Solitary CHRPE

Solitary CHRPE is typically a flat, round, hyperpigmented lesion with smooth or scalloped margins that is well-demarcated from normal-appearing retinal pigment epithelium (RPE) (Fig. 136.2A). The color may vary from light gray, brown to black and is independent of the patient’s race.¹ A marginal halo of depigmentation may surround the lesion and “punched-out” inner lacunae with hypopigmentation may be present in larger lesions. Both depigmented zones show the tendency to progress gradually over time, and eventually, may involve the entire lesion.^4–7 The overlying retina and its vasculature appear normal in most cases, however discrete focal intraretinal pigmentation may become visible near the margin on biomicroscopy.⁴ Some lesions may be associated with retinal vascular abnormalities including capillary and large-vessel obliteration, microaneurysmal changes, chorioretinal anastomoses, and neovascularization. The size may vary from 100 µm to several disc diameters, occasionally occupying an entire quadrant. Lesions may be found anywhere in the fundus, with predominance in the superotemporal and equatorial region while the macula is rarely involved. Solitary CHRPE enlarge in 46–83% of cases over three or more years of follow-up. Extension into the fovea may result in reduced visual acuity.⁸ Some heavily pigmented nodular lesions may develop within CHRPE.⁹ Histopathologically nodular lesions proved to be adenocarcinomas in two reports.^10,11 Untreated nodular lesions may enlarge to form pedunculated tumors of >7 mm thickness with serous retinal detachment.¹¹

Fig. 136.2 (A) Solitary congenital hypertrophy of the retinal pigment epithelium (CHRPE): A large CHRPE OD with a diameter of 3 disc diameters. (B) Grouped CHRPE: The sectorial pattern of grouped CHRPE with smaller lesions at the optic disc and larger lesions in the periphery. Larger hyperpigmentations may be separated during growth into smaller spots, surrounded by normal pigmented cells. The shape of these lesions may be sickle or oval shaped with convex borders, fitting into the concave borders of adjacent lesions. (C) Multiple CHRPE lesions in familial adenomatous polyposis are generally smaller (50–100 µm in diameter) compared with solitary CHRPE. The ovoid, often spindle-shaped hyperplastic lesions are black, brown, or light gray in color. Lesions have a nearly meridional orientation towards the optic disc and are haphazardly distributed with no obvious predilection for any quadrant.

Grouped CHRPE

When several lesions of varying size are arranged in a cluster, resembling the footprint of an animal (‘bear tracks’), they are named “grouped CHRPE” (233800, OMIM). Grouped lesions are flat, well-demarcated round oval or geographic black spots with increasing size towards the fundus periphery. Each cluster includes approximately 3–30 lesions, which may vary in size from 100 to 300 µm lesions (Fig. 136.2B). Etiology and development of grouped CHRPE remain unknown. The presence of grouped CHRPE and additional ipsilateral sectorial pigmented skin lesions following the “cutaneous lines of Blaschko” gave evidence for possible pigmentary mosaicism in both the eye and skin.¹² Therefore, grouped CHRPE are considered as a cluster of atypical hyperpigmented RPE cells, that derive from the edge of the optic nerve and migrate along the stream of embryologic tissue lines, analogous to the “cutaneous lines of Blaschko.” The sectorial pattern of grouped CHRPE obviously reflects the stream, outgrowth and migration path of RPE cells during embryogenesis.¹³ Bilateral grouped CHRPE has rarely been observed. There are no systemic associations in patients with solitary and grouped CHRPE.

Multiple CHRPE

Multiple CHRPE lesions in FAP are generally smaller (50–100 µm in diameter) compared with solitary CHRPE. They are black, brown, or light gray (Fig. 136.2C). Larger lesions may be surrounded by a depigmented halo, mottled RPE,¹⁴ window-defect-type changes adjacent to retinal vessels,¹⁵ may contain depigmented lacunae, and can be accompanied by small pigmented satellite lesions. Retinal invasion and glial, capillary and pigment epithelial proliferation and hypertrophy are typical. More than four widely spaced lesions per eye or bilateral involvement are suggestive of FAP.¹⁶ Traboulsi et al. examined 16 GS families for multiple CHRPE. Of 41 GS patients, 37 (90%) had multiple CHRPE lesions.¹⁴ Lesions were bilateral in 32 patients (78%). The presence of bilateral lesions or multiple unilateral lesions (>4) appeared to be a useful clinical marker (specificity, 0.95; sensitivity, 0.78) for GS. In view of the multiple, bilateral character of retinal lesions observed in FAP, they can be considered a clinical disease marker. However, the absence of CHRPE has no predictive value for absence of GS or FAP.

Associated extraocular findings

Solitary, unilateral lesions and grouped CHRPE are restricted to the RPE with no other ocular or extracellular findings.¹⁸ Multiple or bilateral CHRPE may be associated with autosomal dominant FAP or GS (175100, OMIM)). Gardner syndrome is characterized by FAP of the large and small intestine, hamartomas of the skeleton and various soft-tissue tumefactions.^19,20 Intestinal polyps generally appear during the third decade of life and invariably progress to adenocarcinomas by the fifth decade. Skeletal hamartomas, most commonly benign osteomas of mandible skull, orbits and long bones, become apparent in the third decade of life, as well as soft-tissue abnormalities including epidermoid and sebaceous cysts, dermal fibromas, lipomas, leiomyomas, desmoid, and mesenteric fibromatosis. Further extracolonic manifestations of GS include tumors of the thyroid, adrenal, and bladder, as well as sarcomas and hepatoblastomas. Turcot syndrome (233800, OMIM) is associated with FAP and brain tumors, e.g., astrocytomas, medulloblastomas, and ependymomas.

Pathophysiology/histopathology

Histopathologic studies demonstrated that most solitary^1,4 and grouped CHRPE lesions are a monocellular layer of hypertrophied RPE cells, densely packed with large round pigment granules instead of the wedge-shaped melanin granules frequently found in normal RPE cell lesions (Fig. 136.3A). These large round granules represent primarily macromelanosomes.²¹ The underlying Bruch’s membrane may be thickened^1,4,22,23 due to widening of the basement membrane of the hypertrophied RPE cells. The remaining layers of Bruch’s membrane, the choriocapillaris, and choroid appear normal. The subjacent photoreceptor layer degenerates progressively with increasing age. The inner retinal layers, including the retinal vasculature, remain normal. In the area of depigmented lacunae, both the hypertrophied RPE and photoreceptor cell layers are absent and replaced by glial cells.⁴ The transition from the margin of CHRPE lesions to normal RPE lesions occurs abruptly. A surrounding hypopigmented halo corresponds to areas of less pigmented hypertrophied RPE cells. All lesions remain flat.

Fig. 136.3 (A) Light microscopy shows the abrupt transition from normal to abnormal retinal pigment epithelium (RPE) and retina (H&E ×500). (Reproduced with permission from Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1975;79:177–89.) (B) Scanning electron micrograph of a pigmented fundus lesion 100 µm in diameter composed of a cluster of enlarged RPE cells (arrow) (×500).

(Courtesy of Traboulsi EI, Murphy SF, de la Cruz ZC, et al. A clinicopathologic study of the eyes in familial adenomatous polyposis with extracolonic manifestations (Gardner’s syndrome). Am J Ophthalmol 1990;110:550–61. With permission from the American Academy of Ophthalmology.)

Multiple lesions associated with FAP show hypertrophy and hyperplasia of plump RPE cells, retinal invasion as well as retinal partially vascular changes. Hyperplastic lesions with multiple layers of hypertrophied RPE cells are resembling “hamartomas,” causing an elevated appearance and present as clusters of enlarged RPE cells on scanning electron microscopy (Fig. 136.3B).^21,22 In another lesion, hypertrophied RPE cells traversed the full thickness of the retina. These histopathologic characteristics allow the classification of the pigmented ocular lesions in FAP as hamartomas of the RPE.²⁴ To distinguish these lesions nosologically the terms “polyposis-associated congenital hamartoma of the RPE” and “multiple RPE hamartomas (MRPEH)” from the classic lesion of CHRPE have been proposed.²⁵ In grossly normal-appearing areas of the fundus, individual and small clusters of enlarged RPE cells contain the same large spherical melanin pigment granules found in the pigmented lesions.

Clinical examination/ancillary testing

The vast majority of pigmented fundus lesions are easily recognized by indirect ophthalmoscopy or three-mirror contact lens examination after dilatation of the pupil. Color fundus photography is conventionally used to document the location, color, size and appearance of the lesions (Fig. 136.4) and novel ultra wide-field scanning-laser ophthalmoscopy has been recommended as a screening tool.^2,26 However, absence of CHRPE lesions in a family with FAP does not indicate absence of the gene, since variable phenotype expression may exist or tiny lesions can be overlooked.

Fig. 136.4 Color fundus photography is used to document the location, color, size and appearance of the lesions. Larger lesions may present punched-out inner lacunae with hypopigmentation and tend to expand slightly in size with aging.

As small or lightly pigmented lesions may easily be missed, fundus autofluorescence (FAF) may be helpful to identify these lesions. Since CHRPE contains predominantly melanin and only small amounts of lipofuscin these lesions typically demonstrate hypoautofluorescence. Only areas with lacunae or nonpigmented halos show a trace to moderate autofluorescence (Fig. 136.5A).^27,28

Fig. 136.5 (A) Fundus autofluorescence is helpful to determine congenital hypertrophy of the retinal pigment epithelium here since the lesion contains predominantly melanin and only little lipofuscin lesions presenting in dark hypoautofluorescence. (B) Microperimetry reveals a scotoma corresponding in size and location to the lesions. The central best-corrected visual acuity is 20/80 and the central fixation was intact although the patient noticed moderate increase of the scotoma during computer work.

The majority of lesions remain asymptomatic and show no leakage of dye on fluorescence angiography (FA) or indocyanine green angiography (ICGA). CHRPE lesions appear as dark spots blocking choroidal fluorescence and augment the brightness of retinal vasculature. Only in depigmented lacunae or hypopigmented halos is a normal choriocapillaris flush observed. Leakage from retinal vessels overlying CHRPE has been reported during late phases of the angiogram.

The electroretinogram (ERG) and electro-oculogram (EOG) remain normal in eyes with CHRPE, providing evidence for the localized nature of this disease. The axial resolution of A- and B-scan ultrasound sonography is too low to document the CHRPE lesion, since the lesions demonstrate minimal or no elevation.

Spectral domain optical coherence tomography (SD-OCT) highlights the cross-sectional retinal anatomy of CHRPE lesions. A general thinning of the neural retina with a predominant photoreceptor loss becomes apparent over the CHRPE lesion (Fig. 136.5A). Darkly pigmented CHRPE shadows the underlying choroidal structures. Areas of lacunae show absence of RPE and increased transmission of light. Retinal thinning and photoreceptor loss over CHRPE account directly for related visual field loss. Patients with CHRPE rarely complain of related symptoms, except when the fovea is involved. Microperimetry may reveal a relative or absolute scotomata corresponding in size and location to the lesions. Microperimetric defects tend to progress from relative to absolute scotoma and expand slightly in size with aging (Fig. 136.5B).

Familial adenomatous polyposis prognosis and management options

FAP, a precancerous condition, appears with hundreds to thousands of adenomatous polyps in the colon and rectum, harboring a high risk of malignant transformation and making prophylactic total colectomy necessary in the majority of patients. Untreated patients die from colorectal cancer at an average age of 40 years.

The gene responsible for FAP, called the adenomatous polyposis coli (APC) gene, is localized on the long arm of chromosome 5 (5q21–q22), encoding a tumor suppressor protein consisting of 2843 amino acids. The APC protein influences cell cycle, cell migration and adhesion.

The presence of extracolonic symptoms and the severity of disease correlate with the location of the mutation on the APC gene. Attenuated FAP (AFAP, <100 colorectal adenomas) is caused by mutations localized after codon 1595, before codon 157 and in the spliced region of exon 9. Severe FAP (>1000 adenomas) is seen in patients with mutations between codons 1250 and 1464. Mutations in the remaining APC gene lead to intermediate FAP (100–1000 adenomas) (Fig. 136.6).^29–31

Fig. 136.6 Distribution of the APC-germline mutations and clinical manifestation. The red box indicates the colonic manifestation and its severity. Filled black boxes present the APC coding region split into 15 exons. The spliced exon 9 is marked in gray. The yellow box assigns the mutation region of the APC gene to the multiple CHRPE fundus lesions. FAP, familial adenomatous polyposis; CHRPE, congenital hypertrophy of the retinal pigment epithelium.

Phenotypic expression of CHRPE correlates with the localization of mutations. FAP patients with mutations between codon 446 and codon 1338 regularly present with CHRPE lesions, whereas FAP patients with mutations between 1445–1578 lack multiple CHRPE at the retinal fundus. This relationship between CHRPE manifestations and the site of the APC mutation points out a specific role of the APC protein in development of retinal tissue. Moreover, the CHRPE status adds important information about the location of the genetic mutation and plays a critical role in the detection of the corresponding APC mutations. Recent well-defined assessment criteria necessitate the presence of at least four CHRPE lesions whatever their size or at least two lesions, of which one is large, to support the diagnosis of FAP.^32,33