Key words: congenital hypertrophy of the retinal pigment epithelium, familial ... documented with fundus photography and fluorescein angiography was ...
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International Ophthalmology 21: 205–208, 1998. c 1998 Kluwer Academic Publishers. Printed in the Netherlands.
Ocular findings in familial adenomatous polyposis ¨ Gelisken1 , A. Y¨ucel1 , K. G¨uler2 & A. Zorluoglu3 O. 1 3
Ophthalmology Dept., Uludag University, Faculty of Medicine, Bursa, Turkey; 2 State Hospital, Bursa, Turkey; General Surgery Dept., Uludag University, Faculty of Medicine, Bursa, Turkey
Received 20 February 1997; accepted 2 January 1998
Key words: congenital hypertrophy of the retinal pigment epithelium, familial adenomatous polyposis, peripheric vascular alterations Abstract Background: Retinal pigment epithelium (RPE) lesions are predictive congenital phenotypic markers for familial adenomatous polyposis (FAP). This prospective screening study aims at assessing the incidence and significance of these lesions in FAP patients and their family members. Methods: Sixty-two members from three families including five patients with the diagnosis of FAP have been ophthalmologically surveyed. All RPE lesions were documented with fundus photography and fluorescein angiography was performed in 13 subjects. Sigmoidoscopy and/or radiological examination were performed annually in 9 family members with typical RPE lesions during 4 years to allow early diagnosis of FAP. Results: Typical RPE lesions were present in five FAP patients and 15 family members. Telangiectatic dilatations in the retinal periphery with small dot-like hemorrhages were detected in 6 subjects from 3 families These lesions were particularly evident on fluorescein angiography. Annual colon analysis showed polyps in 3 out of 9 subjects who were positive for RPE lesions. Conclusion: RPE lesions are valuable as a clinical marker in predicting FAP. The co-existing peripheral vascular alterations which have not been reported before, are probably related to FAP. signs, with the aim to predict early diagnosis of the subjects at risk.
Introduction Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease characterized by the appearance of thousands of polyps throughout the large bowel. These polyps show malignant transformation around the second or third decades; and if left surgically untreated, cancer develops resulting in death [1]. The association of congenital hypertrophy of retinal pigment epithelium (CHRPE) with FAP was first reported in 1935 [2]. Studies showed that these CHRPE lesions are important markers for this disease, and can be used to identify carriers before polyps develop [3– 7]. The presence of four or more lesions was found as indicative for ocular trait [6, 7]. In this prospective screening study, fundi of patients with FAP and their family members were examined to assess the incidence and the significance of these RPE This study has been presented as a poster in Jules Gonin Club meeting in Vienna, 1992
Subjects and methods Sixty-two members from 3 unrelated Turkish FAP families (45 from family 1, 8 from family 2, 9 from family 3) including five patients with documented FAP, diagnosed and followed in the gastroenterology and surgery departments of Uludag University Medical Center have been included in this study. During a survey program,all subjects have been examined with binocular indirect ophthalmoscopy. Subjects (N=20) showing fundus lesions had full ophthalmological examination, including colour fundus photography. Fundus fluorescein angiography was performed in 13 subjects. The examined eyes were reported to have typical lesions when at least 4 RPE lesions could be detected in one or both eyes. Nine subjects with typical lesions were
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Figure 1. Pedigree of 5 FAP patients of familiy 1-3 and summary of the findings.
followed during 4 years; and sigmoidoscopy and/or radiological examination were performed annually to determine the presence of polyps.
Results The pedigree of three families of five FAP patients, and the summary of findings are presented in Figure 1. The most common ocular findings were either a round, linear or rectangular shaped large hyperpigmentation and small spot pigmentations. These spot pigmentations were scattered in the mid-peripheral retina whereas the large ones were localized in the posterior pole show-
ing a dark pigmentation surrounded with a depigmented halo usually at the site of first caliber vessels. We found typical fundus lesions in all five FAP patients and fifteen family members which were bilateral except in 3 subjects. Apart from these pigmentary changes, peculiar alterations in the retinal periphery were noted in six subjects. (2 from family 1, aged 28 and 29, 1 from family 2, aged 27, 3 from family 3, aged 10, 14 and 30). These alterations which were bilateral in 5, consisted of discrete telangiectatic dilatations with small dot-like hemorrhages. There were no exudates. Fluorescein angiography disclosed the classical finding of dye blockage at the pigmented site of the
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Figure 2. Peripheral vascular alterations in the temporal periphery; small teleangiectatic dilatations and circumferential configuration of the vascular pattern.
large lesions with surrounding not-leaking hyperfluorescence. The spot pigmentations remained hypofluorescent . The peculiar peripheral alterations were evident on fluorescein angiography, disclosing small telangiectatic dilatations with slight dye leakage, and circumferential configuration of the vascular pattern in these areas (Figure 2). Annual sigmoidoscopy and/or radiological examination revealed multiple polyps in three subjects with typical lesions (in the first, in the third, and in the fourth year). The remaining 6 with typical lesions did not show any polyps during four years follow-up.
this phenotypic marker. lt is of utmost importance that these examinations should be annually repeated since polyps may appear at later ages [11]. The presence of peculiar peripheral vascular alterations in six cases from three families is suggestive for a probable association with FAP. This finding which was more evident on fluorescein angiography has not been reported before. lt is possible that these alterations have been overlooked due to their discrete appearance in the retinal periphery. Only a limited number of subjects underwent fluorescein angiographic examination, and not all angiograms had sufficient data to assess the presence of these signs. lt is therefore not possible to state the real prevalance of this coexistent finding. Electrophysiologic studies showed no detectable functional diffuse abnormality [12] although the histopathologic studies revealed a generalized defect in melanogenesis in RPE of FAP patients [13, 14]. No vascular pathologic change was stated in these studies. We do not know if this finding is a primary or secondary related expression of the genetic disturbance of FAP, although it may be just a coincidental sign. Other conditions like hypertension and arteriosclerosis associated with similar changes should also be considered in differential diagnosis.Further studies are necessary to enlighten the significance, if it exists, of these peripheral vascular alterations in FAP.
References 1.
2.
Discussion All the FAP patients and one- fourth of their family members in our study showed typical fundus lesions. The differing percentages of retinal pigmentation in FAP patients and in their kindred [4–8] may be due to the methods of ophthalmoscopic examination as well as sampling errors in a comparatively small group of subjects or the different positions of adenomatous polyposis coli gene mutations on the long arm of chromosome 5 [9]. Gene linkage analysis providing a definite DNA diagnosis may serve to determine the exact sensitivity and specifity of these RPE lesions in FAP [9, 10]. The detection of polyps in sigmoidoscopy and/or radiological examination in three subjects showing typical lesions once more clenches the predictive value of
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Gardner EI, Richard RC. Multiple cutaneous and subcutaneous lesions occuring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953; 5: 139. Mc Kittrick LS, Talbott JH, Mallory TB et al. Case records of the Massachusetts General Hospital: Case 21061. N Engl J Med 1935; 212: 213–217. Blair NP, Trempe CL. Hypertrophy of the retinal pigment epithelium associated with Gardner’s syndrome. Am J Ophthalmol: 1980; 90: 661–667. Lewis RA, Crowder WE, Elerman LA, Nussbaum RI, Ferrel RE. The Gardner syndrome: Significance of ocular features. Ophthalmology 1984; 91: 916–925. Llopis MD, Menezo JL. Congenital Hypertrophy of the retinal pigment epithelium and Familial Polyposis of the colon. Am J Ophthalmol 1987; 103: 235. Traboulsi EI, Krush AJ, Gardner EI et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner’s syndrome. N Engl J Med 1987; 316: 661–667 Romania A, Zakov ZN, Mc Gannon E et al. Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology 1989; 96: 879–884. Baba S, Tsuchiya M, Watanabe J, Machida H. Importance of retinal pigmentation as a subclinical marker in Familial Adenomatous Polyposis. Dis Colon Rectum 1990; 33: 660– 665.
inte1090.tex; 27/05/1998; 9:06; v.7; p.3
208 9. Olschwang S, Tiret A, Laurent-Puing P, Muleris M, Parc R, Thomas G. Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell 1993; 75: 959–968. 10. Traboulsi EI, Apostolides J, Giardiello FM, Krush AJ, Booker SV, Hamilton SR, Hussels IEM. Pigmented ocular fundus lesions and APC mutations in familial adenomatous polyposis. Ophthalmic Genetics 1996; 17: 167–174. 11. Romania A, Zakov N, Church JM, Jagelmon DG. Retinal pigment epithelium lesions as a biomarker of disease in patients with Familial Adrenomatous Polyposis; A follow-up report. Ophthalmology 1992; 99: 911–913. 12. Santos A, Morales L, Quintela EV, Jimenes-Sierra JM, Villalobos JJ, Panduro A. Congenital hypertrophy of the retinal pigment epithelium associated with Familial Adenomatous Polyposis. Retina 1994; 14: 6–9.
13.
14.
Traboulsi EI, Murphy SF, de la Cruz ZC, Maumenee I, Green R. A clinicopathologic study of the eyes in Familial Adenomotous Polyposis with extracolonic manifestations (Gardner Syndrome). Am J Ophthalmol 1990; 110: 550–561. Kassner L, Traboulsi EI, de la Cruz Z, Green WC. A histopathologic study of the pigmented fundus lesions in Familial Adenomatous Polyposis. Retina 1992; 12: 35–42.
¨ Gelisken, Uludag Univ., Faculty Address for correspondence: O. of Medicine, Ophthalmology Department, 16059 G¨or¨ukle, Bursa, Turkey
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