Fatal toxicity following radio‐ and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen Breakage Syndrome

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Abstract
Background: In large‐scale pediatric chemo‐ and radiotherapy trials a proportion of patients as high as 10–15% is usually reported as having severe treatment related toxicity occasionally resulting in toxic death. Little is known on the underlying predisposition of the individual child. Several hereditary disorders including immunodeficiency (ID) syndromes or repair disorders, Ataxia Telangiectasia (AT), and Nijmegen breakage syndrome (NBS) were associated with an elevated risk for severe treatment related toxicity.Procedure: This report involves the case of a 7‐year‐old boy with medulloblastoma who suffered from remarkably severe side effects during and after postoperative radio‐ and chemotherapy. Several months following craniospinal radiation with a total dose of 36 Gy, late normal tissue side effects were observed within the treated volume. Eighteen months after initiation of treatment the patient died due to protracted cardiopulmonary failure.Results: To quantify the intrinsic radiation sensitivity, lymphoblastoid cells were used to examine chromosomal aberrations by fluorescence in situ hybridization detecting between two to ninefold higher chromosomal breakage rates in comparison to cells of average cancer patients. Skin fibroblasts showed in the clonogenic survival assays a twofold increased sensitivity. Western blotting demonstrated a typical lack of Nbs1. PCR‐SSCP analysis followed by direct sequencing of positive samples revealed a homozygous truncating mutation of the NBS1 gene (657del5).Conclusions: This case highlights that severe treatment related complications in pediatric cancer patients may be the result of increased intrinsic radio‐ and chemosensitivity due to NBS, AT, and other ID syndromes. It is suggested to exclude such conditions in all patients with anthropometric parameters below the 3rd centile and other signs suggestive for repair disorders or ID syndromes. Med Pediatr Oncol 2003;41:44–48.