Omenn Syndrome

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

RAG2, RAG1, DCLRE1C, IL7R, IL2RG, ADA, RMRP, JAK3, IL2RA, ZAP70, CD3E, CHD7, AK2, CORO1A, IL21R, PTPRC, TFRC, LIG4, CD3D, AIRE, FOXP3, IL5, ISG20, PNP, CTLA4, PRM3, CD40LG, CDR3, TNFSF13B, IFNG

RAG2, RAG1, DCLRE1C, IL7R, IL2RG, ADA, RMRP, JAK3, IL2RA, ZAP70, CD3E, CHD7, AK2, CORO1A, IL21R, PTPRC, TFRC, LIG4, CD3D, AIRE, FOXP3, IL5, ISG20, PNP, CTLA4, PRM3, CD40LG, CDR3, TNFSF13B, IFNG, IL1RN, TRBV20OR9-2, IL4, IL10, CARD11

Drugs

Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

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Omenn syndrome (OS) is an inflammatory condition characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency (SCID; see this term).

Epidemiology

Prevalence is unknown.

Clinical description

OS presents during the first year of life with features of SCID including chronic diarrhea, pneumonitis and failure to thrive. In addition, patients present with inflammatory symptoms including lymphadenopathy, hepatosplenomegaly and generalized erythroderma, which may often cause alopecia and loss of eyebrows and eyelashes; protein loss may lead to generalized edema and metabolic disturbances. The signs and symptoms of OS can evolve over time and may not appear simultaneously. Some patients present with some but not all of these symptoms and may be described as having atypical Omenn syndrome. OS may also be associated with syndromic disorders including cartilage-hair hypoplasia (CHH), adenosine deaminase (ADA) deficiency, monosomy 22q11, coloboma of the eye, CHARGE syndrome and ligase 4 deficiency (see these terms).

Etiology

OS is not caused by a defined genetic defect. Rather than a distinct form of SCID, it is a distinct inflammatory phenotype that can be associated with genetically diverse SCIDs. The majority of cases reported to date have hypomorphic mutations in RAG1 and RAG2 genes (11p13). The other cases have mutations in the RMRP, ADA, IL2RG, IL7RA, DCLRE1C, CHD7 and LIG4 genes (9p21-p12, 20q13.11, Xq13, 5p13, 10p, 8q12.2 and 13q22-q34).

Diagnostic methods

OS may pose a diagnostic challenge because lymphocyte counts may be normal or high, unlike in typical SCID. Diagnosis is based on inflammation with evidence of abnormal expansion of one or more T-cell clones in peripheral blood and tissue, skin biopsies showing acanthosis and parakeratosis on staining with hematoxylin and eosin, evidence of dysplastic thymus with few remnant lymphoid cells and lymphadenopathy. Typically B cells are absent, as are immunoglobulins apart from IgE which is often raised. Eosinophilia is also observed.

Differential diagnosis

Differential diagnoses include graft-versus-host disease, histiocytosis, Job syndrome, Netherton syndrome, and severe combined immunodeficiencies (see these terms), particularly those associated with maternal T-cell engraftment.

Antenatal diagnosis

OS is not a single genetic disorder, but if the causative gene is identified in the index patient, prenatal diagnosis may be offered, although subsequent individuals are likely to have SCID.

Genetic counseling

Transmission is autosomal recessive.

Management and treatment

Initial treatment is based on immunosuppressive drugs including prednisone and cyclosporin followed by hematopoietic stem cell transplantation, in a centre recognized as treating such disorders ideally using HLA-identical family donors or, if this is not available, other appropriate donors after use of appropriate conditioning regimens.

Prognosis

If untreated, prognosis is poor and the disease is fatal. Skin inflammation worsens with time leading to severe barrier problems that facilitate life-threatening and overwhelming bacterial and fungal infections in already severely immunocompromised patients. Viral infections are most severe and life-threatening. Survival rates with treatment have been reported as greater than 80%.