Severe combined immunodeficiency (SCID) is a congenital immunodeficiency characterized by significant numerical or functional defects in T lymphocytes and is often accompanied by B lymphocyte dysfunction. It presents early in life with severe, recurrent opportunistic infections. Early diagnosis and hematopoietic stem cell transplantation (HSCT) are vital for patient survival. Cernunnos/XLF deficiency is an autosomal recessive form of SCID caused by mutations in the NHEJ1 gene, which plays a critical role in repairing DNA double-strand breaks. First described in 2006, this condition remains exceedingly rare, with only about 55 cases reported to date. This study aimed to describe a novel infant with Cernunnos/XLF deficiency and to review previously reported patients carrying the same variant, thereby expanding the clinical spectrum of this rare disease. With written informed consent, we retrospectively evaluated a pediatric patient with Cernunnos/XLF deficiency followed at our clinic. Demographic, clinical, laboratory, and radiological findings were reviewed. The diagnosis was based on clinical and immunological features and confirmed via clinical exome sequencing. A literature review was conducted to compare the genotype-phenotype correlations of previously reported patients carrying the same NHEJ1 variant. We report an infant who was hospitalized at 6.5 months of age with a preliminary diagnosis of meningitis and was subsequently diagnosed with Cernunnos/XLF deficiency. The patient exhibited microcephaly, growth retardation, recurrent infections, prolonged SARS-CoV-2 PCR positivity, and localized BCGitis following live Bacillus Calmette-Guérin (BCG) vaccination. Immunological evaluation revealed T- and B-cell lymphopenia and hypogammaglobulinemia. Genetic testing confirmed a homozygous nonsense mutation in NHEJ1. HSCT from a matched sibling donor was performed. This study describes a rare case of Cernunnos/XLF deficiency diagnosed in early infancy, underscoring the value of early recognition and the critical role of genetic testing and HSCT. It also expands the clinical spectrum of the disease and provides a comparative perspective with previously reported patients carrying the same mutation. In infants presenting with unexplained infections or complications related to live vaccines, inborn errors of immunity should be considered. Our findings emphasize the importance of timely diagnosis and comprehensive, multidisciplinary follow-up, particularly in patients with additional complications.

Cernunnos/XLF deficiency is a rare, severe combined immunodeficiency, inherited in an autosomal recessive pattern (OMIM number: 611290), related to the NHEJ1 gene. This gene participates in the DNA non-homologous end-joining pathway, repairing double-strand breaks in the DNA of mammalian cells. The clinical features include growth retardation, microcephaly, triangle-shaped face, recurrent infections, fibroblast's excessive sensitivity to gamma-ionizing radiation, and hypogammaglobulinemia; also, low counts of subpopulations of B and T lymphocytes, with normal values of natural-killer cells. This manuscript aims to present an extremely rare case of combined immunodeficiency in a twenty-years-old man with non-consanguineous parents and a homozygote variant of the NHEJ1 gene. This case is the fiftieth reported in the literature and the first in Colombia, given the low prevalence of NHEJ1-related immunodeficiency and its difficult diagnosis due to scarce knowledge. La deficiencia de Cernunnos XLF es una inmunodeficiencia combinada grave y poco frecuente, heredada de forma autosómica recesiva (número OMIM: 611290), relacionada con el gen NHEJ. Este gen participa en la vía de unión de extremos no homólogos reparando rupturas del ADN de doble cadena en las células de mamíferos. Las características clínicas de la deficiencia de Cernunnos XLF incluyen retraso del crecimiento, microcefalia, cara en forma de triángulo, infecciones recurrentes, sensibilidad excesiva de los fibroblastos a la radiación ionizante gamma, hipogammaglobulinemia y recuentos bajos de subpoblaciones de linfocitos B y T, pero valores normales de células natural killer. El objetivo de este manuscrito es presentar un caso extremadamente raro de inmunodeficiencia combinada en un hombre de veinte años, hijo de padres no consanguíneos, que tiene una variante homocigota del gen NHEJ1. Este es el caso número 50 reportado en la literatura y el primero en Colombia, dada la baja prevalencia de la inmunodeficiencia y las dificultades en su diagnóstico por desconocimiento de la enfermedad. La deficiencia de Cernunnos XLF es una inmunodeficiencia combinada grave y poco frecuente, heredada de forma autosómica recesiva (número OMIM: 611290), relacionada con el gen NHEJ. Este gen participa en la vía de unión de extremos no homólogos reparando rupturas del ADN de doble cadena en las células de mamíferos. Las características clínicas de la deficiencia de Cernunnos XLF incluyen retraso del crecimiento, microcefalia, cara en forma de triángulo, infecciones recurrentes, sensibilidad excesiva de los fibroblastos a la radiación ionizante gamma, hipogammaglobulinemia y recuentos bajos de subpoblaciones de linfocitos B y T, pero valores normales de células natural killer. El objetivo de este manuscrito es presentar un caso extremadamente raro de inmunodeficiencia combinada en un hombre de veinte años, hijo de padres no consanguíneos, que tiene una variante homocigota del gen NHEJ1. Este es el caso número 50 reportado en la literatura y el primero en Colombia, dada la baja prevalencia de la inmunodeficiencia y las dificultades en su diagnóstico por desconocimiento de la enfermedad.

The ubiquitous presence of enzymes required for repair of DNA double strand breaks renders patients with defects in these pathways susceptible to immunodeficiency, an increased risk of infection, autoimmunity, bone marrow failure and malignancies, which are commonly associated with Epstein Barr virus (EBV) infection. Treatment of malignancies is particularly difficult, as the nature of the systemic defect means that patients are sensitive to chemotherapy and radiotherapy. Increasing numbers of patients with Nijmegen Breakage syndrome, Ligase 4 deficiency and Cernunnos-XLF deficiency have been successfully transplanted. Best results are obtained with the use of reduced intensity conditioning. Patients with ataxia-telangiectasia have particularly poor outcomes and the best treatment approach for these patients is still to be determined.

Xlf/Cernunnos is unique among the core factors of the non-homologous end joining (NHEJ) DNA double strand breaks (DSBs) repair pathway, in the sense that it is not essential for V(D)J recombination in vivo and in vitro. Unlike other NHEJ deficient mice showing a SCID phenotype, Xlf-/- mice present a unique immune phenotype with a moderate B- and T-cell lymphopenia, a decreased cellularity in the thymus, and a characteristic TCRα repertoire bias associated with the P53-dependent apoptosis of CD4+CD8+ DP thymocytes. Here, we thoroughly analyzed Xlf-/- mice immune phenotype and showed that it is specifically related to the DP stage but independent of the MHC-driven antigen presentation and T-cell activation during positive selection. Instead, we show that V(D)J recombination is subefficient in Xlf-/- mice in vivo, exemplified by the presence of unrepaired DSBs in the thymus. This results in a moderate developmental delay of both B- and T-lymphocytes at key V(D)J recombination dependent stages. Furthermore, subefficient V(D)J recombination waves are accumulating during TCRα rearrangement, causing the typical TCRα repertoire bias with loss of distal Vα and Jα rearrangements.