Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Nonhomologous end joining (NHEJ) pathway DNA repair genes, including Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF, are crucial for radiosensitive severe combined immunodeficiency (SCID).
• Clinical presentation of a 3-year-old girl included severe growth retardation, distinctive facial features, recurrent infections, pancytopenia, and polydactyly, initially suggesting Fanconi anemia.

Purpose of the Study:

• To investigate the genetic basis of primary immunodeficiency in a pediatric patient with complex clinical symptoms.
• To identify the specific gene mutation responsible for the patient's radiosensitive SCID and associated features.

Main Methods:

• Chromosomal analysis to detect spontaneous DNA breaks.
• Differential-ly enhanced breakage (DEB) test to exclude Fanconi anemia.
• Genetic analysis, including mutation screening of the NBS1 gene and subsequent investigation of the Cernunnos/XLF (NHEJ1) gene.

Main Results:

• Fanconi anemia was excluded due to a normal DEB test.
• The patient exhibited hypogammaglobulinemia (low IgG, IgA) and B cell absence, indicative of primary immunodeficiency.
• A homozygous mutation in the Cernunnos/XLF (NHEJ1) gene was identified as the cause of the patient's condition.

Conclusions:

• Cernunnos/XLF deficiency is a significant cause of radiosensitive SCID, presenting with microcephaly, distinctive facial features, and severe growth retardation.
• Early evaluation for hypogammaglobulinemia and primary immunodeficiency is recommended for patients with these clinical characteristics.
• Intravenous immunoglobulin (IVIG) prophylaxis is initiated, and bone marrow transplantation is being pursued as a curative treatment.