BASICS

DESCRIPTION

• Congenital hamartias/hamartomas: Placoid melanocytic lesions of the retinal pigment epithelium, solitary, grouped, or multiple in one or both eyes, the latter maybe associated with familial adenomatous polyposis (FAP) and – historically – Gardner or Turcot syndrome (1).

• Solitary lesions: Flat, well demarcated round, oval, or geographic with smooth or scalloped margins. The color is gray brown or jet black with a surrounding halo of depigmentation and/or central depigmented lacunae which bare the underlying choroidal vessels. The depigmentation may progress to involve the entire lesion (1). The usual size is 1–2 disc diameters (DD), however, can occupy one entire quadrant of the fundus. Slow concentric enlargement has been noted and seems to be the rule (2) The most common location is superotemporal and equatorial. Macular involvement is rare. There are few, if any, systemic associations. (3).

• Grouped lesions: Flat, well demarcated round, oval, or geographic smaller black spots (0.1–0.5 DD) arranged in groups reminiscent of “bear tracks”. These are usually found in one sector, however can involve a large area of the fundus. Smaller lesions are found more posteriorly, larger ones are located peripherally. Bilateral involvement does occur. Cutaneous sectorial pigmentations, the lines of Blaschko, may be seen, suggesting patterns of pigmentary mosaicism in both eye and skin. There are no systemic associations (1–3).

• Multiple small ovoid hyperplastic lesions associated with familial adenomatous polyposis (FAP): Slightly raised, oval, with irregular borders and fishtail – shaped areas of depigmentation at one or both poles of the lesion. The lesions have a meridional orientation and haphazard distribution. Retinal invasion and glial, capillary and pigment epithelial proliferation and hypertrophy are typical. More than 4 widely spaced small (<0.5 DD) lesions per eye and bilateral involvement are suggestive of FAP (4).

EPIDEMIOLOGY

Incidence

Stevenson described 3 cases in 2,400 examinations in 1891.

Prevalence

• The prevalence of CHRPE was found to be 1.2% in the optometric population in 2007.

• Familial adenomatous polyposis occurs in approximately 1 of 13–18,000 live births.

• 70–80% of patients with FAP have pigmented ocular fundus lesions.

RISK FACTORS

Multiple small ovoid “typical” lesions, more than 4, and involving both eyes.

Genetics

• Solitary and grouped lesions can be familial

• Multiple lesions may indicate a mutation in the adenomatous polyposis coli (APC) gene in which case the inheritance pattern is autosomal dominant.

• The APC gene is a tumor suppressor gene, affecting cell cycle, cell adhesion, and migration.

• Germline truncating mutation in the APC gene causes the disease by not inhibiting tumorigenesis.

• The APC gene is located on the long arm of chromosome 5 (5q21).

• The APC gene encodes for a 312-kDa protein, 2,843 amino acids long.

• CHRPE lesions help to predict the mutation site on the APC gene; mutations between codons 543 and 1309 are associated with a high incidence of CHRPE.

• More than 700 of disease-causing APC mutations have been reported. An updated database is available at http://www.cancer-genetics.org.

COMMONLY ASSOCIATED CONDITIONS

• Solitary and grouped lesions are restricted to the eye (3)

• Multiple bilateral ocular lesions: Familial adenomatous polyposis (FAP), and/or attenuated FAP, if fewer than 100 adenomas in a more proximal colonic location are present

• Extracolonic manifestations: Dental anomalies, osteomas of mandible skull and orbits, fibromas, lipomas, epidermal and sebaceous cysts, adrenal, thyroid, bladder tumors, sarcomas, and hepatoblastomas

• Gardner syndrome (historic term): FAP and prominent extracolonic manifestations (see above)

• Turcot Syndrome (historic term): FAP and brain tumors, that is, medulloblastomas, astrocytomas, ependymomas (4)

DIAGNOSIS

HISTORY

• Solitary and grouped lesions rarely have systemic implications (1–3).

• Multiple and bilateral lesions may be markers of FAP and must not be missed. The family health history is a “21st century genetic tool” inquiring about gastrointestinal polyps or other tumors and, about

• Abdominal pain, rectal bleeding, diarrhea, mucous discharge in any family member.

• In patients with FAP, hundreds of adenomatous colorectal polyps variably develop around puberty to 30 years of age. Patients with polyps develop symptoms 10 years after onset of polyposis by which time (35–40 years of age) carcinomatous transformations is present in a majority of cases.

PHYSICAL EXAM

• Ophthalmoscopy, looking for placoid solitary, grouped and multiple melanocytic lesions of the pigmented epithelium

– Characteristic widely spaced meridionally oriented hyperplastic lesions, bilateral involvement, and more than 4 lesions are reason to suspect FAP (4)

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• Fundus photography is used to document the size, color, and appearance of the lesions. Growth, depigmentation with age, as well as the rare (case report) malignant change have been documented.

• Fluorescein angiography: Capillary leakage, capillary nonperfusion

• Visual Field testing: Relative or absolute scotomas in large and old solitary lesions

Follow-up & special considerations

Solitary CHRPE grows in size in 46–83% over 3 or more years follow-up (2).

Imaging

All lesions of CHRPE show reduced autofluorescence, since they contain mostly melanin and little lipofuscin.

Diagnostic Procedures/Other

If FAP is suspected, annual flexible sigmoidoscopy should be performed starting at age 10 years. Depending on the polyp burden, endoscopy of the stomach, duodenum, and periampullary region should be performed every 6 months to 4 years.

Pathological Findings

• Solitary and grouped lesions are composed of a single layer of enlarged pigmented cells which contain macromelanosomes and little lipofuscin. The basement membrane may be thickened and there maybe degeneration and atrophy of the overlying outer retina. Halos and lacunae correspond to areas of neuroepithelial atrophy. The lesions are flat and have no mass, resembling “hamartias.”

• Multiple lesions associated with familial polyposis may be similar to grouped lesions, however, more often show hypertrophy and hyperplasia of plump retinal pigment epithelial cells, retinal invasion as well as retinal vascular changes. Lesions are multilayered and have thickness, resembling “hamartomas” (5).

DIFFERENTIAL DIAGNOSIS

• Malignant melanoma

• Reactive retinal pigment epithelial hyperplasia

• Pigment epithelial adenoma/adenocarcinoma

• Albinotic nevi of the RPE

• Black sunburst lesion of sickle cell retinopathy

• Choroidal nevi

TREATMENT

ADDITIONAL TREATMENT

Issues for Referral

Gastrointestinal evaluation, APC gene testing.

SURGERY/OTHER PROCEDURES

• Solitary and grouped pigmentations of the RPE: None

• Multiple, bilateral, associated with FAP: Flexible sigmoidoscopy, colonoscopy, subtotal colectomy

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patients with multiple CHRPE and a diagnosis of FAP: Annual colonoscopy.

PROGNOSIS

Solitary and grouped CHRPE typically enlarge. Retinal atrophy can contribute to visual field defects.

COMPLICATIONS

Carcinomatous transformation

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