In some cases, significant impairment of T-cell immunity is associated with residual development and function of T lymphocytes. These conditions are also known as CID to distinguish them from SCID, in which T-cell development and function are abrogated. The clinical features of CID overlap with SCID, but also include autoimmunity and/or inflammatory manifestations reflecting unbalanced immune homeostasis. CID is caused by two main mechanisms: (1) hypomorphic mutations in SCID-causing genes that allow for some T-cell development; and (2) genetic defects that affect late stages in T-cell development or peripheral T-cell function.
Originally described in 1965, Omenn syndrome is characterized by severe infections, associated with early onset diffuse rash or generalized erythroderma, alopecia, eosinophilia, lymphadenopathy, hepatosplenomegaly, hypoproteinemia with edema, and oligoclonal expansion of anergic, activated autologous T lymphocytes that infiltrate and damage target tissues.92,93
Various gene defects can cause this syndrome. Hypomorphic mutations in the RAG1 and RAG2 genes are most common,94 but mutations of DCLRE1C (Artemis),95 IL7R,96 LIG4,97 RMRP,98 IL2RG,99 ADA,100 and ZAP70101 have been also reported. All these defects severely restrict, but do not completely abrogate, T-cell development.
Defects of immunologic tolerance have been implied in the pathophysiology of Omenn syndrome. Thymic expression of AIRE (autoimmune regulator), a transcription factor involved in presentation of self-antigens and negative selection of autoreactive thymocytes, is reduced.102 Impaired generation of natural regulatory T cells, and homeostatic proliferation of T lymphocytes in a lymphopenic environment, may also play a critical role in the pathophysiology of the disease.103
Laboratory investigations show that leukocytosis with eosinophilia is common, immunoglobulin levels are low, but serum IgE is often elevated. The number of circulating T lymphocytes may vary, but they have a characteristic activated/memory (CD45R0+) phenotype. T cells have a restricted repertoire, and the distribution of CD4 and CD8 subsets is generally skewed. There is also a skewing to a Th2 profile, with increased production of IL-4 and IL-5. The in vitro lymphocyte response to antigens is abrogated; responses to mitogens are variable, but in general are reduced.104 The number of circulating B and NK lymphocytes may vary, depending on the nature of the underlying genetic defect. Absence of invariant natural killer T cells has been reported in RAG-deficient Omenn syndrome.105
Differential diagnosis includes maternal T-cell engraftment in patients with SCID, complete atypical DiGeorge syndrome, and CHARGE syndrome.106,107 CHARGE is an acronym derived from coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and development, genital and urinary abnormalities, and ear abnormalities and deafness. Those features are no longer used in making a diagnosis of this complex disorder. The syndrome is considered if a nonrandom pattern of congenital anomalies occurs together more frequently than one would expect on the basis of chance. Very few children with CHARGE will have all of its known features. Most cases have a mutation of the CHD7 gene on chromosome 8. Male infants with NEMO deficiency can also present with severe skin manifestations resembling Omenn syndrome.
Treatment- allogeneic hematopoietic stem cell transplantation for Omenn Syndrome
In preparation for allogeneic hematopoietic stem cell transplantation, the only curative treatment available,81 patients require aggressive nutritional support, correction of hypoproteinemia, and treatment or prevention of infections with antibiotics, antifungals, and immunoglobulin replacement therapy. Immune suppression with glucocorticoids or cyclosporine A is beneficial in controlling T-cell–mediated tissue damage.