Cernunnos-XLF deficiency

Cernunnos-XLF deficiency, also known as immunodeficiency with microcephaly or nonhomologous end-joining factor 1 (NHEJ1) deficiency, is an extremely rare autosomal recessive primary immunodeficiency disorder caused by mutations in the NHEJ1 gene (also called CERNUNNOS or XLF). This gene encodes a protein essential for the nonhomologous end-joining (NHEJ) DNA repair pathway, which is critical for both V(D)J recombination in immune cell development and for general DNA double-strand break repair throughout the body. The disease primarily affects the immune system and the central nervous system. Patients present with severe combined immunodeficiency (SCID) or combined immunodeficiency characterized by profound T-cell and B-cell lymphopenia, hypogammaglobulinemia, and increased susceptibility to severe and recurrent infections. A hallmark feature is microcephaly (abnormally small head), which is present from birth and reflects the role of NHEJ1 in brain development. Additional features may include intrauterine growth retardation, bird-like facial features, and increased cellular sensitivity to ionizing radiation. Some patients may also exhibit developmental delay and bone marrow failure. Treatment is primarily supportive and includes antimicrobial prophylaxis, immunoglobulin replacement therapy, and management of infections. Hematopoietic stem cell transplantation (HSCT) is the definitive treatment for the immunological component of the disease and can restore immune function, although it does not correct the microcephaly or neurological features. Due to the underlying DNA repair defect, conditioning regimens for transplantation must be carefully adjusted to minimize toxicity, as patients have heightened sensitivity to DNA-damaging agents. The prognosis without transplantation is poor due to life-threatening infections.

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