Omenn Syndrome 

Updated: Apr 28, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD 

Overview

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 (see the image below).

A unique dermatitis characterizes Omenn syndrome. 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.

Cutaneous manifestations are common in primary immunodeficiency disorders. Erythroderma of infancy with diffuse alopecia is closely linked with children having SCID.[1] These patients may also 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.[2] 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 (see the image below).

This severe combined immunodeficiency disease has been linked to mutations in the RAG1/RAG2 gene.[3, 4]

Common viral infections are fatal in severe combin 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

Impaired V(D)J recombination process leads to the generation of a few T cells expanding in the periphery, infiltrating target organs such as skin and gut, resulting in the erythroderma and colitis typical of this syndrome.[5] Thus, 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-lineage and B-lineage cells occurs. In Omenn syndrome, the mutated RAG-1 and RAG-2 proteins remain normally distributed in the nucleus of cells.[6]

Early recognition of this condition is important for genetic counseling and early treatment.[7] The inflammation may be triggered by clonally expanded T cells, predominantly of the Th2 type.[8] 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.

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.[9]

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, 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. A novel homozygous frameshift mutation in IL7R (c.562delC) was indentified in the proband with both parents being Taiwanese aborigines who were delineated as carriers, none of whom had Omenn syndrome.[10] Mutations in the DCLRE1C gene, which encodes ARTEMIS, have been described in a number of patients.[11, 12] 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. Cutaneous Barrier Leakage may provide pivotal skin-gut interaction to sustain skin inflammation in OS.[13]

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.[14, 15]

Epidemiology

Frequency

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.

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.

Demographics

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.

 

Presentation

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.

A child with Omenn syndrome and the rare bone marrow disorder of reticular dysgenesis has been described.[16]

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 (see the image below). Protein loss via the skin and gut may result in generalized edema.

A unique dermatitis characterizes Omenn syndrome. 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

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, deletion, 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.

Various mutations are associated with the Omenn phenotype characterized by skin erythroderma, oligoclonal-activated T cells and elevated IgE in the absence of circulating B cells.[5] Omenn syndrome is usually due to hypomorphic defects in genes involved in V(D)J recombination, mainly RAG genes, whereas Omenn-like features are linked with mutations in genes involved in the maturation steps of lymphoid cells other than V(D)J recombination.

 

DDx

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.

Noninfectious cutaneous granulomas may rarely be evident in patients with the Omenn syndrome.[17, 18]

Differential Diagnoses

 

Workup

Laboratory Studies

Since the prognosis depends on a presymptomatic diagnosis and early treatment before complications occur, a simplified, practical and economic newborn screening method would be highly desirable and has been suggested.[19, 20]

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.

See the Differential Diagnosis section of the Medscape Reference article Pediatric 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.

Procedures

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 skin may show an infiltration of CD4+ (helper) T cells typically, but has been described with CD8+ (cytotoxic) T cells instead.[21]

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

Medical Care

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). Thus, gene therapy (GT) might represent a good alternative to stem cell transplantation, particularly in those without a matched donor.[22]

Consultations

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.

Diet

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.

Activity

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

Medication Summary

Dilute topical hypochlorite and skin pH restoration may be beneficial in controlling the erythroderma of Omenn syndrome.[23] Specific therapy for dermatitis and lymphadenitis involves immunosuppression with cyclosporine and the down-regulation of interleukin 4 (IL-4)[24] 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.[25] Although HSCT is the treatment of choice, allogeneic cord blood transplantation is another option recently used in one child.[26]

Replacement therapy with IV immunoglobulin

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.[27] 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 (see the Table below).

Table. Immune Globulin, Intravenous [28, 29, 27, 30] (Open Table in a new window)

Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)

Parenteral Form and Final Concentrations

IgA Content (mcg/mL)

Carimune NF

(CSL Behring)

Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25M glycine

Ready-for-use Liquid 10%

37

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Contains no sugar, contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Privigen Liquid 10%

(CSL Behring)

Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration

4.6-5

L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)

Ready-for use liquid 10%

< 25

Immunosuppressive Agents

Class Summary

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

Class Summary

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

Further Outpatient Care

As noted, 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.

Further Inpatient Care

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.

Transfer

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.

Deterrence/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. Transplantation outcomes have been assessed.[31]

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 and 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. Ruxolitinib may be utilized for graft-versus-host like disease in Omenn syndrome and successfully bridging to HSCT.[32]

Diagnosis at birth may protect from infection and improve transplantation outcome. Neonatal screening for this disorder is desirable.[33, 34, 20]

Patient Education

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.

 

Questions & Answers

Overview

What is Omenn syndrome?

What is the pathophysiology of Omenn syndrome?

What is the prevalence of Omenn syndrome?

What are the racial predilections of Omenn syndrome?

What is the mortality and morbidity associated with Omenn syndrome?

Which patient groups have the highest prevalence of Omenn syndrome?

At what age does Omenn syndrome typically present?

Presentation

Which clinical history findings are characteristic of Omenn syndrome?

Which physical findings are characteristic of Omenn syndrome?

What causes Omenn syndrome?

DDX

Which conditions are included in the differential diagnoses of Omenn syndrome?

What are the differential diagnoses for Omenn Syndrome?

Workup

What is the role of lab tests in the workup of Omenn syndrome?

What is the role of imaging studies in the workup of Omenn syndrome?

What is the role of genetic testing in the workup of Omenn syndrome?

Which findings of serum interleukin 4 and 5 are characteristic of Omenn syndrome?

What is the role of molecular analysis of HLA alleles in the workup of Omenn syndrome?

What is the role of biopsy in the workup of Omenn syndrome?

What is the role of bronchoscopy in the workup of Omenn syndrome?

Which histologic findings are characteristic of Omenn syndrome?

Treatment

How is Omenn syndrome treated?

Which specialist consultations are beneficial to patients with Omenn syndrome?

Which dietary modifications are used in the treatment of Omenn syndrome?

Which activity modifications are used in the treatment of Omenn syndrome?

Medications

What is the role of medications in the treatment of Omenn syndrome?

What is the role of IV replacement immunoglobulin in the treatment of Omenn syndrome?

Which medications in the drug class Interferons are used in the treatment of Omenn Syndrome?

Which medications in the drug class Immunosuppressive Agents are used in the treatment of Omenn Syndrome?

Follow-up

What is the role of isolation in the treatment of Omenn syndrome?

When is inpatient care indicated for Omenn syndrome?

When is patient transfer indicated for the treatment of Omenn syndrome?

How is Omenn syndrome diagnosed prenatally?

What are the possible complications of Omenn syndrome?

What is the prognosis of Omenn syndrome?

What is included in patient education about Omenn syndrome?