Omenn Syndrome, Severe Combined Immunodeficiency

Omenn’s syndrome is an autosomal recessive early-onset form of severe combined immunodeficiency (SCID) characterized by increased susceptibility to opportunistic infections, hypereosinophilia, protracted diarrhea, rashes, and the enlargement of the lymph nodes and the spleen. Its presentation is very similar to that of graft-versus host disease (GVHD) insofar as T cells in individuals with Omenn’s syndrome recognize and attack self cells. Omenn syndrome is a form of severe combined immunodeficiency associated with high mortality. Early recognition is required in order to initiate life-saving therapy. The clinical symptoms, laboratory parameters and pathology of the disease, supporting early diagnosis in suspected patients. A literature search was performed using Medline, encompassing the period 1965-1999. Sixty-seven cases were identified and with the addition of a recently diagnosed patient at our hospital, 68 children were included. Median age at onset of symptoms was 4 weeks. Key symptoms were erythematous rash (98%), hepatosplenomegaly (88%), lymphadenopathy (80%), often accompanied by recurrent infections (72%) and alopecia (57%). An elevated WBC (55%) was frequently observed, due to eosinophilia and/or lymphocytosis. B-cell counts were significantly decreased whereas T-cell counts were elevated. A high serum IgE was another frequent finding (91%). Therapeutic options include bone marrow transplantation or cord blood stem cell transplantation; however, the mortality still was 46%.  Omenn syndrome is a fatal disease if untreated. The mortality may be reduced when diagnosis is established early and treatment is initiated rapidly by using early compatible bone marrow transplantation or cord blood stem cell transplantation.

Omenn syndrome is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by erythroderma (skin redness), desquamation (peeling skin), alopecia (hair loss), chronic diarrhea, failure to thrive, lymphadenopathy (enlarged lymph nodes), eosinophilia, hepatosplenomegaly, and elevated serum IgE levels.[1][2][3] Patients are highly susceptible to infection and develop fungal, bacterial, and viral infections typical of SCID. In this syndrome, the SCID is associated with low IgG, IgA, and IgM and the virtual absence of B cells. There is an elevated number of T cells, but their function is impaired.Omenn syndrome has been found to be caused by mutations in the RAG1 or RAG2 genes.Additional causative genes have been identified.Early recognition of this condition is important for genetic counseling and early treatment. If left untreated, Omenn syndrome is fatal. The prognosis may be improved  with early diagnosis and treatment with  compatible bone marrow or cord blood stem cell transplantation

Omenn’s syndrome, a rare autosomal recessive severe combined immunodeficiency, was first described in 1965. Except for recurrent infections, clinical manifestation is variable. The syndrome is characterised by the occurrence of diffuse erythrodermia, hepatosplenomegaly, generalised lymphadenopathy, and protracted diarrhoea, causing failure to thrive and evolving within the first weeks of life. Laboratory investigations typically show notable eosinophilia and highly increased serum IgE.Activated, autoreactive T lymphocytes infiltrate skin, liver, spleen, and intestine, and lead to autologous graft versus host disease-like reaction. The T cell repertoire shows a restricted heterogeneity. Recently, it has been shown that a mutation in either RAG-1 or RAG-2 involved in the creation of T cell variety may be one cause of Omenn’s syndrome.

Unless treated with allogenic haematopoetic stem cell transplantation (SCT), prognosis of Omenn’s syndrome is fatal.However, poor clinical status before SCT results in a high transplantation related mortality. Control of T cell activation and proliferation as well as nutritional support before SCT has been shown to reduce the risk of fatal complications

Omenn syndrome is an autosomal recessive severe combined immunodeficiency[1] associated with mutations in the recombination activating genes (RAG1 and RAG2), affecting circulating levels of both B-cells and T-cells. 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. Omenn syndrome is an autosomal recessive severe combined immunodeficiency associated with mutations in the recombination activating genes (RAG1 and RAG2), affecting circulating levels of both B-cells and T-cells.

A unique dermatitis characterizes Omenn syndrome. The dermatitis initially resembles eczema, but with a pachydermia, as observed here. The lesions progress to desquamation. Failure to thrive is evident. This infant weighed 6 pounds at age 6 months; his weight had not changed since birth. Patients develop fungal, bacterial, and viral infections typical of SCID. In this syndrome, the SCID is associated with the virtual absence of B cells and the presence of oligoclonal autoreactive T cells.

Lymphocytosis results from the expansion of an oligoclonal population of activated and antigen-stimulated T helper 2 (TH 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.

Common viral infections are fatal in severe combined immunodeficiency (SCID). This female infant died before bone marrow stem cell engraftment could occur, when varicella became resistant to acyclovir. The nasal bridge reveals superinfection with Klebsiella pneumoniae. Lymphedema, a characteristic of Omenn syndrome, is also shown.

Pathophysiology

  • Early recognition of this condition is important for genetic counseling and early treatment. The inflammation may be triggered by clonally expanded T cells, predominantly of the Th2 type. 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.
  • Individuals with Omenn’s syndrome exhibit a normal or a high level of circulating T cells in the blood and in the tissues of the skin, the intestine, the spleen, and the liver. The thymus, however, is almost completely devoid of T cells. T cells in individuals with Omenn’s syndrome exhibit an abnormal and very narrow T-cell antigen receptor (TCR) repertoire  in the peripheral lymphoid organs; the CDR3 variable region of the TCR β chain in both CD4 and CD8 T cells shows only a very limited diversity. The presence of abundant quantities of T cells in specific tissues  indicates that the limited TCR repertoire may target antigens present in these tissues. This explains both the rashes and the diarrhea associated with Omenn’s syndrome .
  • T cells in individuals with Omenn’s syndrome respond poorly to antigens and to allogeneic cells, explaining the susceptibility to opportunistic infections. Elevated serum levels of IL-4, IL-5, and IL-10 indicate the Omenn’s syndrome leads to an overexpression of Th2 cells.
  • Individuals with Omenn’s syndrome usually lack circulating B cells, resulting in severe hypogammaglobulinemia, or decreased levels of circulating IgG in the serum. Unexpectedly, elevated serum levels of IgE accompany the hypogammaglobulinemia
  • 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.
  • 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, the nuclease 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. Mutations in the DCLRE1C gene, which encodes ARTEMIS, have been described in a number of patients. Many of the mutations were gross deletions of exons 1-3 or exons 1-4.
  • 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.
  • B and T cells in individuals with Omenn’s syndrome completely lack ecto-5′-nucleotidase activity. Ecto-5′-nucleotidase is an enzyme that functions in purine metabolism and plays a role in normal lymphocyte development. Its absence from T and B cells in individuals with Omenn’s syndrome distinguishes this disease from GVHD, in which ecto-5′-nucleotidase activity may be decreased but not absent

Epidemiology

  • 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. Omenn syndrome has been reported in patients from throughout the world, mainly North America and Europe.
  • 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.
  • Patients have been identified in the United States, Canada, Europe, and India. The incidences are equal among male and female infants; this observation is consistent with the autosomal recessive etiology of Omenn syndrome.
  • 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 Manifestation

The symptoms are very similar to graft-versus-host disease (GVHD). This is because the patients have some T cells with limited levels of recombination with the mutant RAG genes. These T cells are abnormal and have a very specific affinity for self antigens found in the thymus and in the periphery. Therefore, these T cells are auto-reactive and cause the GVHD phenotype.

Symptoms :

  • Desquamation (shedding the outer layers of skin)
  • Chronic diarrhea
  • Erythroderma (widespread reddening of the skin)
  • Hepatosplenomegaly (simultaneous enlargement of both the liver and the spleen)
  • Leukocytosis (elevation of the white blood cell count)
  • Lymphadenopathy (swelling of one or more lymph nodes)
  • Persistent bacterial infections
  • Elevated serum IgE
  • 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.
  • 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 (see the image below). Protein loss via the skin and gut may result in generalized edema.
  • A unique dermatitis characterizes Omenn syndrome. The dermatitis initially resembles eczema, but with a pachydermia, as observed here. The lesions progress to desquamation. Failure to thrive is evident. This infant weighed 6 pounds at age 6 months; his weight had not changed since birth.
    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

  • Omenn’s syndrome may arise from any one of multiple genetic mutations.
  • Some individuals with Omenn’s syndrome possess missense mutations in the genes encoding the lymphoid-specific enzymes RAG-1 and RAG-2, which play a central role in the V(D)J recombination activities that result in TCR diversity. These mutations restrict the enzymes’ activities but do not entirely eliminate their functions. Four of these mutations, Rag-1 R561H, Rag-1 D429G, Rag-2 C41W, and Rag-2 M285R disrupt the interactions between the two enzymes when they form RAG-1/RAG-2 recombinase prior to beginning their role in V(D)J recombination. Another missense mutation, Rag-1 R396, reduces the capability of RAG-1 to bind to the recombination signal sequences (RSSs) that flank the gene segments involved in V(D)J recombination. The resulting low-affinity binding of RAG-1 to RSSs might drive V(D)J recombination in a specific direction, explaining the narrow TCR repertoire in individuals with Omenn’s syndrome
  • Other Rag-1 mutations are characterized by the deletion of one or two nucleotides from the N-terminus encoding end of the gene for RAG-1, resulting in a frameshift mutation that leads to the early termination of the enzyme at the C terminus. It appears as though the mutated Rag-1 gene is transcribed starting at the first methionine-encoding sequence downstream from the frameshift mutation. This maintains the proper reading frame at the C terminus of the protein. The resulting truncated protein is capable of performing limited V(D)J recombination. It appears that, although RAG-1 will function with a mutant N terminus, efficient recombinase functioning requires an intact RAG-1 N terminus.
  • Mutations in the gene encoding Artemis, an enzyme involved in opening the covalently closed DNA hairpin that forms during V(D)J recombination, also lead to Omenn’s syndrome. The mutant phenotype leads to a decrease in the number of recombination events occurring within an individual’s T cells. The mutation appears to be located  in the gene’s translation initiation codon and results in a 25% V(D)J recombination efficiency rate
  • A missense mutation in the IL7RA gene, which encodes for the α chain of the interleukin-7 receptor, also appears to lead to Omenn’s syndrome. This mutation affects T-cell development without affecting B-cell development, accounting for a subset of individuals with Omenn’s syndrome who possess circulating B cells
  • 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.

Diagnostic Considerations

  • The major reason for a missed or delayed diagnosis of Omenn syndrome is the eczematoid appearance of the dermatitis when the infections have not yet appeared. The eczema associated with diarrhea raises the possibility of a food allergy. Nevertheless, Omenn syndrome is usually accompanied by a failure to thrive not expected with common atopic dermatitis and by hypereosinophilia. Furthermore, the dermatitis has the unique appearance of pachydermia, which progresses to desquamation.
  • The clinical presentation also may suggest the possibility of other forms of severe combined immunodeficiency (SCID) complicated by maternal T-cell engraftment or transfusion-related graft versus host disease (GVHD). Patients with these conditions are typically more lymphopenic than those with other diseases.
  • Hyperimmunoglobulin E (HIE) syndrome in infants may need to be considered because these infants have eczema and infections with Candida species and S aureus. However, patients with Omenn syndrome are likely to have invasive infections, such as staphylococcal sepsis, whereas patients with HIE syndrome have infections limited to the lung, skin, and mucosal surfaces.

Differentials

  • Atopic Dermatitis
  • Graft Versus Host Disease
  • Histiocytosis
  • Hyperimmunoglobulinemia E (Job) Syndrome
  • Severe Combined Immunodeficiency
  • T-Cell Disorders

Diagnosis

  • In patients with Omenn syndrome, the peripheral WBC count may be normal or elevated with a predominance of lymphocytes. Eosinophilia is invariably present.
  • Flow cytometry should include the customary T, B, and natural killer cell (NKC) markers with additional T-cell markers including CD25, CD30, human leukocyte antigen (HLA)–DR, CD95, and CD69. CD25 is expressed in Treg cells as well as in the effector T cells while CD30 is expressed in activated T and B cells. CD45RO and CD45RA are used to identify cells responding to antigen stimulation and naïve T cells.
  • Severe Combined Immunodeficiency for a table of the lymphocyte profiles characteristic for various T-cell disorders.
  • The results show the presence of an oligoclonal set of activated antigen-stimulated Th2 cells.
  • B cells are absent, and NKC are present. T cells may have normal distribution of CD4 and CD8 or a predominance of CD8.
  • Immunoglobulin levels show absent immunoglobulin A (IgA) and immunoglobulin M (IgM), elevated IgE levels, and immunoglobulin G (IgG) that is maternal in origin. IgG antibodies against T-dependent antigens, such as tetanus, are nonprotective. Specific IgM antibodies, such as isohemagglutinins, are absent.
  • Lymphocyte mitogen responses to phytohemagglutinin (PHA), concanavalin A (conA), and pokeweed mitogen (PWM) are absent or profoundly decreased. In contrast, response to anti-CD3, superantigens, and phorbol myristate acetate (PMA)/ionomycin may be detectable. Addition of interleukin 2 (IL-2) can enhance the latter responses.
  • Cultures and the histologic examination of tissues and body fluids for infectious agents are mandatory for appropriate management of the infections.
  • When a T-cell disorder is suspected, the Immune Deficiency Foundation has a consultative service for physicians. Laboratories in New York City and at the University of Washington in Seattle and at the Children’s Hospital in Boston are funded by the Jeffrey Modell Foundation. They provide molecular analysis or assistance in contacting other research facilities.

Imaging Studies

  • The thymus is absent on chest radiographs of most forms of severe combined immunodeficiency (SCID), including Omenn syndrome.
  • In the initial workup or if fever develops, look for pulmonary infiltrates due to viral infections and interstitial pneumonitis caused by P carinii.

Other Tests

  • Perform mutational analysis for RAG-1 and RAG-2 to permit genetic counseling and prenatal diagnosis in subsequent pregnancies. Other mutation analysis may be indicated depending on clinical features.
  • Serum interleukin 4 (IL-4) and interleukin 5 (IL-5) levels are typically increased. In vitro cells produce decreased levels of IL-2 and interferon-gamma (IFN-γ) compared with the elevated IL-4 and IL-5 production by Th2 cells. These findings are consistent with decreased T helper 1 (Th1) cell activity.
  • Molecular analysis of HLA alleles by means of the polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) may be needed to detect engraftment of maternal T cells or graft versus host disease (GVHD) from transfusion-associated cells.
  • Skin biopsy may be considered, although an experienced immunologist may be able to make the diagnosis without this data in the appropriate clinical setting. The presence of maternally engrafted cells is more sensitively assessed with DNA techniques and peripheral blood lymphocytes, as indicated above.
  • Lymph node biopsy is unlikely to contribute additional information; fluorocytometric analysis of peripheral blood lymphocytes and lymphocyte mitogen assays provide more detailed diagnostic data.
  • Bronchoscopy is frequently necessary to identify P carinii, viral, and fungal etiologies of pulmonary infection.
  • Histologic Findings Skin biopsy findings reveal psoriasiform hyperplasia of the epidermis with parakeratosis, cellular dyskeratosis, and necrosis. The partial T-cell defects result in infiltration of the skin, with activated autoreactive T cells expressing CD30 and CD45RO. Eosinophils and histiocytes also populate the skin. Reactive lymph nodes show infiltrating eosinophils and histiocytic cells but lack germinal centers and cortical T lymphocytes. The gut lacks lymphocytes in Peyer patches and in the lamina propria. Rudimentary thymic tissue shows poorly formed and decreased Hassall corpuscles with few lymphocytes

Treatment

  • There is no known cure for Omenn’s syndrome.
  • Unless treated with a bone marrow (haematopoetic stem cell) transplantation, Omenn’s syndrome is fatal within the first few months of life.
  • In a successful bone marrow transplant, the individual is irradiated to kill all T cells with the Omenn’s syndrome phenotype before healthy bone marrow is transplanted into the recipient. A regimen of immunosuppressant drugs prevents graft regection, and antibiotics protect the recipient from common diseases.
  • Because  individuals with Omenn’s syndrome are severely immunocompromised, there is a high transplantation mortality rate. Controlling T-cell activation and proliferation with immunosuppressive drugs, administering antibiotics, applying topical steroid creams to control the rash, and providing proper nutrition to compensate for diarrhea before the transplant increases the likelihood of success. Pre-transplantation treatment with cyclosporin A, an immunosuppressive drug, leads both to an improved disease phenotype and to a greater likelihood of a successful transplant
  • Omenn syndrome is sometimes treated with bone marrow transplantation and cord blood stem cells. Conventional care for any patient with severe combined immunodeficiency (SCID) includes isolation to prevent infection and also meticulous skin and mucosal hygienic care while the patient is awaiting stem cell reconstitution. Signs of sepsis and pulmonary infections may be subtle; thus, fever alone requires a detailed search for infectious agents. Empirical broad-spectrum antibiotics are administered parenterally while cultures and body fluid analyses are in progress. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis. In individual cases, prophylaxis with antiviral agents (eg, acyclovir) or antibiotics may be appropriate. Parenteral nutrition is customarily provided as therapy for diarrhea and failure to thrive.
  • Bone marrow or other stem cell reconstitution is first-line conventional therapy for most forms of SCID, including Omenn syndrome, although the mortality rate is higher when compared to other types of SCID. Workup includes major histocompatibility complex (MHC) typing to identify a fully matched sibling, or, in the case of consanguinity, possibly a parent. Reconstitution by using a matched unrelated donor or haploidentical parent has also been successful, although more complications and higher mortality have been reported. Preparatory immunosuppression of malfunctioning activated T cells has decreased the incidence of graft failure in Omenn syndrome. Nutritional support and T-cell suppression prior to BMT may reduce the risk of complications. Pretransplantional evaluation routinely includes testing of the recipient and the donor for infectious agents, such as cytomegalovirus (CMV), HIV, and hepatitis viruses.
  • Specific therapy for dermatitis and eosinophilia in Omenn syndrome is immunosuppression with cyclosporine. Interferon gamma has been administered in an attempt to down-regulate interleukin 4 (IL-4) and interleukin 5 (IL-5) production by the oligoclonal Th2 cells. Interferon gamma may independently modulate the inflammatory reaction by enhancing phagocytic functions.
  • Ancillary therapy includes intravenous immunoglobulin (IVIG) replacement. Live viral vaccines should not be administered.
  • In the future, the identification of the recombinase mutations as the cause of Omenn syndrome should enable gene transfer therapy. At this time, successful gene therapy is available only for the X-linked T-B+ form of SCID, in which mutations in the common γ chain are necessary for function of the cell surface receptors of interleukin 2 (IL-2), IL-4, interleukin 7 (IL-7), interleukin 9 (IL-9), and interleukin 15 (IL-15).
  • Surgical intervention is not routinely considered.
  • Promptly initiate workup for stem cell reconstitution with the bone marrow transplant (BMT) team. In the meantime, consult a gastroenterologist and a nutritionist for important support.
  • A patient with chronic diarrhea and a failure to thrive requires consultation with a gastroenterologist and nutritionist to adequately provide calories, nutrients, and vitamins. Parenteral or enteral nutrition supplementation is usually necessary.
  • Infants with any form of SCID should be isolated to decrease the risk of common viral and bacterial infections. Patients should avoid crowds in locations such as stores, doctors’ offices, and hospitals, and they and their caregivers should engage in customary hygiene practices such as strict hand washing.

Medication

  • Specific therapy for dermatitis and lymphadenitis involves immunosuppression with cyclosporine and the down-regulation of interleukin 4 (IL-4) and interleukin 5 (IL-5) with interferon gamma. Broad-spectrum antibiotics are needed to treat invasive infections, especially those due to the common S aureus and gram-negative enteric bacteria. Prophylactic antibiotics and antifungal agents are often appropriate. Ancillary treatment with intravenous immunoglobulin (IVIG) replacement further decreases the risk of infection. Nutritional supplementation is mandatory to decrease the risk of infection and increase the likelihood of successful stem cell reconstitution.
  • Because Omenn syndrome tends to be fatal unless treated. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a curative approach, but treatment-related complications and graft rejection must be overcome. One successful innovative effort used reduced-intensity conditioning allogeneic HSCT from a sibling donor, achieving full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation. Although HSCT is the treatment of choice, allogeneic cord blood transplantation is another option recently used in one child.
  • Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies
  • The overall consensus among clinical immunologists is that an intravenous immunoglobulin (IVIG) dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. Patients with meningoencephalitis (X-linked agammaglobulinemia) require higher doses (1 g/kg) and, perhaps, intrathecal therapy. The measurement of preinfusion (ie, trough serum IgG levels every 3 mo until a steady state is achieved and then every 6 mo if the patient is stable) may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons in whom the catabolism of infused immunoglobulin G (IgG) is high, more frequent (eg, every 2-3 wk) infusions of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during active infection; measuring serum IgG levels and adjusting to higher doses or shorter intervals may be required.
  • For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes (eg, solvent detergent versus pasteurization and liquid versus lyophilized) are recognized. The choice of brands may depend on the hospital or home care formulary and on local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording of all adverse effects that occur during the infusion is crucial.
  • Periodic liver and renal function testing, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) advises that, in patients at risk for renal failure, the recommended doses should not be exceeded and that infusion rates and concentrations should be the practical minimum levels. Examples of patients at risk for renal failure include those older than 65 years; those who use nephrotoxic drugs; and those with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia.
  • The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and in those in whom immune complexes form. In patients with active infection, infusion rates may need to be slower, and the dose halved (ie, 200-300 mg/kg). The remaining half should be given the next day to achieve a full dose. Treatment should not be discontinued. After normal serum IgG levels are achieved, adverse reactions are uncommon unless patients have active infections.
  • With the new generation of IVIG products, adverse effects are reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency and patients with active infections have more severe reactions.
  • The anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with fragment crystallizable (Fc) receptors and that trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose; maximum, 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, therapy with analgesics and antihistamines may be repeated.
  • Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products with sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg/kg/min based on the amount of sucrose. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring the blood urea nitrogen and creatinine levels before starting the treatment and prior to each infusion is necessary. If the patient’s renal function deteriorates, the treatment should be discontinued.
  • Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few cases of true anaphylaxis have been reported in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience this is rare. In addition, this is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or in those with severe combined immunodeficiency (SCID). Caution should be exercised in patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG-subclass deficiencies. IVIG preparations with low concentrations of contaminating IgA are advised
  • Unless treated with haematopoetic stem cell transplantation, Omenn’s syndrome, a rare variant of severe combined immunodeficiency, is associated with a fatal outcome. All of  the typical features of Omenn’s syndrome, who was successfully treated with cyclosporin A to improve clinical condition prior to haematopoetic stem cell transplantation.
  • Inform families about the risks of infection so that appropriate steps to avoid exposure to infection can be instituted. They should be aware that live viral vaccines are contraindicated.
  • In obtaining adequate informed consent for stem cell reconstitution, the physician must review the high rate of GVHD, the risk of the failure to engraft, and the high risk for life-threatening infection during the preparative immunosuppressive regimen. Although successful complete immune reconstitution with BMT is reported with the use of fully matched related and unrelated donors or haploidentical parents, a failure to engraft may occur in patients with Omenn syndrome, or they may have posttransplantational GVHD.
  • The Immune Deficiency Foundation is an important resource for the education and support of patients and families with any primary immunodeficiency disease. Its current address is 25 W Chesapeake Ave, Suite 206, Towson, MD 21204; some states have local chapters. The Jeffrey Modell Foundation at 43 W 47th St, New York, NY 10036 also provides support and patient education.

Immunosuppressive Agents
Specific therapy for dermatitis and lymphadenitis involves immunosuppression with cyclosporine and the down-regulation of IL-4 and IL-5 with INF-γ.

  • Cyclosporine (Sandimmune, Neoral)
    Diarrhea and the youth of patients make high doses customary. Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and GVHD in various organs. Dose based on patient’s ideal body weight.
  • Interferons
    These agents are naturally occurring cytokines that possess various biologic functions, including immunosuppressive action. They are produced by cells in response to viruses, double-stranded RNA, antigens, or mitogens, and they are classified in relation to biochemical properties and the cell of origin. These agents are commercially produced by means of recombinant DNA technology. Interferon gamma has been administered subcutaneously on a daily basis to interrupt processes mediated by IL-4 and IL-5 and to enhance a functional inflammatory response to infection.
  • Interferon gamma-1b (Actimmune)
    Recombinant-derived cytokine possessing antiviral, immunomodulatory, and antiproliferative activity. Differs from interferon alfa and interferon beta by possessing significant antiproliferative activity. The immunomodulatory effects also differ, unlike interferon alfa or interferon beta; interferon gamma has potent macrophage activating effects.

Follow-up

  • Coordinating medical management of Omenn syndrome between immunologists, infectious disease specialists, pulmonologists, and gastroenterologists can be challenging. Bone marrow transplantation (BMT) is best coordinated between the immunologist and the BMT team.
  • The necessity for excellent laboratory and radiology support mandates hospitalization of the patient in a tertiary children’s medical facility.
  • As noted above, patient isolation to prevent the transmission of infection is compulsory.
  • Usually, contacts are restricted to immediate family members and friends whose risks for infection can be monitored.
  • Carefully orchestrate visits to doctors’ offices and hospitals to prevent exposing the patient to infectious agents.
  • The great complexity of medical problems for any primary immunodeficiency disease requires that an immunologist treat the patient.
  • The subtle signs of infection, the need to offer stem cell transplantation, and the early deaths in Omenn syndrome indicate that frequent monitoring by a clinical immunologist is essential.

Prevention

  • In families in whom the exact mutations have been established, prenatal diagnosis is possible by means of chorionic villus sampling or amniocentesis with DNA methods.
  • Fetal blood sampling for fluorocytometric testing and mitogen response assessments can aid in the diagnosis when DNA analysis is not available.

Complications

  • Graft failure with BMT and posttransplantational graft versus host disease (GVHD) are well recognized, although the incidences of both have decreased because of improved BMT preparatory regimens and techniques.
  • Donor lymphocyte infusion with donor cord blood–derived activated CD4+ T cells has been reported to be an effective method to overcome the risk of graft rejection in stem cell transplant with residual cell-mediated immunity without compounding GVHD.

Prognosis

  • Patients with Omenn syndrome have fully recovered after BMT, with or without pretransplantation immunosuppression. As with any BMT procedure, a risk of GVHD is recognized, even with a fully major histocompatibility complex (MHC)-matched donor.
  • Patients who do not receive BMT have not survived with the supportive management involving prophylactic antibiotics and parenteral nutrition alone. Interferon gamma has been administered in an effort to down-regulate interleukin 4 (IL-4) and interleukin 5 (IL-5) production. Cyclosporine therapy does improve the dermatitis and diarrhea while the workup for BMT is in progress.
  • A review of 68 patients with Omenn syndrome treated between 1965-1999 found the mortality rate of 28 patients who received BMT to be 47%. The main cause of death was respiratory failure and sepsis. More recently, an 18.2% mortality rate was reported in a series of hematopoietic stem cell transplantations (HSCT) in 11 patients with Omenn syndrome.
  • Diagnosis at birth may protect from infection and improve transplantation outcome. Neonatal screening for this disorder is desirable.

References

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