Mutations of Lig4 are exclusively hypomorphic and have only been described in six patients, four exhibiting mild immunodeficiency associated with microcephaly and developmental delay, while two patient had leukemia.
DNA ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder characterized by microcephaly, growth retardation, low birth weight, dysmorphic facial findings, immunodeficiency, pancytopenia, and radiosensitivity due to impaired repair of DNA double-strand breaks by non-homologous end-joining.
Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency.
Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome).
This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations.
Here we present an unusual case of DNA ligase IV deficiency syndrome without dysmorphic facial findings and microcephaly complicated with Epstein-Barr virus-associated large B-cell lymphoma with the right lung involvement and a massive brain tumor lesion in a two-year-old female.