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.

Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity

“…LIG1 deficiency represents an extremely rare form of inborn error of immunity characterized by diverse clinical manifestations. Including this study, only eight cases have been documented since its initial description 32 years ago [ 10 , 12 , 14 ], as summarized in Table 1 . Clinical onset typically occurs from birth to two years of age.…”

“…Management strategies include immunoglobulin therapy, prophylactic antibiotics, and HSCT. To date four patients have undergone HSCT, with three receiving reduced-intensity conditioning due to concerns about chemotherapy-induced toxicity in DNA repair defects [ 14 , 20 ]. One of these patients achieved 100% donor lymphoid and myeloid engraftment, curing both the immune defect and anemia.…”

“…DNA substrate experiments demonstrated that these mutant residues either were affected by non-canonical base pairing architecture, such as failure to ligate nicked DNA containing 3’end 8-oxoGuanine (oxoG), or inactive [ 13 ]. Recently a severe combined immunodeficiency (SCID) patient was described with Omenn-like features, bearing compound heterozygosity in LIG1 for a missense mutation and a splice site (truncating) mutation [ 14 ]. Intriguingly, all reported LIG1 patients have at least one hypomorphic allele that preserves some residual function, suggesting that full loss of function may be incompatible with life.…”

Infections in DNA Repair Defects

“…DNA ligase 1 (LIG1) is the major ligase used in DNA replication. LIG1 deficiency is characterized by growth retardation, variable severity of immune deficiency ranging from early onset hypogammaglobulinemia to severe combined immune deficiency, Omenn-like phenotype, reduced α/βT cells and increased proportions of circulating γδ T cells, and erythrocyte macrocytosis without deficiency of vitamin B12 or folate [ 67 , 68 , 69 ].…”

“…Patients develop respiratory viral (Rhinovirus, Adenovirus, Metapneumovirus, and RSV), Herpes zoster infection, gastrointestinal viral (rotavirus), and bacterial urinary tract infections [ 68 , 70 ]. Some of these patients with severe combined immunodeficiency phenotype have been successfully transplanted with hematopoietic stem cell transplantation (HSCT) [ 69 , 70 ]. In contrast to other DNA repair defects, no increased risk of malignancies has been reported in LIG1 deficiency.…”