Diseases of the Colon & Rectum

, Volume 45, Issue 1, pp 127–134 | Cite as

Attenuated Familial Adenomatous Polyposis

An Evolving and Poorly Understood Entity
  • James M. Church
  • Gerald S. Hernegger
  • Harvey G. Moore
  • Jose G. Guillem
Current Status


PURPOSE: Familial adenomatous polyposis is a well-described, autosomal dominant, inherited syndrome characterized by diffuse polyposis of the colon and rectum as well as various upper gastrointestinal and extraintestinal manifestations. A subset of patients present with fewer colorectal polyps, later age of onset of polyps and cancer, and a predilection toward involvement of the proximal colon. This variant of familial adenomatous polyposis is known as attenuated familial adenomatous polyposis. The purpose of this review is to summarize current knowledge regarding this poorly understood entity and propose guidelines for diagnosis, surveillance, and surgical management. METHODS: The MEDLINE database was searched from 1985 onward using the keywords, “attenuated familial adenomatous polyposis,” “AFAP,” “adenomatous polyposis coli gene,” and “APC gene.” Additional articles were identified through the reference sections of retrieved papers. All papers that pertained to attenuated familial adenomatous polyposis or mutations in the APC gene producing an attenuated phenotype were included. RESULTS: Attenuated familial adenomatous polyposis is transmitted in an autosomal dominant fashion. Several distinct mutations within the APC gene have been associated with an attenuated phenotype, but variability of disease expression within kindreds possessing identical mutations makes classification difficult. Polyps are diagnosed at a mean age of 44 years, with cancer diagnosed at a mean of 56 years of age. Frequent involvement of the proximal colon necessitates the use of colonoscopy for surveillance, and infrequent involvement of the rectum supports the role of a total abdominal colectomy and ileorectal anastomosis. CONCLUSIONS: Although currently recognized as a distinct clinical entity, attenuated familial adenomatous polyposis may be part of a spectrum of disease that includes familial adenomatous polyposis and is caused by different mutations within the APC gene. Because of its unique characteristics, yet apparent overlap with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, increased awareness of attenuated familial adenomatous polyposis should improve diagnosis, surveillance, and treatment strategies in this unique subset of familial polyposis syndromes.


AFAP FAP Familial adenomatous polyposis Attenuated familial adenomatous polyposis Colorectal neoplasms 


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  1. 1.
    Muto, T, Kamiya, J, Sawada, T,  et al. 1985Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features.Dis Colon Rectum28847851Google Scholar
  2. 2.
    Lynch, HT, Smyrk, T, Lanspa, SJ,  et al. 1988Flat adenomas in a colon cancer-prone kindred.J Natl Cancer Inst80278282Google Scholar
  3. 3.
    Lynch, HT, Smyrk, TC, Lanspa, SJ,  et al. 1990Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome.Cancer66909915Google Scholar
  4. 4.
    Leppert, M, Burt, R, Hughes, JP,  et al. 1990Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps.N Engl J Med322904908Google Scholar
  5. 5.
    Spirio, L, Otterud, B, Stauffer, D,  et al. 1992Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus.Am J Hum Genet5192100Google Scholar
  6. 6.
    Lynch, HT, Smyrk, TC, Lanspa, SJ,  et al. 1993Upper gastrointestinal manifestations in families with hereditary flat adenoma syndrome.Cancer7127092714Google Scholar
  7. 7.
    Lynch, HT, Smyrk, T, McGinn, T,  et al. 1995Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP.Cancer7624272433Google Scholar
  8. 8.
    Shih, IM, Yu, J, He, TC, Vogelstein, B, Kinzler, KW 2000The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression.Cancer Res6016711676Google Scholar
  9. 9.
    Rubinfeld, B, Souza, B, Albert, I,  et al. 1993Association of the APC gene product with beta-catenin.Science26217311734Google Scholar
  10. 10.
    Church, JM 1998Anatomy of a gene:Semin Colon Rectal Surg94952Google Scholar
  11. 11.
    Bodmer, WF, Bailey, CJ, Bodmer, J,  et al. 1987Localization of the gene for familial adenomatous polyposis on chromosome 5.Nature328614616Google Scholar
  12. 12.
    Groden, J, Thliveris, A, Samowitz, W,  et al. 1991Identification and characterization of the familial adenomatous polyposis coli gene.Cell66589600Google Scholar
  13. 13.
    Kinzler, KW, Nilbert, MC, Su, LK,  et al. 1991Identification of FAP locus genes from chromosome 5q21.Science253661665Google Scholar
  14. 14.
    Joslyn, G, Carlson, M, Thliveris, A,  et al. 1991Identification of deletion mutations and three new genes at the familial polyposis locus.Cell66601613Google Scholar
  15. 15.
    Giardiello, FM, Brensinger, JD, Luce, MC,  et al. 1997Phenotypic expression of disease in families that have mutations in the 5′ region of the adenomatous polyposis coli gene.Ann Intern Med126514519Google Scholar
  16. 16.
    Dobbie, Z, Spycher, M, Mary, JL,  et al. 1996Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene.J Med Genet33274280Google Scholar
  17. 17.
    Spirio, L, Green, J, Robertson, J,  et al. 1999The identical 5′ splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect.Hum Genet105388398Google Scholar
  18. 18.
    Spirio, L, Olschwang, S, Groden, J,  et al. 1993Alleles of the APC gene:Cell75951957Google Scholar
  19. 19.
    Dobbie, Z, Spycher, M, Hurliman, R,  et al. 1994Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene.Eur J Cancer1117091713Google Scholar
  20. 20.
    Soravia, C, Berk, T, Madlensky, L,  et al. 1998Genotype-phenotype correlations in attenuated adenomatous polyposis coli.Am J Hum Genet6212901301Google Scholar
  21. 21.
    Smith-Ravin, J, Pack, K, Hodgson, S, Tay, SK, Phillips, R, Bodmer, W 1994APC mutation associated with late onset of familial adenomatous polyposis.J Med Genet31888890Google Scholar
  22. 22.
    Su, LK, Barnes, CJ, Yao, W, Yi, Q, Lynch, PM, Steinbach, G 2000Inactivation of germline mutant APC alleles by attenuated somatic mutations:Am J Hum Genet67582590Google Scholar
  23. 23.
    van der Luijt, RB, Vasen, HF, Tops, CM, Breukel, C, Fodde, R, Meera Khan, P 1995APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis.Hum Genet96705710Google Scholar
  24. 24.
    Curia, MC, Esposito, DL, Aceto, G,  et al. 1998Transcript dosage effect in familial adenomatous polyposis:Hum Mutat11197201Google Scholar
  25. 25.
    Ficari, F, Cama, A, Valanzano, R,  et al. 2000APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis.Br J Cancer82348353Google Scholar
  26. 26.
    Young, J, Simms, LA, Tarish, J,  et al. 1998A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9.Hum Mutat11450455Google Scholar
  27. 27.
    Varesco, L, Gismondi, V, Presciuttini, S,  et al. 1994Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death.Hum Genet93281286Google Scholar
  28. 28.
    Scarano, MI, De Rosa, M, Panariello, L,  et al. 1999Familial adenomatous polyposis coli:Hum Mutat13256257Google Scholar
  29. 29.
    Friedl, W, Meuschel, S, Caspari, R,  et al. 1996Attenuated familial adenomatous polyposis due to a mutation in the 3′ part of the APC gene. A clue for understanding the function of the APC protein.Hum Genet97579584Google Scholar
  30. 30.
    van der Luijt, RB, Meera Khan, P, Vasen, HF,  et al. 1996Germline mutations in the 3′ part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli.Hum Genet98727734Google Scholar
  31. 31.
    Eccles, DM, van der Luijt, R, Breukel, C,  et al. 1996Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.Am J Hum Genet5911931201Google Scholar
  32. 32.
    Scott, RJ, Froggatt, NJ, Trembath, RC, Evans, DG, Hodgson, SV, Maher, ER 1996Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3′ APC gene mutation.Hum Mol Genet519211924Google Scholar
  33. 33.
    Brensinger, JD, Laken, SJ, Luce, MC,  et al. 1998Variable phenotype of familial adenomatous polyposis in pedigrees with 3′ mutation in the APC gene.Gut43548552Google Scholar
  34. 34.
    Scott, RJ, van der Luijt, R, Spycher, M,  et al. 1995Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes.Gut36731736Google Scholar
  35. 35.
    Couture, J, Mitri, A, Lagace, R,  et al. 2000A germline mutation at the extreme 3′ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor.Clin Genet57205212Google Scholar
  36. 36.
    Matsubara, N, Isozaki, H, Tanaka, N 2000The farthest 3′ distal end APC mutation identified in attenuated adenomatous polyposis coli with extracolonic manifestations.Dis Colon Rectum43720721Google Scholar
  37. 37.
    Pilarski, RT, Brothman, AR, Benn, P, Shulman Rosengren, S 1999Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q.Am J Med Genet86321324Google Scholar
  38. 38.
    Lamlum, H, Ilyas, M, Rowan, A,  et al. 1999The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation:Nat Med510711075Google Scholar
  39. 39.
    Rowan, AJ, Lamlum, H, Ilyas, M,  et al. 2000APC mutations in sporadic colorectal tumors:Proc Natl Acad Sci U S A9733523357Google Scholar
  40. 40.
    Zwick, A, Munir, M, Ryan, CK,  et al. 1997Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.Gastroenterology113659663Google Scholar
  41. 41.
    Hofgartner, WT, Thorp, M, Ramus, MW,  et al. 1999Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis.Am J Gastroenterol9422752281Google Scholar
  42. 42.
    Lynch, HT, Smyrk, TC 1998Classification of familial adenomatous polyposis:Am J Hum Genet6212881289Google Scholar
  43. 43.
    Powell, SM, Petersen, GM, Krush, AJ,  et al. 1993Molecular diagnosis of familial adenomatous polyposis.N Engl J Med32919821987Google Scholar
  44. 44.
    Rabelo, R, Foulkes, W, Gordon, PH,  et al. 2001Role of molecular diagnostic testing in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families.Dis Colon Rectum44437446Google Scholar
  45. 45.
    Giardiello, FM, Brensinger, JD, Petersen, GM,  et al. 1997The use and interpretation of commercial APC gene testing for familial adenomatous polyposis.N Engl J Med336823827Google Scholar
  46. 46.
    Frazier, ML, Su, LK, Amos, CI, Lynch, PM 2000Current applications of genetic technology in predisposition testing and microsatellite instability assays.J Clin Oncol187074Google Scholar
  47. 47.
    Wallace, MH, Frayling, IM, Clark, SK, Neale, K, Phillips, RK 1999Attenuated adenomatous polyposis coli:Dis Colon Rectum4210781080Google Scholar
  48. 48.
    Lynch, HT, Watson, P 1998AFAP:Gut43451452Google Scholar
  49. 49.
    Steinbach, G, Lynch, PM, Phillips, RK,  et al. 2000The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med34219461952Google Scholar
  50. 50.
    Giardiello, FM, Hamilton, SR, Krush, AJ,  et al. 1993Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.N Engl J Med32813131316Google Scholar
  51. 51.
    Lynch, HT, Thorson, AG, Smyrk, T 1995Rectal cancer after prolonged sulindac chemoprevention. A case report.Cancer75936938Google Scholar
  52. 52.
    Niv, Y, Fraser, GM 1994Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy.Gastroenterology107854857Google Scholar
  53. 53.
    Guillem, JG, Smith, AJ, Calle, JP, Ruo, L 1999Gastrointestinal polyposis syndromes.Curr Probl Surg36217323Google Scholar

Copyright information

© The American Society of Colon and Rectal Surgeons 2002

Authors and Affiliations

  • James M. Church
  • Gerald S. Hernegger
  • Harvey G. Moore
  • Jose G. Guillem

There are no affiliations available

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