Congenital hypertrophy of the retinal pigment epithelium and APC mutations in Chinese with familial adenomatous polyposis.

Mutations in the adenomatous polyposis coli gene (APC) often cause both congenital hypertrophy of the retinal pigment epithelium (CHRPE) and familial adenomatous polyposis (FAP). To investigate the relationship between APC mutations, CHRPE and FAP, all FAP patients at the Prince of Wales Hospital, Hong Kong, were asked to participate in a study. Ten Chinese patients from 6 kindreds and their family members volunteered, along with 12 healthy control subjects selected among hospital visitors and staff. All were examined for dilated fundus by indirect ophthalmoscopy. Mutations in APC coding exons were detected by sequencing. In one FAP patient, a novel A insertion at codon 1023 was detected. Three previously reported mutations were detected in 6 FAP patients: a deletion of ACAAA at codon 1061, and 2 truncating point substitutions at codons 216 and 283. In 3 FAP patients, no APC mutation was found, suggesting that mutations in APC coding regions are not the sole cause of FAP or CHRPE. A total of 64 CHRPE lesions were found in FAP patients and some relatives with and without APC mutations. Contrary to most reports, APC mutations before exon 9 did cause CHRPE lesions, albeit relatively few.     

家族性腺瘤性息肉病患者中先天性视网膜色素上皮肥厚的FFA研究

目的:研究家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)患者中双眼多灶性先天性视网膜色素上皮肥厚(congenital hypertrophy of the retinal pigment epithelium,CHRPE)患者的眼底荧光素血管造影(fundus fluoresceinangiography,FFA)的特点。方法:我们对22例有65处CHRPE病灶的FAP患者前瞻性进行FFA和眼底检查。结果:发现86%CHRPE病损面积>0.5个视盘直径,74%的CHRPE病变接近视网膜血管,视网膜血管有以下变化:46%CHRPE病变中出现毛细血管无灌注区,8%穿过病灶的视网膜血管部分阻塞,6%出现脉络膜视网膜吻合支,3%病变有毛细血管微血管瘤,5%可观察到脉络膜毛细血管,20%的脉络膜毛细血管出现在脱色素边缘晕环中。约10%的CHRPE病变眼底检查未发现,只能通过FFA观测到。结论:虽然通过眼底检查能诊断CHRPE,但有些病变仍需通过FFA确诊,其对此病变仍是非常有用的诊断方法。     

Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis, and Gardner syndrome.

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. CONCLUSIONS: 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.     

Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis

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.     

Diagnostic value of fundus examination in familial adenomatous polyposis

BACKGROUND—Multiple, bilateral lesions of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in patients suffering from familial adenomatous polyposis (FAP) since 1980. This study aimed to determine a reliable diagnostic criterion, based on the size and number of retinal CHRPE lesions, allowing the screening of patient carriers of the gene responsible for FAP.
METHODS—32 control subjects and 144 patients belonging to 85 FAP families were studied, divided into 124 carriers of the genetic alteration and 20 non-carriers.
RESULTS—In carriers of the deleted gene, multiple, bilateral retinal lesions were consistently observed. Lesion situation, size, shape, and degree of pigmentation were variable however. A positive criterion for FAP was defined as the presence of at least four lesions whatever their size, or at least two lesions one of which is large. This criterion showed a high sensitivity (0.68) and a maximal specificity (1). Within each family, the retinal phenotypic expression was homogeneous. CHRPE lesions were observed in two thirds of the FAP families and absent from the remaining third.
CONCLUSION—By using this new positive diagnostic criterion, fundus examination allows early detection of those children carrying the gene responsible for FAP in families positive at ocular examination.

     

Fluorescein Angiographic Features of the Congenital Hypertrophy of the Retinal Pigment Epithelium in the Familial Adenomatous Polyposis

Purpose To asses the prevalence of fluorescein angiographic features in bilateral and multifocal Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) in patients with a diagnosis of familial adenomatous polyposis. Methods We performed prospective angiographic and clinical examination of 49 CHPRE lesions in 15 patients. Results About 77.5% of CHRPE lesions were close to retinal vessels. The retinal vascular changes observed overlying and surrounding the CHRPE were: capillary non-perfusion with an area greater than 0.5 disc diameters (41%), capillary microaneurysms (4%), chorioretinal anastomoses (6.2%), attenuation of retinal vessels (4%), choriocapillary vessels inside the lacunae (6.2%) and in the depigmented marginal halo (18.4%). Depigmented streaks in contact with one or both edges of the CHRPE were observed in 79.6% of the lesions. About 9.6% of the lesions were not seen on ophthalmoscopy and could only be detected by angiography. Conclusions Even though the diagnosis of CHRPE is clinical, fluorescein angiography may be useful in confirming the diagnosis, as well as detecting additional lesions not seen by means of ophthalmoscopic examination.     

In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: A systematic review

In classic familial adenomatous polyposis (FAP) adenomas become malignant. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a retinal pigmented lesion and is the earliest and most common potential extraintestinal manifestation of FAP. This review aims to summarize and analyse all of the published data on CHRPE in patients with classic FAP and then ascertain whether these patients should undergo a relatively cheap and non‐invasive dilated fundus examination to screen for CHRPE. Adhering to Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines our database search identified 102 relevant articles of which 13 were selected for further analysis. The percentage of FAP patients with CHRPE was found to be 80.00%, whereas the percentage of at‐risk patients with CHRPE was 31.12%. Despite various statistically significant findings, CHRPE alone cannot be used as a surrogate for diagnosing FAP in those with a positive family history. The authors advocate a combined approach of eye examinations, colonoscopy and genetic testing.     

先天性视网膜色素上皮肥大对家族性腺瘤性息肉病的筛查

对8例家族性腺瘤性息肉病(FAP)5名I级高危亲属和100例对照组作眼底色素病变研究。结果表明：先天性视网膜色素上皮肥大对FAP有筛检价值，若色素斑有晕圈、数量≥4颗、病变为双眼且位于后极部，则FAP的可能性很大。 （中华眼底病杂志，1995，11：1-3）     

Congenital hypertrophy of retinal pigment epithelium: a marker in familial adenomatous polyposis]

PURPOSE: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder with marked propensity for malignant transformation. The potential for congenital hypertrophy of retinal pigment epithelium (CHRPE) as a phenotypic marker for this disease is recognized. MATERIAL AND METHODS: We report our investigations in 11 families with familial adenomatous polyposis. CHRPE characteristics were described and the relations between genotype and phenotype and those between CHRPE and severity of FAP are discussed. DISCUSSION: All members of the family should undergo retinal examination at the earliest age possible. The results give an indication of the severity of the intestinal disease and allow an approximate localization of the mutation in the coding sequence, leading to a more rapid genetic analysis.     

Retinal changes in patients with familial adenomatous polyposis

PURPOSE: The aim of study was to evaluate retinal changes in patients diagnosed with familial adenomatous polyposis (FAP) and in patients with family history of FAP. MATERIAL AND METHODS: The study was conducted on 51 patients diagnosed with FAP and 35 subjects with family history of FAP. RESULTS: In 44 patients diagnosed with FAP (86.2%), typical pigmentation of fundus lesions were observed, in 1 patient atypical fundus changes were evident. However, in the group of patients with family history of FAP, the presence of typical fundus lesions was observed in 9 patients (25.7%). In the period of at least 6 month observation, no changes in fundus lesions were present in both groups. CONCLUSIONS: The occurrence of retinal changes typical for FAP, especially in patients with family history of the disease, should imply the higher risk of FAP.     

Ocular findings in familial adenomatous polyposis

Background: Retinal pigment epithelium (RPE)lesions are predictive congenital phenotypic markersfor familial adenomatous polyposis (FAP). Thisprospective screening study aims at assessing theincidence and significance of these lesions in FAPpatients and their family members.Methods: Sixty-two members from three familiesincluding five patients with the diagnosis of FAP havebeen ophthalmologically surveyed. All RPE lesions weredocumented with fundus photography and fluoresceinangiography was performed in 13 subjects.Sigmoidoscopy and/or radiological examination wereperformed annually in 9 family members with typicalRPE lesions during 4 years to allow early diagnosis ofFAP.Results: Typical RPE lesions were present infive FAP patients and 15 family members.Telangiectatic dilatations in the retinal peripherywith small dot-like hemorrhages were detected in 6subjects from 3 families These lesions wereparticularly evident on fluorescein angiography.Annual colon analysis showed polyps in 3 out of 9subjects who were positive for RPE lesions.Conclusion: RPE lesions are valuable as aclinical marker in predicting FAP. The co-existingperipheral vascular alterations which have not beenreported before, are probably related to FAP.     

Congenital hypertrophy of the retinal pigment epithelium: prevalence and ocular features in the optometric population

AIM: In this study we aimed to determine the prevalence, features and associations of congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the optometric population. METHOD: The Optomap imaging system uses an ultra-wide-field scanning-laser ophthalmoscope to image the fundus at the choroidal and retinal levels, non-mydriatically, capturing an image of up to 200 degrees . Optomap images of 1745 consecutive patients obtained at a recent optometric examination were examined retrospectively. RESULTS: The prevalence of CHRPE was found to be 1.20%. CHRPE was found to be most commonly located temporally to the optic disc within the peripheral fundus. All lesions found were of previously documented shapes and sizes, and divided approximately evenly between those with and without depigmented haloes and lacunae; all were monocular. The progression of the condition could not be accurately described without follow-up. The evidence found appears to support the theory that increasing atrophy is related to flat, overall enlargement of the lesion. No symptoms or associations were found, and no abnormalities were found in the fellow eye. No evidence was found to suggest a relationship between true CHRPE and familial adenomatous polyposis coli, Gardner's or Turcot's syndromes.     

A Unique Presentation of Grouped Congenital Hypertrophy of the Retinal Pigment Epithelium

Purpose: To describe a unique presentation of grouped congenital hypertrophy of the retinal pigment epithelium (CHRPE) and to review the clinical features which differentiate grouped CHRPE from the pigmented ocular fundus lesions (POFLs) associated with familial cancer syndromes.

Methods: Report of a case.

Results: A 28-year-old asymptomatic, Caucasian female demonstrated multiple small, flat, dark brown to black clusters of retinal pigment epithelium (RPE) hypertrophy on dilated fundus examination of both eyes. These plaque-like lesions were circumferential along the peripheral fundus and were associated with smaller foci of pigmentation oriented towards the posterior pole. The appearance was consistent with grouped pigmented CHRPE. A unique, co-existing feature was the presence of non-pigmented, punctate lesions located within the maculae suggestive of grouped non-pigmented CHRPE. Fluorescein angiography demonstrated persistent hypofluorescence correlating with the clinically observed areas of hyperpigmentation and hypopigmentation.

Conclusions: The combination of both pigmented and non-pigmented lesions occurring in the same individual with grouped CHRPE is rare. It is important to distinguish grouped CHRPE lesions from the POFLs associated with familial cancer syndromes.     

Fundus lesions of adenomatous polyposis.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is the most frequent extraintestinal manifestation of familial adenomatous polyposis. Present in 70% of families with familial adenomatous polyposis, CHRPE is a highly reliable and early marker of the disease. Studies over the past 5 years have addressed the histologic characteristics of the pigmented fundus lesions, the definition of universal positive fundus criteria, and mostly the genotype-phenotype correlation. Indeed, the position of the mutation site of the APC (adenomatous polyposis coli) gene on chromosome 5 influences the retinal expressivity because CHRPE is present only if the mutation is located between exons 9 and 15. In CHRPE-positive families, fundus examination is simple, noninvasive, reproducible, inexpensive, and allows early detection of the mutant gene carriers. Knowing the CHRPE status of patients in a family with familial adenomatous polyposis helps to identify constitutional APC mutations. The combination of genetic analysis and fundus examination offers a 100% diagnostic predictability.     

Topographical distribution of typical unifocal congenital hypertrophy of retinal pigment epithelium

Purpose To describe the topographical distribution of typical congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions in the ocular fundi. Methods Retrospective review of the clinical records of 52 patients with typical unifocal CHRPE. Results The 52 CHRPE lesions ranged from 2.5 mm to 11.5 mm in maximal basal diameter (mean=6.6 mm, SD=2.6 mm). The central point of the lesion was in the peripheral fundus in 44 eyes and in the intermediate fundus in eight eyes. The footprint of the lesion involved the peripheral fundus only in 25 eyes, both the intermediate and peripheral fundus in 22 eyes, and the intermediate fundus only in five eyes. The central point of the lesion was located in the temporal quadrant in 24 eyes, the inferior quadrant in 12 eyes, the nasal quadrant in nine eyes, and the superior quadrant in seven eyes. No lesion in this series involved the posterior fundus. Conclusions The most common fundus location for typical unifocal CHRPE in this series was the peripheral fundus temporally. Although posterior fundus location of CHRPE has been reported occasionally, our study suggests that such a location is very uncommon.     

Pigmented ocular fundus lesions in the inherited gastrointestinal polyposis syndromes and in hereditary nonpolyposis colorectal cancer

The authors studied pigmented ocular fundus lesions in three different forms of hereditary gastrointestinal polyposis and in hereditary nonpolyposis colorectal cancer. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) was present in at least one member of 23 families with Gardner's syndrome. By contrast, CHRPE was not found in three families with familial polyposis coli, four families with hereditary nonpolyposis colorectal cancer, and three families with Peutz-Jeghers syndrome. Pigmented ocular fundus lesions of the CHRPE-type appear to be specific to Gardner's syndrome among inherited diseases with gastrointestinal polyposis.     

Congenital hypertrophy of the retinal pigment epithelium and familial adenomatous polyposis

Congenital hypertrophy of the retinal pigment epithelium is a common eye sign in patients with familial adenomatous polyposis (FAP). FAP has autosomal dominant inheritance with virtually 100% risk of colonic malignancy in adult life. There may be other associated systemic abnormalities including extracolonic malignancy. Early detection of disease is desirable, but has in the past been reliant on regular endoscopic examination. The nature of congenital hypertrophy of the retinal pigment epithelium and its usefulness as a predictive marker of the disease are discussed     

Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features and frequency of enlargement in 330 patients

OBJECTIVE: To describe the clinical features of solitary congenital hypertrophy of the retinal pigment epithelium (CHRPE) and to determine the frequency of enlargement of this lesion DESIGN: Retrospective, observational, noncomparative case series. PARTICIPANTS: Three hundred thirty consecutive patients with solitary CHRPE. MAIN OUTCOME MEASURES: The 3 main outcome measures included flat lesion enlargement, intralesional lacunae enlargement, and development of an elevated nodule within the lesion. The clinical features at the time of presentation were analyzed for their impact on the main outcomes using a series of Cox proportional hazards regressions. RESULTS: The most common referring diagnosis included choroidal nevus (26%), choroidal melanoma (15%), CHRPE (9%), and unspecified lesion (48%). The median age at diagnosis was 45 years (range, 1-80 years), and there were no patients with familial adenomatous polyposis or related colon cancer, although a history of cancer was noted in 8% of patients, most commonly breast cancer (3%). The lesion most frequently was located inferotemporally (31%) and at the equatorial region (45%). Rarely, it was located in the macula (1%) or peripapillary region (1%). The median largest basal diameter was 4.5 mm, and the lesion was flat in all cases except in 5 (1.5%), in which there was an intralesional lesion nodule. The lesion was pigmented in 88% of cases and nonpigmented in 12%. Lacunae were noted in 43% of the pigmented CHRPE, and the lacunae showed gradual enlargement in 32%. Factors related to lacunae enlargement included number and relative size of lacunae. Flat enlargement of the lesion was documented in 46% of patients with comparative photographic follow-up and in 83% of those followed up for more than 3 years. The median rate of enlargement was 10 micro m per month. The most important factor associated with flat lesion enlargement was relative size of the lacunae within CHRPE. There were no cases of CHRPE in which a nodule developed while the patient was being followed up. Of the 5 lesions that had a nodule, progressive enlargement of the nodule was found in 3. CONCLUSIONS: Congenital hypertrophy of the retinal pigment epithelium generally has been regarded as a benign, stable lesion, but subtle, flat enlargement was noted in most patients (83%) followed up for 3 or more years using meticulous photographic comparison. Flat enlargement of the lesion appeared to be related to percentage of the mass occupied by lacunae.     

Autofluorescence of congenital hypertrophy of the retinal pigment epithelium

PURPOSE: To describe the autofluorescence features of CHRPE. DESIGN: Noncomparative case series. PARTICIPANTS: Thirteen consecutive eyes with CHRPE. METHODS:: CHRPE was studied with fundus photography and autofluorescence. Autofluorescence was judged relative to the surrounding retinal pigment epithelium. MAIN OUTCOME MEASURE: Autofluorescence features of CHRPE. RESULTS: The mean CHRPE basal dimension was 4.75 mm and the tumor location was between the macular and equator (n = 10) or equator and ora serrata (n = 3). Overall, CHRPE show hypoautofluorescence in every case and was classified as trace (n = 1), moderate (n = 6), or marked (n = 6) hypoautofluorescence. Compared to the central portion of CHRPE, the margin showed isoautofluorescence (n = 8) or trace hyperautofluorescence (n = 5). There were eight lesions with lacunae and this feature generally showed trace to moderate hyperautofluorescence (n = 6). A nonpigmented halo was present surrounding six lesions, generally showing trace hyperautofluorescence (n = 3). A pigmented halo was present surrounding eight lesions, usually showing isoautofluorescence (n = 6). CONCLUSIONS: CHRPE shows striking hypoautofluorescence and this correlates with known histopathologic evidence of lack of lipofuscin in the retinal pigment epithelium of CHRPE. The lacunae showed general mild hyperautofluorescence that might correlate with scleral autofluorescence.     

Pigmented ocular fundus lesions and APC mutations in familial adenomatous polyposis

Background Familial adenomatous polyposis (FAP) results from a germline mutation in the adenomatous polypsis coli (APC) gene on chromosome 5q21. The extracolonic manifestations of FAP include pigmented ocular fundus lesions (POFLS), cutaneous cysts, osteomas, occult radio-opaque jaw lesions, odontomas, desmoids, and extracolonic cancers. POFLS are present at birth in about 80% of patients with FAP and are excellent clinical congenital markers for the disease. We studied the distribution of POFLS by number and APC mutation in families of the Johns Hopkins Polyposis Registry. Materials and methods Of the 51 families with FAP, 42 (82%) had an identifiable APC mutation. We correlated the presence/absence and distribution by number of POFLS with the type and location of the mutation in the APC gene in 21 families where an ocular examination had been performed in at least one affected member, and where a systematic search for mutations in the APC gene had been undertaken. Families were considered POFL-positive if the average number of lesions per patient was three or more, or if at least one family member had three or more lesions. Results Fifteen of the 21 families (71.4%) were POFL-positive. Mutations of the APC gene were detected in 15 of the 21 families. Of these, 12 (80%) were POFL-positive. Families with mutations at codons 215 (exon 5) and 302 (exon 8) were POFL-negative. Families with mutations at codons 541, 625, 1055, 1059, 1061, 1230, 1309, 1465, and 1546 (exons 12-15) were POFL-positive. One patient with a mutation at codon 2621 (exon 15) had no POFLS. Conclusions Mutations in exons 1-8 and the distal portion of exon 15 of the APC gene are associated with a POFL-negative phenotype, while those in exons 10 to the proximal portion of exon 15 are generally associated with a POFL-positive phenotype.