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

OMIM number: 175100   175400  

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

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[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.
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[29] Hoffmann DC, Brooke BN. Familial sarcoma of bone in a polyposis coli family. Dis Colon Rectum 1970; 13(2):119-120.
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[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.
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