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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Allergy Clin Immunol. Author manuscript; available in PMC 2010 April 1.
Published in final edited form as:
PMCID: PMC2688768

Novel Presentation of Omenn Syndrome in Association with Aniridia

William J. Sheehan, MD,a,b Ottavia M. Delmonte, MD,a,b,c David T. Miller, MD, PhD,b,d Amy E. Roberts, MD,b,d Francisco A. Bonilla, MD, PhD,a,b Massimo Morra, MD, PhD,e Silvia Giliani, PhD,f Sung-Yun Pai, MD,b,g,h Luigi D. Notarangelo, MD,a,b and Hans C. Oettgen, MD, PhDa,b


We report a case of Omenn Syndrome presenting in association with aniridia arising from 3 maternally-inherited RAG mutations compounded by a deletion encompassing RAG and PAX6 genes on the paternally-inherited chromosome.

Keywords: Omenn Syndrome, Aniridia, Recombination-Activating Genes, PAX 6, Wilm’s Tumor, Immunodeficiency

To the Editor

Omenn Syndrome (OS) is an autosomal recessive combined immunodeficiency characterized by infiltration of the skin and gastrointestinal tract by activated oligoclonal T lymphocytes.1 Patients are profoundly hypogammaglobulinemic with few or absent circulating B lymphocytes, but high IgE levels. The most common causes of OS are hypomorphic mutations of the Recombination-Activating Genes (RAG).1 Mutations of Artemis (DCLRE1), IL7RA, RMRP, IL2RG, and CHD7 genes may also result in the OS phenotype. RAG1 and RAG2 are located on chromosome 11p13 in close proximity to a cluster of genes which are deleted in Microdeletion 11p13 Syndrome. This syndrome, also known as WAGR (Wilms tumor susceptibility, Aniridia, Genitourinary abnormalities, and mental Retardation), arises from deletions encompassing PAX6 and WT1 genes. PAX6 encodes a transcription regulatory protein and is essential for the development of multiple tissues in the eye including the iris, lens, and neuroretina. Heterozygous PAX6 mutations often cause hereditary aniridia.2 Additionally, PAXNEB (PAX6 neighbor gene) mutations on 11p13 have been studied for a possible association with aniridia.

We describe a novel presentation of OS associated with aniridia. We show evidence that this unique phenotype results from compound heterozygosity for RAG point mutations on the maternal allele along with a contiguous deletion encompassing both RAG genes and PAX6 on the corresponding region of the paternally-derived chromosome 11.

The patient was a 3-month-old male admitted for treatment of a purulent pericardial effusion with blood cultures positive for Achromobacter xylosoxidans. Previously, he had been a full term infant with aniridia who developed an erythematous, peeling rash on his entire body during the first week of life. This was treated as eczema with temporary improvement followed by progressive worsening. He experienced poor weight gain through his first 3 months. He was the only child of nonconsanguinous, healthy parents of Western European descent. The family history was negative both for immunodeficiency and aniridia.

The physical exam was notable for severe erythema with diffuse skin peeling, seborrheic dermatitis, and paucity of hair. Aniridia was noted. A 2/6 holosystolic murmur was present. The rest of the physical exam was normal. Of note, there were no genital abnormalities, lymphadenopathy, or organomegaly. Initial lab studies included: WBC 81,970 cells/μL with 15% segmented neutrophils, 73% lymphocytes, 8% eosinophils, and 2% basophils; hemoglobin 9.1 g/dL; hematocrit 30%; platelet count 263 × 103/μL; IgG 41 mg/dL; IgA 9 mg/dL; IgM 8 mg/dL; and IgE 196 mg/dL. Additional studies revealed an absolute lymphocyte count of 59,840 cells/μL, absolute CD3+ 50,226 cells/μL (96%), absolute CD4+ 18,737 cells/μL (32%), absolute CD8+ 36,142 cells/μL (62%), absolute CD19+ 37 cells/μL (0%), and absolute CD16+/CD56+ 1,107 cells/μL ( 2%). The patient’s lymphocytes were unresponsive to phytohemagglutinin, concanavalin A, and pokeweed mitogen. His karyotype was normal 46, XY. Maternal engraftment was excluded by fluorescent in situ hybridization (FISH). PCR amplification of lymphocyte Vγ – Jγ segments showed oligoclonality with profoundly limited T-cell diversity consistent with OS. (See Figure 1) The presenting laboratory evaluation was consistent with OS. The initial WBC and ALC are relatively high and may be reflective of coexistent infections, but are within published ranges for OS.3 The IgE level, although not markedly elevated is also in the range reported for OS.

Figure 1
TCR γ gene rearrangement clonality analysis. Multiplex PCR amplification using primers to the variable and joining regions of TCR γ was used to evaluate the V-D-J rearrangements for diversity. PCR product sizes are shown on the x-axis ...

DNA sequencing identified 2 apparently homozygous missense mutations in RAG1 (p.Met435Val and p.Met1006Val) and 1 apparently homozygous missense mutation in RAG2 (p.Met502Val). The p.Met435Val mutation in RAG1 and the p.Met502Val mutation in RAG2 have previously been reported in OS.4, 5 Chromosomal microarray analysis revealed a deletion of approximately 9.5 Mb extending from 11p12 to 11p14.1. This deletion encompassed both RAG genes, WT1, and PAX6. Mother was heterozygous for the same 3 missense mutations on RAG1 and RAG2. Father’s sequences were normal. Paternal DNA was unavailable for further analysis, but the absence of aniridia in the father along with the large size of the deletion provide strong evidence that it arose de novo.

Taken together, these data indicate that the RAG1 and RAG2 missense mutations identified in the proband lie in cis on the non-deleted maternally-inherited chromosome while a deletion encompassing RAG1/RAG2/PAX6 arose de novo on the paternally inherited chromosome. This combination results in a partial loss of RAG1/RAG2 function and consequent OS. The heterozygous deletion of the PAX6 gene is responsible for the aniridia. (See Figure 2) This contiguous deletion also includes the WT1 gene. With the excepetion of aniridia, our patient has not yet manifested any other features of Microdeletion 11p13 (WAGR) Syndrome. He has been evaluated for genitourinary malformations and is being closely monitored for Wilms tumor.

Figure 2
Schematic representation of chromosome 11p with the deletion and RAG1/RAG2 gene mutations (circles) in the patient’s paternally (P) and maternally (M) derived alleles. The deletion encompasses approximately 9.5 Mb extending from 11p12 to 11p14.1 ...

After clearance of infection, the patient underwent bone marrow transplantation from a 10/10 matched unrelated donor after myeloablative conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin. He is doing well off of immunosuppression with no evidence of graft vs. host disease one year later.

This represents the first report of OS arising from a combination of a mutation and deletion with resultant loss of function, and represents a novel clinical presentation of aniridia in association with OS. One report of several patients with aniridia due to large deletions mentioned a single patient who also had immunodeficiency but with no specific details.6 Deletions on chromosome 11 are a well documented cause of aniridia,6, 7 but the connection between aniridia and immunodeficiency has not been recognized explicitly. As deletions in this region are not uncommon, this case underscores the importance of testing for large deletions to assess the risk of WT1 deletion in patients presenting with Omenn syndrome-related immunodeficiency in whom genetic analysis suggests apparent homozygosity and where parental sequencing does not establish inheritance of both maternal and paternal loss-of-function RAG alleles. A deletion could include the RAG genes and the WT1 gene and not be obvious clinically if the PAX6 gene were not deleted. Additionally, screening for immunodeficiency in patients with aniridia due to a deletion becomes a consideration. Screening could be accomplished with a complete blood count with differential, lymphocyte subsets, and immunoglobulin levels. Any results consistent with OS would prompt further genetic testing. In these cases detailed deletion analysis and/or sequencing of the RAG genes would be indicated, since coincident inheritance of a RAG1 or RAG2 mutation would be the only way that OS would arise in conjunction with Microdeletion 11p13 Syndrome.

A number of other primary immunodeficiencies exhibit autosomal recessive inheritance and as such require abnormality in both alleles for phenotypic expression. It is predictable that any of these diseases might result from a heterozygous mutation complemented by a deletion. This scenario has previously been reported for the gene encoding Artemis protein in which small deletions encompassing several exons result in loss of function and Severe Combined Immunodeficiency (SCID).8 Additionally, ADA deficient SCID has been reported to be caused by gene deletion in 14% of cases.9 However, the gross deletion of multiple contiguous genes, compounded by point mutations and leading to a recessive phenotype has not been reported previously. To date, the available clinical genetic testing for SCID is primarily sequence-based. Our findings and the reports of other cases of autosomal recessive SCID in which a deletion was found on one allele suggest that microarray analysis or other focused deletion testing might be considered if sequencing only reveals mutations on one allele.


We thank Yiping Shen and Bai-Lin Wu for their assistance while working in the Department of Laboratory Medicine at Children’s Hospital Boston, Boston, MA.

Declaration of funding: W.J. Sheehan is supported by an NIH NRSA grant (T32-AI-007512).


Omenn Syndrome
Recombination-Activating Genes
Wilms Tumor 1 Gene
Wilms tumor susceptibility, Aniridia, Genitourinary abnormalities, and Mental Retardation
Fluorescent In Situ Hybridization


Disclosure of potential conflict of interest: Massimo Morra is employed by Correlagen Diagnostics.

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