DNA Ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder caused by mutations in the DNA ligase IV gene (LIG4), which is essential for the repair of DNA double-strand breaks in mamalian cells by non-homologous end joining (O’Driscoll et al, 2001; Critchlow et al, 1998). LIG4-deficient patients are characterized by microcephaly, growth retardation, developmental delay, low birth weight, dysmorphic facial findings called bird-like face, immunodeficiency, pancytopenia, and pronounced clinical and cellular radiosensitivity (O’Driscoll et al, 2001). Herein, we report two siblings with a novel DNA ligase IV mutation, one of whom underwent hematopoietic stem cell transplantation (HSCT). Case 1, was a 10 year-old girl, whose pancytopenia started at 4 years of age. History revealed a birth weight of 2400 g. There was a first-degree consanguinity between parents. Body weight, height, and head circumference were below the third percentile. Low anterior hairline, prominent nasal bridge and bilateral epicanthus were present. Recurrent upper respiratory infection (URI) history was striking. Serum IgM was low for age. Pancytopenia deepened progressively and HSCT was performed from 6/6 HLA matched father after non-myeloablative conditioning; however autologous reconstruction developed and a 2nd HSCT was performed after busulfan, cyclophosphamide and ATG conditioning. Engraftment was achieved by +12 day. Case 2 was a 6 year-old boy, presented with widespread echymoses at three years of age. Microcephaly, body weight and height below the third percentile, inguinal hernia, prominent nasal bridge and bilateral epicanthi were positive findings. History revealed recurrent URI. Serum IgG and IgM were low for age. DEB and mitomycin-C induced chromosomal analyses were within normal limits, whereas spontaneous breakage was found to be increased. Bone marrow examination revealed hypercellularity in both siblings. Alpha-fetoprotein levels were within normal limits. Mutation analysis for Nijmegen breakage syndrome was negative, however sequencing revealed a novel mutation in the LIG4 gene. A homozygous sequence variant, 1762delAAG, which results in the amino acid deletion 588delK, was identified in case 2. Both parents were heterozygous for the alteration. This novel mutation is located in a highly conserved peptide in the ligase IV protein, adjacent to the ligase domain, with previously unknown function (Wei et al, 1995). Our results demonstrate that non-myeloablative conditioning may not be adequate for LIG4 syndrome patients with hypercellular bone marrow. However, successful treatment of LIG4 syndrome can be achieved by HSCT after more potent conditioning.
Disclosure: No relevant conflicts of interest to declare.