Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that is associated with a high risk of developing colorectal, stomach, endometrial, and several other types of cancers. HNPCC accounts for about 1% of colorectal cancers, and its prevalence is estimated to be 1:3000. Some populations, e.g. Finns, show a founder effect. Despite the availability of genetic tests for Lynch syndrome, family history remains the most important tool for the diagnosis of this disease.
HNPCC is defined by variations in genes that encodes components of the DNA mismatch repair (MMR) system. Mutations in these genes lead to failure of the repair mechanism and the errors introduced into DNA during DNA replication gets accumulated over time resulting in cells with very high rates of somatic mutation. These cellular events may prompt the inactivation of tumor suppressor genes or activation of cellular oncogenes, thereby, triggering cancer development. To date, mutations in four genes - MSH2, MLH1, PMS2, and MSH6, all of which encodes components of the mismatch repair pathway have been shown to increase the risk of developing Lynch syndrome. MSH2 and MLH1 variations account for approximately 90% of HNPCC and service provision is generally based on analysis of these two genes. Mutations in EPCAM gene involved in MSH2 gene regulation have also been known to cause Lynch syndrome.
Farah et al. (2001) studied the history of a Lebanese family consisting of ten siblings with Lynch syndrome type II. The father died at the age of 51 years from colon cancer and nine of the siblings (90%) presented varied spectrum of tumors in addition to that in the colon. One of these siblings presented at the age of 69 a metachronous colonic adenocarcinoma at the splenic flexure, and an ampullary adenocarcinoma. Four years later, he presented an obstructing metachronous tumor of the descending colon. Another sibling was admitted at 40 years of age for surgery to remove an adrenocarcinoma of the right colon. Seventeen years later, he had a subtotal colectomy with ileo-rectal anatomosis for a metachronous tumor in the descending colon. Two years later, he developed a third metachronous adenocarcinoma in the rectal remnant. Two more years later, he showed a mass in the region of the rectum, and erosion of the sacrum anteriorly with thickening of the mesenteries and fluid in the pelvis suggestive of mesenteric seeding. He died at the age of 63. Three of the other siblings had carcinoma of the colon resected, one also had a gastric leimyoma, and a fourth underwent colonic removal of polyps. Some of the siblings also suffered from kidney tumor, breast and uterus, and hepatic tumor [See also: Syria > Farah et al., 2001].
[Farah S, Abyad A, Mourad FH, Uthman S. Lynch syndrome: report of two Families from Lebanon and clinical review. Emirates Med J. 200; 19(3):181-5.]
Farah et al. (2001) reported a Syrian family diagnosed with Lynch syndrome. The father and the four siblings showed many features of Lynch syndrome I. The father died at the age of 71 because of colon cancer. The index case was 41 years old when she became pregnant and presented a transverse colon tumor. Follow-up colonoscopy revealed a metachronous splenic fleure tumor. The eldest brother had an ascending colon carcinoma and presented symptoms of post-prandial crampy abdominal pain and distension. The other sibling died prior to the time of analysis. However, sigmoidoscopy with biopsies showed adenocarcinoma of the colon 8 cm from the anal verge. This tumor was not completely respectable because of adherence to the bony pelvis posteriorly. The fourth sibling was 50 years old and revealed three polyps which were removed. Two of the polyps showed mild to moderate dysplasia. The third polyp from the sigmoid colon had adenocarcinoma in situ with a free base and pedicle.