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Figure. Fundus photographs from the initial visit show multiple, scattered, hyperplastic retinal pigment epithelial lesions (white arrows) that are small (<200-μm diameter) in the right eye (A) and small to medium sized (300-μm to 3-mm diameter) in the left eye (B) as well as an epiretinal membrane, causing minimal vascular dragging and foveal distortion, in the left eye (black arrow) (B). Fluorescein angiography confirmed these findings without related edema in the right (C) and left (D) eyes.

Figure. Fundus photographs from the initial visit show multiple, scattered, hyperplastic retinal pigment epithelial lesions (white arrows) that are small (<200-μm diameter) in the right eye (A) and small to medium sized (300-μm to 3-mm diameter) in the left eye (B) as well as an epiretinal membrane, causing minimal vascular dragging and foveal distortion, in the left eye (black arrow) (B). Fluorescein angiography confirmed these findings without related edema in the right (C) and left (D) eyes.

1.
Half E, Bercovich D, Rozen P. Familial adenomatous polyposis.  Orphanet J Rare Dis. 2009;4:22PubMedArticle
2.
Traboulsi EI, Krush AJ, Gardner EJ,  et al.  Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome.  N Engl J Med. 1987;316(11):661-667PubMedArticle
3.
Aiello LP, Traboulsi EI. Pigmented fundus lesions in a preterm infant with familial adenomatous polyposis.  Arch Ophthalmol. 1993;111(3):302-303PubMedArticle
4.
Universal Mutation Database.  The APC mutations database. http://www.umd.be/APC/. Accessed September 11, 2011
5.
Kodish ED. Testing children for cancer genes: the rule of earliest onset.  J Pediatr. 1999;135(3):390-395PubMedArticle
6.
Machemer R, van Horn D, Aaberg TM. Pigment epithelial proliferation in human retinal detachment with massive periretinal proliferation.  Am J Ophthalmol. 1978;85(2):181-191PubMed
7.
Liou GI, Samuel S, Matragoon S,  et al.  Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium.  Mol Vis. 2004;10:383-391PubMed
Research Letters
Aug 2012

Epiretinal Membrane and Retinal Pigment Epithelial Lesions in a Young Child and Detection of De Novo APC Mutation

Author Affiliations

Author Affiliations: Ocular Oncology Service (Drs Ganesh, Kaliki, and Shields) and Pediatric Ophthalmology and Ocular Genetics Services (Drs Ganesh and Levin), Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.

Arch Ophthalmol. 2012;130(8):1071-1073. doi:10.1001/archophthalmol.2012.217

Familial adenomatous polyposis (FAP; OMIM #175100) is an autosomal dominant condition with multiple (>100) adenomatous colonic polyps developing at a mean age of 16 years.1 Colorectal carcinoma is inevitable without prophylactic colorectal surgery. Familial adenomatous polyposis is caused by germline mutation in the adenomatous polyposis coli gene (APC ; GenBank NC_000005) at chromosome 5q21. These mutations are almost 100% penetrant. Familial adenomatous polyposis is associated with well-demarcated, cometoid retinal pigment epithelial (RPE) lesions. When multiple and bilateral, these lesions indicate FAP with approximately 80% sensitivity and 100% specificity.2 The fundus lesions are congenital and have been reported in neonates and even a premature infant.3 Epiretinal membrane (ERM) has not yet been identified as feature of FAP. We describe a child with ERM and characteristic RPE lesions that led to detection of an APC mutation and at-risk status for FAP.

Report of a Case

A 17-month-old healthy boy had exotropia of the left eye. Family history was negative for gastrointestinal cancer. Ophthalmic examination revealed age-appropriate visual responses and central, steady, and maintained fixation in both eyes. A comitant, left exotropia of 15 prism diopters was noted. Ocular motility and anterior segment examination findings were normal in both eyes. Ophthalmoscopy revealed 4 RPE lesions smaller than 200 μm in diameter in the right eye and 6 RPE lesions 300 μm to 3.0 mm in diameter in the left eye. The lesions were round to cometoid in shape, and the larger lesions had a nonpigmented halo (Figure). A translucent, gray ERM causing mild vascular dragging and foveal distortion was noted in the left eye (Figure).

The RPE lesions in both eyes suggested a possibility of FAP, and sequencing of APC was performed with the parents' informed consent. This revealed a frameshift mutation (3793G>T), predicted to result in a truncated APC protein at amino acid position 1265 of APC. Mutations in this region of the gene are associated with polyposis.4 Both parents (father aged 36 years and mother aged 34 years) had normal testing results, implying de novo mutation in the child. Screening for gastrointestinal polyps has been recommended to begin when the child is 8 to 10 years old.

Comment

Familial adenomatous polyposis, attenuated FAP (<100 polyps), Gardner syndrome (FAP and extraintestinal osteomas and fibromas), and Turcot syndrome (FAP and medulloblastoma) are hereditary, precancerous, adenomatous polyposis syndromes caused by mutations in APC. Early detection is the key to reducing mortality from colorectal cancer in these conditions. Ophthalmoscopy of at-risk children is recommended for early detection of FAP gene carrier status, and screening colonoscopy is recommended from age 10 years, although intestinal polyps have been reported as early as age 7 years.

Ethical concerns have been raised about presymptomatic genetic testing at an age when no intervention would be indicated. Kodish5 refers to the rule of earliest onset when testing children for cancer genes. We justify genetic testing in our patient because finding the mutation not only serves to emphasize the need for later gastrointestinal screening in the proband but also helps in determining the APC mutation status in first-degree relatives, who may not otherwise know they are at risk for colon cancer.

Epiretinal membrane, a degenerative condition most often detected in adults, is hypothesized to arise from fibrocytic transformation of RPE cells dispersed in the vitreous.6 In young patients, ERM is uniquely rare but can be found in inflammatory conditions and tumors such as combined hamartoma of the retina and RPE and neurofibromatosis type 2. To our knowledge, ERM has not been previously reported with FAP. Liou et al7 found that the APC protein plays an important role in cell-cycle cessation and regulates the potential for RPE cells to migrate and proliferate. In a study of human and murine RPE, they noted that downregulation of APC resulted in RPE proliferation and differentiation into the RPE-like cells of ERM.6 We speculate that the ERM in our young patient could be related to the APC mutation and might have led to the left exotropia. We have no reason to explain its occurrence other than as hypothesized. Epiretinal membrane might be another, albeit uncommon, ophthalmic feature of FAP. We suggest that patients with RPE lesions consistent with FAP and patients known to have APC mutations be carefully screened for ERM.

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Article Information

Correspondence: Dr Shields, Ocular Oncology Service, Wills Eye Institute, 840 Walnut St, Ste 1440, Philadelphia, PA 19107 (carol.shields@shieldsoncology.com).

Author Contributions: Dr Shields had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This work was supported by the Eye Tumor Research Foundation (Dr Shields) and the Foerderer Fund (Dr Levin).

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

References
1.
Half E, Bercovich D, Rozen P. Familial adenomatous polyposis.  Orphanet J Rare Dis. 2009;4:22PubMedArticle
2.
Traboulsi EI, Krush AJ, Gardner EJ,  et al.  Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome.  N Engl J Med. 1987;316(11):661-667PubMedArticle
3.
Aiello LP, Traboulsi EI. Pigmented fundus lesions in a preterm infant with familial adenomatous polyposis.  Arch Ophthalmol. 1993;111(3):302-303PubMedArticle
4.
Universal Mutation Database.  The APC mutations database. http://www.umd.be/APC/. Accessed September 11, 2011
5.
Kodish ED. Testing children for cancer genes: the rule of earliest onset.  J Pediatr. 1999;135(3):390-395PubMedArticle
6.
Machemer R, van Horn D, Aaberg TM. Pigment epithelial proliferation in human retinal detachment with massive periretinal proliferation.  Am J Ophthalmol. 1978;85(2):181-191PubMed
7.
Liou GI, Samuel S, Matragoon S,  et al.  Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium.  Mol Vis. 2004;10:383-391PubMed
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