Lynch syndrome in a 15-year-old boy
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Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, dominantly inherited, is characterized by the development of a variety of cancers due to germline mutations in DNA mismatch repair genes (MMR). This syndrome was diagnosed in a 15-year-old boy because his father and grandmother were also found to have the same kind of cancer. Microsatellite instability prompted a search for germline mutations in the MLH1, MSH2, MSH6, and PMS2 genes. Use of immunohistochemical staining for MMR proteins, genomic sequencing, and deletion studies, evidenced MSH2 axonal deletion. Neoplastic lesions of colon are most often encountered in the adult population but can, on rare occasions, be found in younger patients. We would like to emphasize the importance of suspecting Lynch syndrome and performing genetic studies, even in young patients, when there is a familiy history of colorectal cancer.
KeywordsLynch syndrome Colorectal cancer Microsatellite instability
hereditary nonpolyposis colorectal cancer
mismatch repair genes
Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is a dominantly inherited syndrome characterized by the development of a variety of cancers including colorectum, endometrium and, less frequently, small bowel, stomach, urinary tract, ovaries, and brain [2, 6]. HNPCC is due to germline mutations in DNA mismatch repair (MMR) genes, mainly MSH2 and MLH1. Defects on this pathway lead to changes in the length of nucleotide repeat sequences of DNA, termed microsatellite instability [1, 3].
Colonoscopy demonstrated one large and pedicle villous polypoid lesion in the transverse colon, about 50 cm proximal to the anus. The polyp was removed and showed histologic characteristics consistent with villous adenoma (3 × 5 cm). A subtotal colectomy was performed. The postoperative period was uneventful, and the patient was completely symptom free throughout 4 years of follow-up.
In this patient and his father, screening results were positive for microsatellite instability. Germline mutations in the MLH1, MSH2, MSH6, and 23 PMS2 genes were evidenced with immunohistochemical staining for MMR proteins, genomic sequencing, and deletion studies showing in MSH2 axonal deletion (axons 7 to 12).
Approximately 10–15% of patients with colorectal cancer (CRC) have a family history of CRC, and 5% have early-onset CRC (<45 years) . Genetic factors play a dominant role in a small fraction of cases. HNPCC (Lynch syndrome) is the most common dominantly inherited CRC. This syndrome is due to a mutation in one of the following DNA MMR genes: MSH2, MLH1, MSH6, or PMS2, that leads to multiple errors in repetitive DNA sequences (microsatellites) throughout the genome of tumors. This form of genomic instability is called microsatellite instability (MSI) and is the hallmark of Lynch syndrome [1, 3].
Tumors with high-frequency MSI have a better prognosis. Thus, determining the MMR status (with genotyping for MSI or immunohistochemical analysis) of all patients with CRC has not only prognostic implications but may also serve as a guide to optimal chemotherapy .
Neoplastic lesions of the colon are most often encountered in the adult population but can, on rare occasions, be found in younger patients. Some studies have shown that age at diagnosis of CRC decreases in succesive generations of Lynch families, and this could be applied to the patient in this study. We would like to emphasize the importance of suspecting Lynch syndrome and performing a genetic study, even in young patients, especially if there is a familiy history of CRC. It has been suggested that the presence of a germline mutation in one of the MMR genes at birth is responsible for the early onset of Lynch syndrome .
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