Late-Onset Biallelic Mismatch Repair Deficiency Syndrome

Abstract

A 33-year-old man with a history of successfully treated low-grade follicular lymphoma 2-years prior was evaluated for recurrent aching upper abdominal pain, early satiety, and fatigue. He denied overt gastrointestinal bleeding, but reported occasional night sweats, chills, and weight loss. His family history was notable for esophageal cancer in his father and gastric cancer in his mother. Physical examination showed 2 café-au-lait macules on the lower abdomen but no lymphadenopathy, abdominal tenderness, or mass was appreciated. Laboratory tests showed mild normocytic anemia and normal liver enzyme levels. An abdominal computed tomographic (CT) enterography showed bowel-wall thickening and luminal narrowing extending over the proximal jejunum (Figure A, arrow). Positron emission tomography showed corresponding activity, highlighting the small bowel as the primary source (Figure B). A CT-guided biopsy showed metastatic adenocarcinoma of an unknown primary favoring a gastrointestinal source. Upper endoscopy was unremarkable. Colonoscopy showed multiple large adenomas in the proximal colon (Figure C). The patient underwent small-bowel surgical excision. Histologic examination of the specimen showed a biphasic tumor containing both mucinous and gland-forming parts (Figure D, top, H&E). Immunohistochemistry testing of the adenocarcinoma showed intact MLH1, MSH2, and PMS2 nuclear staining but abnormal (absent) MSH6 nuclear staining in both normal and tumor mucosa (Figure D, bottom). The diagnosis of biallelic mismatch repair deficiency (BMMRD) syndrome (also known as constitutional mismatch repair deficiency) was made, which is a rare autosomal-recessive hereditary cancer syndrome that results from biallelic germline mutations in 1 of the 4 mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. The combination of café-au-lait macules, small-bowel adenocarcinoma, adenomatous colon polyps, and a history of lymphoma was highly suggestive of BMMRD. The absence of MSH6 expression in the tumor and normal tissue indicated biallelic MSH6 mutations. The tumor spectrum of BMMRD is broad, including hematologic, brain, and gastrointestinal tract tumors.1Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Google Scholar These individuals often have dermatologic findings of neurofibromatosis type 1, such as café-au-lait macules. Although most often a childhood cancer syndrome, BMMRD has a less-penetrant phenotype in which individuals remain unaffected until the third or fourth decade of life (as in our patient). In addition, tumor immunohistochemistry testing often is difficult to interpret in BMMRD cases because the control (normal tissue) has absent MMR staining. Unlike the autosomal-dominant mutation of a MMR gene in Lynch syndrome, BMMRD is much less understood.2Vasen H. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium ‘Care for CMMR-D’(C4CMMR-D).J Med Genet. 2014; 51: 283-293Google Scholar, 3Durno C. Boland C.R. Cohen S. et al.Recommendations on surveillance and management of Biallelic Mismatch Repair Deficiency (BMMRD) syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2017; 152: 1605-1614Google Scholar Although BMMRD recommendations for screening young persons have been formulated, the surveillance and tumor spectrum in adults remains less clear.3Durno C. Boland C.R. Cohen S. et al.Recommendations on surveillance and management of Biallelic Mismatch Repair Deficiency (BMMRD) syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2017; 152: 1605-1614Google Scholar This case illustrates several important points. First, one should maintain a high suspicion for hereditary cancer syndromes. Second, the finding of café-au-lait macules can be an important clue to BMMRD. Third, BMMRD has a broad tumor spectrum that includes multiple polyps and should be in the differential diagnosis of colonic adenomatous polyposis. Finally, the syndrome most often presents in childhood but may have a late-onset presentation, highlighting the need for increased awareness of this condition by adult gastroenterologists.