Omenn Syndrome

A number sign (#) is used with this entry because Omenn syndrome can be caused by mutation in the RAG1 (179615) and RAG2 (179616) genes on chromosome 11p and the Artemis gene (DCLRE1C; 605988) on chromosome 10p.

See also T-, B-, NK+ severe combined immunodeficiency (SCID) (601457), a more severe form of immunodeficiency that can also be caused by mutation in the RAG1 and the RAG2 genes. Another distinct form of familial histiocytic reticulocytosis (267700) is caused by mutation in the perforin-1 gene (PRF1; 170280) on chromosome 10q22.

Clinical Features

Omenn (1965) described reticuloendotheliosis with eosinophilia in several individuals in related sibships from an inbred American family of Irish extraction. Barth et al. (1972) concluded that the familial reticuloendotheliosis with eosinophilia described by Omenn is a distinct entity. Pneumocystis carinii, responsible for eosinophilia in other immune deficiency disorders, was not detected in any of Omenn's cases. Velders et al. (1983) described an 18-month-old child with a widespread pruritic skin disorder and fever, lymphadenopathy, anemia, eosinophilia, and chronic diarrhea. The child had sharply demarcated erythematosquamous disseminated lesions on the head, trunk, and limbs. Biopsy of a nodule from one of his extremities revealed a dense infiltrate in the deep dermis consisting of histiocytes, lymphocytes, eosinophils, and mast cells. Ecto-5-nucleotidase was markedly reduced in the patient's lymph node tissue and peripheral blood lymphocytes compared to a control. The patient died of toxic shock syndrome at the age of 20 months. Cohen et al. (1980) observed a decreased presence of ecto-5-nucleotidase on the peripheral lymphocytes of a patient with Omenn syndrome, but concluded that this finding is not specific for the disease. Gelfand et al. (1984) also found absent or greatly diminished activity of ecto-5-prime-nucleotidase in Omenn syndrome.

Hong et al. (1985) described Omenn disease terminating in lymphoma. Jouan et al. (1987) presented 9 cases of Omenn syndrome and suggested that pathologic lesions, particularly the skin and bone marrow changes, were reminiscent of those observed in acute graft-versus-host reaction (see 614395). Although blood chimerism had never been demonstrated, Jouan et al. (1987) supported a hypothesis of graft-versus-host disease in a primary cellular immunodeficiency and the persistence of proliferating maternal cells in peripheral target organs.

Schofer et al. (1991) described an infant who had features compatible with Omenn syndrome, but who also had short-limbed dwarfism caused by metaphyseal chondrodysplasia. Gatti et al. (1969) described identical bone changes in 2 sibs who likewise had the features of Omenn syndrome. (See 200900 for discussion of metaphyseal chondrodysplasia associated with immune defect.) Rybojad et al. (1996) described a Moroccan male infant, born to consanguineous parents, who manifested nephrotic syndrome in addition to typical findings of Omenn syndrome. Renal biopsy confirmed minimal change glomerular disease.

De Saint-Basile et al. (1991) studied 5 unrelated patients with Omenn syndrome; 2 were born of consanguineous parents. One of the patients had a brother and a sister who had died with the same syndrome, and the brother of another patient was said to have died with typical alymphocytosis-type T-, B- SCID (601457). The authors described the syndrome as being characterized by T-cell infiltration of skin, gut, liver, and spleen, leading to diffuse erythroderma, protracted diarrhea, failure to thrive, and hepatosplenomegaly. Although the lesions resembled those in graft-versus-host disease, the blood T cells were shown by DNA haplotype analysis to belong to the patients; the same was true of the T cells infiltrating the gut and skin in 1 patient. A restricted heterogeneity of the T-cell repertoire was indicated by oligoclonality of the T-cell receptor gene rearrangements. The occurrence of an alymphocytosis type of SCID in the brother of one of the patients suggested that the restricted heterogeneity of T-cell receptor gene usage in Omenn syndrome may rise from leakiness, within the context of a genetically determined faulty T-cell differentiation. Cavazzana-Calvo et al. (1993) presented further evidence that the Omenn syndrome is a leaky T-, B- SCID phenotype.

Schwarz et al. (1999) illustrated the characteristic erythematous, scaly rash, involving the entire body in an infant with Omenn syndrome. The authors noted that some clinical hallmarks of the disease, including generalized erythrodermia, lymphadenopathy, massive inflammatory infiltrate leading to pachydermia, and alopecia, are reminiscent of graft-versus-host disease. The engraftment of maternal T cells in infants with SCID may result in clinically overt GVHD, mimicking Omenn syndrome (Pollack et al., 1982; Le Diest et al., 1987). Furthermore, transfusion of unirradiated blood products into SCID babies may also result in severe GVHD that resembles Omenn syndrome (Anderson and Weinstein, 1990).

Ege et al. (2005) described a patient with Omenn syndrome who presented at the age of 5 months with septicemia, failure to thrive, generalized lymphadenopathy, hepatomegaly, splenomegaly, and erythrodermatitis. He exhibited alopecia and skin lesions, which consisted of large ichthyotic scales and scattered erythematous papules. Blood culture revealed Staphylococcus aureus; Pseudomonas aeruginosa was isolated from the feces. At the site of BCG vaccination, ulceration with lymph node involvement was observed. A lymph node taken from the left axilla showed numerous eosinophils, a marked proliferation of T cells, and a complete absence of B-cell lymphocytes. With immunosuppressive treatment, almost complete resolution of the dermatitis, alopecia, hepatosplenomegaly, and lymphadenopathy occurred, with significant weight gain. At the age of 10 months, peripheral blood stem cell transplantation after T-cell depletion and myoloablative conditioning was performed from the HLA-haploidentical mother. The therapy resulted in a complete donor chimerism and normal immune functions. Taken together, the patient presented with all of the clinical signs of Omenn syndrome, a T+, B-, NK+ SCID immunophenotype, and with elevated IgE levels and eosinophilia.

Pathogenesis

Using real-time PCR and immunohistochemistry, Cavadini et al. (2005) analyzed autoimmune regulator (AIRE; 607358) expression in the thymi of 2 Omenn syndrome patients and 1 T-, B-, NK+ SCID patient and found profound reduction of AIRE mRNA and protein compared to a normal control subject. There was no detectable mRNA for the self-antigens insulin (176730), cytochrome P450 1A2 (124060), or fatty acid-binding protein (see 134650) in the immunodeficient patients. Cavadini et al. (2005) concluded that deficiency of AIRE expression occurs in severe immunodeficiencies characterized by abnormal T-cell development and suggested that in Omenn syndrome, the few residual T-cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.

Clinical Management

Gomez et al. (1995) reported the outcome of allogenic bone marrow transplant (BMT) in 9 consecutive patients with Omenn syndrome treated between 1980 and 1989. They concluded that both HLA-identical and haploidentical BMT can cure Omenn syndrome, provided that parenteral nutrition and immunosuppressive therapy are given before transplantation.

Molecular Genetics

Villa et al. (1998) reported that patients with Omenn syndrome had missense mutations in either the RAG1 (179615.0001-179615.0013) or the RAG2 (179616.0003; 179616.0004) gene that result in partial activity of the 2 proteins. Two of the amino acid substitutions mapped within the RAG1 homeodomain and decreased DNA-binding activity, whereas 3 others lowered the efficiency of RAG1/RAG2 interaction. The findings indicated that the immunodeficiency manifested in patients with Omenn syndrome arises from mutations that decrease the efficiency of V(D)J recombination.

In a patient with T-, B- SCID, Corneo et al. (2001) identified compound heterozygosity for 2 mutations in the RAG2 gene (179616.0002; 179616.0008). A sib with Omenn syndrome had the same genotype. In 2 additional unrelated patients with T-, B- SCID, Corneo et al. (2001) identified mutations in the RAG1 gene (179615.0010; 179615.0015). Both mutations were also identified in patients with Omenn syndrome. The authors concluded that there was an additional factor required for the phenotypic expression of Omenn syndrome.

Ege et al. (2005) described a family in which 2 brothers died with manifestations consistent with Omenn syndrome and a third brother with Omenn syndrome was shown to be a compound heterozygote for mutations (605988.0012; 605988.0013) in the DCLRE1C/Artemis gene.

Animal Model

Khiong et al. (2007) characterized mice with a spontaneous mutation in the Rag1 gene and concluded that these mice represent a model for Omenn syndrome.

Marrella et al. (2007) generated a knockin mouse model in which endogenous Rag2 was replaced with Rag2 carrying the arg229-to-gln mutation (R229Q; 179616.0002) identified in patients with Omenn syndrome. They concluded that these mice mimic most symptoms of human Omenn syndrome.