DGM (Dutch-German Mennonite)

Inheritance: autosomal dominant
Genes: APC

APC

Adneomatous intestinal polyposis

Familial adenomatous polyposis

Familial polyposis of the colon

FAP1

Gardner syndrome

GS

Colon cancer

Intestinal polyps

CHRPE

Sebaceous cysts

Dermoid cysts

Dental anomalies

Extra-intestinal tumors

Adenomatous Polyposis of the Colon

Clinical Characteristics

General description (for patients):

The risk of cancer in the GI tract arising from polyps is well known and one of the major reasons why periodic examination of the colon and bowels is so strongly recommended.  Many polyps are not hereditary but in this disorder, the risk for their development is high with a similar risk of colon cancer.  However, benign and malignant tumors may arise in other tissues, including bone, brain, thyroid and bladder.  Dental abnormalities such as impacted and crooked teeth are also seen.  Many tumors can be treated if caught early, and since the risk is as high as 50 per cent that other relatives have the same disease, careful monitoring and frequent medical checkups are important for the entire family.  Such diligence makes this a treatable disease.

Medical description:

This is one of two disorders among plain people in which mutations cause an increased risk of colon cancer (see also hereditary non-polyposis colon cancer, OMIM *120435).  Patients develop large numbers of colon and rectal polyps, some of which become cancerous.  Other frequent tumors include osteomas, leioimyomas, fibromas, lipomata, and fibrosarcomas.  Additional features include sebaceous and dermoid cysts, dental abnormalities, and other extra-colonic cancers such as those of the thyroid and bladder.  Some patients have polyps in the upper GI tract as well, including the stomach.  A condition known as congenital hypertrophy of the retinal pigment epithelium (CHRPE), a benign, stationary retinal condition, can be mistaken for a malignant melanoma, but may also be a sensitive extra-colonic clinical marker for FAP.  Ninety per cent of documented Gardner syndrome patients have such fundus lesions.

Genetics:

Familial adenomatous polyposis is a well known autosomal dominant disorder caused by a mutation in the APC gene located on chromosome 5 (5q21-q22).  It is an allelic disorder to desmoid disease.  Hundreds of mutations in the APC gene have been found but, recently, a novel germline deletion in its 1A promoter region was reported in several Canadian Mennonite kindreds.  The large deletion in the promoter together with deletion of the adjacent 5’ UTR resulted in a lack of transcription of the FAP gene, which normally functions as a tumor suppressor.

Treatment:

There is no treatment for the primary mutation but non-steroidal anti-inflammatory agents such as aspirin and sulindac may lead to some reduction in size or even disappearance of polyps.  Obviously, treatment of tumors including malignancies should be undertaken in the same manner as in other cancer patients.

Prognosis:

The prognosis is highly variable for individual patients due to the wide variation in expression.  Some heterozygotes never develop tumors whereas others develop multiple types in many locations.

Ancillary treatments and support:

The high risk conferred by this mutation requires that relatives at risk be screened for the mutant gene and should have frequent GI evaluations.

Specialists and speciality centres:

Internist, gastroenterologist, oncologist.

References:

Chapman, P.D., Church, W., Burn, J., and Gunn, A.:  Congenital hypertrophy of retinal pigment epithelium: a sign of familial adenomatous polyposis.  Brit. Med. J. 298: 353-354, 1989.  PubMed ID: 2538178

Charames, G.S., Ramyar, L., Mitri, A., Berk, T., Cheng, H., Jung, J., Bocangel, P., Chodirker, B., Greenberg, C., Spriggs, E., and Bapat, B.:  A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred.  Hum. Genet. 124: 535-541, 2008.  PubMed ID: 18982352

Traboulsi, E. I., Krush, A. J., Gardner, E. J., Booker, S. V., Offerhaus, G. J. A., Yardley, J. H., Hamilton, S. R., Luk, G. D., Giardiello, F. M., Welsh, S. B., Hughes, J. P., and Maumenee, I. H.:  Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome.  New Eng. J. Med. 316: 661-667, 1987.  PubMed ID : 3821797

Resources:

NIH Genetics Home Reference

Associated Graphics