eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Omenn Syndrome

Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Robert Y Lin, MD, Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology Section, Medical Advisor, Department of Case Management/Utilization Review, St Vincent's Catholic Medical Centers, St Vincent's of Manhattan
Contributor Information and Disclosures

Updated: Jan 13, 2009

Introduction

Background

Omenn syndrome (MIM 603554) is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly. Patients develop fungal, bacterial, and viral infections typical of SCID. Lymphocytosis results from the expansion of an oligoclonal population of activated and antigen-stimulated T helper 2 (T_H 2) cells that produce elevated levels of interleukin 4 (IL-4) and interleukin 5 (IL-5). The latter cytokines mediate eosinophilia and elevated immunoglobulin E (IgE) levels.

Pathophysiology

Early recognition of this condition is important for genetic counseling and early treatment.¹ The inflammation may be triggered by clonally expanded T cells, predominantly of the Th2 type.² These abnormal T cells presumably secrete cytokines that promote autoimmune as well as allergic inflammation. Omenn syndrome has been identified in leaky SCIDs caused by hypomorphic mutations in recombinase genes RAG-1 and RAG-2, which impair but do not eliminate recombination of variable, diversity, and joining (VDJ) segments of TCR and Ig genes. Most cases of Omenn syndrome reported so far are associated with hypomorphic mutations in RAG-1/RAG-2 genes.  

The inability to productively rearrange VDJ regions in T-cell and B-cell receptors leads to abnormal T cells and absent B cells. The mutations in RAG-1 and RAG-2 in Omenn syndrome differ from T-cell negative (T^-), B-cell negative (B^-), and natural killer cell positive (NKC⁺) SCID caused by RAG-1 or RAG-2 mutations. In these conditions, the mutations affect the active core of the recombinase genes and typically negate the production of the recombinase protein; hence, no development of T and B lineage cells occurs. In Omenn syndrome, the mutated RAG-1 and RAG-2 proteins remain normally distributed in the nucleus of cells. 

A novel mechanism has been suggested: By selectively impairing recombination at certain coding flanks, a RAG mutant can cause primary repertoire restriction, as opposed to a more random, limited repertoire that develops secondary to severely diminished recombination activity, with autoimmune manifestations related to decreased thymic expression of tissue-specific antigens.³

However, Omenn syndrome is now known to occur in other leaky SCIDs with mutations in the RNA component of mitochondrial RNA processing endoribonuclease, adenosine deaminase, interleukin 2 (IL-2) receptor gamma, interleukin 7 (IL-7) receptor alpha, ARTEMIS, and DNA ligase 4. Thus, Omenn syndrome is a distinct inflammatory process that can be associated with genetically diverse, leaky SCIDS. Accordingly, Omenn syndrome is best viewed, not as a specific form of SCID, but rather as an aberrant inflammatory condition that can be associated with multiple genetic abnormalities, which can significantly impair (but not abolish) T-cell development in the thymus.

An oligoclonal expansion of Th2 population is viewed as a result of increased exposure to inadequately cleared antigens. These oligoclonal T cells have a highly restricted receptor repertoire, as well as increased apoptosis due to overexpression of CD95 and underexpression of anti-apoptotic factors, such as bcl -2.

Germinal centers are absent in the lymph nodes, which is consistent with the inability to produce functional antibodies. Hassall corpuscles are poorly formed, and lymphocytes are deficient in the thymus. Paracortical lymphocytes are absent in the spleen.

RAG -deficient mice have been developed. Their defects are restricted to the T^- B^- immunologic abnormalities, as observed in human RAG deficiency. Recently, 2 murine models bearing mutations of the VDJ recombinase analogous to those causing human OS have been developed. These murine models have oligoclonal T cells, an absence of circulating B cells, peripheral eosinophilia, and activated autoreactive T cells infiltrating gut and skin, causing diarrhea, alopecia, and, in some cases, severe erythrodermia.^4,5

Frequency

United States

The frequency of Omenn syndrome is difficult to ascertain. The prevalence of all forms of SCID is estimated to be 1 case per 50,000 population.

International

Omenn syndrome has been reported in patients from throughout the world, mainly North America and Europe.

Mortality/Morbidity

Omenn syndrome is fatal if untreated. Patients have life-threatening viral, bacterial, fungal, and Pneumocystis carinii infections that are observed in other types of SCID. Patients commonly have Staphylococcus aureus sepsis, which is related to the generalized dermatitis. Live viral infections, including those due to attenuated oral poliovirus, may cause death. In addition, chronic diarrhea and resulting inanition may be responsible for death.

Bone marrow transplantation (BMT) is usually successful, but life-threatening acute or chronic graft versus host disease (GVHD) may be a complication. This can occur in any stem cell reconstitution procedure.

Race

Patients have been identified in the United States, Canada, Europe, and India.

Sex

The incidences are equal among male and female infants; this observation is consistent with the autosomal recessive etiology of Omenn syndrome.

Age

Infants present within weeks of birth and usually by age 3 months, as do those with other types of SCID. The characteristic dermatitis, chronic diarrhea, and failure to thrive often precede the onset of infections. Published reports of patients describe presentation by the time the patient is aged 6 months.

Clinical

History

• In the first weeks after birth, infants with Omenn syndrome present with erythrodermia and diarrhea. The severity of the dermatitis is associated with episodes of S aureus sepsis; diarrhea predisposes patients to gram-negative enteric bacterial sepsis.
• As in other forms of severe combined immunodeficiency (SCID), life-threatening infections with common viral, bacterial, and fungal pathogens occur next.
• Chronic diarrhea and infection lead to failure to thrive, which is also characteristic of any other type of SCID.
• Lymphadenopathy and hepatosplenomegaly soon develop; however, these are unusual in other types of SCID unless maternal engraftment or transfusion-associated graft versus host disease (GVHD) occurs.
• P carinii pneumonia and poliomyelitis due to the attenuated oral poliovirus are classic infections in Omenn syndrome and in other types of SCID.

Physical

• Patients present in the first weeks of life with a unique generalized dermatitis that may be mistaken for eczema. However, the dermatitis has a pachydermatis appearance that progresses to desquamation. Protein loss via the skin and gut may result in generalized edema.
• Lymphadenopathy distinguishes Omenn syndrome from most other SCID variants.
• Hepatosplenomegaly is also usually present.
• Failure to thrive associated with chronic diarrhea and dermatitis should always raise the suspicion of SCID.
• Alopecia is another frequent finding.

Causes

• When mutations in the recombinase genes RAG-1 and RAG-2 have been sought, homozygous and heterozygous mutations have been found. In contrast to T^- B^- NKC⁺ SCID in which RAG-1 and RAG-2 mutations affect the active core of the gene, homozygous mutations affecting the active core have not been observed in Omenn syndrome. Approximately half of the mutations are missense mutations, and the remainder are nonsense, deletional, frameshift, duplication, and splice mutations. RAG-1 and RAG-2 genes have been mapped to chromosome band 11p13.
• Although most cases of Omenn syndrome are due to mutations in the RAG genes, recent reports describe Omenn syndrome in the absence of RAG mutations. Omenn syndrome caused by mutations in ARTEMIS, ADA, ILRA2, ILRA7, CHD7, and DNA ligase 4 has been described. Omenn syndrome caused by 22q11 microdeletion syndrome has also been described. Therefore, Omenn syndrome is now defined as a genetically heterogeneous condition in which patients with similar phenotypes may have unidentified genetic defects.

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