A patient with mutations in DNA Ligase IV: Clinical features and overlap with Nijmegen breakage syndrome

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Abstract
The clinical phenotype of Ligase IV syndrome (LIG4 syndrome), an extremely rare autosomal recessive condition caused by mutations in the LIG4 gene, closely resembles that of Nijmegen breakage syndrome (NBS), and is characterized by microcephaly, characteristic facial features, growth retardation, developmental delay, and immunodeficiency. We report a 4½‐year‐old boy who presented with acute T‐cell leukemia. The facial gestalt was strongly reminiscent of NBS. The patient died shortly after the onset of treatment for his T‐cell leukemia. Subsequent chromosome breakage studies showed a high rate of breakage in a fibroblast culture. Radiosensitivity was assessed by a colony survival assay; the results showed radiosensitivity greater than is typically seen in NBS. Mutation screening of the NBS1 gene was negative. Sequencing of the LIG4 gene revealed a homozygous truncating mutation 2440 C>T (R814X). Although this mutation has been previously noted in LIG4 syndrome, this patient is the first reported homozygote for the mutation. In this study, we review the clinical features of this rare syndrome and provide suggestions for differential diagnosis.