Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation

Abstract

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/µL were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.

Keywords: Immunoglobilins; Omenn-like; hematopoietic stem cell transplantation (HCST); immunodeficiency; ligase 1.

Figure 1

The timeline of case report.

Figure 2

Initial presentation and diagnostic hallmarks. (A) Hypercellular bone marrow with suppressed erythroblastic lineage. (B) Erythematous-exfoliative skin lesions.

Figure 3

Diagnostic key-tests in the LIG1 deficiency patient. (A) Distribution of Vβ chain of the TCR receptor is oligoclonal with a significantly increased percentage of Vβ2 and Vβ12 chains among CD4 lymphocytes. (B) Clonogenic survival assay results. Fibroblasts cultured from skin biopsies of the patient and an Artemis-deficient SCID patient were exposed to increasing dose of irradiation and the percentage survival (axe Y) was determined after 8 days. S1- sample 1, S2- sample 2. RAG1 SCID patient sample was used as a control. (C) The cDNA sequencing results showing the splice site variant in the LIG1 which leads to an insertion of sixteen nucleotides in the exon 9 resulting in a shift of a reading frame and a premature protein termination at position 260.