Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature

Abstract

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

“…LIG4 mediates the final ligation step in the NHEJ pathway, a process utilized not only for NHEJ-mediated DSB repair but also for V(D)J recombination (131, 132). Approximately 40 cases have been reported with hypomorphic LIG4 mutations that correlate with clinical severity (133,134). Patients present at variable ages with common features including microcephaly, facial dysmorphism, growth failure, infections, and severe immunodeficiency as well as hematological manifestations such as BMF and leukemia/lymphoma (134,135).…”

“…Approximately 40 cases have been reported with hypomorphic LIG4 mutations that correlate with clinical severity (133,134). Patients present at variable ages with common features including microcephaly, facial dysmorphism, growth failure, infections, and severe immunodeficiency as well as hematological manifestations such as BMF and leukemia/lymphoma (134,135). The immunologic phenotype can range from a radiosensitive T-B-NK+ severe combined immunodeficiency (SCID) to mild hypogammaglobulinemia and lymphopenia with restricted receptor repertoire (136).…”

“…The immunologic phenotype can range from a radiosensitive T-B-NK+ severe combined immunodeficiency (SCID) to mild hypogammaglobulinemia and lymphopenia with restricted receptor repertoire (136). Hematological manifestations are largely due to accumulation of ionizing radiation and other genotoxic insults, resulting in BMF in 44% (134,137,138) and cancers in 24% of the patient population (134). Cancers of the hematopoietic system are most common and include lymphoid leukemia and lymphomas (EBV positive and negative) and AML (130,134,135,139,140).…”

“…Hematological manifestations are largely due to accumulation of ionizing radiation and other genotoxic insults, resulting in BMF in 44% (134,137,138) and cancers in 24% of the patient population (134). Cancers of the hematopoietic system are most common and include lymphoid leukemia and lymphomas (EBV positive and negative) and AML (130,134,135,139,140). Recently, in a cohort of patients with BMF/MDS, a novel homozygous mutation in LIG4 (c.2440C>T, p.R814X) was found in a 10-year-old boy presenting with MDS and monosomy 7 (141).…”

LIG4 syndrome: clinical and molecular characterization in a Chinese cohort

“…The LIG4 gene maps to chromosome 13q33-q34, and it has a complex structure formed by four domains: the DNA-binding domain (DBD), adenylation domain (AdD), oligo-binding domain (OBD) and XRCC4binding domain (XBD). LIG4 syndrome is caused by homozygous or compound heterozygous mutations in the LIG4 gene, and the most common genotype is p.R814X/p.K424Rfs*20 [3]. Murray et al [4] first proposed a genotype-phenotype correlation between the position of truncating mutations associated with p.R814X and disease severity.…”