Novel Presentation of Omenn Syndrome in Association with Aniridia

Abstract

Omenn Syndrome (OS) can result from hypomorphic mutations of RAG1/RAG2 genes. They are located on chromosome 11p13 in close proximity to the PAX6 gene. Heterozygous mutations of PAX6 cause aniridia. We describe the first reported presentation of OS associated with aniridia. We hypothesized that this phenotype was due to compound heterozygosity for a RAG point mutation on one allele and a contiguous deletion encompassing both RAG genes and PAX6 on the other. 3 month old male presented with rash, diarrhea, failure to thrive, and infections. Exam was notable for erythroderma, edema, organomegaly, and aniridia. Laboratory evaluation showed lymphocytosis, eosinophilia, hypogammaglobulinemia (elevated IgE), and impaired lymphocyte proliferation. Lymphocyte spectratyping revealed T-cell oligoclonality. The clinical picture was consistent with OS. DNA sequence analysis of RAG1/RAG2 genes was performed. Subsequent evaluation included DNA testing by multiplex ligation and probe amplification (MLPA) searching for a chromosomal deletion on 11p13. DNA sequencing demonstrated 2 missense mutations in RAG1 (p.M1006V and p.M435V, previously described as causing OS) and 1 missense mutation in RAG2 (p.M502V). MLPA identified a deletion in the chromosomal 11p12-14 region on one allele. Maternal DNA analysis revealed heterozygosity (in cis) of the same 3 missense mutations on RAG1/RAG2. Paternal DNA analysis was normal. Our patient inherited 3 in cis missense mutations (RAG1/RAG2) from his mother. The other allele has a de novo deletion encompassing RAG1/RAG2/PAX6. The missense mutations in combination with the deletion result in homozygous loss of RAG1/RAG2 function and consequent OS. Heterozygous deletion of the PAX6 gene is responsible for aniridia.