FaCD Online Syndrome Fact Sheet

Last updated: 24 Oct 2012

Name: Familial Adenomatous Polyposis

Synonym: FAP, incl.: Gardner s., Attenuated FAP, Flat Adenoma s., Oldfield s,

Mode of Inheritance: AD

Genes

APC, mapped to 5q21-q22

Tumor features

adenomatous polyps in the small intestine
adrenal adenoma
astrocytoma
craniopharyngioma
craniopharyngioma (ectopic)
desmoid
ependymoma
exostoses
gastric fundic gland polyps
gastric hamartomatous polyps
gastrointestinal cancer
gastrointestinal polyps
hepatoblastoma
hepatocellular cancer (hepatoma)
medulloblastoma
nasal neuromas
nasopharyngeal angiofibroma
osteomas
pancreatic adenocarcinoma
pilomatrixoma
thyroid cancer, papillary

Tumor features (possible)

adrenal cancer
biliary tract cancer (incl. gallbladder)
chondrosarcoma
endometrial cancer
fibrosarcoma
gastrointestinal stromal tumor (GIST)
lung/bronchial cancer
malignant fibrous histiocytoma
meningioma
osteosarcoma
ovarian cancer (i.e. epithelial origin)
prolactinoma
rhabdomyosarcoma
salivary gland tumor
testicular Sertoli-Leydig cell tumor
urinary bladder cancer

Non-tumor features

congenital hypertrophy of retinal pigment epithelium (CHRPE)
cranial faciitis
del(5)(q21 and/or q22) (constitutional)
dental abnormalities
epidermoid cysts
sebaceous cysts

Comment

Familial Adenomatous Polyposis (FAP) is characterized by the occurrence of many (> 100 per definition) adenomatous polyps in the intestine and predominantly in the more distal colorectal region[1]. In approximately 70 % of cases a germline mutation in the APC gene can be detected. In approximately 1/3 of cases these mutations arise de novo, the index patients being the first in his family. Several clinical variants of the disorder are known[2]:

- The name Gardner Syndrome was used in the past to refer to Familial Adenomatous Polyposis with extra-gastrointestinal manifestations: jaw osteomas & cysts and dental anomalies[3], exostoses, epidermoid cysts, desmoids and congenital hyperpigmentation of the retinal pigment epithelium (CHRPE's)[3;4]. Multiple familial pilomatrixomas have been observed in association with the Gardner variant[5,50]. Cranial fasciitis is a fibroproliferative lesion that occurs in the scalp of infants. A subset is associated with dysregulation of the Wnt/beta-catenin pathway and cranial faciitis has been observed in a few patients with germline APC mutations[47].

- Attenuated FAP (AFAP)[6], also referred to in the past as Flat Adenoma syndrome[7], is a variant characterized by a later age of onset, a much lower number of polyps and more proximal localization of the polyps. Diagnosing AFAP can be difficult on clinical grounds if the number of polyps is relatively low. However, Wallace et al.[8] have suggested that dye-spraying the colonic mucosa during endoscopy will reveal large numbers of smaller polyps in true (i.e. APC-gene associated) AFAP patients). Mutations in the APC gene are found in specific regions.

- A subset of FAP patients develop brain tumors[9,35]. In addition, a hereditary polyposis-brain tumor syndrome might exists which is not associated with APC (or MMR, Lynch syndrome associated gene) mutations and has been referred to as Turcot syndrome.
- FAP probably includes the combination of polyposis and multiple sebaceous gland cysts referred to by some as Oldfield syndrome/disease[10;11]

A wide range of tumors is associated with FAP. If a prophylactic colectomy is not performed then inevitably colorectal cancer develops, on average in the fourth decade. After prophylactic colectomy, duodenal cancer (often around the ampulla of Vater where most duodenal adenomatous polyps develop[12]) is the leading cause of death, followed by the complications of desmoid disease. As much as 8 % of the total gastric cancer burden has been attributed to Familial Adenomatous Polyposis (FAP)[13]. However, contrary to Japanese and Korean FAP patients, gastric cancer risk appears not to be significantly increased in Western-European FAP patients[1], which might be due to differences in environmental (dietary) risk factors. Gastric adenocarcinoma in FAP usually originates from adenomatous polyps. In contrast, the most common type of gastric polyps in FAP, referred to as fundic gland polyps, are regarded as either hyperplastic or hamartomatous[14,15] and rarely show malignant transformation[16,17].

Other tumors reported in FAP include[18]: hepatoblastoma [19,20,49], hepatocellular cancer and adenomas[42,46], pancreatic adenocarcinoma (Relative Risk (RR) = 4.5[21])[22], thyroid cancer(RR = 7.6[21,23,49]), cancer of the biliary tree[21,24], ovarian adenocarcinoma[25], salivary pleomorphic gland adenoma[26], fetal type adenocarcinoma of the lung[27], endometrial cancer[25,28], bladder cancer[18], osteosarcoma and fibrosarcoma of bone, fibro/fibro-mixoid sarcoma and malignant fibrous histiocytoma of the soft tissues[29,39,40,45], rhabdomyosarcoma[41], nasopharyngeal angiofibroma[30], adrenal adenomas[31,43,44,49], adrenal cancer[21,32-34], GIST[36], prolactinoma[37], meningioma[38], craniopharyngioma[48] bilateral testicular Sertoli cell tumor[51].

References

[1] Phillips RKS, Spiegelman AD, Thomson JPS. Familial Adenomatous Polyposis and other polyposis syndromes. London: Edward Arnold, 1994.
[2] Lynch HT, Smyrk TC. Classification of familial adenomatous polyposis: A diagnostic nightmare. Am J Hum Genet 62[6], 1288-1289. 1998.
[3] Thakker N, Davies R, Horner K, Armstrong J, Clancy T, Guy S, Harris R, Sloan P, Evans G. The dental phenotype in familial adenomatous polyposis: Diagnostic application of a weighted scoring system for changes on dental panoramic radiographs. J Med Genet 1995; 32:458-464.
[4] Houlston RS, Fallon T, Harocopos C, Williams CB, Davey G, Slack J. Congenital hypotrophy of retinal pigment epithelium in patients with colonic polyps associated with cancer family syndrome. Clin Genet 1992; 42:16-18.
[5] Pujol RM, Casanova JM, Egido R, Pujol J, de Moragas JM. Multiple familial pilomatricomas: a cutaneous marker for Gardner syndrome? Pediatr Dermatol 1995; 12(4):331-335.
[6] Lynch HT, Smyrk T, Mcginn T, Lanspa S, Cavalieri J, Lynch J, Slominski-Castor S, Cayouette MC, Priluck I, Luce MC. Attenuated familial adenomatous polyposis (AFAP): A phenotypically and genotypically distinctive variant of FAP. Cancer 1995; 76:2427-2433.
[7] Lynch HT, Smyrk TC, Watson P, Lanspa S, Lynch PM, Jenkins JX, Rouse J, Cavalieri J, Howard L, Lynch J. Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis. Dis Colon Rectum 1992; 35:411-421.
[8] Wallace MH, Frayling IM, Clark SK, Neale K, Phillips RK. Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 1999; 42(8):1078-1080.
[9] Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GH, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler KW. The molecular basis of Turcot's syndrome. N Engl J Med 1995; 332:839-847.
[10] Oldfield MC. Tha association of familial polyposis of the colon with multiple sebaceous cysts. Br J Surg 1954; 41:534-541.
[11] Muller Hj. Dominant inheritance in human cancer. Anticancer Res 1990; 10:505-512.
[12] Wallace MH, Phillips RKS. Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Surg 85[6], 742-750. 1998.
[13] Peddanna N, Holt S, Verma RS. Genetics of gastric cancer. Anticancer Res 1995; 15(5B):2055-2064.
[14] Wu TT, Kornacki S, Rashid A, Yardley JH, Hamilton SR. Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis. Am J Surg Pathol 22[3], 293-298. 1998.
[15] Odze RD, Marcial MA, Antonioli D. Gastric fundic gland polyps: A morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry. Hum Pathol 27[9], 896-903. 1996.
[16] Zwick A, Munir M, Ryan CK, Gian J, Burt RW, Leppert M, Spirio L, Chey WY. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. GASTROENTEROLOGY 113[2], 659-663. 1997.
[17] Hofgartner WT, Thorp M, Ramus MW, Delorefice G, Chey WY, Ryan CK, Takahashi GW, Lobitz JR. Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol 1999; 94(8):2275-2281.
[18] Nugent KP, Spigelman AD, Phillips RKS. Risk of extracolonic cancer in familial adenomatous polyposis. Br J Surg 83[8], 1121-1122. 1996.
[19] Giardiello FM, Offerhaus GJA, Krush AJ, Booker SV, Tersmette AC, Mulder JWR, Kelley CN, Hamilton SR. Risk of hepatoblastoma in familial adenomatous polyposis. J Pediat 1991; 119(5):766-768.
[20] Hughes LJ, Michels VV. Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 1992; 43(6):1023-1025.
[21] Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, Kelley NC, Hamilton SR. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 1993; 34(10):1394-1396.
[22] Stewart CJR, Imrie CW, Foulis AK. Pancreatic islet cell tumour in a patient with familial adenomatous polyposis. J Clin Pathol 1994; 47:860-861.
[23] Cetta F, Toti P, Petracci M, Montalto G, Disanto A, Lore F, Fusco A. Thyroid carcinoma associated with familial adenomatous polyposis. Histopathology 31[3], 231-236. 1997.
[24] Walsh N, Qizilbash A, Banerjee R, Waugh GA. Biliary neoplasia in Gardner's syndrome. Arch Pathol Lab Med 1987; 111:76-77.
[25] Sohrabi AK, Nowzari P. Spectrum of clinical manifestations of familial adenomatous polyposis. W V Med J 1992; 88(5):193-194.
[26] Gerrard DJ, Donaldson DR. Salivary pleomorphic adenoma in familial adenomatous polyposis. J R Soc Med 91[2], 86-87. 1998.
[27] Wong RP, Hwang WS, Field SK. Familial adenomatous polyposis and lung cancer. J Surg Oncol 1995; 60(3):213-214.
[28] Honore LH, Davey SJ. Endometrial carcinoma in young women. A report of four cases. J Reprod Med 1989; 34(10):845-849.
[29] Hoffmann DC, Brooke BN. Familial sarcoma of bone in a polyposis coli family. Dis Colon Rectum 1970; 13(2):119-120.
[30] Giardiello FM, Hamilton SR, Krush AJ, Offerhaus JA, Booker SV, Petersen GM. Nasopharyngeal angiofibroma in patients with familial adenomatous polyposis. GASTROENTEROLOGY 1993; 105:1550-1552.
[31] Kartheuser A, Walon C, West S, Breukel C, Detry R, Gribomont AC, Hamzehloei T, Hoang P, Maiter D, Pringot J, Rahier J, Khan PM, Curtis A, Burn J, Fodde R, Verellen-Dumoulin C. Familial adenomatous polyposis associated with multiple adrenal adenomas in a patient with a rare 3' APC mutation. J Med Genet 36, 65-67. 1999.
[32] Wakatsuki S, Sasano H, Matsui T, Nagashima K, Toyota T, Horii A. Adrenocortical tumor in a patient with familial adenomatous polyposis: A case associated with a complete inactivating mutation of the APC gene and unusual histological features. Hum Pathol 29[3], 302-306. 1998.
[33] Painter TA, Jagelman DG. Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum. Cancer 1985; 55:2001-2004.
[34] Naylor EW, Gardner EJ. Adrenal adenomas in a patient with Gardner's syndrome. Clin Genet 1981; 20:67-73.
[35] Attard TM, Giglio P, Koppula S, Snyder C, Lynch HT. Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis. Cancer 2007; 109(4):761-6.
[36] Moschos J, Tzilves D, Paikos D, Tagarakis G, Pilpilidis I, Antonopoulos Z, Kadis S, Katsos I, Tarpagos A. Large mesenteric gastrointestinal stromal tumor in a patient with familial adenomatous polyposis syndrome. Wiener klinische Wochenschrift 2006; 118(11-12):355-7.
[37] Goodin GS, McCarville MB, Thibodeau SN, Skapek SX, Khoury JD, Spunt SL. Prolactinoma as the first manifestation of Gardner's syndrome. Pediatric blood & cancer 2008; 50(2):409-12.
[38] Leblanc R. Familial adenomatous polyposis and benign intracranial tumors: a new variant of Gardner's syndrome. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 2000; 27(4):341-6.
[39] Jannasch O, Dombrowski F, Lippert H, Meyer F. Rare coincidence of familial adenomatous polyposis and a retroperitoneal fibromyxoid sarcoma: report of a case. Diseases of the colon and rectum 2008; 51(4):477-81.
[40] Tulchinsky H, Keidar A, Strul H, Goldman G, Klausner JM, Rabau M. Extracolonic manifestations of familial adenomatous polyposis after proctocolectomy. Archives of surgery 2005; 140(2):159-63; discussion 164.
[41] Armstrong SJ, Duncan AW, Mott MG. Rhabdomyosarcoma associated with familial adenomatous polyposis. Pediatric radiology 1991; 21(6):445-6.
[42] Gruner BA, DeNapoli TS, Andrews W, Tomlinson G, Bowman L, Weitman SD. Hepatocellular carcinoma in children associated with Gardner syndrome or familial adenomatous polyposis. Journal of pediatric hematology/oncology 1998 May-Jun; 20(3):274-8.
[43] Roos A, Groen EJ, van Beek AP. Cushing's syndrome due to unilateral multiple adrenal adenomas as an extraintestinal manifestation of familial adenomatous polyposis. International journal of colorectal disease 2008; epub ahead of print .
[44] Beuschlein F, Reincke M, Königer M, D'Orazio D, Dobbie Z, Rump LC. Cortisol producing adrenal adenoma--a new manifestation of Gardner's syndrome. Endocrine research 2000; 26(4):783-90.
[45] Jannasch O, Dombrowski F, Lippert H, Meyer F.Rare coincidence of familial adenomatous polyposis and a retroperitoneal fibromyxoid sarcoma: report of a case. Dis Colon Rectum. 2008 Apr;51(4):477-81.
[46] Okamura Y, Maeda A, Matsunaga K, Kanemoto H, Furukawa H, Sasaki K, Yamaguchi S, Uesaka K.J. Hepatocellular adenoma in a male with familial adenomatous polyposis coli. Hepatobiliary Pancreat Surg. 2009 Mar 14. [Epub ahead of print]
[47] Rakheja D, Cunningham JC, Mitui M, Patel AS, Tomlinson GE, Weinberg AG. A subset of cranial fasciitis is associated with dysregulation of the Wnt/beta-catenin pathway. Mod Pathol. 2008 Nov;21(11):1330-6.
[48] Bozbuga M, Turan Suslu H, Hicdonmez T, Bayindir C. Primary cerebellopontine angle craniopharyngioma in a patient with Gardner syndrome. J Clin Neurosci. 2011 Jan 6. [Epub ahead of print]
[49] Groen EJ, Roos A, Muntinghe FL, Enting RH, de Vries J, Kleibeuker JH, Witjes MJ, Links TP, van Beek AP. Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg Oncol. 2008 Sep;15(9):2439-50
[50] Trufant J et al. Familial multiple pilomatrixomas as a presentation of attenuated adenomatosis polyposis coli. Journal of cutaneous pathology 2012; 39:440-3.
[51] Xiao GQ, Granato RC, Unger PD. Bilateral Sertoli cell tumors of the testis-a likely new extracolonic manifestation of familial adenomatous polyposis. Virchows Arch. 2012 Oct 23. [Epub ahead of print]