Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus

Abstract

Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is an autosomal dominant condition caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. Rare cases have been reported of an inherited bi-allelic deficiency of MMR genes, associated with multiple café-au-lait spots, early onset CNS tumors, hematological malignancies, and early onset gastrointestinal neoplasia. We report on a patient with vitiligo in segments of the integument who developed systemic lupus erythematosus (SLE) at the age of 16, and four synchronous colorectal cancers at age 17 years. Examination of the colorectal cancer tissue showed high microsatellite instability (MSI-H) and an exclusive loss of expression of the MSH6 protein. Immunohistochemical analysis of normal colon tissue also showed loss of MSH6, pointing to a bi-allelic MSH6 mutation. Sequencing of the MSH6 gene showed the two germline mutations; c.1806_1809delAAAG;p.Glu604LeufsX5 and c.3226C > T;p.Arg1076Cys. We confirmed that the two mutations are on two different alleles by allele-specific PCR. To our knowledge, neither parent is clinically affected. They did not wish to be tested for the mutations identified in their daughter. These data suggest that bi-allelic mutations of one of the MMR genes should be considered in patients who develop early-onset multiple HNPCC-associated tumors and autoimmune disorders, even in absence of either hematological malignancies or brain tumors.

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

“…So far there is only one compound heterozygous MSH6 mutation carrier who is explicitly reported to lack CLS or other signs of NF1 (Rahner et al 2008). This patient as well as five additional patients (Etzler et al 2008;Scott et al 2007a, b) presented with hypopigmented skin areas which may be an additional or alternative cutaneous feature indicative of CMMR-D syndrome.…”

“…This patient as well as five additional patients (Etzler et al 2008;Scott et al 2007a, b) presented with hypopigmented skin areas which may be an additional or alternative cutaneous feature indicative of CMMR-D syndrome. Further, two patients compound heterozygous for the MSH6 missense mutation p.Arg1076Cys developed Lupus erythematosus (Plaschke et al 2006;Rahner et al 2008). IgA deficiency is a feature reported so far in one patient with a homozygous MSH2 mutation (Whiteside et al 2002) and three patients carrying biallelic MSH6 mutations one of whom presented also with IgG2 deficiency (Ostergaard et al 2005;Scott et al 2007b).…”

Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

“…Blood samples were collected from eight MSH6-deficient patients from five families [one of which has already been reported (34)]. The samples were obtained after provision of informed consent by the patients themselves or (for children) their parents.…”

Constitutional mismatch repair-deficiency syndrome

“…[12][13][14][15] However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.…”

“…There are only 2 patients explicitly reported to lack CALMs or other signs of NF1. 9,13 Interestingly, several reports stress that CALMs in patients with CMMR-D differ from typical NF1-associated CALMs in that they vary in their degree of pigmentation, have irregular borders, and may display a segmental distribution. Other features of NF1 found in CMMR-D patients include skinfold freckling, Lisch nodules, neurofibromas and tibial pseudarthrosis.…”