Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation

Omenn syndrome is a rare inherited primary immunodeficiency characterized by severe combined immunodeficiency in combination with autoimmune features leading to squamous erythrodermia, alopecia, lymphadenopathy, hepatosplenomegaly, and intractable diarrhea. Recent advances include characterizing the genetic basis of the syndrome and integrating the genetic defects into knowledge of tolerance induction.

Molecular studies have shown that besides the well-known hypomorphic recombination activating gene defects, mutations in the nonhomologous end-joining factor Artemis and in the interleukin-7 receptor alpha chain can contribute to the development of Omenn syndrome. These investigations established that Omenn syndrome is a genetically heterogeneous condition. Whereas the majority of patients with Omenn syndrome bear hypomorphic gene alterations, some exhibit somatic mosaicism due to second-site reversions of null alleles. A lack of central tolerance contributes to the autoimmune pathology of the disease.

Research has begun to clarify the genetic defects and the conditions underlying the lack of tolerance enforcement that predispose to Omenn syndrome. Clinical applications of this research include the identification of the causative genetic defect in the majority of Omenn syndrome cases and the use of this genetic knowledge in family and prenatal analyses and in difficult differential autoimmune diagnoses.