Congenital Hypertrophy Of The Retinal Pigment Epithelium Research Articles

Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis.

A study was carried out to evaluate congenital hypertrophy of the retinal pigment epithelium (CHRPE) as a disease marker in a defined population with familial adenomatous polyposis (FAP). Indirect ophthalmoscopy was performed on 75 individuals from 25 known families with FAP, of whom 32 were known to be affected and 43 were at a 50 per cent prior risk of developing the disease. A further ten individuals from five families with hereditary non-polyposis colorectal cancer (HNPCC) were also tested. CHRPE was seen in 28 of the 32 affected individuals, 27 of whom met the criteria for a positive examination. Three individuals at risk of FAP also had positive examinations. Five individuals from the families with HNPCC also had CHRPE, although none met the criteria for a positive examination. Of four types of CHRPE analysed, one (small pigmented dots) was found to be more frequent in older family members (P = 0.012), suggesting that this type of lesion may proliferate with age. Compliance with ophthalmic screening was 97 per cent in families with FAP. Using a combined set of diagnostic criteria, CHRPE identified affected individuals with a specificity of at least 94 per cent and a sensitivity of 84 per cent. Results argue for a combined screening programme for FAP of DNA analysis, indirect ophthalmoscopy and bowel examination.

Adenocarcinoma arising from congenital hypertrophy of the retinal pigment epithelium

Adenocarcinoma of the retinal pigment epithelium (RPE) is a rare primary malignant intraocular neoplasm. We report a histopathologically confirmed case of adenocarcinoma of the retinal pigment epithelium arising from congenital hypertrophy of the retinal pigment epithelium (CHRPE). The clinical features, surgical management, and histopathological features of a melanotic tumor arising from CHRPE are presented. The tumor was excised by transcleral resection. Histopathological and immunohistochemical study of the tumor showed it to be an adenocarcinoma of the RPE. Adenocarcinoma of the RPE arising from CHRPE is extremely rare. Such a tumor can resemble a choroidal melanoma. In spite of the rarity of this association, periodic monitoring of CHRPE for development of a nodular tumor of the RPE is probably warranted.

Grouped Congenital Hypertrophy of the Retinal Pigment Epithelium Follows Developmental Patterns of Pigmentary Mosaicism

To determine whether sectorial-oriented grouped pigmentations of the retina follow developmental patterns of pigmentary mosaicism. Systematic literature review. Fundus images from patients with grouped congenital hypertrophy of the retinal pigment epithelium (CHRPE). An extensive Internet and library search was performed to obtain articles dealing with grouped CHRPE. Each article was carefully screened for fundus images and inclusion criteria. Fundus images of sufficient quality were scanned, digitized, and matched in size using Adobe Photo Shop to compare the pattern location and extension of the pigmented lesion. These obtained patterns of grouped CHRPE were than mapped and superimposed. Forty-five images were retrieved from 32 articles with grouped CHRPE. The lesions extended from the margin of the optic disc and radiated in sectors to the fundus periphery. The stream of growth did not follow the pattern of the retinal nerve fiber layer, because the clusters of pigmented cells crossed the midline raphe not sparing the macular area. Smaller lesion clusters were mainly located near the optic disc, whereas larger lesions were found in the periphery. The growth pattern of grouped CHRPE is similar to cutaneous sectorial pigmentations. We speculate that pigmentary mosaicisms may be a modified wild-type allele in a somatic cell clone during early embryogenesis following developmental lines analogous to the cutaneous lines of Blaschko. The sectorial pigmentations on the ocular fundus may reflect the stream, outgrowth, and migration of retinal pigment epithelium cells during embryogenesis.

Familial Adenomatous Polyposis

Familial adenomatous polyposis is an inherited, autosomal-dominant syndrome that is caused by a germline mutation of the adenomatous polyposis gene (APC). The syndrome is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum with nearly all patients developing colorectal cancer if prophylactic surgery is not performed. Benign extracolonic manifestations are seen with this syndrome and include upper gastrointestinal polyps, desmoids, epidermoid cysts, osteomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE). Malignant extracolonic manifestations have also been associated with this syndrome. The most common sites of extracolonic cancers that develop in these patients are duodenal, thyroid, brain, and liver. Prophylactic surgery should be performed shortly after the diagnosis of polyposis. Surgical options include total proctocolectomy with end ileostomy, total colectomy with ileorectal anastomosis, or total proctocolectomy with ileopouch anal anastomosis. The literature is reviewed with regard to these different procedures. Genetic testing has evolved over the past decade to play a key role in identifying at-risk individuals and assisting in recommendations made to these patients and their families with regard to screening, surgical treatment, and surveillance.

Value of the congenital hypertrophy of the retinal pigment epithelium in the diagnosis of familial adenomatous polyposis.

Several kinds of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in patients with familial adenomatous polyposis (FAP). This study aims to assess which properties of CHRPE better predict FAP and investigate whether a relationship exists between specific CHRPE characteristics and FAP variants. We examined 286 subjects, Group I--patients with FAP plus individuals "at risk"; n = 173; Group II--controls n = 113. Retinal lesions were classified in five types (A-E) and different characteristics (distribution, number, shape, size, pigmentation and site) were evaluated. The most common lesions in affected subjects were types A-D (83.4%) whilst in the "at risk" and control groups were type E. Greater numbers of lesions and bilateral distribution occurred more frequently among affected subjects than in other participants (p < 0.001). Large lesions with mixed pigmentation were associated with polyposis (p > 0.5). Controls had solitary CHRPE lesions (3.5%) and types C and E lesions (23%). The cumulative sensitivities and specificities of CHRPE were 42 and 97%, respectively. CHRPE was most common among those with classical FAP, but no specific characteristic was associated with any particular FAP variant. Pigmented fundal lesions are highly pleomorphic and represent the variable expression of a common genetic defect of growth regulation. No association was found between CHRPE characteristics and specific FAP variants.

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 μm 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.

Unilateral linear hyperpigmentation of the skin with ipsilateral sectorial hyperpigmentation of the retina

A 32-year-old Caucasian man had a mosaic hyperpigmentation on his left arm, arranged in a pattern following the lines of Blaschko. In addition, a mosaic hyperpigmentation was noted in his left eye, in the form of grouped congenital hypertrophy of the retinal pigment epithelium (CHRPE). Such "bear tracks" are segmentally oriented, well-demarcated, flat, hyperpigmented lesions originating with small dots at the optic disk and expanding towards the periphery. We hypothesize that these mosaic pigmentary lesions involving the skin and the eye on the same side of the body may have originated from an early postzygotic mutation and thus may be etiologically related.

Congenital simple hamartoma of the retinal pigment epithelium: A study of five cases

Purpose To report 5 patients with presumed congenital, simple hamartoma of the retinal pigment epithelium (RPE). Design Retrospective, observational small case series. Participants Five patients with a black macular tumor of the RPE. Main outcome measures Initial tumor features, initial associated fundus features, tumor course on follow-up, and visual acuity outcome. Results In all 5 cases, the tumor involved the macula and the mean distance to the foveola was 0.4 mm (median, 0.2 mm; range, 0.2–1.2 mm). In all cases, the tumor was darkly pigmented, with full-thickness retinal and RPE involvement and minimal protrusion into the vitreous cavity. The mean ultrasonographic tumor thickness was 1.6 mm (median, 1.4 mm; range, 1.1–2.5 mm). Associated features included minimally dilated retinal feeding artery and draining vein (100%), surrounding mild retinal traction (80%), retinal exudation (20%), and vitreous pigmented cells (20%). None of the lesions had associated subretinal fluid, macular edema, or macular hole. Visual acuity was 20/20 in 3 cases and slightly decreased in the other 2 cases because of foveal traction. The findings remained stable in 3 patients who had adequate follow-up. We chose to classify this lesion as congenital simple hamartoma of the RPE to differentiate it from combined hamartoma of the retina and RPE, congenital hypertrophy of the RPE, adenoma or adenocarcinoma of the RPE, and acquired hyperplasia of the RPE, which are different clinical entities. Conclusions Congenital hamartoma of the RPE is typically a black, full-thickness retinal mass, often adjacent to the foveola. Despite such location, the visual acuity was affected minimally.

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.

Electro-oculogram in patients with neurofibromatosis type 1.

The electro-oculogram (EOG) is a powerful test to evaluate the functional status of the retinal pigment epithelium (RPE). Clinically detectable changes of the RPE desribed in neurofibromatosis type 1 (NF-1) patients include combined hamartoma of the retina/RPE and congenital hypertrophy of the RPE. The goal of this study was to determine whether the function of RPE as measured by EOG is also changed in individuals with NF-1. Studies were undertaken in 20 patients with clinically diagnosed NF-1 and compared to 16 normal healthy controls. Standard EOG and flash ERG recordings were performed in accordance with International Society for Clinical Electrophysiology of Vision (ISCEV) standards. In NF-1 patients the Arden indexes of the EOG test were significantly higher primarily due to the lower values of dark troughs. Supernormal EOGs were present in 60% of NF-1 patients in comparison to the control group mean +2 SD. No one patient showed so high abnormalities during flash ERG examination. Dysfunction of the RPE may be characteristic feature of individuals with NF- 1.

ACQUIRED TUMORS ARISING FROM CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM

Background Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is widely recognized to be a flat, stationary condition. Although it can show minimal increase in diameter, it has not been known to spawn nodular tumor that is evident ophthalmoscopically. Objectives To report 5 cases of CHRPE that gave rise to an elevated lesion and to describe the clinical features of these unusual nodules. Methods Retrospective medical record review. Results Of 5 patients with a nodular lesion arising from CHRPE, there were 4 women and 1 man, 4 whites and 1 black. Three patients were followed up for typical CHRPE for longer than 10 years before the tumor developed; 2 patients were recognized to have CHRPE and the elevated tumor concurrently. Visual acuity was decreased in 3 patients, mainly due to cystoid macular edema. The tumor was located between the equator and ora serrata in all 5 patients. There was no predilection for quadrant of the fundus. The flat part of the lesion was black and had visible lacunae in all 5 patients. The CHRPE ranged in basal diameter from 3 × 3 mm to 13 × 11 mm. The size of the elevated lesion ranged from 2 × 2 × 2 mm to 8 × 8 × 4 mm. The nodular component in all cases was supplied and drained by slightly prominent, nontortuous retinal blood vessels. Yellow retinal exudation occurred adjacent to the nodule in all 5 patients and 1 patient developed a secondary retinal detachment. Two tumors that showed progressive enlargement, increasing exudation, and progressive visual loss were treated with iodine 125–labeled plaque brachytherapy, resulting in deceased tumor size but no improvement in the visual acuity. Conclusions Congenital hypertrophy of the retinal pigment epithelium can spawn a nodular growth that slowly enlarges, attains a retinal blood supply, and causes exudative retinopathy and chronic cystoid macular edema. Although no histopathologic evidence is yet available, we believe that the tumor probably represents either an acquired adenoma or a reactive proliferation of the retinal pigment epithelium. The best treatment of these lesions is not yet established.

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

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) exists almost exclusively among familial adenomatous polyposis (FAP) patients with adenomatous polyposis coli (APC) mutations between codon 413 in exon 9 and codon 1387 in exon 15. We investigated the locality of APC mutations in relationship to the occurrence of CHRPE in two Chinese families with FAP. Genomic DNA of available members of two unrelated Chinese FAP families was investigated for sequence alteration in the APC gene by polymerase chain reaction and direct sequencing. All subjects were examined by binocular indirect ophthalmoscopy (BIO) for CHRPE. A mutation in exon 6, Arg216Stop, was identified in one patient with FAP and CHRPE. An Arg283Stop mutation in exon 8 was found in 5 members in another family; 4 of them had FAP and all had small hypopigmented white lesions, probably a new type of CHRPE. We found two mutations, Arg216Stop and Arg283Stop, upstream of codon 413 in FAP patients presenting with CHRPE. Arg283Stop has not previously been reported in such patients. A large-scale study on CHRPE and APC mutations in Chinese FAP patients is required to affirm their inter-relationships and the significance of the hypopigmented white lesions.

APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients.

Familial adenomatous polyposis (FAP) is a familial form of colon cancer caused by mutation of the adenomatous polyposis coli (APC) gene. Although the APC gene has been extensively studied in the Caucasian population, it has not been previously described in the Chinese population. In the present study, we investigated APC mutation and phenotypic spectrum in the Singapore FAP families who are predominantly Chinese. The protein truncation test (PTT) was used to screen the entire APC gene for germline mutations in 28 unrelated families. Fifteen different mutations were identified in 22 families. Eight mutations were 1-11 basepair deletions or insertions; three involved deletions of whole exons and four were nonsense mutations. Nine of the mutations, including two complex rearrangements, are novel. Eight families including three de novo cases have the same (AAAGA) deletion at codon 1309, indicating that like the Western families, codon 1309 is also the mutation 'hot spot' for Singapore FAP families. In contrast, we did not find any mutation in codon 1061, the second hot spot for the Western population. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is consistently associated with the prescribed domain (codons 463 to 1387) and is the only phenotype with no intra-family variation. Other than CHRPE, differences in the type and frequency of extracolonic manifestations within the FAP families suggest the influence of modifying genes and environmental factors.

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.

The relationship between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and germline mutations in the adenomatous polyposis coli (APC) gene

The relationship between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and germline mutations in the adenomatous polyposis coli (APC) gene

Microcephaly with normal intelligence, and chorioretinopathy

An 18-year-old girl had microcephaly without mental or neurological disabilities. She had hypoplastic mandible, long cup-shaped ears, bilateral incurved little fingers, bilateral retinal pigmentation, and scattered areas of depigmentation as well as a history of osteochondroma. However, genetic test for mutation analysis of exon 15 of the APC gene showed negative results. To the best of our knowledge, this is the third case to be reported with microcephaly, normal intelligence, and bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE).

Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.

Germ-line mutations of the adenomatous polyposis (APC) gene, responsible for familial adenomatous polyposis (FAP) were analyzed in 15 patients with FAP-associated papillary thyroid carcinomas: 13 had the mutation between codons 778 and 1309 (exon 15), 1 at codon 593 (exon 14), and 1 at codon 140 (exon 3). Therefore APC gene mutations clustered in the genomic area associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE) (codons 463-1387). Ocular patches were documented in 12 patients. In particular, 4 of the 15 patients, all women with a mean age of 23.5 (range 20-32), were found during the study of 15 consecutive kindreds who had undergone systematic screening for extra-colonic manifestations. Three of them belonged to the same kindred and were asymptomatic. These four patients were also screened for loss of heterozygosity of APC in the thyroid tumoral tissue. No biallelic inactivation of the APC gene was found. In contrast, three of these four patients had activation of the ret-PTC oncogene. In particular, there was activation of the ret-PTC1 isoform, a chimeric gene resulting from fusion of a gene named H4 with the RET gene. On histologic examination, three of the four patients showed Hashimoto-like lymphocytic infiltration. Present data suggest that: (1) the incidence of FAP-associated thyroid cancer probably has been underestimated in the past; (2) intensive screening could detect a larger than expected number of thyroid carcinomas; (3) systematic screening is recommended in patients with ocular patches and genetic mutation in exon 15; (4) Hashimoto-like findings do not exclude carcinoma but are a frequent accompanying finding; (5) despite frequent multicentricity and early lymph node involvement, FAP-associated thyroid tumors seem to have an excellent prognosis, in particular those showing ret-PTC activation.

Rapid RT-PCR-based protein truncation test in the screening for 5′ located mutations of the APC gene

Althoughin vitroprotein synthesis is a rapid method to screen for translational stops in the adenomatous polyposis coli (APC) gene, truncating mutations at the 5′ most end are at risk of being overseen due to their small size. The authors describe a reverse transcriptase-polymerase chain reaction (RT-PCR)-based protein truncation test specifically designed for detecting truncated polypeptide chains of less than 10 kDa. Using this detection system, three novel germline mutations in familial adenomatous polyposis (FAP) patients were identified, i.e. a Gly101Ter non-sense mutation in exon 3, an exon 4 splice acceptor mutation and a 555delC deletion in exon 5. Moreover, a patient manifesting congenital hypertrophy of the retinal pigmented epithelium (CHRPE) was detected with an Arg232Ter mutation in exon 6. This is, to the authors» knowledge, the fourth exception to the rule that FAP patients manifesting CHRPE harbour genetic alterations downstream from APC exon 9. Hence, an alternative hotspot for non-sense mutations associated with CHRPE appears to encompass the codons 215, 216 and 232. Patients reported in this study, exhibited relatively mild clinical symptoms with respect to the age of onset of malignancy (>50 years of age) and the number of polyps (70–100 adenomas). However, manifestation of severe duodenal adenomatosis was independent of the attenuated colorectal FAP phenotype.

Ophthalmic and Genetic Screening in Pedigrees With Familial Adenomatous Polyposis

Purpose: To study the possible association between ophthalmic findings, genetic status, and clinical course of the disease in Austrian pedigrees with familial adenomatous polyposis (FAP). Methods: Thirty-nine members of 16 consecutive FAP families with 20 affected patients and 19 relatives with a 50% a priori risk to develop the disease were examined ophthalmologically. The intestinal status of all persons was established by colonoscopy. Direct or indirect molecular genetic analysis, or both, was possible in eight of the 16 FAP families. Results: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) was discovered in 15 (75%) of the 20 persons affected by familial adenomatous polyposis. Five (25%) of the patients with an established FAP were CHRPE-negative. Four of the 19 at-risk individuals were CHRPE-positive. According to DNA analysis, five of the 19 at-risk relatives had a high risk to develop a manifest disease. The ophthalmoscopic tests were in complete agreement with the molecular risk estimation. Furthermore, the combined results of endoscopy and ophthalmoscopy suggested a relationship between a positive CHRPE status and the severity of FAP. Conclusions: Ophthalmic examinations facilitate predictive diagnosis in FAP patients and first-degree relatives, permitting a noninvasive, highly reliable risk assessment. When present, CHRPE lesions are a reliable clinical marker for FAP in CHRPE-positive families. In CHRPE negative families, negative ophthalmic examinations are of no predictive value. The CHRPE status can add information about the location of the genetic mutation. The combination of an ophthalmic examination with DNA analysis and endoscopy improves the risk assessment of FAP carriers.

Hepatoblastoma and thyroid carcinoma co-segregate with congenital hypertrophy of the retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis

Hepatoblastoma and thyroid carcinoma co-segregate with congenital hypertrophy of the retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis