Table 1

Hereditary disorders in which CRC is an integral lesion

Hereditary form of colorectal cancer (CRC)Inheritance patternGenePolypsCancer
Familial adenomatous polyposis (FAP)AD APCgene at chromosome 5q, mutation distal to 5′Adenomatous, often start in distal colon/rectum; usually >100; adenomas may occur in small bowel; gastric polyps common, usually fundic gland polypsCRC, average age onset 39; many cases teens and twenties; cancer of small bowel; stomach (particularly in Japan), papillary thyroid cancer, periampullary carcinoma, sarcoma, brain tumour

Attenuated familial adenomatous polyposis coli (AFAP)AD APC gene at chromosome 5q, proximal to 5′Ordinary adenomas but also flat adenomas with proximal colonic predominance; may be few (5–10), sometimes >100CRC with average age onset at 55; occasional periampullary carcinoma
Ashkenazi Jewish 11307K mutationAD11307K mutation inAPC Occasional adenomatous colonic polypsCRC, “young” but average age of onset not known
Turcot’s syndrome (HNPCC)AD(Both FAP (APC) and HNPCC,hPMS2, hMLH1mutation variants)Multiple colonic adenomas, but may not be floridCRC and central nervous system, particularly brain tumours. In APC (FAP families) cerebellar medulloblastomas. In hMLH1 andhPMS2 (HNPCC families) glioblastoma multiforme
Juvenile polyposis coliADProtein tyrosine phosphate gene (PTEN) SMAD4/DPC4Diffuse harmatomatous polyps (may have adenomatous component) of colon, but may occur in small bowel and stomachCRC
Peutz-Jeghers syndromeADGene encoding serine threonine kinase (STK11) on chromosome 19p13.3LKB1/STK11 Peutz-Jeghers polyps (may have adenomatous features) in stomach, small bowel, and colonStomach, small bowel, colon, sex cord tumours of ovary and testes
Hereditary mixed polyposis syndrome (IMPS)ADUnknown; possible site on chromosome 6qAtypical colonic juvenile polyps, adenomatous and hyperplastic polyps; usually less than 15 colon polypsCRC
Discrete colonic adenomatous polyps and CRC of BurtAD; may be similar to some familial CRCOccasional (never florid) adenomatous colonic polypsCRC, average age in accord with population expectations
Hereditary non-polyposis colorectal cancer (HNPCC)ADGermline mutations of any of the mismatch repair genes: hMSH2 at chromosome 2p; hMLH1 at chromosome 3p;hPMS1 at chromosome 2q;hPMS2 at chromosome 7qOccasional colonic adenomas which are on average larger, more villous, and at younger age than general population. Colonic polyps no more frequent than general populationCRC most common with proximal predominance, an excess of synchronous and metachronous CRC. Others include cancer of the endometrium, ovary, small bowel, stomach, and transitional cell carcinoma of ureter and renal pelvis. Average age of cancer onset is 44; may show rapid progression from adenoma to CRC
Familial CRCEmpirical risk 3 fold increase for CRC in patients with one or more first degree relatives with CRC; likely multifactorial and/or low penetrant genesUnknownIn accord with population expectationsCRC, comparabe to general population for age of onset and colonic location
Inflammatory bowel disease (ulcerative colitis (UC) and Crohn’s disease (CD))

Unknown; possible AD in some families; polygenic also likelyLinkage to chromosome 16 (IBD1) and 12 (IBD2), findings which are tentativePseudopolyps (non-adenomatous)CRC, lymphoma of GI tract
Non-cancer featuresScreeningSurgical management/prophylaxisPresymptomatic DNA testingGenetic counselling
Gardner’s variant-epidermoid cysts of skin, osteomas of mandible, congenital hypertrophy of the retinal pigment epithelium. Desmoid tumours (intrabodiminal) do not metastasise but may kill by direct extension; desmoids may be initiated by surgery (dissected surfaces); adrenal adenomasBaseline flexible sigmoidoscopy age 10–12, and annually thereafter, for APCgermline positive. If at risk but not tested forAPC, same strategy. If eventually found to be APC negative, then baseline flexible sigmoidoscopy at age 15–20; if negative, no further screening. Upper endoscopy every 1–3 years starting when colonic polyps first appear. Screen remaining rectal segment (annually) after surgical prophylaxisProphylactic subtotal colectomy with low ileorectal anastomosis when phenotype (florid polyposis) identified; may be considered rectal mucosectomy with ileal pouch anal anastomosis if too many rectal polyps to manage or if compliance for rectal segment follow up is poor. Consider sulindac chemoprevention (while reducing polyps, cancer may still occur)Test for APCgermline mutation as early as age 10–12Initiate pre-teens, include parents
Fundic gland polyps in stomach; adenomas in duodenumColonoscopy and upper endoscopy, initiate at age 20 and annually forAPC germline positive patients or every 2 years if at genetic risk but not tested forAPC Prophylactic subtotal colectomy if too many polyps to manage; consider chemo-preventative sulindacTest forAPC germline mutation at age 20Initiate at age 20, include parents
None knownFull colonoscopy, start at age 30–35 in gene carriersStandard CRC surgeryAshkenazi APC mutationStart at age 25
Rare examples of multiple café au lait spots and pigmented naevi but not clear if truly integral to the syndromeBaseline flexible sigmoidoscopy age 10–12 and annual flexible sigmoidoscopy thereafter; consider CT scan or MRI of brain

Prophylactic subtotal colectomy if colonic polyps present, as in FAP. In HNPCC variant, colonoscopyTwo DNA variants:
(1) APC gene with predominance of cerebellar medulloblastoma,
(2)hMLH1 or hPMS2 with predominance of glioblastoma multiforme
Initiate age 10–12, include parents
Children may manifest diarrhoea (may be severe)Initiate colonoscopy age 10–12Prophylactic subtotal colectomy when phenotype present with too many polyps to manageTyrosine phosphate gene (PTEN)Initiate preteens, include parents
Mucocutaneous melanin pigmentationBaseline colonoscopy and upper endoscopy, initiate age 20; flexible sigmoidoscopy annually thereafterConsider prophylactic subtotal colectomy if too many polyps to manage and if mixed adenomatous featuresSerine threonine kinase (STK11) on chromosone 19p13.3Initiate teens, include parents
None knownColonoscopy, initiate at age 20, 2–3 yearsPolypectomy; consider prophylactic colectomy if polyps too many to manageNone knownInclude initiation in teens
None knownInitiate baseline flexible sigmoidoscopy at age 40 and every 3 years thereafter

Standard CRC surgical approachNone knownInitiate at age 25–30
Muir-Torre syndrome variant shows cancer features of HNPCC but includes sebaceous adenomas, sebacous epitheliomas, basal cell epitheliomas with sebaceous differentiation, meibomian gland carcinomas and sebaceous carcinomas; single or multiple keratoacanthomas 
Colonoscopy, initiate age 20–25, annually for germline muttion carriers; every other year when mutation studies are lacking; endometrial aspiration biopsy at the same time as colonoscopySubtotal colectomy for initial CRC; consider option of prophylactic subtotal colectomy for germline carriers; consider prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy for patients with initial CRC who have completed their familiesTest for germline mutations no earlier than age 18–20Initiate at age 18, before any consideration for gene testing
NoneBaseline flexible sigmoidoscopy at age 35, repeat every 3 years; if two first degree relatives affected or one less than age 50 years, risk is 4–6 fold increased and full colonoscopy every 3–5 years is indicatedStandard surgical procedure for CRCNone knownInitiate at age 30–35
UC: arthritis, pyoderma gangrenosum, annular erythemas, and vascular thromboses, sclerosing cholangitis
CD: similar to UC but small bowel involvement prominent, and may involve colon
UC: colonoscopy, annual in patients with chronic pancolitis of 8 or more years duration; check for high grade dysplasia of colonic mucosa.
CD: BE may help;x ray of small bowel may show rigidity, narrowing submucosal oedema or stenosis, inflammation, “cobblestoned appearance” may see clinical and genetic overlap in UC and CD
Subtotal colectomy for CRC; consider prophylactic subtotal colectomy for patients with persistent high grade dysplasia of colonic mucosa in UC. Proctocolectomy if IBD mandatesNone knownInitiate at age 18–20
  • AD=autosomal dominant. CRC=colorectal cancer. IBD=inflammatory bowel disease. UC=familial ulcerative colitis. CD=Crohn’s disease.

  • Adapted with permission from Lynch et al.Eur J Cancer1995;31A:1039-46.