Cernunnos-XLF-deficiency D81.0

Very rare autosomal recessive Cernunnos XLF deficiency (mutation in the NHEJ1 gene) which manifests as a "combined immunodeficiency". It is characterized by:

• Microcephaly, growth retardation and T and B cell lymphopenia.
• as well as
• by an increased sensitivity to ionizing radiation.

The prevalence is not known. To date, <10 cases have been described.

This disease is caused by mutations in the NHEJ1(also known as Cernunos) gene located on chromosome 2q35. The resulting defect in Cernunnos/XLF, a central protein in the non-homologous end-joining(NHEJ) process, impairs the major DNA repair mechanism in double-strand breaks.

In childhood, there is retarded growth, microcephaly, genitourinary and bone malformations, dysmorphia (e.g., 'bird-like' face), and features of "Combined immunodeficiency with recurrent opportunistic viral and bacterial infections. In some patients, autoimmune cytopenia is detectable (anemia and thrombocytopenia). Patients share a number of clinical symptoms with Nijmegen breakage syndrome and LIG 4 deficiency.

The diagnosis is based on the totality of clinical symptoms and evidence of B- and T-cell lymphocytopenia with normal numbers of natural killer (NK) cells. Increased radiosensitivity is detectable on fibroblasts.

Differential diagnoses are Nijmegen breakage syndrome and LIG4 syndrome.

Treatment consists of antibiotic treatment of infections, replacement of immunoglobulin, antiviral prophylaxis and transplantation of allogeneic hematopoietic stem cells (HSCT). Radiation therapy should be avoided when preparing patients (increased radiation sensitivity).

If left untreated, immunodeficiency leads to severe infections, sepsis and early death.

Ahnesorg P et al. (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124: 301-313.

Buck D et al. (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287-299.

Callebaut I et al. (2006) Cernunnos interacts with the XRCC4-DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 281: 13857-13860.

Dai Y et al. (2003) Nonhomologous end joining and V(D)J recombination require an additional factor. Proc. Nat. Acad. Sci. 100: 2462-2467.