Lack of Association among Typical Congenital Hypertrophy of the Retinal Pigment Epithelium, Adenomatous Polyposis, and Gardner Syndrome Jerry A. Shields, MD, Carol L. Shields, MD, Pankajkumar G. Shah, MD, Domenic]. Pastore, MD, S. Michael Imperiale, Jr., MD Background: It has been recently documented that multiple bilateral pigmented lesions at the level of the retinal pigment epithelium may be an indicator of patients with familial adenomatous polyposis who are prone to develop intestinal cancer, particularly if there is a positive family history of these intestinal disorders. Although atypical, such lesions have been called congenital hypertrophy of the retinal pigment epithelium (CHRPE). This study was undertaken to determine whether the typical lesions of CHRPE, seen frequently by ophthalmologists, also were indicators of familial adenomatous polyposis. Methods: Review of charts and follow-up studies were performed on all patients diagnosed and coded as having solitary CHRPE or its multifocal variant (congenital grouped pigmentation; bear tracks). Patients and their physicians were contacted by telephone to complete a detailed questionnaire designed to detect signs or symptoms of familial adenomatous polyposis or Gardner syndrome among these patients with CHRPE and their relatives. Results: Of the 132 patients with previously diagnosed CHRPE, there were none with familial adenomatous polyposis, Gardner syndrome, or intestinal cancer, and only one patient had a history of intestinal polyps. Among more than 2000 of their blood relatives, only 20 had intestinal polyposis or colonic cancer (1 %). This is much lower than would be expected from a survey of patients with the typical fundus lesions seen with familial adenomatous polyposis. Conclusion: It appears that solitary CHRPE and congenital grouped pigmentation differ clinically from the multiple pigmented lesions seen with familial adenomatous polyposis and that patients with these conditions, as well as their relatives, are not at a greater risk of developing intestinal cancer. Ophthalmology 1992;99:1709-1713
Originally received: February 28, 1992. Revision accepted: June 5, 1992, From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia. Supported by the Eye Tumor Research Foundation, Inc, Philadelphia, Pennsylvania. Reprint requests to Jerry A. Shields, MD, Director, Ocular Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.
Familial adenomatous polyposis (FAP) is an autosomaldominant condition characterized by multiple intestinal polyps .. ,2 Greater than 100 polyps are considered diagnostic of this condition, even in the absence of a positive family history. Gardner syndrome is a variant of this condition, consisting of F AP associated with a variety of extracolonic findings such as osteomas and a variety of soft tissue tumors. 1,2 If untreated, patients with FAP and
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Gardner syndrome have a statistically high chance (nearly 100%) of developing adenocarcinoma of the colorectal region. 1.2 Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a flat, well-circumscribed, benign lesion of the RPE that has no malignant potential. 3 It is usually solitary, and its major clinical importance is that it must be differentiated from malignant melanoma of the choroid. 3-6 Congenital hypertrophy of the retinal pigment epithelium also can occur in a multifocal variant, which has been called congenital grouped pigmentation or "bear tracks.,,3.? The typical clinical features of solitary CHRPE and congenital grouped pigmentation have been clearly delineated in the literature. 3- 5 Several reports have pointed out that multiple pigmented fundus lesions similar to CHRPE may be an indicator of both FAP and Gardner syndrome, particularly in patients with a positive family history of those conditions. 8- 19 These studies have generally been surveys ofpatients or relatives of patients known to have FAP or Gardner syndrome who have undergone ophthalmic examination in search of the fundus lesions. Because of these reports, we have had frequent inquiries as to whether the typical lesions of CHRPE seen by ophthalmologists are suggestive ofFAP and whether these patients should have extensive gastrointestinal evaluations. Therefore, we designed this study to determine the frequency of FAP or Gardner syndrome among patients who, when first seen by an ophthalmologist, had either solitary CHRPE or congenital grouped pigmentation of the retina.
Figure 2. Solitary congenital hypertrophy of the retinal pigment epithelium shows depigmented lacunae and marginal halo.
We reviewed the records of all patients with the diagnosis of either solitary CHRPE or congenital grouped pigmentation of the retina in the computerized data base of the Ocular Oncology Service of Wills Eye Hospital. All patients in the study with CHRPE were examined by the senior author (JAS). The clinical drawings and fundus
photographs of these patients were studied to substantiate the diagnosis of CHRPE. Our diagnostic criteria for solitary CHRPE included a flat, variably pigmented, welldelineated lesion of the RPE with either a homogeneous appearance (Fig 1) or with a surrounding halo and/or depigmented lacunae in the lesion (Fig 2). 3 Our diagnostic criteria for congenital grouped pigmentation of the retina were identical except that the pigmented plaques were multiple and were characterized by a larger lesion surrounded by several smaller ones, resembling the paw and toes of an animal ("bear tracks") (Fig 3). 3 As part of the routine evaluation of patients seen on the Oncology Service, a thorough medical history and family history had been recorded on each patient's record, and these records were reviewed specifically for a history of intestinal polyps, intestinal cancer, or other lesions compatible with Gardner syndrome. To update and verify the recorded histories, we also attempted to reach each patient by telephone. Following a detailed checklist, we specifically asked each patient
Figure 1. Typical solitary congenital hypertrophy of the retinal pigment epithelium.
Figure 3. Multifocal congenital hypertrophy of the retinal pigment epithelium (congenital grouped pigmentation; bear tracks).
Patients and Methods
Shields et al . CHRPE and Gardner Syndrome whether he or she or any blood relatives (parents, grandparents, siblings, children, uncles, aunts, or others) had a history of prolonged diarrhea, rectal bleeding, or abdominal pain, or tumors of the bowel, pancreas, bladder, thyroid, adrenal glands, bone, teeth, or jaws. Specific inquiry was made as to the presence of fibroma, lipoma, desmoid tumor, Gardner syndrome, familial polyposis of the colon, or a history of pigmented lesions in the ocular fundi. Each patient was asked whether he or she had ever undergone colonoscopy or barium enema and, if so, what the results of such studies were. When patients were uncertain about the results, their personal physicians were contacted for more precise details.
Results There were 132 patients with the diagnosis ofCHRPE in the files of the Oncology Service who were seen between February 1974 and November 1989. Of the 132 patients, 98 were reached by telephone and they responded to all questions on the checklist survey. Information on the other 34 patients was obtained by calling their personal physicians. Of the 132 patients, 118 had solitary CHRPE and 14 had congenital grouped pigmentation. The condition was bilateral in 6 of the 118 solitary types and in 2 of the 14 cases of grouped pigmentation. The patients' ages at the time of diagnosis ranged from 8 months to 69 years (mean, 39 years). Of the 132 patients, there were 58 males and 74 females; 120 patients were white and and 12 were black. The pigmented lesions in the 132 patients showed no predilection for any specific quadrant or location. None of the 132 affected patients had a history of colonic cancer. Only one patient, a 61-year-old man with a typical solitary CHRPE, had a history of a few benign intestinal polyps that had been surgically excised and found to have no histopathologic evidence of malignancy. The patient's gastroenterologist did not believe that he had familial adenomatous polyposis. Fifteen of the 128 patients with CHRPE recalled having a relative with intestinal polyps or possible intestinal cancer. Of these 15, II had I relative, 3 had 2 relatives, and I had 3 relatives with intestinal polyps, for a total of 20 affected individuals among more than 2000 relatives (approximately 1%) about whom inquiry was made. The affected relative was the patient's mother in two cases, father in two cases, a grandparent in seven cases, sibling or child in no cases, and more distant relatives in the remaining nine cases. The patient who had 3 relatives with colonic cancer was an 8-month-old child with bilateral sporadic retinoblastoma who was discovered to have typical congenital grouped pigmentation in both eyes. The child's paternal grandfather and two paternal great uncles had colonic cancer. Results of our evaluation of the parents of the child showed normal fundi, and both parents had been specifically evaluated for intestinal cancer and results were found to be within normal limits. Two additional patients with congenital grouped pigmentation had one grandparent with intestinal polyps. The other II patients with
congenital grouped pigmentation had no relatives with colonic cancer. Of the patients surveyed, barium enema had been done in 19 patients, colonoscopy in 13 patients, and both procedures in 15 patients. These studies had been performed because of mild anemia, rectal bleeding, or chronic diarrhea. Diverticulosis was diagnosed in five cases, ulcerative colitis in one patient, and hemorrhoids in one patient. No cases of colorectal cancer were found in these studies. No patient responded positively to the questions related to the extracolonic tumors seen with Gardner syndrome.
Discussion Familial adenomatous polyposis and Gardner syndrome are variants of the same autosomal-dominant entity characterized by intestinal polyposis and intestinal cancer. The recognized ophthalmic manifestations of these disorders include epidermoid cysts of the eyelids,2.9.19 orbital osteomas,19-21 and multiple pigmented fundus lesions. s- Is The gene responsible for FAP and Gardner syndrome has been recently localized to the 5q21 region of chromosome 5. 22,23 The important observation that multiple pigmented fundus lesions similar to CHRPE could be an indicator of FAP and Gardner syndrome was first reported by Blair and Trempe s in 1980. Since then, several other investigators have confirmed their observations and have expanded on this relationship.9-ls A recent prospective study of offspring of patients with Gardner syndrome showed that 14 of 18 individuals with the pigmented fundus lesions had colorectal adenomatous polyposis, whereas all 16 patients without the fundus lesions remained free of polyps.17 It is now well established that the presence of these characteristic multiple pigmented fundus lesions is an important and highly reliable sign that colorectal cancer will eventually develop in the affected person, particularly if there is a family history of that disease. Both solitary CHRPE and its multifocal variant called congenital grouped pigmentation are well known to ophthalmologists. Traditionally, these lesions have been considered to have little clinical significance. However, the authors of the recent articles on the relationship of pigmented fundus lesions to FAP and Gardner syndrome have frequently used the term congenital hypertrophy of the retinal pigment epithelium to describe these pigmented lesions. s- Is This is perhaps unfortunate, because we have received a number of telephone calls and letters from ophthalmic colleagues inquiring whether the solitary or multifocal variants of CHRPE, which are commonly observed by ophthalmologists, also may be an indicator of FAP or Gardner syndrome. Those inquiries prompted us to undertake the current study. In our review of 118 patients with the solitary form of CHRPE, we found no relationship between the pigmented fundus lesions and FAP or Gardner syndrome. None of the affected patients had signs or symptoms of these intestinal disorders, and only one patient had intestinal polyposis. Inquiries regarding more than 2000 relatives of these patients showed only 20 individuals with a history
Ophthalmology Volume 99, Number 11, November 1992 of colonic polyps or possible cancer. In contrast, in the vast majority of patients with the multiple, bilateral pigmented fundus lesions, FAP or Gardner syndrome will eventually develop, particularly if they have a positive family history of such intestinal disorders. 8- 19 Because the fundus lesions seen with FAP and Gardner syndrome are characteristically multifocal, one might be more concerned that patients with the congenital grouped pigmentation of the retina might have a higher incidence ofFAP or Gardner syndrome. However, our study of 14 affected patients also failed to detect a convincing relationship between this fundus condition and familial intestinal cancer. The only possible exception was a child with bilateral sporadic retinoblastoma and bilateral congenital grouped pigmentation who had three older relatives with colonic cancer. The other 13 patients with congenital grouped pigmentation had no history of familial intestinal cancer. Thus, it appears that congenital grouped pigmentation has no convincing relationship to FAP or Gardner syndrome. However, our number of patients with congenital grouped pigmentation is small, and a survey of a larger group of patients would be desirable. In reviewing our cases of CHRPE seen initially by ophthalmologists and the photographs of cases reported in patients with Gardner syndrome, we have concluded that there are several ophthalmoscopic differences in the two fundus conditions. The typical lesion of CHRPE is solitary and has a well-delineated smooth border that may show scalloping (Fig 1). Particularly in older patients, there may be well-demarcated depigmented lacunae within the lesion and a marginal depigmented halo (Fig 2). The lesion is most often unilateral. Congenital grouped pigmentation usually is unilateral and characteristically occupies a sector or quadrant of the fundus. It typically has a more regular pattern with a larger lesion and multiple adjacent smaller
Figure 4. Pigmented fundus lesions in a patient with Gardner syndrome. Notice the surrounding halo similar to typical congenital hypertrophy of the retinal pigment epithelium. However, the lesions are multiple and have a characteristic tail of irregular white depigmentation on the margins (arrows). (Photograph courtesy of Dr. Norman Blair. Am ] Ophthalmol 1980;90:661-667. Published with permission from the American Journal of Ophthalmology. Copyright by the Ophthalmic Publishing Company.)
Figure 5. Pigmented lesions in a patient with Gardner syndrome. Notice the depigmented lacuna in the larger lesion and the irregular pisciform white area adjacent to the smaller lesion (arrows). (photograph courtesy of Dr. Norman Blair. Am] OphthalmoI1980;90:661-667. Published with permission from the American Journal of Ophthalmology. Copyright by the Ophthalmic Publishing Company.)
lesions resembling "bear tracks" (Fig 3). The lesions tend to become larger toward the more peripheral region of the fundus. In contrast, the individual RPE lesions seen with familial adenomatous polyposis and Gardner syndrome are multifocal and bilateral and often have an irregular border, often with a white tail of depigmentation on one margin (Figs 4 and 5). They appear to more closely resemble what has been described as reactive proliferation (hyperplasia) of the RPE (Fig 6).3 They are distributed more haphazardly in the fundus and assume a more peripheral location. They do not show the organized sectorial arrangement that characterizes congenital grouped pigmentation. At least four lesions in each eye are generally considered necessary to suggest the presence of FAP or Gardner syndrome. Histopathologically, the lesions have been characterized as hamartomatous malformations of the RPE, with features ranging from hypertrophy to hyperplasia, and even a small mushroom-shaped configuration. IS One patient was found to have 44 lesions in the right eye and 26 lesions in the left eye. 18 One limitation of our study is that all patients and their relatives were not subjected to an extensive gastrointestinal evaluation including colonoscopy. However, such evaluations would be highly impractical and probably not indicated based on the lack of intestinal symptoms and negative family histories for gastrointestinal disorders. The incidence of colorectal cancer in the United States is approximately 36 cases per 100,000. 24 Based on our observations, we believe that both solitary CHRPE and its multi focal variant, congenital grouped pigmentation, are isolated ophthalmic entities that are not associated with FAP and Gardner syndrome. Furthermore, they have ophthalmoscopic features that are quite different from the bilateral multifocal lesions that are highly indicative of familial adenomatous polyposis and Gardner syn-
Shields et al . CHRPE and Gardner Syndrome
Figure 6. Nonspecific reactive proliferation of the retinal pigment epithelium, presumably due to prior trauma or inflammation. The patient was a 71-year-old woman with no personal or family findings of Gardner syndrome. This condition can be very similar to the lesions characteristic of Gardner syndrome.
drome. We believe that patients with these isolated ocular conditions should be advised that their chances of developing cancer of the colorectal region are possibly no greater than the general population. Conversely, patients with characteristic bilateral, multiple, haphazardly arranged pigmented fundus lesions and their relatives should be evaluated for these potentially lethal colorectal tumors.
References I. Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951;3:167-76. 2. Jones EL, Cornell WP. Gardner's syndrome: Review of the literature and report on a family. Arch Surg 1966;92:287300. 3. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: WB Saunders, 1992;440-1. 4. Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1975;79: 177-89. 5. Purcell 11 Jr, Shields JA. Hypertrophy with hyperpigmentation of the retinal pigment epithelium. Arch Ophthalmol 1975;93:1122-6. 6. Lloyd WC III, Eagle RC Jr, Shields JA, et al. Congenital hypertrophy of the retinal pigment epithelium. Electron microscopic and morphometric observations. Ophthalmology 1990;97: 1052-60. 7. Shields JA, Tso MOM. Congenital grouped pigmentation of the retina. Histopathologic description and report of a case. Arch Ophthalmol 1975;93: 1153-5.
8. Blair NP, Trempe CL. Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. Am J Ophthalmol 1980;90:661-7. 9. Lewis RA, Crowder WE, Eierman LA, et al. The Gardner syndrome: significance of ocular features. Ophthalmology 1984;91 :916-25. 10. Traboulsi EI, Krush AJ, Gardner EJ, et aI. Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med 1987;316:661-7. II. Lynch HT, Priluck I, Fitzsimmons ML. Congenital hypertrophy of retinal pigment epithelium in non-Gardner's polyposis kindreds [letter]. Lancet 1987;2:333. 12. Diaz L10pis M, Menezo JL. Congenital hypertrophy of retinal pigment epithelium and familial polyposis of the colon [letter]. Am J Ophthalmol 1987;103:235-6. 13. Traboulsi EI, Maumenee IH, Krush AJ, et al. Pigmented ocular fundus lesions in the inherited gastrointestinal polyposis syndromes and in hereditary nonpolyposis colorectal cancer. Ophthalmology 1988;95:964-9. 14. Berk T, Cohen Z, McLeod RS, Parker JA. Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis. Dis Colon Rectum 1988;31 :253-7. 15. Baker RH, Heinemann MH, Miller HH, DeCosse 11. Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis. Am J Med Genet 1988;31: 427-35. 16. Romania A, Zakov ZN, McGannon E, et al. Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology 1989;96:879-84. 17. Traboulsi EI, Maumenee IH, Krush AJ, et al. Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch Ophthalmol 1990;108:525-6. 18. Traboulsi EI, Murphy SF, de la Cruz Z, et al. A clinicopathologic study of the eyes in familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome). Am J Ophthalmol 1990;110:550-61. 19. Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953;5: 13947. 20. Whitson WE, Orcutt JC, Wallcinshaw MD. Orbital osteoma in Gardner's syndrome. Am J Ophthalmol 1986; 10 I :23641. 21. Shields JA. Diagnosis and Management of Orbital Tumors. Philadelphia: WB Saunders, 1989;206-8. 22. Kinzler KW, Nilbert MC, Su L-K, et al. Identification of the F AP locus genes from chromosome 5q21 . Science 1991 ;253:661-5 . 23. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991 ;253:665-9. 24. Cohen AM, Shank B, Friedman MA. Colorectal cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology, 3rd ed. Philadelphia: JB Lippincott, 1989;899.