Identifying Children with Constitutional Mismatch Repair Deficiency Syndrome in the Expanding Lynch Syndrome Population in Cape Town, South Africa

<i>Introduction</i>: Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is a rare tumour predisposition and polyposis syndrome that presents in childhood. It is caused by mutations in mismatch repair (MMR) genes that result in a tumour spectrum including colorectal cancers, high-grade gliomas, non-Hodgkin T-cell lymphomas and leukaemias. It is characterized by biallelic germline mutation of one of four MMR genes that can be identified by immunohistochemistry. Immunohistochemistry is used in screening for Lynch syndrome (LS); however, the pattern of loss-of-staining in the background, non-tumour tissue is unique to CMMR-D syndrome. CMMR-D syndrome is seen in LS families and occurs as a result of consanguinity or founder effect. In South Africa, LS families in the Western and Northern Cape Provinces show a unique <I>MLH1</I> c1528C>T mutation. The diagnosis of CMMR-D syndrome includes clinical findings outlined in the European Consortium’s Care of CMMRD document and confirmation of biallelic mutation in one MMR gene. Immunohistochemistry can be used in the diagnosis of CMMR-D syndrome by identifying cases for targeted molecular genetic tests. Loss of staining of the affected gene in the background, non-tumour tissue, is a key feature of CMMR-D syndrome. <i>Methods</i>: A retrospective analysis of archival, formalin fixed paraffin embedded tissue was performed on specimens of children attending Red Cross Children’s Hospital with tumours that form part of the CMMR-D spectrum, outlined by the Care for CMMRD criteria. We used the criteria of high-grade gliomas (WHO Grade III or IV) occurring before 25 years of age, cutaneous lesions suggestive of CMMR-D syndrome and patients with a first or second degree relative diagnosed with LS. Immunohistochemistry was performed and the staining pattern was documented using a modified Allred Scoring system. Specific attention was given to the characterization of the staining pattern of the background normal tissue. <i>Results</i>: 21 samples evaluated from 18 patients. 16 samples represented brain tumours. Three inadequate samples were excluded. 12 samples showed intact staining. Two samples showed staining of unknown significance. Four samples from 3 different patients showed staining patterns compatible with MMR deficiency. Of these four samples, three samples showed loss of staining in background non-tumour tissue with positive external control. <i>Conclusion</i>: MMR immunohistochemistry can be used in the evaluation of CMMR-D syndrome. The pattern and scoring of both the tumour and the background non-tumour tissue is critical. The diagnosis of CMMR-D syndrome depends on clinical application of Care for CMMRD criteria, MMR immunohistochemistry in conjunction with molecular genetic testing.