Allergology International. 2006;55:115-119 REVIEW ARTICLE

Omenn Syndrome!Review of Several Phenotypes of Omenn Syndrome and RAG1!RAG2 Mutations in Japan

Masahiko Kato1,2, Hirokazu Kimura2, Mitsuru Seki3, Akira Shimada4, Yasuhide Hayashi4, Tomo- hiro Morio5, Satoru Kumaki6, Yasushi Ishida7, Yoshiro Kamachi8 and Akihiro Yachie9

ABSTRACT Omenn syndrome (OS) is a form of severe combined (SCID) characterized by erythroder- mia, hepatosplenomegaly, , and alopecia. In patients with OS, B cells are mostly absent, T- cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 (RAG1!2) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1 -deficient SCID. In this review, we will focus on the variation of several phenotypes of OS. KEY WORDS immunodeficiency, Japan, Omenn syndrome, RAG1 or RAG2 mutation

INTRODUCTION Omenn in 1985, one of a rare SCID characterized by the presence of a substantial number of oligoclonal, The common characteristic of severe combined im- activated T cells, and the lack of B lymphocytes, asso- munodeficiency (SCID), a group of rare monogenic ciated with particular clinical features such as gener- disorders, is the occurrence of a block in differ- alized , lymphadenopathy , hepa- entiation, always associated with a direct or indirect tosplenomegaly , and increased occurrence of life- impairment of immunity.1,2 The resulting com- threatening .3 bined immunodeficiency is responsible for the clini- In OS patients, circulating B lymphocytes are usu- cal severity of SCID, which, without treatment, leads ally absent, whereas various numbers of activated to death within the first year of life. At least, eleven and oligoclonal T lymphocytes are present in periph- distinct SCID phenotypes have been identified to eral blood and infiltrate the skin , gut , and date. Mutations of several genes have been found to , causing a graft-versus-host-like disease.4-7 OS cause SCID as shown in Table 1. Identifying the is caused by mutations of the recombination activat- pathophysiological basis of most SCID conditions has ing genes (RAG1 and RAG2) 2 that are essential for V led to the possibility of molecular as an alter- (D) J recombination. 8,9 Unless treated with hema- native to allogeneic hematopoietic stem cell trans- topoietic stem cell transplantation, OS patients usu- plantation. ally succumb early in life to overwhelming opportun- Omenn syndrome ( OS ) , was first reported by istic infections.7

1Departments of and , 3Internal , 4He- sity Graduate School of Medicine, Aichi and 9Department of Labo- matology and , Gunma Children’s Medical Center, ratory Sciences, School of Health Sciences, Faculty of Medicine, 2Gunma Prefectural Institute of and Environmental Kanazawa University, Ishikawa, Japan. Sciences, Gunma, 5Department of and Developmental Correspondence: Dr. Masahiko Kato, Departments of Allergy and Biology, Graduate School, Tokyo Medical and Dental University, Immunology, Gunma Children’s Medical Center, 779 Shimohak- Tokyo, 6Department of Pediatric Oncology, Institute of Develop- oda, Hokkitsu, Gunma 377−8577, Japan. ment, Aging and Cancer, Tohoku University, Miyagi, 7Department Email: mkato@shibukawa, gcmc.pref.gunma.jp of Pediatrics, Ehime University School of Medicine, Ehime, 8De- Received 28 September 2005. partment of Pediatrics!Developmental Pediatrics, Nagoya Univer- !2006 Japanese Society of Allergology

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Table 1 Major phenotypes of SCID Phenotypes Diagnosis Bearing gene T (－ ) B (－ ) NK (－ ) SCID ADA deficiency ADA T (－ ) B (－ ) NK (＋ ) SCID RAG1, RAG2 deficiency RAG1, RAG2 deficiency Artemis T (－ ) B (＋ ) NK (－ ) SCID X-SCID gc chain Jak3 deficiency Jak3 CD45 deficiency CD45 T (－ ) B (＋ ) NK (＋ ) SCID IL-7Ra deficiency IL-7Ra T (＋ ) B (－ ) NK (＋ ) SCID Omenn syndrome RAG1, RAG2 ADA; adenosine deaminase, SCID; severe combined immunodeficiency RAG; recombination activating genes

Table 2 Clinical features of six cases of RAG1/RAG2 mutaitons in Japan Age at Di- Case Clinical Feature Mutation Outcome Others agnosis 1＊ 2 m Hepatosplenomegaly, lymphnode swelling, RAG1; R396C, Dead at 5 m Typical Omenn eczema, , IgE elevation L885R syndrome 2＊ 0 m Hepatosplenomegaly, lymphnode swelling, RAG1; R396C, Dead at 21 Typical Omenn eczema, eosinophilia, IgE elevation L885R days syndrome 3 4 m Lymphnode swelling, eczema, eosinophilia, RAG1; R559S, post BMT, live Materno-fetal IgE elevation R897stop at 10 y transplantation 4 0 m Hepatosplenomegaly, lymphnode swelling, RAG2; A73H, post SCT, live Typical Omenn eczema, eosinophilia, IgE elevation Q258stop at 2 y 10 m syndrome RAG1; R142stop, post BMT, live Atypical Omenn 5 10 m Poor growth weight, respiratory distress R396H at 2 y 11 m syndrome 6 3 m RAG1; del 2441 post SCT, live Hepatosplenomegaly, eczema, eosinophilia 2nd site mutations framshift at 1y 8 m ＊ sibling SCT; stem cell transplantation, BMT; bone marrow transplantation, m; month, y; year

SEVERAL PHENOTYPES OF OMENN SYN- cluded that:(1) null mutations on both alleles lead to DROME the T-B-SCID phenotype ; ( 2 ) patients manifesting classic OS have missense mutations on at least one al- SCID represent a heterogeneous group of hereditary lele and maintain partial V (D) J recombination activ- defects of the immune system that affect both T and ity, which accounts for the generation of residual, oli- B cells and whose etiology has only recently begun to goclonal T-lymphocytes;(3) in a third group of pa- be understood. A portion of these SCID patients bear tients, findings were only partially compatible with a defect in either of the two recombination-activating OS, and these patients, who also carried at least one genes, RAG1 or RAG2,4 while others have mutations missense mutation, may be considered to have atypi- in a newly identified gene, Artemis.10 cal SCID!OS;(4) patients with engraftment of mater- OS is an unusual severe immunodeficiency with T nal T cells as a complication of a transplacental trans- cells but no B cells, and peculiar features also due to fusion represented a fourth group, and these patients, a defect in RAG1 or RAG2 genes.8,9 All these three who often presented with a clinical phenotype mim- forms are characterized by an impairment of the V icking OS, may be observed regardless of the type of (D) J recombination, the process that insures the so- RAG gene mutation. These results suggest that clini- matic diversification of immunoglobulin and T cell cal and immunologic phenotypes of patients bearing receptor-encoding genes. Recent findings have en- RAG mutation are more diverse than previously re- abled us to better understand the pathophysiology of ported and that this diversity is related to the specific these three , which affect the V type of RAG mutation. (D) J recombination process to a different extent and et al OUR RECENT CASE AND REVIEW OF in different ways. Villa . reported the clinical and RAG1!RAG2 MUTATIONS IN JAPAN immunological observations of V (D) J recombination defects in lymphocytes due to RAG mutations.5 They Recently , we encountered a 3-month-old boy with analyzed 44 such patients from 41 families, and con- generalized exudative erythrodermia , hepa-

116 Allergology International Vol 55, No2, 2006 www.jsaweb.jp! Omenn Syndrome in Japan

Normal B- T- SCID Typical Omenn

RAG RAG Absence of mature B T B or T cells BT

IgE

Polyclonal Polyclonal B cells T cells Oligoclonal expansion of autoreactive T cells

B- T-SCID Atypical Omenn Omenn with MFT with reversions

RAG RAG RAG BT B MFT T

IgE Oligoclonal T cells

Oligoclonal expansion Oligoclonal expansion of of alloreactive T cells autoreactive T cells with multiple reversions

Fig. 1 Various phenotypes of Omenn syndrome. Omenn syndrome (OS) shows various phenotypes. Typical OS has the generation of residual RAG activity, resulting in oligoclonal ex- pansion of autoreactive T cells (Typical Omenn). Atypical OS may result if expansion of activat- ed, oligoclonal T cells do not become predominant. As shown in OS with MFT, patients with engraftment of maternal T cells as a complication of a transplacental transfusion often pre- sented with a clinical phenotype mimicking OS, and may be observed regardless of the type of RAG gene mutation. Our case showed oligoclonal expansion of T lymphocytes with multiple second-site mutations leading to typical OS with RAG1-deficient SCID shown in B- T- SCID with reversions. tosplenomegaly, draining otitis externa, and alopecia, nally, mutation in the RAG1 gene was detected by with a history of Pseudomonas aeruginosa bactremia DNA sequencing.11 The diagnosis of OS was estab- requiring systemic antibiotic treatment. Laboratory lished . Immunosuppressive therapy with predniso- evaluation found mild anemia , leukocytosis with lone was started and then cyclosporin A was added to marked lymphocytosis and eosinophilia, low serum correct autoimmune manifestations. Four months af- immunoglobulin levels, and hypoalbuminemia. Analy- ter admission, the patient underwent allogeneic stem sis of T cell receptor Vβ repertoire in the periphery cell transplantation (SCT) with a full matched unre- showed extremely restricted heterogeneity . There lated cord blood unit, because no matched related do- was no evidence of maternal lymphocyte engraftment nor was available.12 Although the patient is infected due to the result of HLA typing and FISH analysis. Fi- with Mycobacterium avium complex and received anti-

Allergology International Vol 55, No2, 2006 www.jsaweb.jp! 117 Kato M et al. mycobacterium therapy with ethanbutol , rifampin , treatment is initiated rapidly by using early compat- and azithromycin, he no longer suffers from high fe- ible bone marrow transplantation or cord blood stem ver and is in good condition on day + 300 post- cell transplantation! transplant. So, far in Japan, six cases, including ours, of muta- REFERENCES tions of recombination activating genes (RAG 1 or 1. Notarangelo LD, Giliani S, Mazza C et al. Of genes and RAG2) were reported. As shown in Table 2, we sum- phenotypes: the immunological and molecular spectrum marized clinical features and mutation sites of RAG1 of combined immune deficiency: defects of the gamma and RAG2. Cases 1 and 2, which were siblings with (c)-JAK3 signaling pathway as a model. Immunol. Rev. 2000;178:39-48. typical Omenn phenotype, were found to be com- 2. 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