57 20 48 48
10M,8F 41.6 (mean)
High Posterior Renal Blood Renal Hearing Subepithelial Polymorphous Retinal Hematuria Biopsy Pressure Failure Loss Arcus Opacification Dystrophy Lenticonus Cataract Flecks
t
+ + +
+
+ 5
+
t
Failed
+
+ + + + + + + + + +
+ +
+
NP NP NP NP NP NP NP NP NP NP NP NP NP 2
+
+
+ +
+ + +
0
0
t
+ +
+
+
5
+ +
0
18
0
NP = not performed. • Thin glomerular basement membrane. t Asymptomatic proteinuria. t Presbycusia.
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Fig 2. Top, groups of clear vesicles surounded by a gray halo on the posterior corneal surface as seen by slit-lamp biomicroscopy (left, A) and Haag-Streit Endoset (right, B). Fig 3. Second row left, specular microscopy shows islands of dysmofphic lesions surrounded by normal endothelial cells. Fig 4. Second row right, A, irregular subepithelial opacification in a patient with Alport syndrome. Third row left, B, retroillurnination appearance of subepithelial opacification shown in A. Third row right. C, round and patchy subepithelial opacities in another patient. Fig 5. Bottom, anterior lenticonus (left, A) with an oil droplet appearance (right, B).
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Fig 6. Top, posterior corneal vesicles (lefl, A) and anterior lenticonus with lens capsule rupture (righi, B) commonly occurred in an eye. Fig 7. Center, annular pigmented lesion on the apex of anterior lenticonus in direct (lefl, A) and retroillumination (righi, B). Fig 8. BOl/om, yellow macular pigmented lesion.
peared as multiple yellow spots of various sizes and configurations scattering without specific pattern. They tended to spare the retinal vessels. One patient had a large confluent yellow patch close to the fovea (Fig 8). GROUP 2
The patients with posterior polymorphous dystrophy had similar corneal endothelial findings to those in Group 1. Five patients in four families with posterior polymorphous dystrophy had hematuria. Four of these patients had sensorineural hearing loss (Table 2). Two of the four patients had diagnostic renal biopsy but the other two refused biopsy (Fig 9). Another patient from the same
family as the two with positive renal biopsies had sensorineural hearing loss without hematuria. Although renal biopsy in this last patient was inconclusive, sighificant thinning of the glomerular basement membrane was noted (Table 3). Another patient had persistent asymptomatic proteinuria. Renal biopsy was performed but the tissue obtained was inadequate for examination.
DISCUSSION Alport syndrome is characterized clinically by progressive hereditary nephritis and sensorineural hearing loss. It is most commonly transmitted as an X-linked disorder, 1211
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Fig 9. Thickening and splitting of the glomerular basement membrane lamina densa into interwoven lamellae (arrow) and small dense particles (arrowhead) similar to that in Figure I, in a patient with posterior polymorphous dystrophy (original magnification, X30,8(0). GBM = glomerular basement membrane; E = endothelial cytoplasm; FP = epithelial foot processes; L = glomerular capillary lumen; U = urinary space.
although autosomal dominant and recessive patterns have been reported. 3,12,13 Since there are variations in modes of inheritance and clinical manifestations, several types of Alport syndrome have been described. 14- 17 Affected males are more likely to be deaf and to develop renal failure than are females. 18 In some patients, hematuria may be inconspicuous and sensorineural hearing loss may never develop. 14,16,17 qinically and pathologically similar or identical hereditary nephritis has frequently been found in kindreds with or without deafness. 19- 24 Therefore, Alport syndrome is currently considered to be in a class of clinically and histopathologically similar hereditary kidney diseases with various additional nonrenal features. 17 Histopathologic and ultrastructural examination of the kidney in Alport syndrome reveals characteristic diffuse lamellation of the glomerular basement membrane. 17 ,21 Recent studies have suggested the basic defect in the syndrome lies in the noncollagenous portion of the type IV collagen molecule in the basement membrane.25 Various nonrenal manifestations including hearing loss, anterior lenticonus with occasional spontaneous capsular rupture, and retinal flecks also may be the result of basement membrane defects. In the cochlea, there is atrophy of the capillary basement membranes of the stria vascularis. Ultrastructural examination of the anterior lens capsule shows partial dehiscences containing fibrillar material and vacuoles. 26 Fragility of the lens capsule has been suggested to be the cause of progressive lenticonus and anterior polar cataract. A possible defect of Bruch's membrane has been suggested for the pathogenesis of the retinal flecks, since their distribution appears to conform with the thickness of the internal limiting membrane; however, this has not been completely investigated. 25 The defect may be present in basement membranes throughout the body since it has also been demonstrated in epidermal basement membranes, although clinically asyniptomatic. 27 This evidence 1212
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suggests a hereditary widespread disorder of basement membranes. Posterior polymorphous dystrophy is most often reported as an autosomal dominant condition,28 although a recessive inheritance pattern has been described. 29 There .is a large variation in expression among affected members of a given family and a wide spectrum of ocular findings, including isolated or coalescent posterior corneal vesicles, thickening of Descemet's membrane, band-like figures on the posterior corneal surface, diffuse stromal and epithelial edema, and fine peripheral anterior synechiae or broadbased iridocorneal adhesions, occasionally with ectropion uveae, have been described. 3o The condition may evolve without visual impairment and most patients may go undiagnosed. The corneal changes may be so subtle that they remain undetected unless careful examination of the posterior corneal surface is performed. The histopathologic appearance of posterior polymorphous dystrophy consists of epithelialization of the corneal endothelium and thickening of Descemet's membrane. 31 - 33 Descemet's membrane is a true basement membrane derived from the endothelial cells. Biochemical components include basal lamina components, fibronectin and type IV collagen. 34- 36 The collagen is typical of basement membrane collagen in the percentage of hydroxyproline and 3-hydroxylysine. 37 Ultrastructural examination of Descemet's membrane in posterior polymorphous dystrophy reveals deposits of multilaminar fibrillar tissue confined to the posterior nonbanded layer and sparing the anterior banded one. Ocular changes in Alport syndrome have been reported to occur in 11 % to 43% of patients. 1-3 The most frequently reported ocular abnormalities have been anterior lenticonus and retinal flecks. 4 - 9 Only four patients with posterior polymorphous dystrophy have previously been reported. 10,1 I However, we found this to be the most common feature in our patients. Changes in the posterior corneal surface of our patients included isolated or small clusters of vesicles and tiny patches of thickening. The lesions appeared bilateral and identical to posterior polymorphous dystrophy by slit-lamp examination and specular microscopy. Bilateral occurrence and familial transmission helped distinguish them from a sporadic, unilateral form of posterior corneal vesicles reported in patients without Alport syndrome. 38 None of our patients had advanced lesions with corneal decompensation or secondary glaucoma. These subtle lesions would have gone undetected without careful slit-lamp examination and specular microscopy. The high incidence of this condition in our patients compared witb the previous reports obviously reflected our intention on this particular examination. Our patients in Group 2 with posterior polymorphous dystrophy who were later found to have typical renal biopsy or hematuria and sensorineural hearing loss had similar corneal findings to those patients in Group 1. A patient with extensive peripheral anterior synechiae with' secondary angle-closure glaucoma and corneal arcus also had sensorineural hearing loss. Significant thinning of the glomerular basement membrane similar to that in benign familial hematuria was noted. Since such thinning of the
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glomerular basement membrane may occur in the early phase of Alport syndrome,3,15,18,39 it is possible that the lesions may progress and become fully manifest later. Another patient with more severe ocular changes including corneal decompensation, ectropion uveae and extensive peripheral anterior synechiae had persistent asymptomatic proteinuria. Renal biopsy was performed but inadequate tissue was obtained. Ifthese two patients were considered to have Alport syndrome, then the number of patients with posterior polymorphous dystrophy and later found to have Alport syndrome would have been higher. In addition, since hematuria may be inconspicuous and sensorineural hearing loss may be absent in some types of Alport syndrome, 14,16,17 the possibility exists that subclinical glomerular basement membrane changes might have been detected if renal biopsy had been performed in patients who did not have clinical manifestations of Alport syndrome. What remains to be reconciled, however, is that the majority of cases of Alport syndrome appear to fit an Xlinked recessive inheritance pattern, while the majority of kindreds with posterior polymorphous dystrophy appear to be autosomal dominant. It is most probable that a group of genetically heterogeneous disorders with similar phenotypic manifestations of varying severity is involved. The COL4A5 gene, which codes for the alpha-5(IV) collagen chain, has been assigned to the region of the X chromosome containing the Alport syndrome locus. 4O A recent analysis of three kindreds in Utah with X-linked Alport syndrome revealed three different mutations in this gene. 41 Alport antigen and the 28K noncollagenous (NCl) peptides of two basement membrane molecules possibly related to type IV collagen, which are missing from the glomerular basement membrane in Alport syndrome, and which have a limited distribution in adult human tissue, are associated with type IV collagen in the earliest forms of Descemet's membrane and lens capsule, structures which are functionally mature at birth.42 It is also possible that both dominant and recessive X-linked forms exist. It is also possible that Thai patients with Alport syndrome have genetically different but phenotypically similar disease or diseases compared with white patients. The fact that four of our Alport syndrome patients and three of the posterior polymorphous dystrophy patients with hematuria were female is suggestive of at least some of our patients having either a dominant form of the disease or a clinically involved carrier state. Mild involvement by posterior polymorphous dystrophy may be accompanied by clinically insignificant basement membrane alterations elsewhere. The patients in Group 1, from the families with Alport syndrome, had a significantly greater proportion of other ocular findings, such as anterior lenticonus and retinal flecks, than did the patients in Group 2. This suggests that mild posterior polymorphous dystrophy unaccompanied by other clinically evident basement membrane-related abnormalities is similarly often unaccompanied by clinically detectable renal abnormalities, and that patients with renal involvement are more likely to have multiple ocular findings when these are sought for. It is also possible that mild forms of posterior
polymorphous dystrophy may be a clue to identification of carriers, analogous to the lens abnormalities of female carriers of Lowe's syndrome. Posterior polymorphous dystrophy is probably also genetically heterogeneous. Our patients in Group 2 had significantly fewer other ocular findings, such as anterior lenticonus and retinal flecks, despite the approximately equal corneal involvement compared with those patients in Group 1. The common occurrence of these two hereditary conditions may represent single genetic disorders or separate diseases controlled by closely linked genes. However, since the thickening and lamellation of Descemet's membrane reported in posterior polymorphous dystrophy appeared to be similar to the glomerular basement membrane or capillary basement membrane of the striae vascularis, it is more likely that the pathogenesis of posterior polymorphous dystrophy may be a part of the widespread basement membrane disorder of Alport syndrome. Corneal endothelium, a neural crest derived cell, has a propensity for fibroblast transformation following diverse stimuli. These transformed cells then produce abnormal collagen and an abnormal basement membrane-like substance, which become incorporated into the original Descemet's membrane, resulting in a thickened multilaminar pattern. 43 Under conditions of stress, the endothelium may secret abnormal posterior collagen layers containing type I collagen. 35 The occurrence of abnormal basement membrane and fibrillar collagen in posterior polymorphous dystrophy was suggested to be a secretory response of stressed endothelium. 44,45 Epithelial transformation or metaplasia of endothelial cells has been proposed to occur with the primary abnormality being in the endothelium and the changes in Descemet's membrane being secondary.46 Since the basic defect in Alport syndrome lies in the noncollagenous portion of the type IV collagen molecule in the basement membrane, the strong association between posterior polymorphous dystrophy and AIport syndrome suggests the basic pathogenesis of posterior polymorphous dystrophy should also lie in the abnormal production of type IV collagen in Descemet's membrane. In addition to corneal endothelial changes, four of our patients had subepithelial opacities, a finding previously undescribed in association with either Alport syndrome or posterior polymorphous dystrophy. The corneal epithelial basement membrane is a typical basement membrane containing laminin,47 bullous pemphigoid antigen,48 and type IV collagen. 49 Although no pathologic examination was available, we believe that the subepithelial lesions occur in the epithelial basement membrane and represent part of the generalized basement membrane disorder in Alport syndrome. Corneal arcus has been reported in association with Alport syndrome. 4,5o However, the incidence is relatively low and appears of questionable significance, being only slightly more common than in the normal population. 9,11 Only one of our patients with Alport syndrome had corneal arcus. The low incidence may reflect racial differences. Our findings show a strong association between posterior polymorphous dystrophy and Alport syndrome. 1213
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Posterior polymorphous dystrophy may be a clinical manifestation of a generalized basement membrane disorder. All patients with Alport syndrome should undergo complete ocular examination including specular microscopy. Patients with posterior polymorphous dystrophy should undergo renal evaluation and hearing testing.
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46. Henriquez AS, Kenyon KR, Dohlman CH, et al. Morphologic characteristics of posterior polymorphous dystrophy. A study of nine corneas and review of the literature. Surv Ophthalmol1984; 29:139-47. 47. Madri JA, Roll FJ, Furthmayr H, Foidart JM. Ultrastructural localization of fibronectin and laminin in the basement membranes of the murine kidney. J Cell Bioi 1980; 86:682-7. 48. Millin JA, Golub BM, Foster CS. Human basement membrane components of keratoconus and normal corneas. Invest Ophthalmol Vis Sci 1986; 27:604-7. 49. Davison PF, Hong BS, Cannon OJ. Quantitative analysis of the collagens in the bovine cornea. Exp Eye Res 1979; 29:97-107. 50. Chavis RM, Groshong T. Corneal arcus in Alport's syndrome. Am J Ophthalmol1973; 75:793-4. 51. Sohar E. Renal disease, inner ear deafness and ocular changes. A new heredofamilial syndrome. Arch Intem Med 1956; 97:627-30.
52. Perrin D. Le Syndrome d'Alport. (Nephropathies hereditaires avec surdite et atteninte oculaire). Ann Ocu11964; 197:329-46. 53. Ehrlich LH. Spontaneous rupture of the lens capsule in anterior lenticonus. Am J Ophthalmol1946; 29:1274-81. 54. Ohlsson L. Congenital renal disease, deafness and myopia in one family. Acta Med Scand 1963; 174:77-84. 55. Davies PD. Pigment dispersion in a case of Alport's syndrome. Br J Ophthalmol 1970; 54:557-61. 56. Singh OS, Bisht DB, Kapoor S, et al. Lenticonus in Alport's syndrome. A family study. Acta OphthalmoI1977; 55:164-70. 57. Purriel PO, Drets M, Pascale E, et al. Familial hereditary nephropathy (Alport's syndrome). Am J Med 1970; 49:753-73. 58. Gelisken 6, Hendrikse F, Schroder CH, Berden JHM. Retinal abnormalities in Alport's syndrome. Acta Ophthalmol 1988; 66:713-7. 59. Kondra L, Cangemi FE, Pitta CG. Alport's syndrome and retinal telangiectasia. Ann Ophthalmol 1983; 15:550-1.
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Abstract: Seventeen Thai patients from nine families with Alport syndrome underwent complete ocular examination and specular microscopy. Fourteen (82.3%) patients had ocular changes. Eleven (64.7%) had endothelial vesicles compatible with posterior polymorphous dystrophy. Four of these also had subepithelial opacities, a previously undescribed phenomenon. Other ocular changes included lenticonus and macular and midperipheral retinal flecks. A second group of 18 consecutive patients from 14 families with posterior polymorphous dystrophy detected during routine ocular examination underwent renal evaluation. Five had hematuria, four of whom had sensorineural hearing loss. Two of the four patients also had characteristic renal biopsy findings. Another had sensorineural hearing loss without hematuria, and renal biopsy showed a thin glomerular basement membrane. Posterior polymorphous dystrophy is a common but frequently overlooked finding in Alport syndrome. The frequent association of these two hereditary conditions suggests a common defect in basement membrane formation. Patients with posterior polymorphous dystrophy should be examined for renal abnormalities and hearing loss. Ophthalmology 1991; 98: 1207-1215
Alport syndrome is a basement membrane disorder characterized clinically by hereditary nephritis and sensorineural hearing loss. Up to 43% of patients have ocular findings (Table 1).'-3 Anterior lenticonus and retinal flecks Originally received: October 26, 1990. Revision accepted: March 29, 1991. Department Department 3 Department 4 Department New York. 1
2
of Ophthalmology, Ramathibodi Hospital, Bangkok. of Medicine, Siriraj Hospital, Mahidol University, Bangkok. of Pathology, Siriraj Hospital, Mahidol University, Bangkok. of Ophthalmology, The New York Eye and Ear Infirmary,
Presented in part as a poster at the American Academy of Ophthalmology, Annual Meeting, Atlanta, Oct/Nov 1990. Supported in part by The Glaucoma Foundation, New York, New York and the Sang Thai Medical Foundation, Bangkok, Thailand. Reprint requests to Chaiwat Teekhasaenee, MD, Department of Ophthalmology, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
are the most frequently described findings. 4 - 9 A few patients with corneal changes similar to posterior polymorphous dystrophy have been reported. 10.1 1 Posterior polymorphous dystrophy also has basement membrane (Descemet's) abnormalities, but a definite association between these two hereditary disorders has not been established. We performed complete ocular examinations, including specular microscopy, on a sequential series of patients with Alport syndrome. In addition, we examined another series of patients with posterior polymorphous dystrophy for renal and hearing abnormalities.
PATIENTS AND METHODS All patients were of Thai origin. Group 1 consisted of 17 patients (13 men and 4 women) from 9 families known to have typical Alport syndrome (Table 2). Their ages ranged from 8 to 58 years (mean, 26.6 years). Alport syn1207
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merular basement membrane changes. Three patients, two of whom had systemic hypertension, had chronic renal failure with an increase in serum creatinine more than 2 mg/percent. One had advanced renal failure requiring continuous ambulatory peritoneal dialysis. Complete family and medical histories were recorded. Ocular examination included refraction, slit-lamp biomicroscopy, applanation tonometry, gonioscopy, and dilated ophthalmoscopy. Specular microscopy was performed on all patients with a Haag-Streit Endoset (Liebefeld-Berne, Switzerland). The endothelium was photographed with a CooperVision (Rochester, NY) PRO CEM-4 standard field corneal endothelial microscope. Slit-lamp and fundus photography were performed in all patients. Group 2 consisted of 18 patients (10 men and 8 women) from 14 families with typical posterior polymorphous dystrophy detected on routine ocular examination (Table 3). Their ages ranged from 12 to 67 years (mean, 41.6 years). One patient had bilateral secondary angle-closure glaucoma and corneal arcus. One patient had retinal flecks and another had bilateral bullous keratopathy with a transparent membrane on the iris surface and ectropion uveae. The others had endothelial vesicles without evidence of more extensive abnormal endothelial cells. None had anterior lenticonus or subepithelial opacification. The disorder had been diagnosed in these patients before the onset of this study, so that the patients in this group did not have merely very subtle findings that might have been evident only on careful searching. None of them had a history of chronic renal disease or had had a previous renal evaluation. Urinalysis and audiometry were performed on all 18 patients. A complete renal evaluation including renal biopsy was performed in those who had either hematuria or sensorineural hearing loss.
Table 1. Reported Ocular Findings in Alport Syndrome Lens Lenticonus 4.7 Cataract 1.5.9.11.51.52 Capsular rupture 53 Spherophakia 51 Myopia54 Iris Iris atrophy and pigment dispersion syndrome 55 Iris atrophy and heterochromia 7.56 Pupil Anisocoria 5 Cornea Arcus juvenilis50 Superficial white deposits5 Fine punctate changes 57 Thickening of the anterior layers52 Lattice-type dystrophy19 Posterior polymorphous dystrophy10.11 Retina Abnormal macular reflex2.7·8.56 Macular and mid-peripheral retinal flecks2.5.6.8-11.58 Pigment epithelium dystrophy55 Vascular tortuosity and teleangiectasis 58 .59
drome was diagnosed clinically by the presence of hematuria with or without sensorineural hearing loss confirmed by audiometry. At least one member of each family had a typical renal biopsy appearance by electron microscopy showing widespread lamellation of the glomerular basement membrane lamina densa (Fig 1). All patients in Group 1 had hematuria and 8 had sensorineural hearing loss by audiometry. Ten patients had undergone renal biopsy and had had characteristic glo-
Table 2. Group 1: Patients with Alport Syndrome Patient No.
Sex
Age (yrs)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
F M F M M M M M M M M M M F M M F
20 58 35 14 8 27 22 14 27 30 33 17 19 42 20 50 17
13M,4F 26.6 (mean)
Total NP
1208
=
not performed; AC
=
High Posterior Subepithelial Polymorphous Renal Blood Renal Hearing Retinal Dystrophy Lenticonus Cataract Flecks Hematuria Biopsy Pressure Failure Loss Arcus Opacification +
+ + + + + + + + + + + + + + + + +
+ NP + + + NP NP + + NP NP + NP + + '+ NP
+
17
10
2
+
+
+
+ + + + +
anterior cortical; N = nuclear.
+
+ +
3
8
+ +
+
+ +
+
+ + + + +
+
+ + + +
4
11
+
+
+ + + +
+ + +
+AC +N
+ + +
+
+AC
+
8
3
6
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POLYMORPHOUS DYSTROPHY AND ALPORT SYNDROME
endothelial changes identical to those in posterior polymorphous dystrophy. The lesions appeared as clear vesicles on the endothelial surface, either isolated or in groups, surrounded by a gray halo or thickening at the level of Descemet's membrane (Figs 2A, B). None had band-like figures on the posterior corneal surface, corneal decompensation, ectropion uveae, or secondary glaucoma. Results of specular microscopy showed focal annular dystrophic lesions surrounded by normal endothelium (Fig 3). Four patients (23.5%) had bilateral anterior corneal opacities located immediately beneath an intact epithelium. The lesions appeared either as patchy opacification with irregular borders or as a round opacity in the upper third of the cornea (Figs 4A, B, C). The overlying epithelium was smooth and did not stain with fluorescein. There was no associated pannus or vascularization. Only one patient had bilateral arcus senilis. Eight patients (47.1 %) had bilateral anterior lenticonus with a typical oil droplet appearance when retroilluminated (Figs SA, B). One of these had spontaneous anterior lens capsule rupture resulting in cataract formation (Figs 6A, B). One patient had nuclear cataracts and another had anterior subcapsular cataracts. Another had an annular pigmented lesion on the apex of the lenticonus (Figs 7A, B). All patients had open angles. None had peripheral anterior synechia formation. Six patients had midperipheral retinal flecks, three of whom also had macular involvement. The lesions ap-
Fig 1. Electron microscopy of the glomerular basement membrane in a patient with Alport syndrome shows typical thickening and splitting of the lamina densa into interwoven lamellae (arrow) with small dense particles (arrowhead) in between (original magnification, X33,OOO). GBM = glomerular basement membrane; E = endothelial cytoplasm; FP = epithelial foot processes; L = glomerular capillary lumen; M = mesangial cells.
RESULTS GROUP 1
Fourteen patients (82.3%) had bilateral ocular abnormalities (Table 2). Eleven patients (64.7%) had bilateral
Table 3. Group 2: Patients with Posterior Polymorphous Dystrophy Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
17
18
Total
Sex
Age (yrs)
M F F F M F M M M F F M M M F M M F
42 67 14 63 31 49 46 48 32 51 46 51 23 12 57 20 48 48
10M,8F 41.6 (mean)
High Posterior Renal Blood Renal Hearing Subepithelial Polymorphous Retinal Hematuria Biopsy Pressure Failure Loss Arcus Opacification Dystrophy Lenticonus Cataract Flecks
t
+ + +
+
+ 5
+
t
Failed
+
+ + + + + + + + + +
+ +
+
NP NP NP NP NP NP NP NP NP NP NP NP NP 2
+
+
+ +
+ + +
0
0
t
+ +
+
+
5
+ +
0
18
0
NP = not performed. • Thin glomerular basement membrane. t Asymptomatic proteinuria. t Presbycusia.
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Fig 2. Top, groups of clear vesicles surounded by a gray halo on the posterior corneal surface as seen by slit-lamp biomicroscopy (left, A) and Haag-Streit Endoset (right, B). Fig 3. Second row left, specular microscopy shows islands of dysmofphic lesions surrounded by normal endothelial cells. Fig 4. Second row right, A, irregular subepithelial opacification in a patient with Alport syndrome. Third row left, B, retroillurnination appearance of subepithelial opacification shown in A. Third row right. C, round and patchy subepithelial opacities in another patient. Fig 5. Bottom, anterior lenticonus (left, A) with an oil droplet appearance (right, B).
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Fig 6. Top, posterior corneal vesicles (lefl, A) and anterior lenticonus with lens capsule rupture (righi, B) commonly occurred in an eye. Fig 7. Center, annular pigmented lesion on the apex of anterior lenticonus in direct (lefl, A) and retroillumination (righi, B). Fig 8. BOl/om, yellow macular pigmented lesion.
peared as multiple yellow spots of various sizes and configurations scattering without specific pattern. They tended to spare the retinal vessels. One patient had a large confluent yellow patch close to the fovea (Fig 8). GROUP 2
The patients with posterior polymorphous dystrophy had similar corneal endothelial findings to those in Group 1. Five patients in four families with posterior polymorphous dystrophy had hematuria. Four of these patients had sensorineural hearing loss (Table 2). Two of the four patients had diagnostic renal biopsy but the other two refused biopsy (Fig 9). Another patient from the same
family as the two with positive renal biopsies had sensorineural hearing loss without hematuria. Although renal biopsy in this last patient was inconclusive, sighificant thinning of the glomerular basement membrane was noted (Table 3). Another patient had persistent asymptomatic proteinuria. Renal biopsy was performed but the tissue obtained was inadequate for examination.
DISCUSSION Alport syndrome is characterized clinically by progressive hereditary nephritis and sensorineural hearing loss. It is most commonly transmitted as an X-linked disorder, 1211
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Fig 9. Thickening and splitting of the glomerular basement membrane lamina densa into interwoven lamellae (arrow) and small dense particles (arrowhead) similar to that in Figure I, in a patient with posterior polymorphous dystrophy (original magnification, X30,8(0). GBM = glomerular basement membrane; E = endothelial cytoplasm; FP = epithelial foot processes; L = glomerular capillary lumen; U = urinary space.
although autosomal dominant and recessive patterns have been reported. 3,12,13 Since there are variations in modes of inheritance and clinical manifestations, several types of Alport syndrome have been described. 14- 17 Affected males are more likely to be deaf and to develop renal failure than are females. 18 In some patients, hematuria may be inconspicuous and sensorineural hearing loss may never develop. 14,16,17 qinically and pathologically similar or identical hereditary nephritis has frequently been found in kindreds with or without deafness. 19- 24 Therefore, Alport syndrome is currently considered to be in a class of clinically and histopathologically similar hereditary kidney diseases with various additional nonrenal features. 17 Histopathologic and ultrastructural examination of the kidney in Alport syndrome reveals characteristic diffuse lamellation of the glomerular basement membrane. 17 ,21 Recent studies have suggested the basic defect in the syndrome lies in the noncollagenous portion of the type IV collagen molecule in the basement membrane.25 Various nonrenal manifestations including hearing loss, anterior lenticonus with occasional spontaneous capsular rupture, and retinal flecks also may be the result of basement membrane defects. In the cochlea, there is atrophy of the capillary basement membranes of the stria vascularis. Ultrastructural examination of the anterior lens capsule shows partial dehiscences containing fibrillar material and vacuoles. 26 Fragility of the lens capsule has been suggested to be the cause of progressive lenticonus and anterior polar cataract. A possible defect of Bruch's membrane has been suggested for the pathogenesis of the retinal flecks, since their distribution appears to conform with the thickness of the internal limiting membrane; however, this has not been completely investigated. 25 The defect may be present in basement membranes throughout the body since it has also been demonstrated in epidermal basement membranes, although clinically asyniptomatic. 27 This evidence 1212
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suggests a hereditary widespread disorder of basement membranes. Posterior polymorphous dystrophy is most often reported as an autosomal dominant condition,28 although a recessive inheritance pattern has been described. 29 There .is a large variation in expression among affected members of a given family and a wide spectrum of ocular findings, including isolated or coalescent posterior corneal vesicles, thickening of Descemet's membrane, band-like figures on the posterior corneal surface, diffuse stromal and epithelial edema, and fine peripheral anterior synechiae or broadbased iridocorneal adhesions, occasionally with ectropion uveae, have been described. 3o The condition may evolve without visual impairment and most patients may go undiagnosed. The corneal changes may be so subtle that they remain undetected unless careful examination of the posterior corneal surface is performed. The histopathologic appearance of posterior polymorphous dystrophy consists of epithelialization of the corneal endothelium and thickening of Descemet's membrane. 31 - 33 Descemet's membrane is a true basement membrane derived from the endothelial cells. Biochemical components include basal lamina components, fibronectin and type IV collagen. 34- 36 The collagen is typical of basement membrane collagen in the percentage of hydroxyproline and 3-hydroxylysine. 37 Ultrastructural examination of Descemet's membrane in posterior polymorphous dystrophy reveals deposits of multilaminar fibrillar tissue confined to the posterior nonbanded layer and sparing the anterior banded one. Ocular changes in Alport syndrome have been reported to occur in 11 % to 43% of patients. 1-3 The most frequently reported ocular abnormalities have been anterior lenticonus and retinal flecks. 4 - 9 Only four patients with posterior polymorphous dystrophy have previously been reported. 10,1 I However, we found this to be the most common feature in our patients. Changes in the posterior corneal surface of our patients included isolated or small clusters of vesicles and tiny patches of thickening. The lesions appeared bilateral and identical to posterior polymorphous dystrophy by slit-lamp examination and specular microscopy. Bilateral occurrence and familial transmission helped distinguish them from a sporadic, unilateral form of posterior corneal vesicles reported in patients without Alport syndrome. 38 None of our patients had advanced lesions with corneal decompensation or secondary glaucoma. These subtle lesions would have gone undetected without careful slit-lamp examination and specular microscopy. The high incidence of this condition in our patients compared witb the previous reports obviously reflected our intention on this particular examination. Our patients in Group 2 with posterior polymorphous dystrophy who were later found to have typical renal biopsy or hematuria and sensorineural hearing loss had similar corneal findings to those patients in Group 1. A patient with extensive peripheral anterior synechiae with' secondary angle-closure glaucoma and corneal arcus also had sensorineural hearing loss. Significant thinning of the glomerular basement membrane similar to that in benign familial hematuria was noted. Since such thinning of the
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glomerular basement membrane may occur in the early phase of Alport syndrome,3,15,18,39 it is possible that the lesions may progress and become fully manifest later. Another patient with more severe ocular changes including corneal decompensation, ectropion uveae and extensive peripheral anterior synechiae had persistent asymptomatic proteinuria. Renal biopsy was performed but inadequate tissue was obtained. Ifthese two patients were considered to have Alport syndrome, then the number of patients with posterior polymorphous dystrophy and later found to have Alport syndrome would have been higher. In addition, since hematuria may be inconspicuous and sensorineural hearing loss may be absent in some types of Alport syndrome, 14,16,17 the possibility exists that subclinical glomerular basement membrane changes might have been detected if renal biopsy had been performed in patients who did not have clinical manifestations of Alport syndrome. What remains to be reconciled, however, is that the majority of cases of Alport syndrome appear to fit an Xlinked recessive inheritance pattern, while the majority of kindreds with posterior polymorphous dystrophy appear to be autosomal dominant. It is most probable that a group of genetically heterogeneous disorders with similar phenotypic manifestations of varying severity is involved. The COL4A5 gene, which codes for the alpha-5(IV) collagen chain, has been assigned to the region of the X chromosome containing the Alport syndrome locus. 4O A recent analysis of three kindreds in Utah with X-linked Alport syndrome revealed three different mutations in this gene. 41 Alport antigen and the 28K noncollagenous (NCl) peptides of two basement membrane molecules possibly related to type IV collagen, which are missing from the glomerular basement membrane in Alport syndrome, and which have a limited distribution in adult human tissue, are associated with type IV collagen in the earliest forms of Descemet's membrane and lens capsule, structures which are functionally mature at birth.42 It is also possible that both dominant and recessive X-linked forms exist. It is also possible that Thai patients with Alport syndrome have genetically different but phenotypically similar disease or diseases compared with white patients. The fact that four of our Alport syndrome patients and three of the posterior polymorphous dystrophy patients with hematuria were female is suggestive of at least some of our patients having either a dominant form of the disease or a clinically involved carrier state. Mild involvement by posterior polymorphous dystrophy may be accompanied by clinically insignificant basement membrane alterations elsewhere. The patients in Group 1, from the families with Alport syndrome, had a significantly greater proportion of other ocular findings, such as anterior lenticonus and retinal flecks, than did the patients in Group 2. This suggests that mild posterior polymorphous dystrophy unaccompanied by other clinically evident basement membrane-related abnormalities is similarly often unaccompanied by clinically detectable renal abnormalities, and that patients with renal involvement are more likely to have multiple ocular findings when these are sought for. It is also possible that mild forms of posterior
polymorphous dystrophy may be a clue to identification of carriers, analogous to the lens abnormalities of female carriers of Lowe's syndrome. Posterior polymorphous dystrophy is probably also genetically heterogeneous. Our patients in Group 2 had significantly fewer other ocular findings, such as anterior lenticonus and retinal flecks, despite the approximately equal corneal involvement compared with those patients in Group 1. The common occurrence of these two hereditary conditions may represent single genetic disorders or separate diseases controlled by closely linked genes. However, since the thickening and lamellation of Descemet's membrane reported in posterior polymorphous dystrophy appeared to be similar to the glomerular basement membrane or capillary basement membrane of the striae vascularis, it is more likely that the pathogenesis of posterior polymorphous dystrophy may be a part of the widespread basement membrane disorder of Alport syndrome. Corneal endothelium, a neural crest derived cell, has a propensity for fibroblast transformation following diverse stimuli. These transformed cells then produce abnormal collagen and an abnormal basement membrane-like substance, which become incorporated into the original Descemet's membrane, resulting in a thickened multilaminar pattern. 43 Under conditions of stress, the endothelium may secret abnormal posterior collagen layers containing type I collagen. 35 The occurrence of abnormal basement membrane and fibrillar collagen in posterior polymorphous dystrophy was suggested to be a secretory response of stressed endothelium. 44,45 Epithelial transformation or metaplasia of endothelial cells has been proposed to occur with the primary abnormality being in the endothelium and the changes in Descemet's membrane being secondary.46 Since the basic defect in Alport syndrome lies in the noncollagenous portion of the type IV collagen molecule in the basement membrane, the strong association between posterior polymorphous dystrophy and AIport syndrome suggests the basic pathogenesis of posterior polymorphous dystrophy should also lie in the abnormal production of type IV collagen in Descemet's membrane. In addition to corneal endothelial changes, four of our patients had subepithelial opacities, a finding previously undescribed in association with either Alport syndrome or posterior polymorphous dystrophy. The corneal epithelial basement membrane is a typical basement membrane containing laminin,47 bullous pemphigoid antigen,48 and type IV collagen. 49 Although no pathologic examination was available, we believe that the subepithelial lesions occur in the epithelial basement membrane and represent part of the generalized basement membrane disorder in Alport syndrome. Corneal arcus has been reported in association with Alport syndrome. 4,5o However, the incidence is relatively low and appears of questionable significance, being only slightly more common than in the normal population. 9,11 Only one of our patients with Alport syndrome had corneal arcus. The low incidence may reflect racial differences. Our findings show a strong association between posterior polymorphous dystrophy and Alport syndrome. 1213
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Posterior polymorphous dystrophy may be a clinical manifestation of a generalized basement membrane disorder. All patients with Alport syndrome should undergo complete ocular examination including specular microscopy. Patients with posterior polymorphous dystrophy should undergo renal evaluation and hearing testing.
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60. 9. Govan JAA. Ocular manifestations of Alport's syndrome: a hereditary disorder of basement membranes? Br J Ophthalmol 1983; 67:493503. 10. Sabates R, Krachmer JH, Weingeist TA. Ocular findings in Alport's syndrome. Ophthalmologica 1983; 186:204-10. 11 . Thompson SM, Deady JP, Willshaw HE, White RHR. Ocular signs in Alport's syndrome. Eye 1987; 1 :1 46-53. 12. O'Neill WN, Jr, Atkin CL, Bloomer HA. Hereditary nephritis: a re-examination of its clinical and genetic features. Ann Intem Med 1978; 88:176-82. 13. Finegold J, Bois E, Chompret A, et aI. Genetic heterogeneity of Alport's syndrome. Kidney Int 1985; 27:672-7. 14. GrOnfeld J-P, Bois EP, Hinglais N. Progressive and nonprogressive hereditary chronic nephritis. Kidney Int 1973; 4:216-28. 15. Yum M, Bergstein JM. Basement membrane nephropathy: A new classification for Alport's syndrome and asymptomatic hematuria based on ultrastructural findings . Hum Patholl983; 14:996-1003. 16. GrOnfeld J-P. The clinical spectrum of hereditary nephritis. Kidney Int 1985; 27:83-92. 17. Atkin CL, Gregory MC, Border WA. Alport syndrome. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney, 4th ed. Vol. 1. Boston: Little, Brown, 1988; chap 19. 18. Yoshikawa N, White RHR, Cameron AH . Familial hematuria: clinicopathological correlations. Clin Nephrol1982; 17:172-82. 19. Kaufman DB, Mcintosh RM, Smith FG.Jr, Vemier RL. Diffuse familial nephropathy: a clinicopathological study. J Pediatr 1970; 77:37-47. 20. Ferguson AC, Rance CPo Hereditary nephropathy with nerve deafness (Alport's syndrome). Am J Dis Child 1972; 124: 84-8. 21. Hinglais N, GrOnfeld J-P, Bois E. Characteristic ultrastructural lesion of the glomerular basement membrane in progressive hereditary nephritis (Alport's syndrome). Lab Invest 1972; 27:473-87. 22. Gaboardi F, Edefonti A, Imbasciati E, et al. Alport's syndrome (progressive hereditary nephritis) Clin Nephro11974; 2:143-56. 23. Beathard GA, Granholm NA. Development of the characteristic ultrastructure lesion of hereditary nephritis during the course of the disease. Am J Med 1977; 62:751-6.
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40. Myers JC, Jones TA, Pohjolainen ER. et aI. Molecular cloning of a5(IV) collagen and assignment of the gene to the region of the X chromosome containing the Alport syndrome locus. Am J Hum Genet 1990; 46: 1024-33. 41. Barker DF, Hostikka SL, Zhou J. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 1990; 248; 1224-7. 42. Kleppel MM, Michael AF. Expression of novel basement membrane components in the developing human kidney and eye. Am J Anat 1990; 187:165-74. 43. Waring GO, Laibson PR, Rodrigues MM. Clinical and pathologic alterations of Descemet's membrane: with emphasis on endothelial metaplaSia. Surv Ophthalmol1974; 18:325-68. 44. Kenyon KR , Stark WJ, Stone DL. Corneal endothelial degeneration and fibrous proliferation after pars plana vitrectomy. Am J Ophthalmol 1976; 81 :486-90. 45. Waring GO III. Posterior collagenous layer of the cornea. Ultrastructural classification of abnormal collagenous tissue posterior to Descemet's membrane in 30 cases. Arch Ophthalmol1982; 100:122-34.
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POLYMORPHOUS DYSTROPHY AND ALPORT SYNDROME
46. Henriquez AS, Kenyon KR, Dohlman CH, et al. Morphologic characteristics of posterior polymorphous dystrophy. A study of nine corneas and review of the literature. Surv Ophthalmol1984; 29:139-47. 47. Madri JA, Roll FJ, Furthmayr H, Foidart JM. Ultrastructural localization of fibronectin and laminin in the basement membranes of the murine kidney. J Cell Bioi 1980; 86:682-7. 48. Millin JA, Golub BM, Foster CS. Human basement membrane components of keratoconus and normal corneas. Invest Ophthalmol Vis Sci 1986; 27:604-7. 49. Davison PF, Hong BS, Cannon OJ. Quantitative analysis of the collagens in the bovine cornea. Exp Eye Res 1979; 29:97-107. 50. Chavis RM, Groshong T. Corneal arcus in Alport's syndrome. Am J Ophthalmol1973; 75:793-4. 51. Sohar E. Renal disease, inner ear deafness and ocular changes. A new heredofamilial syndrome. Arch Intem Med 1956; 97:627-30.
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