Answer: D - Benign and/or malignant extracolonic manifestations

This is a case of MUTYH-associated polyposis syndrome (MAP), which is an autosomal recessive condition. This attenuated polyposis syndrome is caused by mutation(s) of the MUTYH gene (located on chromosome1).¹ MUTYH is an excision repair gene, the resulting protein repairs oxidative damage to the DNA. Y179C and G396D (previously known as Y165C and G382D) comprise the two most common pathogenic variants of MUTYH gene in North Americans and Western Europeans (several other pathogenic variants are also recognized). Approximately 1-2% of the general population carries a monoallelic pathogenic germline variant of MUTYH gene. Patients with MAP can be homozygous or compound heterozygous for germline variants. Less than 1% of all individuals with colorectal cancer carry biallelic pathogenic MUTHY gene variants.^2,3 Overall, studies indicate MAP is rare and responsible for less than 1% of all colorectal cancers.⁴ 

Affected individuals with pathogenic biallelic mutations have increased lifetime risk of colorectal cancer, intestinal polyps and extraintestinal disease. Patients with MAP often develop numerous colonic adenomas, but serrated adenomas, hyperplastic polyps, and duodenal adenomas can be also encountered. Patients can present with anywhere from 10 to 100 polyps. Although the majority of intestinal cancers in this setting are microsatellite stable, a small number of microsatellite instability-high cancers have been reported. Distinct pathways, APC-gene related and APC-gene nonrelated, have been proposed implicated in developing adenomas and serrated polyps, respectively.^5,6

In addition to the increased risk of developing colorectal/ enteric malignancies, MUTYH-associated polyposis- affected individuals are more prone to develop malignancies of the ovary, thyroid, and bladder. There is also some evidence of increased risk for endometrial and breast cancers in these patients. Non-cancerous extraintestinal manifestations of the disease include thyroid nodules, gastric fundic gland polyps, benign adrenal lesions, jawbone cysts, dental anomalies, and congenital hypertrophy of the retinal pigment epithelium, amongst others.^7,8

Reference:

1.       Patel R, McGinty P, Cuthill V, et al. MUTYH-associated polyposis - colorectal phenotype and management. Colorectal Dis. 2020;22(10):1271-1278.

2.       MUTYH-associated polyposis. https://www.uptodate.com/contents/mutyh-associated-polyposis. Topic last updated June 2022.

3.       MUTHY Gene. https://medlineplus.gov/genetics/gene/mutyh/. Last updated April 2008.

4.       Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009;136(4):1251-1260.

5.       Boparai KS, Dekker E, Van Eeden S, et al. Hyperplastic polyps, and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 2008; 135:2014.

6.       Jo WS, Bandipalliam P, Shannon KM, et al. Correlation of polyp number and family history of colon cancer with germline MYH mutations. Clin Gastroenterol Hepatol 2005; 3:1022.

7.       Nielsen M, Infante E, Brand R. MUTYH Polyposis. NCBI. Ncbi.nlm.nih.gov. Initial posting Oct 2012. Last revision: May 2021.

8.       Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348:791.