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Hill J1, GCM Black2,3, Lalloo F3, N Thakker, DGR Evans3
1 Department of Colorectal Surgery, Manchester Royal Infirmary, Manchester, UK
Academic Unit of Eye and Vision Science, Manchester Royal Eye Hospital, School of
Medicine, University of Manchester, Manchester, UK
Genomic Medicine, University of Manchester and
Regional Genetic Service, St Mary's Hospital, Manchester, UK
Introduction:
Multiple patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in large numbers of individuals with Gardner syndrome and Familial adenomatous polyposis (FAP) ADDIN EN.CITE Baker19884EndNote017<style face='normal' font='default' size='100%'>Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis</style>Berk19883EndNote017<style face='normal' font='default' size='100%'>Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis</style>Chapman19895EndNote017<style face='normal' font='default' size='100%'>Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis</style>Diaz Llopis19871EndNote017<style face='normal' font='default' size='100%'>Congenital hypertrophy of the retinal pigment epithelium and familial polyposis of the colon</style>Morton19927EndNote017<style face='normal' font='default' size='100%'>Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis</style>Polkinghorne19906CHRPE.enlEndNote617<style face='normal' font='default' size='100%'>Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis</style>[1-6]. Although CHRPE was first described by Reese and Jones in 1956 ADDIN EN.CITE Reese19568EndNote017<style face='normal' font='default' size='100%'>Benign melanomas of the retinal pigment epithelium</style>[7], its association with Gardner syndrome was only described by Blair and Trempe in 1980 ADDIN EN.CITE Blair19809EndNote017<style face='normal' font='default' size='100%'>Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome</style>[8]. The condition does not affect sight and has no malignant potential. Other extracolonic manifestations of Gardner syndrome include benign osteomas of the long bone and the skull (in particular jaw bones), dental abnormalities epidermoid skin cysts and desmoid tumours ADDIN EN.CITE Gardner196210EndNote017<style face='normal' font='default' size='100%'>Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts.</style>[9]. The value of CHRPE as a predictive congenital phenotypic marker in FAP kindreds is well recognised with a strong correlation between the genotype and the phenotype (fig 1). CHRPE is usually only present in FAP patients with mutations between codons 463 and 1387 in the APC gene ADDIN EN.CITE Wallis199917EndNote017<style face='normal' font='default' size='100%'>Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition</style>Caspari199514EndNote017<style face='normal' font='default' size='100%'>Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444</style>Bunyan199513EndNote017<style face='normal' font='default' size='100%'>Genotype-phenotype correlations of new causative APC gene mutations in patients with familial adenomatous polyposis</style>Davies199515EndNote017<style face='normal' font='default' size='100%'>Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene</style>Olschwang199312EndNote017<style face='normal' font='default' size='100%'>Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients</style>Giardiello199716EndNote017<style face='normal' font='default' size='100%'>APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis</style>[10-15] and is estimated to occur in 60% of FAP families ADDIN EN.CITE Blair19809EndNote017<style face='normal' font='default' size='100%'>Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome</style>[8] (fig 2).
The majority (81%) of CHRPE in FAP kindred are hyperpigmented lesions compared with 5% hypopigmented lesions. The remaining 14% of lesions are found to have a mixture of hypo and hyperpigmented lesions ADDIN EN.CITE Romania198918CHRPE.enlEndNote1817<style face="normal" font="default" size="100%">Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis</style>[16]. Generally the lesions are distributed in all four quadrants of the retina with the smaller lesions located peripherally and the larger lesions located posterior to the vortex veins. Lesions may be bilateral or as a solitary oval patch (fig 3). ADDIN EN.CITE Berk19882CHRPE.enlEndNote217<style face='normal' font='default' size='100%'>Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis</style>Baker19881CHRPE.enlEndNote117<style face='normal' font='default' size='100%'>Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis</style>Morton19925CHRPE.enlEndNote517<style face='normal' font='default' size='100%'>Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis</style>[1, 2, 5] There have been attempts to define clinically reliable methods for the assessment of FAP-related CHRPE. For example, Morton et al. described a diagnostic criteria in which lesions were considered significant if they were 1) bilateral, 2) three or more in number and 3) any greater than 0.3 optic discs in diameter (sensitivity of 84% in positive examinations). Another author proposed that only oval pigmented areas with a surrounding depigmented halo (type A) should be considered pathognomonic of FAP as it was found in two thirds of the FAP group and none in the control. ADDIN EN.CITE Polkinghorne19906CHRPE.enlEndNote617<style face="normal" font="default" size="100%">Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis</style>[6]
CHRPE is a common incidental finding on ophthalmoscopy, present in 1-40% of the general population ADDIN EN.CITE Tiret199922CHRPE.enlEndNote2217<style face='normal' font='default' size='100%'>Fundus lesions of adenomatous polyposis</style>Tourino200423CHRPE.enlEndNote2317<style face='normal' font='default' size='100%'>Value of the congenital hypertrophy of the retinal pigment epithelium in the diagnosis of familial adenomatous polyposis</style>[17, 18]. Based on retinal examinations, CHRPE are generally classified into four types: oval, pigmented, and surrounded by a halo (type A); round, small, and pigmented (type B); round, large, and pigmented (type C); and round, large, and depigmented (type D) ADDIN EN.CITE Berk19882CHRPE.enlEndNote217<style face='normal' font='default' size='100%'>Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis</style>[2]. Of these, pigmented dot lesions are the commonest type, accounting for 92.5% of all CHRPEs ADDIN EN.CITE Tourino200423CHRPE.enlEndNote2317<style face='normal' font='default' size='100%'>Value of the congenital hypertrophy of the retinal pigment epithelium in the diagnosis of familial adenomatous polyposis</style>[18]. Grouped, but unilateral variants of CHRPEs are also recognised and include multiple pigmented plaques characterised by a larger lesion surrounded by several smaller ones, resembling the paw and toes of an animal (bear tracks or congenital grouped pigmentation of the retinal-pigmented epithelium) (fig 4). Bear track lesions are thought not to be related to FAP by several histological studies ADDIN EN.CITE Kasner199230CHRPE.enlEndNote3017<style face='normal' font='default' size='100%'>A histopathologic study of the pigmented fundus lesions in familial adenomatous polyposis</style>Parker199028CHRPE.enlEndNote2817<style face='normal' font='default' size='100%'>Histopathological features of congenital fundus lesions in familial adenomatous polyposis</style>Traboulsi199029CHRPE.enlEndNote2917<style face='normal' font='default' size='100%'>A clinicopathologic study of the eyes in familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome)</style>[19-21]. A significant proportion of FAP cases (~25-30%) result from new mutations (with no previous family history). Clearly, these could present as incidental CHRPE. At present, we have no reliable data on the contribution of such cases to the frequency of incidental CHRPE. However, of an early study 1-3 CHRPE can occur in the General Population without FAP as 2/94 controls had 3 CHRPE.[22]
Hypothesis: Congenital hypertrophy of the retinal epithelium (CHRPE) is considered to be a pre-adenomatous phenotypic marker for familial adenomatous polyposis (FAP) mutation carriers. Presence of CHRPE can be used clinically to detect asymptomatic carriers in FAP proven families prior to genetic testing. As approximately 25% of FAP cases result from new mutations, FAP may occasionally need to be excluded amongst incidental cases of CHRPE. However, CHRPE may be common in the general population and the great majority of apparently isolated CHRPE may not be due to constitutional APC mutation.
CHRPE occurs with central mutations in APC
70-80% of all APC mutation carriers
However risk of APC is not known in individuals with no FAP FH and no bowel symptoms referred from ophthalmology
De novo mutation rate for APC about 1 in 80,000 births
Only 1 in 100,000 will have CHRPE
1-3 CHRPE can occur in Gen Pop without APC -2/94 controls had 3
Journal of Medical Genetics 1991; 28: 289-296.
Bear track CHRPE not characteristic of APC
Population frequency of CHRPE not known if > 1 in 100 <0.1% of isolated CHRPE will have APC
Need to assess what proportion of isolated CHRPE have de novo APC mutations
All cases of isolated CHRPE referred to each service
Number of lesions and type (bear track or not)
APC testing and endoscopy
Method:
Individuals with CHRPE who are referred for assessment in order to exclude FAP are reviewed. Detailed interview of bowel symptoms, reconstruction of pedigree, confirmation of CHRPE, selective endoscopic colonic evaluation, and genetic testing were carried out in order to determine the possible diagnosis of FAP.
Age
Type of CHRPE (bear track or usual)
APC mutation testing
Endoscopy results
Local
IdentifierAge at assess
-mentNo FH FH FAPNo
bowel
symptomsNo of
Typical
CHRPE (B)No of
Halo
CHRPE
(A)No of
Oval
Large
CHRPE
(C)No of
Bear
trackLater
alityAPC
testingEndoscopyTo qualify must have no FH FAP and no bowel symptoms
Reference:
ADDIN EN.REFLIST 1. Baker, R.H., et al., Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis. Am J Med Genet, 1988. 31(2): p. 427-35.
2. Berk, T., et al., Congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis. Dis Colon Rectum, 1988. 31(4): p. 253-7.
3. Chapman, P.D., et al., Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis. Bmj, 1989. 298(6670): p. 353-4.
4. Diaz Llopis, M. and J.L. Menezo, Congenital hypertrophy of the retinal pigment epithelium and familial polyposis of the colon. Am J Ophthalmol, 1987. 103(2): p. 235-6.
5. Morton, D.G., et al., Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis. Br J Surg, 1992. 79(7): p. 689-93.
6. Polkinghorne, P.J., et al., Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis. Eye, 1990. 4 (Pt 1): p. 216-21.
7. Reese, A.B. and I.S. Jones, Benign melanomas of the retinal pigment epithelium. Am J Ophthalmol, 1956. 42: p. 207-12.
8. Blair, N.P. and C.L. Trempe, Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. Am J Ophthalmol, 1980. 90(5): p. 661-7.
9. Gardner, E.J., Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. AM J Hum Genet, 1962. 14: p. 376-390.
10. Wallis, Y.L., et al., Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition. J Med Genet, 1999. 36(1): p. 14-20.
11. Caspari, R., et al., Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet, 1995. 4(3): p. 337-40.
12. Bunyan, D.J., et al., Genotype-phenotype correlations of new causative APC gene mutations in patients with familial adenomatous polyposis. J Med Genet, 1995. 32(9): p. 728-31.
13. Davies, D.R., et al., Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet, 1995. 57(5): p. 1151-8.
14. Olschwang, S., et al., Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell, 1993. 75(5): p. 959-68.
15. Giardiello, F.M., et al., APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. Gut, 1997. 40(4): p. 521-5.
16. Romania, A., et al., Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology, 1989. 96(6): p. 879-84.
17. Tiret, A. and C. Parc, Fundus lesions of adenomatous polyposis. Curr Opin Ophthalmol, 1999. 10(3): p. 168-72.
18. Tourino, R., et al., Value of the congenital hypertrophy of the retinal pigment epithelium in the diagnosis of familial adenomatous polyposis. Int Ophthalmol, 2004. 25(2): p. 101-12.
19. Kasner, L., et al., A histopathologic study of the pigmented fundus lesions in familial adenomatous polyposis. Retina, 1992. 12(1): p. 35-42.
20. Parker, J.A., et al., Histopathological features of congenital fundus lesions in familial adenomatous polyposis. Can J Ophthalmol, 1990. 25(3): p. 159-63.
21. Traboulsi, E.I., et al., A clinicopathologic study of the eyes in familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome). Am J Ophthalmol, 1990. 110(5): p. 550-61.
22. Burn J, Chapman P, Delhanty J, Wood C, Lalloo F, Cachon-Gonzalez MB, Tsioupra K, Church W, Rhodes M, Gunn A. The UK Northern region genetic register for familial adenomatous polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium, and DNA markers in risk calculations.J Med Genet. 1991 May;28(5):289-9
23. Aiello, L.P. and E.I. Traboulsi, Pigmented fundus lesions in a preterm infant with familial adenomatous polyposis. Arch Ophthalmol, 1993. 111(3): p. 302-3.
24. Shields, J.A., et al., Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis, and Gardner syndrome. Ophthalmology, 1992. 99(11): p. 1709-13.
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