Abstract

Background: Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterized by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumor spectrum of CMMR-D syndrome includes hematological neoplasias, brain tumors and Lynch syndrome associated tumors. Other tumor entities, such as neuroblastoma, Wilm’s tumor, ovarian neuroectodermal tumor or infantile myofibromatosis have so far been found only in individual cases.

Results: We analyzed two consanguineous families with suspected CMMR-D syndrome patients who developed rhabdomyosarcoma among other neoplasias. In the first family we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2 immunohistochemistry analysis showed isolated PMS2-expression loss in all tumors of the affected patients including the rhabdomyosarcoma and in the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumor this strongly suggests an underlying PMS2 alteration also in family 2.

Conclusion: Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumors, such as neuroblastoma and Wilm’s tumor, belong to the tumor spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumors and signs of NF1 as well as analysis of the tumors for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will confirm proper diagnosis of the underlying disorder.