gms | German Medical Science

CMMRD (OMIM #276300, a.k.a. Turcot-syndrome) is a rare disorder with recessive inheritance caused by biallelic mismatch repair gene mutations. The syndrome is associated with multiple childhood tumours, most commonly occurring in brain and digestive tract, and haematological malignancies. We report histopathologic and molecular findings in gliomas from two of three affected sisters.

Three out of six children of consanguineous (second cousins) Afghan parents suffered from cerebral diffuse gliomas. One adolescent girl was treated surgically in Pakistan in 2009, followed by radiation therapy. The patient died from a supposed anaplastic oligodendroglioma (WHO grade III) one year later (reports and tissue not available). In summer 2010 two further sisters (6 and 9 years old) were operated on at a right parietal glioblastoma (WHO grade IV) and at multifocal bilateral diffuse astrocytoma (WHO grade II), respectively. Tumour cells were positive (immunohistochemistry) for GFAP, MAP2, and S100, without significant expression of EGFR. Tumour cell nuclei were positive for p53 in 90% and 15%, and for Ki67 in 50% and 4%, respectively. In both tumours, MGMT gene promoter was unmethylated, and IDH1 (p.R132) and IDH2 (p.R172) were wildtype. Chemotherapy using temozolomide (kindly provided by the manufacturer) was refused by the local authorities. The younger girl died in early 2011, and the older sister in 2012.

Since multiple children from the same (consanguineous) family were affected, a hereditary basis for the gliomas was suspected. A clinical score for CMMRD ≥3 [1] led to genetic testing, revealing homozygous missense germline mutations in one of the mismatch repair proteins (MSH6).

Due to phenotypical overlap with other cancer syndromes (neurofibromatosis type 1, Li-Fraumeni syndrome), CMMRD is frequently unrecognized by clinicians and its incidence is almost certainly underestimated. Furthermore, laboratory diagnosis is hampered by imperfect sensitivity of immunohistochemistry (loss of mismatch repair protein expression) and mutation analysis (pseudogenes, variants of unknown significance).

Further analyses are initiated to clarify the molecular pathogenesis of CMMRD-associated gliomas as well as their relationship to the more common sporadic counterparts.