Congenital Hypertrophy of the Retinal Pigment Epithelium in Familial Adenomatous Polyposis

Congenital Hypertrophy of the Retinal Pigment Epithelium in Familial Adenomatous Polyposis

Congenital Hypertrophy of the Retinal Pigment Epithelium in Familial Adenomatous Polyposis ANTHONY ROMANIA, MD, Z. NICHOLAS ZAKOV, MD, ELLEN McGANNON,...

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Congenital Hypertrophy of the Retinal Pigment Epithelium in Familial Adenomatous Polyposis ANTHONY ROMANIA, MD, Z. NICHOLAS ZAKOV, MD, ELLEN McGANNON, BSW, THOMAS SCHROEDER, MD, FRANCOISE HEYEN, MD, DAVID G. JAGELMAN, MD

Abstract: One hundred fifty-three members of 56 kindreds with familial adenomatous polyposis (FAP) underwent funduscopic examination for congenital hypertrophy of the retinal pigment epithelium (CHRPE). All patients underwent wide-angle fundus photography to document lesions, proctosigmoidoscopy to document polyps, and examination for extracolonic manifestations. Ninety-seven patients were diagnosed as having FAP and 56 patients were offspring of FAP patients and thus at 50% risk of inheriting the disease. In two thirds of the kindreds, CHRPE could be used as a congenital phenotypic marker to predict the presence or development of polyps. In these kindreds, all patients with diagnosed FAP and 39% of the patients at risk had at least four CHRPE lesions. In one third of the kindreds, CHRPE could not be used as a predictive congenital marker, and in these kindreds all patients had zero to three total lesions of CHRPE. The presence of CHRPE did not correlate with any other extracolonic manifestations. In kindreds without any other extracolonic manifestations, CHRPE can still be present and can be used as a predictive congenital phenotypic marker. Ophthalmology 96:879-884, 1989

The observation of "several punctate pigmented areas in the fundi" in a patient with Gardner's syndrome was first documented by McKittrick and associates I in 1935, although its significance was not determined. The association of congenital hypertrophy of the retinal pigment epithelium (CHRPE) with Gardner's syndrome and its clinical significance in identifying patients at risk of developing polyps were first reported by Blair and Trempe2 in 1980. Other articles have followed. 3- 1O Familial adenomatous polyposis (FAP) is an autosomal Originally received: October 9, 1988. Revision accepted: February 7, 1989. From the Departments of Ophthalmology and Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland. Presented at the American Academy of Ophthalmology Annual Meeting, Las Vegas, October 1988. Reprint requests to Anthony Romania, MD, Southwestem Eye Center, 831 Gail Gardner Way, Prescott, AZ 86301.

dominant disease in which multiple adenomatous polyps develop throughout the colon. The malignant potential of these polyps is 100%.11 Familial adenomatous polyposis occurs in approximately 1 of 8000 live births. 12 Recent investigations suggest that the gene abnormality occurs on chromosome 5,13,14 although a subsequent report does not support this finding. 15 Although previously debated, most authorities agree that familial polyposis coli, Gardner's syndrome, and Turcot's syndrome are the same entity and represent variable phenotypic expression of the same genotypic disorder. 16 We will examine this issue in respect to CHRPE, Gardner's syndrome, and extracolonic manifestations, but since multiple adenomatous polyps are the unifying feature found in all patients with these syndromes, we will use the terminology of F AP to include familial polyposis coli, Gardner's syndrome, and Turcot's syndrome. The adenomatous polyps develop over a variable period but usually begin to form around puberty; in the majority of patients, polyps develop before 30 years of age. Polyps 879

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Table 1. Summary of Results

No. (%)

No. of Patients with Polyps

Average Age at Diagnosis of Polyps (yrs)

Significant CHRPE (~4 CHRPE lesions)

34 (65)

61

22.5

Negative fundus examination results

18 (35)

32

32.3

Kindreds

No. of Patients at Risk 13 with ~4 CHRPE lesions 20 with 0-3 CHRPE lesions 18

ECMs in Patients with Polyps

ECM in Kindreds

No. (%)

No. (%)

32 (52) + ECM 29 (48) - ECM

23 (68) + ECM 11 (32) - ECM

11 (34) + ECM 21 (66) - ECM

9 (50) + ECM 9 (50) - ECM

ECMs = extracolonic manifestations; CHRPE = congenital hypertrophy of the retinal pigment epithelium.

have been found in patients as young as 12 months and as old as 80 years of age. II The average interval between the development of polyps and the appearance of symptoms is 10 years. In patients who are symptomatic from the polyps, two thirds already have carcinoma of the colon or rectum. II Many benign and malignant extracolonic manifestations may be present in F AP and usually develop after the formation of polyps. 17 The extracolonic manifestations that may be present before the development of polyps include epidermoid cyst&, osteomas, central nervous system tumors, and hepatoblastomas. II Current recommendations suggest that patients at risk for the disease undergo annual proctosigmoidoscopy commencing at 10 years of age. 17 Once polyps are diagnosed, a prophylactic colectomy is performed. Associated with FAP, CHRPE is the only known congenital phenotypic marker and may be used in predicting the development or presence of adenomatous polyps in individuals with a family history ofFAP.

MATERIALS AND METHODS One hundred fifty-three members of 56 kindreds with F AP were examined. All patients received dilated fundus examinations and underwent wide-angle survey fundus photography to document each CHRPE lesion accurately. A Cannon 60° fundus camera (Canon CF-605, Japan) was used and photography was performed in a leap-frog fashion with extensive overlapping peripheral photographs, resulting in approximately 40 photographs for each patient. All photographs were reviewed by one of us (AR) without knowledge of the patient's diagnosis or relation to other members in this study. Each lesion ofCHRPE documented by photography was evaluated in regard to size, location, and degree of pigmentation. All patients underwent proctoscopy or sigmoidoscopy with biopsy to document the presence of polyps. All patients were evaluated for extracolonic manifestations by personal interviews, physical examinations, and routine skull and Panorex radiographs. Further evaluation 880

was performed as needed when desmoids, central nervous system tumors, or other malignancies were suspected. Relevant information regarding family lineage and medical data on other family members was collected by the Cleveland Clinic Familial Polyposis Registry.

RESULTS Of the 153 patients in this study, 97 patients were diagnosed as having F AP. Fifty-six patients were offspring of F AP patients and thus at 50% risk of inheriting the disease (Table 1). Lesions of CHRPE were classified according to size as A, B, or C lesions. A lesions were less than 0.5 disc diameter (~O) in size, B lesions were between 0.5 and 1.0 DO, and C lesions were greater than 1.0 DO (Fig 1). One thousand seven hundred sixty-two lesions ofCHRPE were documented in 153 patients. Eighty-three percent were A lesions; 11 % were B lesions; and 6% were C lesions. When comparing the 97 patients with F AP and the 56 patients at risk, the distribution in the size of the CHRPE lesions was similar. Eighty-one percent of the lesions of CHRPE were hyperpigmented, whereas 5% of the lesions were mainly hypopigmented. Fourteen percent had roughly an equal degree of hypo- and hyperpigmentation. The majority of A lesions was located peripherally, at the level of or anterior to the vortex veins, whereas the larger lesions were found posterior to the vortex veins. Relatively few lesions were found within the temporal arcades. Thirty-eight percent of the lesions were located in the superior temporal quadrants. Twenty percent of the lesions were located in the superior nasal quadrants, and 25 and 17% were located in inferotemporal and inferonasal quadrants, respectively. The total number of CHRPE lesions in both eyes in patients with diagnosed F AP ranged from 0 to 64 (Fig 2). In 34 (65%) kindreds, all 61 patients with diagnosed FAP had bilateral and at least four CHRPE lesions. In these patients, the range of total CHRPE lesions in both eyes was 4 to 64 (mean ± standard deviation, 23.0 ± 13.3 lesions). These patients had a mean of 18.9 A lesions, 2.6

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CONGENITAL HYPERTROPHY

Fig 1. Congenital hypertrophy of the RPE lesions classified by size. Top left, "A "-size lesions (arrows) less than 0.5 DD in size. Top right, "B"size lesions (arrows) 0.5 to 1.0 DD in size. Bottom, "C"-size lesion greater than 1.0 DD in size.

D

CHRPE NOT SIGNIFICANT AS CONGENITAL MARKER

~ SIGNIFICANT CHRPE Fig 2. Total number of CHRPE lesions in both eyes in patients with a family history ofFAP. The presence of bilateral and at least four CHRPE lesions is a significant congenital phenotypic marker III predicting the presence or development of polyps in two thirds of the kindreds with FAP.

34

36 30 24

24

21

18

12

12 6

O~--UL~U-~~~~~~~~~~~~~~~~~~~~~~-

o

2

3

4

5

6-10 11-15 1620

2125

2630

3135

36- > 41

40

TOTAL NUMBER OF CHRPE LESIONS O.U.

B lesions, and 1.6 C lesions. In 18 (35%) kindreds, all 32 patients with diagnosed F AP had zero to three total CHRPE lesions. Three kindreds were excluded from the above evaluation because only members at risk were examined. One family (#1002) was excluded because it had been considered as two separate families until linked by a questionable family history. In this kindred, two sisters with diagnosed F AP had zero and one CHRPE lesion,

respectively, and a mother and daughter with diagnosed FAP had six and 11 total CHRPE lesions, respectively (Fig 3). Of the 56 patients at risk for inheriting FAP, 18 belonged to the 18 kindreds in which all patients with diagnosed FAP had zero to three total CHRPE lesions. All 18 of these patients also had zero to three total CHRPE lesions. Thirty-three patients belonged to the 34 kindreds 881

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?

Fig 3. Abbreviated lineage of family # 1002. Initially considered as two separate families until a questionable link was found. Interrupted circles indicate patients who received fundus examination; solid figures indicate patients with diagnosed polyps; U) deceased.

I/)

14

ffi

12

~

10

I-

r" :

I II I

Q.

... 8 o 6 II: W

In

::I

4

~ 2

I I

,""'--

--I \

\ \\

\ I 1/

- - - FAP and - - - - FAP and

0-3 CHRPE ~ 4 CHRPE

/ "',,

I

I

I

" °0~~5--~10~~15~~2~0--~25~~30---3L5--4~0--~45---5LO--5L5~60 AGE (yr.) AT TIME OF DIAGNOSIS

Fig 4. Age of patients with F AP at the time of the diagnosis of polyps.

in which all patients with diagnosed F AP had at least four CHRPE lesions. Thirteen (39%) of the 33 patients had at least four CHRPE lesions; the range of CHRPE lesions was 5 to 35 (mean ± standard deviation, 19.3 ± 8.8 lesions). These patients had a mean of 16.0 A lesions, 2.3 B lesions, and 1.0 C lesions. Twenty of the 33 patients at risk had between zero and three total CHRPE lesions. Five patients at risk from three kindreds were excluded from this analysis because no patient with diagnosed F AP from these kindreds received fundus examinations. These five patients had 0, 0, 1, 2, and 17 total CHRPE lesions, respectively. Of the 97 patients with F AP, the average age at the time of diagnosis of adenomatous polyps was 25.8 years (standard deviation, 11.3 years; range, 9-63 years). Of the 63 patients with diagnosed FAP who had at least four CHRPE lesions, the average age at the time of the diagnosis of adenomatous polyps was 22.5 years (standard deviation, 8.4 years; range, 9-45 years). Of the 34 patients with F AP and zero to three CHRPE lesions, the average age at diagnosis of adenomatous polyps was 32.3 years (standard deviation, 13.4 years; range, 12-63 years) (Fig 4). In this study, the average age of all patients at risk for FAP developing was 19.2 years (range, 7-47 years). The average age of the patients at risk who also had at least four CHRPE lesions was l3.9 years (range, 7-32 years). The oldest patient in this group was 32 years of age and had five CHRPE lesions. 882



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Of the 32 patients with diagnosed F AP in the kindreds in which all patients with diagnosed FAP had zero to three total CHRPE lesions, 11 (34%) had extracolonic manifestations. The extracolonic manifestations consisted of seven epidermoid cysts, four osteomas, and three desmoids. Of the 61 patients with diagnosed F AP in the kindreds in which all patients with diagnosed FAP had at least four CHRPE lesions, 32 (52%) had extracolonic manifestations. The extracolonic manifestations consisted of 18 epidermoid cysts, 15 osteomas, 10 desmoids, 2 fibromas, and 2 central nervous system tumors. Of the 18 kindreds in which all patients with diagnosed FAP had zero to three total CHRPE lesions, 9 (50%) had members with extracolonic manifestations and 9 (50%) had no members with extracolonic manifestations. Of the 34 kindreds in which all patients with diagnosed F AP had at least four total CHRPE lesions, 23 (68%) had members with extracolonic manifestations and 11 (32%) had no members with extracolonic manifestations. Of the four patients with diagnosed FAP who belonged to family # 1002 and therefore were excluded from analysis, none had extracolonic manifestations. Of the 18 patients at risk belonging to the kindreds in which all patients with diagnosed FAP had between zero and three CHRPE lesions, none had extracolonic manifestations. Thirty-three patients at risk belonged to the kindreds in which all patients with diagnosed FAP had at least four CHRPE lesions. Thirteen of the 33 patients at risk had at least four CHRPE lesions and four of these patients had extracolonic manifestations, which consisted of four epidermoid cysts. Twenty of 33 patients at risk had between zero and three CHRPE lesions and only one had a single epidermoid cyst. Of the five patients at risk who were excluded from analysis because in their three kindreds only patients at risk were examined, four patients did not have any extracolonic manifestations, and one patient had a single epidermoid cyst. We considered 8 of the 97 cases of diagnosed F AP to be due to mutations. Extensive review of the family lineage disclosed no evidence of FAP. Thus, 8 (14%) of the 56 kindreds examined stemmed from a proband whose disease was due to a mutation. Two (25%) patients did not have any CHRPE lesions and belonged to the kindreds in which all patients with diagnosed FAP had between zero and three CHRPE lesions. Six (75%) patients had at least four CHRPE lesions and belonged to the kindreds in which all patients with diagnosed F AP had at least four CHRPE lesions. These six patients had a mean of 16.8 total CHRPE lesions (range, 4-31 lesions).

DISCUSSION Isolated CHRPE and congenital grouped pigmentation of the retina, known as bear tracks, are found in the normal population. In 1956, Reese and Jones lS reported nine cases of "benign melanoma of the RPE." In 1962, Kurz and Zimmerman l9 provided histopathologic documentation that these lesions were hypertrophy of the RPE. Parsons,20 and later Shields and Tso,zl described similar

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histopathology for bear tracks. Congenital hypertrophy of the RPE is characterized clinically as an isolated, welldelineated, flat, pigmented lesion at the level of the RPE. The lesions range from less than 0.1 to greater than 14 DD in size. 22 The pigmentation may be variable; there may be depigmented lacunae, and a hypopigmented halo may surround the lesion. Histologically, CHRPE is described as a single layer of enlarged RPE cells, with an increased concentration of pigment granules within the cells and degeneration of overlying photoreceptors. 23 In contrast, CHRPE associated with F AP appears as multiple, bilateral lesions, the vast majority of which are less than 0.5 DD in size. The lesions are distributed throughout all four quadrants, with the smaller lesions located peripherally and the larger lesions located posterior to the vortex veins. Currently, there is no histopathologic conformation of these lesions. After reviewing the data from patients with FAP in reference to kindreds, we concluded that the presence of bilateral lesions and at least four CHRPE lesions is a significant congenital phenotypic marker in predicting the presence of polyps. Although other studies have recorded the number of CHRPE lesions in individual patients, to our knowledge, this is the first study to interpret the number of CHRPE lesions with regard to kindreds. In two thirds of the kindreds examined, all patients with diagnosed FAP had bilateral and at least four CHRPE lesions (mean, 23.0 lesions) (95% confidence interval, 19.7-26.4). In one third of the kindreds, all patients with diagnosed FAP had zero to three total CHRPE lesions. Therefore, in one third of the kindreds with FAP, CHRPE could not be used as a congenital phenotypic marker in predicting the presence of polyps. In two thirds of the kindreds with F AP, CHRPE could be used as a congenital phenotypic marker predicting the presence or development of polyps in all patients with at least four total CHRPE lesions. This interpretation held true for all kindreds with the single exception of family # 1002. Two sisters with diagnosed FAP, from one side of this kindred, each had less than three CHRPE lesions, whereas a mother and daughter with diagnosed FAP from the other side of this family each had greater than four CHRPE lesions. This family has questionable lineage and probably should be considered as two separate families, in which case our interpretation would hold true without exception. Further investigation of family # 1002 is in progress. Of the offspring of F AP patients who are at 50% risk of inheriting the disease, 18 belonged to the kindreds in which CHRPE could not be used as a congenital phenotypic marker. All 18 patients had zero to three CHRPE lesions. Thirty-three patients at risk for inheriting the disease belonged to the kindreds in which CHRPE could be used as a congenital phenotypic marker predicting the presence or development of polyps. Thirteen (39%) of these patients had at least four CHRPE lesions (mean, 19.3 lesions) (95% confidence interval, 14.5-24.1). We predict that polyps will eventually develop in these patients. The oldest patient in this group is 32 years of age and has five CHRPE lesions. Of 33 of these patients at risk, 20 (61 %) had zero to

three CHRPE lesions and we predict that polyps will not develop in any of them. The oldest patient in this group is 24 years of age and has three CHRPE lesions. The average age of the patients at the time of the diagnosis of adenomatous polyps was 25.8 years. The average age of the patients with at least four CHRPE lesions at the time of the diagnosis of adenomatous polyps was 22.5 years, whereas the average age of the patients with zero to three CHRPE lesions at the time of the diagnosis of polyps was 32.3 years of age. This difference is statistically significant (P < 0.001) and suggests that polyps may develop at an earlier age in patients in whom CHRPE can be used as a predictive congenital phenotypic marker. The average age of the patients at 50% risk for FAP developing was 19.2 years. The average age of the 13 patients at risk who had at least four CHRPE lesions was 13.9 years (range, 7-32 years). These 13 patients will be followed closely, because we predict that polyps will develop in all of them. Because some debate remains as to whether Gardner's syndrome is a separate entity, all 153 patients in this study were extensively examined for extracolonic manifestations. A previous report suggested that Gardner's syndrome is the only polyposis disorder associated with CHRPE. 8 We found no statistical difference between the F AP patients with at least four CHRPE lesions and the F AP patients with zero to three CHRPE lesions in regard to the presence of extracolonic manifestations (P = 0.10). In the kindreds in which CHRPE could not be used as a predictive congenital marker, 9 (50%) of 18 kindreds had members with extracolonic manifestations. In the kindreds in which CHRPE could be used as a predictive congenital marker, 23 (68%) of34 kindreds had members with extracolonic manifestations. If these kindreds are evaluated in regard to the classic definition of Gardner's syndrome, we found that CHRPE can be used as a predictive congenital marker in only 23 (72%) of 32 kindreds with Gardner's syndrome. In 11 (55%) of 20 kindreds with adenomatous polyps and without any extracolonic manifestations, CHRPE lesions were present in sufficient number (~4) to be used as a congenital phenotypic marker to predict the presence or development of polyps. Congenital hypertrophy ofthe RPE correlated with the presence of polyps in two thirds of the kindred studied, and there was no correlation with any other extraclonic manifestation. Previous studies showed that approximately 20% of the patients with F AP do not have a family history of the disease and are thought to have it as a result of spontaneous genetic mutation. ll In our study, 8 (14%) of 56 kindreds stemmed from a proband whose disease was most likely due to a mutation. These patients did not differ from the other kindreds in regard to the presence ofCHRPE.

CONCLUSION This is the largest study to date examining the significance of CHRPE in patients with familial adenomatous 883

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polyposis. We have used the term FAP to include familial polyposis coli, Gardner's syndrome, and Turcot's syndrome. In two thirds of the kindreds with FAP, CHRPE could be used as a congenital phenotypic marker to predict the presence or development of polyps. In these kindreds, all patients with diagnosed polyps had bilateral and at least four CHRPE lesions (mean, approximately 20 lesions). In these kindreds, we found that 39% of the patients at 50% risk of inheriting the disease had bilateral and at least four CHRPE lesions (mean, approximately 20 lesions). We predict that polyps will develop in these patients. In one third of the kindreds with FAP, CHRPE could not be used as a predictive congenital marker, and all patients in these kindreds had between zero and three CHRPE lesions. In this study, all lesions were documented by fundus photography. In patients with less than four CHRPE lesions, we advocate wide-angle survey fundus photography to document the precise number oflesions. At the current stage of this research, lack of CHRPE should not be interpreted as being free from disease, and patients at risk should continue to undergo annual proctosigmoidoscopic examination. The size of the CHRPE lesions is not significant. We found that the vast majority of lesions was less than one half disc diameter in size. The number ofCHRPE lesions is important; bilateral and at least four lesions was a significant congenital phenotypic marker in predicting the presence or development of polyps. Patients with at least four CHRPE lesions may develop polyps at an earlier age than those with fewer lesions. Therefore, any patient at risk for inheriting the disease should have a fundus examination early in life. Patients with FAP who are thought to have the disease as a result of spontaneous genetic mutation do not differ from other patients with FAP in regard to the presence ofCHRPE. The presence of CHRPE does not appear to correlate with any other extracolonic manifestation. Therefore, CHRPE is not specific for Gardner's syndrome, and Gardner's syndrome does not appear to be a separate entity from either a colorectal or ophthalmologic perspective. In kindreds without any extracolonic manifestations, CHRPE may be present and can be used as a congenital marker predicting the presence or development of polyps.

REFERENCES 1. McKittrick LS, Talbott JH, Mallory TB, et al. Case records of the Massachusetts General Hospital: case 21061 . N Engl J Med 1935; 212: 263-7.

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2. Blair NP, Trempe CL. Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. Am J Ophthalmol 1980; 90: 661-7. 3. Lewis RA, Crowder WE, Eierman LA, et al. The Gardner syndrome: significance of ocular features. Ophthalmology 1984; 91 :916-25. 4. Diaz-Llopis M, Menezo JL. Congenital hypertrophy of the retinal pigment epithelium and familial polyposis of the colon [Letter]. Am J Ophthalmol1987; 103:235-6. 5. Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med 1987; 316:661-7. 6. Diaz-Llopis M, Menezo JL. Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Arch Ophthalmol 1988; 106:412-3. 7. 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. 8. 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. 9. Lyons LA, Lewis RA, Strong LC, et al. A genetic study of Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium. Am J Hum Genet 1988; 42:290-6. 10. Lynch HT, Priluck I, Fitzsimmons ML. Congenital hypertrophy of retinal pigment epithelium in non-Gardner's polyposis kind reds [Letter]. Lancet 1987; 2:333. 11. Gebert HF, Jagelman DG, McGannon E. Familial polyposis coli. Am Fam Physician 1986; 33:127-37. 12. Winawer SJ. Neoplasms of the large and small intestine. In: Wyngaarden JB, Smith LH Jr, eds. Cecil Textbook of Medicine, 17th ed. Vol. 1. Philadelphia: WB Saunders Co, 1985, 763-4. 13. Herrera L, Kakati S, Gibas L, et al. Gardner syndrome in a man with an interstitial deletion of 5q. Am J Med Genet 1986; 25:473-6. 14. Bodmer WF, Bailey CJ, Bodmer J, et aI. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328: 614-6. 15. Endo A, Kasukawa T. Gardner syndrome and interstitial chromosome deletion [Letter]. Am J Med Genet 1987; 28:511-2. 16. Schuchardt WA Jr, Ponsky JL. Familial polyposis and Gardner's syndrome. Surg, Gynecol Obstet 1979; 148:97-103. 17. Jagelman DG. Familial polyposis coli and hereditary cancer of the colon. Curr Ther Gastroeneterol Liver Dis 1986; 2:328-33. 18. Reese AB, Jones IS. Benign melanomas of the retinal pigment epithelium. Am J Ophthalmol1956; 42:207-12. 19. Kurz GH, Zimmerman LE. Vagaries of the retinal pigment epithelium. Int Ophthalmol Clin 1962; 2:441-64. 20. Parsons JH. Some anomalies of pigmentation. In: Dixieme Congres International d'Ophthalmologie: Lucerne, Sept. 13-17, 1904. Lausanne: Georges Bridel 1905; B152. 21. Shields JA, Tso MOM. Congenital grouped pigmentation of the retina: histopathologic description and report of a case. Arch Ophthalmol 1975; 93:1153-5. 22. Purcell JJ Jr, Shields JA. Hypertrophy with hyperpigmentation of the retinal pigment epithelium. Arch Ophthalmol 1975; 93:1122-6. 23. Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1975; 79:177-89.