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.     

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.     

Retinal pigment epithelium lesions as a biomarker of disease in patients with familial adenomatous polyposis. A follow-up report.

BACKGROUND: The sensitivity of retinal pigment epithelium (RPE) lesions as a predictive congenital marker for the development of familial adenomatous polyposis (FAP) is evaluated. METHODS: In a prospective study, 34 patients at 50% risk of inheriting FAP were examined. Based on the presence or absence of four or more RPE lesions, patients were categorized as those who had inherited or those who lacked the FAP genes. All patients received dilated fundus examinations with binocular indirect ophthalmoscopy and all RPE lesions were documented with fundus photography. All patients underwent annual sigmoidoscopy to determine the presence or absence of polyps. RESULTS: A 3-year follow-up analysis showed that 8 of 14 patients who were positive for RPE lesions later developed polyps. Of the 20 patients considered negative for FAP based on normal fundus examination, none has developed polyps. CONCLUSION: The authors urge all patient at risk of inheriting FAP to undergo dilated fundus examination with binocular indirect ophthalmoscopy and wide-angle fundus photography at the earliest age possible. All patients with 4 or more RPE lesions should undergo annual sigmoidoscopic examinations beginning before 10 years of age.     

The importance of congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis

We describe a family with familial adenomatous polyposis (FAP) and congenital hypertrophy of the retinal pigment epithelium (RPE). Three of five members with FAP showed flat, well-demarcated, round to oval pigmented patches of congenital hypertrophy of the RPE. We stress the importance of congenital hypertrophy of the RPE as a clinical marker in identifying patients with FAP since they are at risk for cancer.     

Pattern dystrophies of the retinal pigment epithelium

Three members of a family in one generation were affected by a pattern dystrophy of the retinal pigment epithelium. The patients present typical hyperpigmented macular RPE lesions in a butterfly-shaped to (macro-)reticular pattern, and were all asymptomatic. Examination of 26 family members in 3 generations suggests autosomal recessive inheritance. The family showed some cases of congenital deutanomaly, and a female subject presented both disorders.     

Value of the Congenital Hypertrophy of the Retinal Pigment Epithelium in the Diagnosis of Familial Adenomatous Polyposis

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

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.

     

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.     

Retinal pigment epithelial tears after pegaptanib injection for exudative age-related macular degeneration

PURPOSE: To report two cases of retinal pigment epithelium (RPE) tears following intravitreal pegaptanib injections for occult choroidal neovascularization. DESIGN: Noncomparative case series. METHODS: The charts of two patients with pigment epithelial tears after receiving intravitreal pegaptanib were reviewed. Approval from the institutional review board and informed consent were obtained before chart review. Fundus photos, intravenous fluorescein angiograms, and optical coherence tomography (OCT) were obtained before and after therapy confirmed the diagnosis. RESULTS: Two patients had turbid pigment epithelial detachments (PEDs) and occult choroidal neovascular membranes (CNVMs) treated with intravitreal pegaptanib. Both patients developed RPE tears weeks following one intravitreal pegaptanib injection. CONCLUSIONS: This report describes the development of RPE tears after intravitreal pegaptanib injection. Caution should be taken in cases of turbid pigment epithelial detachments in the monocular patient when treatment with intravitreal pegaptanib is entertained. Future studies should be performed to evaluate which subtypes of lesions are most susceptible to this devastating visual complication.     

Focal retinal pigment epithelial dysplasia associated with fundus flavimaculatus.

BACKGROUND: One or more focal dysplastic lesions of the retinal pigment epithelium (RPE) occurred in 15 eyes of 10 patients with fundus flavimaculatus. METHODS: Review of patient records including an attempt to obtain follow-up information concerning a history of previous ocular trauma. RESULTS: Mild antecedent ocular trauma occurred to the eye with a dysplastic lesion in two patients. Dysplastic lesions were most frequently solitary and located temporal to the macula. Subretinal neovascularization accompanied two of the dysplastic lesions. The lesions were multifocal and present bilaterally in two patients. CONCLUSIONS: In fundus flavimaculatus, progressive lipofuscin storage is responsible for engorgement and hypertrophy of the RPE. Dysplastic lesions of the RPE probably result from reactive hyperplasia and fibrous metaplasia of RPE cells in response to acute disruption of fragile, hypertrophied RPE cells that may be enormously enlarged in the area of yellow flecks. This disruption may occur in response to trauma, focal inflammation, or other localized stimuli. Patients with fundus flavimaculatus should be cautioned concerning the possible role of trauma in causing dysplastic changes in the RPE and visual loss.     

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。     

Clinical phenotype of juvenile open-angle glaucoma linked to chromosome 1q in a Danish family.

PURPOSE: To describe in a Danish family the phenotype of members with autosomal dominant juvenile open-angle glaucoma linked to chromosome 1q, GLCA1, and to assess possible biometric differences between the eyes of affected and unaffected subjects. METHODS: Thirty-five subjects in a six generation family were examined. The records of five additional affected family members were available. Records from former examinations and treatments were also obtained. In 18 affected subjects and 13 unaffected subjects above 24 years biometric parameters were assessed and compared between the groups. RESULTS: The age at diagnosis of glaucoma was on average 18 years (range 8 to 33 years). Bilateral intraocular pressure was high at the time of diagnosis (mean 37 mmHg, range 28-69 mmHg). All subjects except two needed filtering surgery shortly after diagnosis (mean 1 year, range 0-8 years). Gonioscopy displayed open chamber angle and goniodysgenesis in all affected subjects, but no dysgenesis in unaffected subjects. A comparison of biometric parameters of affected and unaffected subjects showed a deeper anterior chamber, but no other differences were found. CONCLUSION: The phenotype of the affected family members is characterized by juvenile onset of glaucoma, open chamber angle with goniodysgenesis, high initial intraocular pressure, and the need for filtering surgery to control pressure. The deeper anterior chamber in affected subjects could indicate more extensive maldevelopment in affected subjects.     

Adult-onset foveomacular vitelliform dystrophy.

BACKGROUND: Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a condition that presents classically as bilateral, symmetrical, grayish-yellow, round or oval-shaped lesions within the macular area. These lesions are mildly elevated and are typically one third to one half disc diameter in size. The onset of the disease is usually between 30 and 50 years of age with variable genetic inheritance, although some have suggested an autosomal dominance inheritance pattern. Patients with AOFVD typically present with symptoms of blurred vision or mild metamorphopsia. Results of diagnostic testing show a normal or mildly subnormal electro-oculogram (EOG). Fluorescein angiography results (FA) typically show hypofluorescence in the area corresponding to the vitelliform lesion and a surrounding ring of hyperfluorescence. Results of optical coherence tomography (OCT) show the vitelliform lesion as being located in the retinal pigment epithelium (RPE) layer or between the RPE and photoreceptor layer. CASE REPORTS: Two cases of AOFVD are presented with each patient having different macular appearances owing to the different stage of the disease process. In case 1, a 76-year-old white man presented with stage II AOFVD characterized by typical vitelliform lesions. His best-corrected acuities were 20/70+ in the right eye (O.D.) and 20/80- in the left eye (O.S.). In case 2, a 54-year-old white man presented with stage V AOFVD with bilateral atrophic maculae with best-corrected acuities of 10/60- O.D. and 10/160- O.S. CONCLUSION: Patients with adult-onset foveomacular vitelliform dystrophy typically have slow progressive vision loss. However, patients can develop dramatically decreased vision owing to subfoveal choroidal neovascularization (CNV). Thus, it is important to establish the correct diagnosis and monitor this condition. Furthermore, because there are reports of AOFVD having an autosomal dominance inheritance pattern with variable penetrance, it is recommended that the patient's family members have a comprehensive eye examination to rule out any early signs of this rare eye condition.     

Photodynamic therapy using Lu-Tex induces apoptosis in vitro, and its effect is potentiated by angiostatin in retinal capillary endothelial cells

PURPOSE: To examine the effect of combining angiostatin with photodynamic therapy (PDT) using Lutetium Texaphyrin (Lu-Tex; Alcon, Fort Worth, TX) as a photosensitizer in bovine retinal capillary endothelial (BRCE) and retinal pigment epithelial (RPE) cells and to determine the mode of PDT-induced cell death in these cell lines. METHODS: Cultured BRCE and RPE cells were incubated with angiostatin (500 ng/ml) for 18 hours and subjected to Lu-Tex/PDT, using treatment parameters previously optimized (3 microgram/ml Lu-Tex for 30 minutes followed by timed irradiation at 732 nm). Cellular survival was assessed after a 1-week cellular proliferation. Data were analyzed using Student's t-test. Caspase 3 activity was monitored in cells after PDT using a fluorogenic substrate, (Asp-Glu-Val-Asp)-AFC (7-amino-4-trifluoromethyl coumarin) [DEVD-AFC], of caspase 3. After PDT, expression of Bcl-2, Bcl-x(L), Bax, and Bak was also examined in cell lysates by Western blot analysis. RESULTS: A synergistic cytotoxic effect of angiostatin and Lu-Tex/PDT was observed in BRCE cells at all fluences used (5, 10, and 20 J/cm(2); P 相似文献   

中国人Meesmann角膜营养不良家族KRT12基因突变检测分析

目的探讨中国Meesmann角膜营养不良家系的致病相关基因。方法对一具有3代患者的角膜营养不良家系进行详细的临床遗传学诊断,确定遗传方式与遗传特点,然后对该家系成员包括患者和正常人,进行详细的眼科检查,获得血液标本,提取基因组DNA。对已知基因KRT12、KRT3周围标记物D17S800、D17S930、D12S390、D12S96分别进行基因扫描,然后进行连锁分析,计算最大对数优势记分值。对连锁区域内已知基因所有外显子聚合酶链反应（PCR）扩增产物进行直接测序。结果该家系角膜营养不良的遗传方式为常染色体显性遗传,临床诊断为Meesmann角膜营养不良,连锁的染色体微卫星标记物为D17S800和D17S930,分值为2．41（θ=0．00）,与KRT12基因连锁。对全部8个外显子测序后发现该基因第一外显子（exon 1）第419碱基突变（T419A）,其编码的亮氨酸突变为组氨酸（L132H）。结论KRT12基因突变（T419A,L132H）可能是该中国人家系Meesmann角膜营养不良家族发病的分子基础。     

The expanded clinical spectrum of deferoxamine retinopathy.

OBJECTIVE: To describe early and unusual features in 16 patients with deferoxamine-induced retinal toxicity and to assess the role of diagnostic tests in the diagnosis and management of patients with the disorder. DESIGN: Retrospective, observational case series. PARTICIPANTS: Sixteen patients with deferoxamine retinopathy identified from members of the Vitreous, Retina, and Macula societies of the United States. INTERVENTION/TESTING: The patients underwent complete ophthalmologic examination. Most patients were also evaluated by fluorescein angiography and electrophysiologic testing. The diagnosis was based on the medical history, systemic and ocular findings, and the results of electrophysiologic tests. MAIN OUTCOME MEASURES: Ocular symptoms, ophthalmoscopic, fluoroangiographic, and electrophysiologic findings. RESULTS: We confirmed previously reported findings in patients with established disease, including macular and/or peripheral pigmentary changes, reduced electroretinographic (ERG) amplitudes, and reduced electrooculographic (EOG) light-peak to dark-trough ratios. Peripapillary, papillomacular, and paramacular patterns of retinal pigment epithelial (RPE) degeneration were each observed in one patient. Diffuse RPE or outer retinal fluorescence by fluorescein angiography was a marker for active retinopathy both at the onset of disease and during recurrence and preceded the development of RPE pigment mottling. CONCLUSIONS: Unusual patterns of deferoxamine retinopathy may occur in addition to the foveomacular and/or peripheral patterns previously described. Fluorescein angiography is particularly useful for determining whether there is ongoing retinal/RPE injury. ERG and EOG testing may indicate earlier or more widespread injury than is suggested by fundus examination alone. Patients who do not discontinue deferoxamine after the development of retinopathy risk further retinal/RPE injury and visual deterioration.     

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）     

Distinct functions between toll-like receptors 3 and 9 in retinal pigment epithelial cells

Retinal pigment epithelial cells (RPE cells) are key players in the first-line defense against invading organisms such as viruses and bacteria. The interaction between RPE cells and viral or bacterial components is very important for clearance of these organisms. Toll-like receptors are a family of recognition receptors involved in innate immunity. Each TLR acts as a primary sensor of conserved microbial components and drives the induction of specific biological responses. TLR 3 is involved in the recognition of viral components, such as double-stranded RNA (dsRNA) and poly(I:C), while TLR 9 recognizes viral or bacterial DNA without methylation at CpG motifs. In the present study, we investigated the expression and function of TLR 3 and 9 in RPE cells. PCR analysis revealed expression of genes for TLR 3 and 9 in RPE cells. Expression of TLR 3 and 9 protein was detected in RPE cells by flow cytometry. TLR 3 and 9 showed strong intracellular expression. To detect angiogenetic factors produced by RPE cells, culture supernatant was examined with the Human Angiogenesis Antibody Array, which can simultaneously detect 20 different angiogenetic factors including cytokines, chemokines, soluble cytokine receptors, and growth factors. RPE cells showed high production of interleukin-8 (IL-8) and monocyte chemotactic protein-I (MCP-I). Furthermore, stimulation of RPE cells with the dsRNA analogue poly(I:C) enhanced the secretion of IL-8 and MCP-I, as well as enhancing the expression of junctional adhesion molecule-I (Jam-I) and intracellular adhesion molecule-I (ICAM-I), and promoted the adhesion of monocyte to these cells. In contrast, stimulation with the CpG-DNA motif only enhanced the secretion of IL-8. However, CpG-DNA motif enhanced phagocytosis in RPE cells. These results may indicate that TLR 3 and 9 play a distinct role in the inflammatory response that clears viruses from the retina.     

Mapping of the retinal pigment epithelium in exudative age related macular degeneration

Purpose To evaluate a novel technique for three-dimensional mapping of the retinal pigment epithelium (RPE) layer in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration. Methods Scanning with a recent generation retinal thickness analyzer (RTA) was performed in consecutive patients undergoing fluorescein angiography. From a 3×3mm area centered on the fovea, three-dimensional area maps of the RPE level were calculated by external spreadsheet software. Included were 18 eyes with classic CNV, 18 eyes with occult CNV and 18 eyes from age-matched normal subjects. Repeatability was assessed by measuring 17 eyes with CNV 3 times. In ten additional patients, RTA imaging results were compared with cross-sections obtained by optical coherence tomography. Results By both methods, distinctive changes in RPE level maps were observed in classic and occult CNV. In classic CNV with the lesion extending over the RPE, only focal irregularities in the anteriorly displaced RPE surface were observed. In contrast, mapping of occult CNV showed a more irregular displacement of the RPE layer. The RPE map standard deviation indicating surface irregularity differed statistically significantly between the groups, with coefficients of variance of 5.9% for controls, 6.1% for classic and 8.8% for occult CNV (P<0.001). Regarding repeatability, RPE level maps showed 1.2% coefficient of variance and an intra-class correlation coefficient of 0.87 for triplicate measurements in CNV patients. Conclusions Topographic mapping of CNV lesions offers a fast, reproducible method for obtaining three-dimensional morphometric information on the RPE level and to quantify changes.