DNA ligase IV deficiency is a rare primary immunodeficiency,
LIG4 syndrome, often associated with other systemic features.
DNA ligase IV is part of the non-homologous end joining mechanism, required to repair
DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from
DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by
reactive oxygen species and ionising radiation.Within developing lymphocytes,
DNA ligase IV is required to repair programmed
DNA double stranded breaks induced during lymphocyte receptor development.Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to
severe combined immunodeficiency. All, however, manifest sensitivity to ionising radiation. Commonly associated features include primordial growth failure with severe
microcephaly and a spectrum of learning difficulties, marrow hypoplasia and a predisposition to lymphoid
malignancy. Diagnostic investigations include immunophenotyping, and testing for radiosensitivity. Some patients present with
microcephaly as a predominant feature, but seemingly normal immunity. Treatment is mainly supportive, although haematopoietic
stem cell transplantation has been used in a few cases.