D1.433 - DNA Ligase I Deficiency Masquerading as CVID-Like Phenotype: Implications for Long-Term Surveillance

Introduction

DNA ligase I (LIG1) deficiency is an exceptionally rare autosomal recessive inborn error of immunity characterized by impaired DNA replication and repair, genomic instability, and immune dysfunction. Increased risks of malignancy, severe infections, chronic lung disease, bone marrow failure, and autoimmunity were reported in this context. In the era of next-generation sequencing, our case highlights the importance of continuously reassessing the diagnosis of patients presenting with early-onset hypogammaglobulinemia, given the possible implications for their long-term surveillance.

Case

We present a 33-year-old woman featuring short stature and chronic dyserythropoietic anemia diagnosed since 2 months of age, when she was first admitted for pneumonia. She was born to non-consanguineous parents, with an unremarkable family history. From early childhood, she developed recurrent lower respiratory tract infections, with multiple pneumonias, and started immunoglobulin replacement therapy at age 5, based on persistent hypogammaglobulinemia. Despite trough serum IgG levels above 1000mg/dL, she continued to experience recurrent infections, leading to bilateral bronchiectasis predominantly affecting the middle and lower lobes. Additional findings included chronic non-atopic rhino-sinusitis, intermittent cervical lymphadenopathies and moderate splenomegaly since 15 and chronic gastritis with lymphoid hyperplasia, diagnosed at 25. Immunological evaluation (10 years old) showed impaired specific antibody responses to pneumococcal polysaccharide vaccine and tetanus toxoid. Extensive immunophenotyping (24 years old) revealed reduced switched memory B cells (1.2% of B cells), expanded CD21^low B cells (17.0%), an inverted CD4/CD8 ratio  and reduced naïve CD4 T cells (23.4%), Whole-exome sequencing recently identified compound heterozygous LIG1 variants: a pathogenic c.2311C>T (p.Arg771Trp) variant and a variant of uncertain significance c.1764_1766del (p.Ser588del), according to ACMG criteria.

Discussion

We present a rare case with clinical and immunological features compatible with LIG1 deficiency. Segregation studies and functional assays will be instrumental to establish variants pathogenicity. CVID-like phenotypes may mask rare monogenic disorders with distinct prognostic and therapeutic implications. LIG1 deficiency is associated with genomic instability and increased sensitivity to DNA-damaging agents, potentially increasing malignancy risk. This diagnosis should thus prompt structured malignancy surveillance, periodic hematologic monitoring and minimization of ionizing radiation exposure. Reporting long-term clinical and immunological evolution is crucial to refine genotype–phenotype correlations and inform future decisions regarding conservative management versus hematopoietic stem cell transplantation.