A novel bi-allelic MSH2 mutation associated with constitutional mismatch repair deficiency syndrome, and review of the clinical phenotype. P.-Y. B. Au1, R. Perrier1, E. G. Puffenberger3, S. Hume4, R. Anderson5, L. Lafay-Cousin5, D. Strother5, B. McInnes1, J. Parboosingh1,2, F. Bernier1,2 1) Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada; 2) Alberta Children's Hospital Research Institute for Child and Maternal Health; 3) The Clinic for Special Children, Strasburg, Pennsylvania; 4) Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada; 5) Department of Hematology and Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada.

   DNA mismatch repair (MMR) is important for genomic stability and DNA replication fidelity. Lynch syndrome is due to mono-allelic mutations of MMR genes. However, bi-allelic mutations that affect MMR genes result in constitutional mismatch repair deficiency syndrome (CMMR-D). Patients with CMMR-D frequently develop malignancy in childhood, often within the first decade. Malignancies include childhood leukemia, lymphoma, and brain tumours. Lynch related tumours such as colorectal cancer are also possible, and can present in adolescence. Interestingly, these patients have skin findings similar to neurofibromatosis type 1 (NF1). We report a novel mutation in MSH2 causing CMMR-D in several children in a large extended consanguineous Southeast Asian family. The index patient presented at 4 years with T cell lymphoblastic lymphoma, and then developed gliobastoma multiforme at age 10. His sister and his first cousin once removed also developed glioblastoma at ages 7 and 6 respectively. Another cousin developed a primitive neuroectodermal tumour at 7 years. All 4 children had multiple café au lait macules and axillary freckling. However, unlike NF-1, many of their café au lait macules were atypical. SNP array homozygosity mapping identified a region identical by descent on chromosome 2, corresponding to both MSH2 and MSH6 loci. MSH2 and MSH6 were absent on immunohistochemical staining of tumour tissue. Sequencing of MSH6 revealed no mutation. MSH2 was sequenced, and the mutation hMSH2 c.[1276+3A>C] was identified on both alleles in the index patient. The other affected children of this extended family were also homozygous for this mutation. This mutation affects the MSH2 intron donor sequence and is predicted to be pathogenic. Mutations affecting the +1 and +2 donor positions of this donor site have been described for Lynch syndrome and are known to affect splicing, but this mutation at +3 is novel, particularly in the context of bi-allelic mismatch repair deficiency. PMS2 is the most common MMR gene associated with CMMR-D. However, MLH1, MSH6 and MSH2 related CMMR-D have also been described, with MSH2 being more rare. There are now at least 10 cases of MSH2 related CMMR-D in the literature, involving 5 families. We will review the literature around CMMR-D and MSH2 mutations, and describe the skin pigmentary abnormalities seen in these children. The skin phenotype has not been well characterized for CMMR-D and exhibits some differences from NF-1.

You may contact the first author (during and after the meeting) at