Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome

Background: Omenn syndrome is a variant of severe combined immunodeficiency disease, which most prominently presents with erythroderma, eosinophilia, and susceptibility to various pathogens. Mutations in the nucleases of recombination activating genes 1 and 2 (RAG1/RAG2) or Artemis were found in some, but not all, patients with Omenn syndrome. We identified 2 patients who presented with clinical features consistent with Omenn syndrome but had no mutations in RAG or Artemis. Both patients also had cartilage-hair hypoplasia (CHH). Objectives: We sought to define the molecular basis and characterize the features of severe combined immunodeficiency and Omenn syndrome in these patients. Methods: We have studied Immoral and cellular immunity using standard assays. T-cell repertoire was investigated by quantitating V beta families. The RNase mitochondrial RNA processing (RMRP) RNA gene was sequenced by using standard techniques. Results: Sequence analysis of the RMRP RNA gene showed that each patient had an insertion-duplication on one allele and a point mutation on the other allele. These point mutations were novel, and they might be related to the unusual presentation of Omenn syndrome in addition to CHH in these patients. Indeed, analysis of the thymus showed residual mature T lymphocytes. This leaky thymus might be responsible for the skewed release of some T-cell clones into the circulation, which might trigger the phenotype of Omenn syndrome. Conclusion: We have demonstrated that mutations in the RMRP RNA gene might be associated with Omenn syndrome. Clinical implications: This discovery will aid clinicians in the early recognition and treatment of CHH-associated Omenn syndrome.