AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

This article discusses partial T-cell disorders. For reviews of complete T-cell deficiencies, see the articles titled Severe Combined Immunodeficiency (SCID), Omenn Syndrome, and Cartilage-Hair Hypoplasia.

The nomenclature for T lymphocytes is based on the role of the thymus in the differentiation and maturation of T lymphocytes. The prototypic T-cell disorder in which the thymus is absent, small, or in an aberrant location is DiGeorge Syndrome (DGS). Other well-known partial deficiencies in T-cell function include the chromosomal breakage syndromes (CBSs) B-Cell and T-Cell Combined Disorders (ataxia telangiectasia [AT]) and Wiskott-Aldrich Syndrome (WAS), which are discussed in separate articles.

Partial T-cell disorders typically have limited T-cell defects that predispose patients to more frequent or extensive infections; these disorders often include immune dysregulation that allows autoimmune phenomena, lymphoproliferation, and malignancies. For example, patients with partial DGS rarely lack T-cell function as measured by in vitro T-cell proliferation to nonspecific mitogens. When T-cell function is absent in T-cell disorders, the disorder can be lethal. Conventional clinical management for absent T-cell function consists of immune reconstitution using stem cell or bone marrow transplantation.

Partial T-cell defects commonly cause abnormalities of immune regulation. Thus, T- to B-cell communication is defective, with partial defects in antibody production and increased incidence of atopy and autoimmune disorders. Inadequate antibody responses directed against bacterial polysaccharide antigens cause an increased risk for bacterial sinopulmonary infections. The increased risk for reactive airway disease and thyroiditis in patients with DGS and the high incidence of autoimmune hemolytic anemia in patients with WAS are examples of defective T-cell/B-cell interactions that produce self-reactive antibodies.

T-cell disorders in which autoimmunity and polyendocrinopathy predominate have recently been elucidated, and more will certainly be discovered as pathways for T-cell signal transduction are understood better. Mutations in the CD3⁺ T-cell complex are associated with autoimmune cytopenias, autoimmune enteropathy, and recurrent sinopulmonary infections. Defects in CD95/Fas and Fas ligand lead to autoimmune cytopenias, lymphadenopathy, and hepatosplenomegaly. A syndrome of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene coding for autoimmune regulator.

Newly discovered mutations in the gene coding for scurfin at chromosome band Xp11.22 are manifested as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (also termed X-linked syndrome with polyendocrinopathy, immune dysfunction, and diarrhea [XPID]). Mutations in the gene coding for interleukin 2a receptor (IL-2Ra) have similarly caused diarrhea, candidiasis, and lymphoproliferation.

Knockout and transgenic mice have been developed for specific T-cell disorders and are recognized to have helped predict human genetic disorders.

Pathophysiology

Mature functional T cells undergo differentiation and maturation in the thymus; therefore, the thymus is critical for intact cell-mediated immunity. The thymus also regulates central tolerance by deleting T cells that recognize self-antigens. Thus, defects in the thymic microenvironment, as in DGS, result in poor T-cell function. The ability of T cells to recognize and respond appropriately to antigen depends on a complex pathway of surface glycoproteins and transmembrane molecules involved in signal transduction, many of which can be ascertained by flow cytometry using monoclonal antibodies directed against these antigens.

Critical components of T-cell antigen recognition include the CD3 complex, CD4, CD8, and the T-cell receptor heterodimers TCRa/b and TCRg/d. These molecules act in a coordinated manner to regulate intracellular pathways, which then induce or inhibit the specific immune response.

Antigen recognition through CD4 depends on antigen presentation by major histocompatibility complex (MHC) class II, while CD8 requires antigen presentation by MHC class I. Additional molecules, such as Fas and Fas ligand, mediate apoptosis of T cells that recognize self-antigens. The scurfin protein is a newly identified transcription factor, encoded by the FOXP3 gene, that is expressed both in the thymus and in peripheral T cells, functioning to regulate T-cell activation and, possibly, T-cell number. Immune regulation occurs centrally in the thymus and in peripheral T cells, lymphoid tissues, and nonlymphoid tissues (eg, gut, skin).

Defects in cytotoxicity by T cells and natural killer (NK) cells in Chediak-Higashi syndrome (CHS) reflect a global error in packaging of lysosomal enzymes caused by a mutation in the gene coding for lysosomal-trafficking regulator.

For a more detailed discussion of the intricate pathways of T-cell signaling, see the articles on specific T-cell deficiency syndromes listed in Differentials.

Frequency

United States

Overall frequency of T-cell disorders has been estimated at 1 case per 70,000 people. Specific T-cell disorders are even more infrequent. DGS has an estimated incidence of 1 case per 10,000 live births, but many of these children have minimal immune dysfunction that improves with age.

International

Partial T-cell defects are seen in persons of all ethnic backgrounds. This is well established for specific syndromes such as DGS and WAS. Some autosomal recessive disorders are seen more frequently in inbred populations. As mutation analysis becomes more routine, heterozygous mutations have been frequently defined in some disorders, such as AT.

Mortality/Morbidity

Patients with partial T-cell disorders usually have chronic illness from sinopulmonary infections, autoimmune cytopenias, diarrhea, and polyendocrinopathies, especially insulin-dependent diabetes mellitus (IDDM). Depending upon the specific mutation, severe disease may cause death in infancy or the patient may survive into middle childhood. Lymphoproliferative disease and malignancy are features of WAS, AT, and immune dysregulation/autoimmunity syndromes.

• DGS (partial) is the single T-cell disorder in which the incidence of respiratory and candidal infections often decreases in patients older than 2 years. However, the incidence of hypothyroidism increases in mid childhood.
• Bone marrow transplantation is the best treatment in patients with WAS and CHS younger than 2 years because outcome studies show higher rates of cure at earlier ages. CHS is difficult to treat once it enters the accelerated phase.
• Progressive neurologic deterioration is a feature of AT and CHS.

Race

T-cell disorders affect all ethnic populations. Isolated inbred populations in Europe and the Middle East have been identified with a number of rare partial T-cell disorders that were subsequently found to occur sporadically in the United States. Studies of unique large extended families with rare immunodeficiencies have been an important source in documenting clinical manifestations, and these detailed genetic studies have improved understanding of specific gene function.

Sex

A number of genes regulating immune function are located on the X chromosome. The gene defect in X-linked SCID (mutations in the common g chain for interleukin [IL]–2, IL-4, IL-7, IL-9, and IL-15) is located at chromosome band Xq13. The BTK gene for X-linked agammaglobulinemia is at band Xq21.3. X-linked hyperimmunoglobulin M (XHIM; CD40 ligand deficiency) is caused by mutations at band Xq26.2. X-linked lymphoproliferative disease is caused by mutations in the gene for signaling lymphocyte activation molecule (SLAM)–associated protein at band Xq25. The gene responsible for WAS is located at band Xp11.22, and the gene coding for scurfin for X-linked polyendocrinopathy and enteropathy is nearby, between bands Xp11.23 and Xq13.3.

T-cell disorders with autosomal genes include DGS at band 22q11, AT at band 11q22, and CHS at bands 1q42-43. The gene for CD3 complex is localized to chromosome band 11q23. The AIRE gene for APECED is on band 21q22.3. The gene for CD95/Fas is at band 10q23.

Age

Most T-cell disorders present in early infancy with unusually severe or frequent infections. A search for nonimmunologic features of specific syndromes may aid in the diagnosis of specific syndromes.

• DGS can be recognized by facial features and cardiac anomalies at birth.
• WAS can be diagnosed at birth by the small size of platelets, although the platelet count is within reference ranges. Clinical manifestations of bleeding and eczema appear within the first weeks to months before infections begin.
• AT is another T-cell disorder in which noninfectious signs (hypotonia and ataxia) often antedate infection.
• CHS, a global error in packaging of lysosomal enzymes, is associated with oculocutaneous albinism prior to the onset of recurrent cervical lymphadenopathy and the development of the accelerated phase with bleeding.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Unusually severe common viral infections (eg, respiratory syncytial virus [RSV], enterovirus, rotavirus), mucocutaneous candidiasis, diarrhea, and eczematous or erythrodermatous rashes should prompt suspicion of a T-cell disorder. Failure to thrive and cachexia are late signs of a T-cell defect. Opportunistic infection develops more commonly in an infant who has become wasted, although it may be the presenting illness.

• Late diagnosis of a partial T-cell defect may occur in patients with DGS when the facial anomalies are subtle and cardiac lesions are absent. These individuals have recurrent respiratory infections consisting of sinusitis and viral infections. In addition, patients have more extensive mucocutaneous candidiasis than anticipated in a healthy host taking antibiotics.
• In patients with AT, late diagnosis is often based on the progressive loss of mobility and the appearance of telangiectasia in children aged approximately 4-5 years.
• A diagnosis of WAS may be delayed until recurrent sinopulmonary infections develop if petechiae and bloody diarrhea are minor and intermittent and if eczema is misinterpreted as common atopy. Additionally, more than 70% of patients with WAS have at least one associated autoimmune disease.
• Patients with CHS are often treated for recurrent otitis, sinusitis, and lymphadenitis caused by staphylococci and streptococci before the massive lymphadenopathy and hepatosplenomegaly of the accelerated phase make the diagnosis obvious.
• Epstein-Barr virus (EBV) infection is the predominant lethal infection in X-linked lymphoproliferative disease, and EBV infection is usually associated with development of the accelerated phase of CHS.
• The diagnosis of IDDM and diarrhea in a male infant younger than 1 year raises the possibility of IPEX syndrome. IDDM and enteropathy also are components of the autosomal recessive mutations found in patients with APECED.
• Lymphadenopathy and hepatosplenomegaly characterize mutations in the genes coding for CD3 complex and CD95/Fas.
• Patients with WAS in whom the immune system is not reconstituted using bone marrow transplantation usually die in the third decade of life from malignancies; lymphoid and CNS tumors are most common.
• Patients with AT and Nijmegen breakage syndrome (NBS) are at a higher risk for malignancies, usually lymphoid, that increases with age.
• Neurologic disorders are increasingly reported in patients with partial T-cell disorders.
• • Progressive neurologic dysfunction is well known in patients with CBSs (eg, AT, NBS) and in CHS.
  • Patients with DGS have learning and behavioral dysfunction that becomes more apparent at school age.
  • Seizure disorders frequently accompany immune dysregulation/autoimmunity syndromes such as the X-linked mutation in the gene encoding for the protein scurfin (IPEX syndrome).

Physical

The physical examination features of DGS, WAS, and AT are presented in detail in other respective articles.

• Rash often occurs in infants with a T-cell disorder, commonly as a generalized eczema or erythroderma. Urticarial rashes and cutaneous vasculitis are present in CD95/Fas and Fas ligand deficiencies. Ectodermal dystrophy characterizes APECED syndrome.
• Patients with AT have telangiectasia of the conjunctiva and pinna; these features present after the diagnosis should already have been confirmed by the presence of ataxia and infections.
• Candidiasis is a common feature of partial and complete T-cell disorders. In partial T-cell disorders (eg, DGS, WAS, APECED syndrome, IPEX syndrome) dissemination is unlikely, even when the autoimmune disease is treated with immunosuppressive agents. Disseminated invasive candidiasis suggests SCID or a phagocytic disorder.
• Patients with the classic presentation have a complete absence of T cells (ie, SCID) and lack peripheral lymphoid tissue. However, patients with partial T-cell disorders often have palpable lymph nodes.
• • Lymphadenopathy and hepatosplenomegaly may be progressive in immune dysregulation/autoimmunity syndromes, such as Fas and Fas ligand deficiencies and mutations in the gene coding for CD3 complex.
  • Lymphadenopathy suggests the possibility of lymphoma or leukemia in older patients with WAS and CBSs.
• Neurologic deterioration with hypotonia and progressive ataxia may occur before infection, raising a suspicion of immunodeficiency in patients with AT and NBS.
• Bleeding in patients with WAS is a result of decreased volume and numbers of platelets.
• In infants, the first sign of WAS is often bloody diarrhea that occurs before petechiae and epistaxis.
• In the accelerated phase, CHS is accompanied by bleeding.

Causes

Many of the exact functions of the gene products that are mutated in partial T-cell disorders have yet to be elucidated. For a more complete discussion of the genes responsible for DGS, AT, WAS, and CHS, see Pathophysiology and the specific articles for each disorder. CHS is caused by mutations in the gene encoding for the lysosomal-trafficking regulator. This mutation leads to abnormal distribution of lysosomal proteins in phagocytes (impairing bactericidal activity), in melanosomes (explaining partial albinism), and in neurologic function and to cytotoxicity by T cells and NK cells, predisposing patients to aberrant responses to EBV and leading to the accelerated phase.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Partial defects in T-cell function have been ascertained in a number of genetic disorders, particularly Down syndrome and Turner syndrome. These abnormalities help in understanding the clinical infections in these patients, but they play a minor role in the overall problems.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Partial T-cell disorders are usually difficult to identify using routine screening tests. The absolute lymphocyte count determined by the CBC is often within reference ranges, although lymphopenia should be sought.
• • In CHS, the presence of giant granules in lymphocytic and phagocytic cells confirms a definitive diagnosis by morphologic analysis.
  • WAS is characterized by small platelets and variable but often-decreased platelet numbers.
• In vivo lymphocyte function is assessed by delayed hypersensitivity skin test responses using tetanus and candidal antigens. Anergy is characteristic in patients with AT, WAS, and CHS. Patients with chronic mucocutaneous candidiasis have normal responses except for anergy to candidal antigens.
• Flow cytometric assessment of T- and B-cell populations is essential to categorize partial T-cell disorders. The markers are expanded to include TCRa/b and TCRg/d, CD45RA (ie, "naïve" T cells), CD45RO (ie, "educated" T cells), and activation markers. See Severe Combined Immunodeficiency for a table of the lymphocyte profile characteristics for various T-cell disorders.
• • Patients with AT have decreased numbers of CD4⁺ T cells, resulting in a decreased CD4/CD8 ratio, while patients with WAS have an elevated ratio caused by decreased numbers of CD8 T cells.
  • Patients with AT and CHS have an increased proportion of TCRg/d cells.
  • Patients with IPEX syndrome may initially present with strikingly increased levels of T-activation markers. T-cell activation may be detected in CD95/Fas and Fas ligand deficiencies. An elevated population of double-negative CD4^-/CD8^- T cells that express TCRa/b also characterize these mutations.
  • Assessment of CD3 complex defects is particularly subtle: CD3 expression is present in a normal proportion of T cells, but the intensity (ie, mean fluorescence intensity) is decreased, and TCRa/b expression is low.
• In vitro lymphocyte proliferative responses require stimulation with allogeneic lymphocytes, nonspecific mitogens including phytohemagglutinin antigen (PHA), concanavalin A (conA), pokeweed mitogen, and specific antigens including tetanus and candidal antigens. Partial T-cell defects are most likely to have decreased responses to specific antigens and variable responses to nonspecific mitogens. Mutated CD3 complex lacks lymphoproliferative responses to anti-CD3.
• Humoral immunity typically shows nonspecific abnormalities in immunoglobulin class and immunoglobulin G (IgG) subclass levels with relatively preserved antibody function.
• • Classic WAS is accompanied by low immunoglobulin M (IgM) levels, absent isohemagglutinin IgM against the A and B blood group polysaccharides, and poor IgG responses to bacterial polysaccharide antigens.
  • AT manifests with low-to-absent immunoglobulin A (IgA) levels in 70% of patients, low levels of IgG2 and IgG4, and diminished antibodies to antipolysaccharide antigens.
  • Low antipolysaccharide antibody responses also occur in patients with immune dysregulation/autoimmunity syndromes (eg, mutations in the CD3 gene, IPEX syndrome).
• AT is usually diagnosed easily by detecting elevated a-fetoprotein levels in serum. However, patients with other CBSs (ie, NBS, Bloom syndrome) do not demonstrate increased a-fetoprotein levels. These 3 CBSs with immune deficiency (AT, NBS, Bloom syndrome) can be diagnosed by assessing spontaneous or induced chromosomal breakage in vitro.
• Detection of infectious agents by culture and hematoxylin and eosin (H & E) staining of biopsy material is usually required. Polymerase chain reaction (PCR) techniques for viral detection have become an evaluation mainstay and are performed on body fluids and tissues.

Imaging Studies

• Cardiac studies, including echocardiography and catheterization, are appropriate in most patients with DGS.
• Chest radiography is useful only to confirm the absence of thymic tissue, although the thymus may be involuted in an immunologically healthy host undergoing severe stress or the thymus may be malpositioned in a patient with DGS.
• The atrophy in CHS is diffuse in both the brain
  and the spinal cord in contrast to AT where the
  cerebellar area is specifically affected.

Other Tests

• Mutational analysis is available in specific laboratories for many T-cell deficiency syndromes. These tests must be made available to families to assess carrier status and to perform prenatal diagnosis.
• In the past, subtle T-cell dysfunction has been confirmed by delayed rejection of skin grafts in disorders such as AT.
• Research studies of autoimmune phenomenon in partial T-cell defects have shown failure to delete T cells that recognize self-antigens. Fas and Fas ligand defects caused by mutations are the prototypic T-cell disorders of this type.
• Analysis of additional T-cell functions, such as cytotoxicity in patients with CHS, is only available from specific research laboratories. Such tests are rarely needed to establish the diagnosis.

Procedures

• As in complete T-cell defects, obtaining appropriate culture material to identify infectious agents is critical. The most common procedures are bronchoscopy, culture of the sinuses, and biopsies performed in lymph nodes and the liver.
• Biopsies of lymphoid tissue are necessary to distinguish lymphoproliferative states from malignancy.

Histologic Findings

The thymus has been studied histologically in patients with DGS and AT. In patients with DGS, the thymus has a wide spectrum of morphology, ranging from apparently intact thymic size and structure to disruption of the medulla and absent Hassall corpuscles to complete thymic absence. Patients with AT have a small thymus, are markedly deficient in thymocytes and Hassall corpuscles, and have poor corticomedullary demarcation. CD3 complex deficiencies show thymic defects similar to those in AT. Histologic analysis has not been available for many partial T-cell disorders until chronic disease and corticosteroid therapy have altered the histologic findings.

Lymphoid hyperplasia is present in Fas and Fas ligand deficiencies and in other immune dysregulation/autoimmunity syndromes. In situ T-cell markers may show excessive CD4⁺ T cells, a high proportion of CD4^-/CD8^- T cells, or an imbalance of TCRa/b and TCRg/d T cells. The histologic appearance may resemble immunoblastic lymphoma.

The accelerated phase of CHS may be confused with lymphoma or erythrophagocytic lymphohistiocytosis.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Sinopulmonary infections with common viral and bacterial agents are characteristic of partial T-cell disorders. Conventional therapy appropriate for the immunologically healthy host is administered, although patients with T-cell defects characteristically have more prolonged and severe clinical courses. Prophylaxis against infection by RSV using RSV-polyclonal immunoglobulin or the humanized monoclonal antibody, palivizumab, is specifically indicated in patients with T-cell disorders. Mucocutaneous candidiasis is more frequent, but it is conventionally treated in patients, and the disease uncommonly disseminates.

• Bone marrow transplantation must be offered early in infancy to patients with WAS to ensure better outcome. In addition, transplantation is the only effective treatment in most patients with CHS and is indicated prior to development of the accelerated phase. Patients with DGS rarely have complete absence of T-cell function; these few patients require stem cell reconstitution, usually via bone marrow transplantation.
• Routine childhood immunizations are usually indicated because patients with partial T-cell defects, even those with abnormalities in immunoglobulin levels, often respond with adequate specific antibody titers, although the levels may be lower than normal. However, administration of the oral live-attenuated poliovirus vaccine is contraindicated and should be replaced with the inactivated poliovirus vaccine. As a result of the frequency of bacterial sinopulmonary infections, administration of the conjugated pneumococcal vaccine (Prevnar) is particularly important.
• Usually, treatment in persons with autoimmune disorders mirrors that for hosts who are immunocompetent. However, infectious complications pose a greater risk in patients with T-cell disorders who receive systemic steroids and other immunosuppressive drugs.
• • Overproduction of cytokines by T cells and other effector cells of the immune system can be controlled through use of anticytokine monoclonal antibodies, such as anti–tumor necrosis factor (TNF)–a (infliximab), for inflammatory bowel disease.
  • IDDM, hypoadrenalism, hypothyroidism, glomerulonephritis, and autoimmune enteropathy present in patients at unusually young ages, typically in patients younger than 1 year who have immune dysregulation/autoimmunity disorders.
  • Patients with WAS and older patients who have CBSs have a high risk of malignancy. Chemotherapy in patients with AT and NBS is not usually tolerated at conventional doses because of deoxyribonucleic acid (DNA) instability. Thus, lower doses and longer intervals between doses are usually used.
• Gene therapy is being studied as a possible alternative to allogeneic hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency (Cavazzana-Calvo, 2005), as well as a treatment for WAS (Chinen, 2004).
• Several drugs that block the lymphocyte voltage-gated potassium channel, kv1.3, as well as biologic therapies, are being explored as autoimmune disease treatments (Norton, 2004; Lee, 2005).
• Graft versus host disease (GVHD) has been prevented successfully in mice through ex vivo selection and expansion of CD4(+)CD25(+) immunoregulatory T cells, specific for recipient alloantigens (Trenado, 2004).
• Mesenchymal stem cells have shown some promise in enhancing engraftment and both preventing and treating GVHD in bone marrow transplant recipients (Le Blanc, 2005).
• Antithymocyte globulin has been shown to reduce acute and chronic GVHD in randomized trials (Bacigalupo, 2005).

Surgical Care

• With the exception of cardiac procedures in patients with DGS, surgery is not usually required for patients with partial T-cell disorders.
• Splenectomy has been used to control autoimmune hemolytic anemia and thrombocytopenia in patients with WAS and immune dysregulation/autoimmunity syndromes. In patients with WAS and Fas and Fas ligand deficiencies, overwhelming postsplenectomy sepsis has occurred despite immunization and antibiotic prophylaxis directed against Streptococcus pneumoniae.

Consultations

• Clinical immunologists and geneticists are integral to the evaluation and treatment in patients with partial T-cell disorders.
• Intervention performed by neurologists is important in patients with CBSs and CHS.
• Physical therapists and rehabilitation specialists are critical to achieving optimal functioning in patients with CBSs and CHS.
• Autoimmune disorders are best controlled with the help of collaboration by hematologists, endocrinologists, and gastroenterologists.
• The malignancies in CBSs may require alteration of chemotherapeutic regimens because of the increased DNA instability of host cells.
• When a T-cell disorder is suspected, the Immune Deficiency Foundation offers a consultation service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital Boston), and New York City (The Jeffrey Modell Foundation) are funded to provide molecular analysis or can assist in contacting other research facilities.

Diet

As with other primary immunodeficiencies, supplemental nutrition can be an essential component of care for the patient with chronic enteropathy or chronic infection. Unfortunately, many patients remain thin with short stature or become wasted.

Activity

The goal of care is to optimize daily functioning. Care to minimize exposure to certain viruses (eg, RSV, varicella) is important, but complete isolation is not recommended for patients with partial T-cell disorders.

Patients with WAS and CHS who have increased bleeding tendencies must be educated to avoid trauma and, especially, to wear helmets during certain activities.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Patients with partial T-cell deficiencies often have increased viral and bacterial respiratory infections. Conventional antibiotic therapy is administered for bacterial sinopulmonary infections; these infections are frequent but unlikely to be invasive unless the patient has undergone splenectomy. Individual patients may benefit from prophylaxis against infection by RSV or encapsulated bacteria by antibody replacement using intravenous immunoglobulin (IVIG) or specific anti-RSV antibodies.

By taking advantage of residual T-cell function, immunization against viral and bacterial agents may be efficacious. For example, the conjugated pneumococcal vaccine may induce antibody production that the unconjugated vaccine cannot. Most patients with partial T-cell disorders appear to have adequate IgG antibody responses to traditionally T-dependent antigens (eg, diphtheria, tetanus, pertussis, influenza, conjugated Haemophilus influenzae), although information regarding newer vaccines (eg, hepatitis viruses) is inadequate.

Down-regulation of autoimmune reactions requires therapy with corticosteroids and other immunosuppressive agents. These agents include monoclonal antibodies directed against cytokines (ie, TNF-a in autoimmune enteropathy).

Replacement therapy with IVIG in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that a dose of IVIG of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels at greater than 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia with meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, q2-3wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher doses or shorter intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although the viral inactivation processes (eg, solvent detergent vs pasteurization, liquid vs lyophilized) differ. The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, is also recommended.

The US Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, patients with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, age >65 y, or in those taking nephrotoxic drugs), recommended doses of IVIG should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

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 patients who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving serum IgG levels within reference range, 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 or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are believed to be related to adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and 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 q6-8h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, not to exceed 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using 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 sucrose/kg/min. 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 blood urea nitrogen and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Immunoglobulin E (IgE) antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports exist of true anaphylaxis 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 response is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or SCID. Caution should be exercised in patients with IgA deficiency ( <7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the Table below).

Immune Globulin, Intravenous

Brand(Manufacturer)	Manufacturing Process	pH	Additives*	Parenteral Form and Final Concentrations	IgA Content mcg/mL
Carimune NF (ZLB Behring)	Kistler-Nitschmann fractionation; pH 4.0, 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	5.1-6.0	Sucrose free, contains 5% D-sorbitol	Liquid 5%	<50
Gammagard Liquid 10% (Baxter Bioscience)	Cohn-Oncleycold ethanolfractionation,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
Gammar-P IV (ZLB Behring)	Cohn-Oncley fraction II/III;ultrafiltration; pasteurization	6.4-7.2	5% solution: 5% sucrose, 3% albumin, 0.5% NaCl	Lyophilized powder 5%	<20
Gamunex (Talecris Biotherapeutics)	Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation	4.0-4.5	Contains no sugar, contains glycine	Liquid 10%	46
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 exchangechromatography; 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)	Cohn-Oncley fraction II/III;ultrafiltration; low pH incubation; S/D treatment pasteurization	5.1-6.0	10% maltose	Liquid 5%	200
Panglobulin (Swiss Red Cross for the American Red Cross)	Kistler-Nitschmann fractionation; pH 4.0, trace pepsin, nanofiltration	6.6	Per gram of IgG: 1.67 g sucrose, <20 mg NaCl	Lyophilized powder 3, 6, 9, 12%	720

*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).

Contents of table are adapted from the following sources:

1. Manufacturers' literature.
2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.
3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

Drug Category: Respiratory syncytial virus antibodies

Prevention of RSV infection in immunodeficient infants and children is effective using either polyclonal high-titer human IVIG or the humanized mouse monoclonal IgG, palivizumab. The former may provide some protection against other respiratory infections.

Drug Name	Palivizumab (Synagis)
Description	Children with asymptomatic acyanotic congenital cardiac disease may be treated with palivizumab. Since it is a specific anti-RSV antibody, it does not protect against other respiratory infections.
Adult Dose	Severe RSV infection has not been recognized in adults with T-cell disorders
Pediatric Dose	15 mg/kg IM qmo from November to April
Contraindications	Documented hypersensitivity; cyanotic congenital cardiac disease
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in thrombocytopenia or other coagulation disorders; compared to placebo, no increase in fever, rash, liver functions, or local reactions

Drug Category: Immunosuppressive agents

Patients with immune dysregulation and autoimmunity often benefit from immunosuppression. Commonly used drugs include corticosteroids in combination with cyclosporine or tacrolimus. Cyclophosphamide and azathioprine are administered less commonly. These modalities usually are used in collaboration with hematologists, gastroenterologists, and rheumatologists.

Drug Name	Tacrolimus (Prograf)
Description	Suppresses humoral immunity (T lymphocyte) activity. Acts via a separate pathway to decrease T-cell activation, similar to cyclosporine; has been effective in autoimmune enteropathy when response to cyclosporine was insufficient or erratic; most extensive experience is as therapy in liver transplantation.
Adult Dose	0.15-0.3 mg/kg/d PO divided q12h to maintain therapeutic trough blood levels; absorbed better without food Alternative: 0.05-0.15 mg/kg/d IV infusion over 24 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Levels may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, clarithromycin; levels may decrease with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine; metabolized via CYP3A4
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer simultaneously with cyclosporine; tonic clonic seizures may occur; adverse effects are similar to those with cyclosporine; coagulation disorders have been reported; caution in renal or hepatic compromise (decrease dose)

Drug Name	Prednisone (Deltasone)
Description	Prototypic corticosteroid drug; doses of other corticosteroids should be converted to prednisone equivalents; patients with immune dysregulation/autoimmunity syndromes receive chronic therapy over years and, thus, must be monitored for long-term toxicities, especially hypertension, cataracts, and osteoporosis; prednisolone is preferred in patients with hepatic disease because prednisone is converted to prednisolone in the liver.
Adult Dose	1-2 mg/kg/d PO divided q12h; not to exceed 80 mg/d; may be effective at qod intervals when autoimmune disease is in remission
Pediatric Dose	Administer as in adults Liquid preparation has unpalatable bitter taste; therefore, alternative is to crush tabs in small amounts of fruit syrup, applesauce, or foods preferred by children
Contraindications	Documented hypersensitivity; peptic ulcer disease; relatively contraindicated in hepatic dysfunction
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; may cause hypertension, hirsutism, tremor, gingival hyperplasia, and headache; monitoring is required for hypomagnesemia, hyperkalemia, hyperuricemia, hyperglycemia, nephrotoxicity, and hepatotoxicity; severity of disease associated with T-cell disorders requires careful surveillance, and appropriate exposure prophylaxes for certain infectious agents (most notably varicella, viral and fungal infections) are greater risks for infection but are not contraindications for continued steroid therapy

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	Traditional alkylator chemotherapeutic agent effective in various rheumatologic diseases (eg, systemic lupus erythematosus); individual patients with autoimmune hemolytic anemia and autoimmune enteropathy also have responded to therapy; specific dosage depends on the autoimmune disorder type and should be chosen in consultation with a specialist in that disease.
Adult Dose	PO: 50-500 mg qwk (dose depends on size and clinical response) IV: 500-750 mg/m2 qmo after adequate hydration; not to exceed 1 g/dose
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile, particularly neutrophils and platelets, to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; institute adequate hydration before administration; long-term effects include infertility, malignancy, and, possibly, leukoencephalitis; dose-limiting toxicities include leukopenia and cardiomyopathy

Drug Name	Azathioprine (Imuran)
Description	Lengthy experience is available in the use of this drug for long-term management of inflammatory bowel disease and renal disease caused by autoimmunity; efficacy in immune dysregulation/autoimmunity is not as well documented; may allow administration of lower-dose corticosteroids.
Adult Dose	Initial: 3-5 mg/kg/d PO/IV Maintenance: 1-3 mg/kg/d PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT)
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Unsafe in pregnancy
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and monitor liver, renal, and hematologic functions; pancreatitis is rarely associated; adverse effects include myelosuppression, rash, GI tract symptoms, liver toxicity, hair loss, stomatitis, and arthralgias

Drug Category: Vaccines

Sinopulmonary infections in children with T-cell disorders occur frequently. Immunization of children against S pneumoniae infection is an important consideration.

Drug Name	Pneumococcal vaccine (Pneumovax-23, Pnu-Imune 23)
Description	Polyvalent vaccine used for prophylaxis against infection from S pneumoniae. Used in populations at increased risk of pneumococcal pneumonia (ie, age >55 y, chronic infection, asplenia, immunocompromised state).
Adult Dose	0.5 mL IM/SC single dose
Pediatric Dose	<2 years: Contraindicated (antibody response is poor in this age group) >2 years: Administer as in adults
Contraindications	Documented hypersensitivity; hypersensitivity to thimerosal; severe or moderate febrile illness; thrombocytopenia or coagulation disorders that contraindicate IM injection unless potential benefit clearly outweighs risk of administration
Interactions	Immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness; therapy with immunoglobulin preparations is likely to block active immunity induced by pneumococcal vaccination (withhold pneumococcal vaccine for 3 mo after discontinuation of immunoglobulin therapy)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause arthralgia, fever, urticaria, and Guillain-Barré syndrome (rarely)

Drug Category: Tumor necrosis factor inhibitors

TNF is a cytokine in which 2 forms have been identified with similar biologic properties. TNF-a or cachectin is produced predominantly by macrophages, and TNF-b or lymphotoxin is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that contributes to symptoms.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Bronchiolitis caused by RSV, adenovirus, parainfluenza, and influenza is more severe and more likely to result in hospitalization. Conventional treatment includes use of oxygen, bronchodilator therapy, and deep suctioning.
• Patients with DGS may require hospitalization for cardiac evaluation.
• Bleeding diatheses in patients with WAS and CHS usually require inpatient treatment.
• Bone marrow transplantation and other stem cell reconstitution are performed in specialized hospital units.

Further Outpatient Care

• Otitis media, sinusitis, and mucocutaneous candidiasis are common infections that are treated on an outpatient basis. Conventional antibiotics and antifungal agents are administered but may require longer courses.
• Treat eczematous rashes with conventional topical corticosteroids and emollients. Topical tacrolimus has recently been shown to be effective in controlling atopic dermatitis.
• Neurologic dysfunction can occur in patients with AT, CHS, and immune dysfunction/autoimmunity syndromes. Among these dysfunctions are seizure disorders requiring anticonvulsant drug administration.

In/Out Patient Meds

• See Medications.

Transfer

• Treatment in most patients requires a team effort that includes a clinical immunologist and other subspecialists.
• Bone marrow transplantation units usually assume the primary care role for patients undergoing stem cell reconstitution.

Deterrence/Prevention

• Currently, mutation analysis is used to identify most infants with and carriers of partial T-cell disorders. Complete a familial mutation analysis in order to offer prenatal diagnosis.

Complications

• Each partial T-cell disorder has specific complications.
• While patients with DGS are most likely to have fewer complications at an older age, the risk for malignancy increases with age in patients with WAS and AT.
• Patients with AT and CHS develop progressive neurologic dysfunction as they age.
• IDDM, enteropathy, or pulmonary disorders can be fatal in many patients with dysregulation/autoimmunity syndromes as patient's age.
• Splenectomy can be clinically effective in patients with WAS and Fas or Fas ligand deficiencies over the short term, but fatal sepsis is unpredictable.
• Female carriers of AT have increased risk for breast cancer.

Prognosis

• Outcome in patients with partial T-cell deficiencies have improved with better supportive care and improved techniques for bone marrow transplantation. For example, the mean age of survival has increased in patients with WAS. Although stem cell reconstitution offers the possibility of complete cure, control of infections and bleeding increased the mean age of survival from early childhood (in the 1970s) to the third decade of life (in the 1990s).
• Longer survival in patients with AT and CHS is compromised by progressive neurologic deterioration. In patients with CHS, the rates of deafness and blindness are high. In both disorders, patients often become confined to a wheelchair.

Patient Education

• Inform families of patients with partial T-cell disorders regarding the risks of infection so they can institute appropriate steps to avoid exposure to infection. Inform families that bacille Calmette-Guérin vaccine (BCG) and live poliovirus vaccine are contraindicated.
• Genetic counseling is an essential part of medical care for the family. Parents must be informed of the 25% risk that an affected infant will be born to parents each carrying autosomal recessive gene mutations and the 50% risk that an affected male infant will be born to mothers carrying X-linked mutations.
• Adequate informed consent for stem cell reconstitution must review (1) the high risk for life-threatening infection during the immunosuppressive regimen used in preparation for stem cell reconstitution, (2) the risk that the graft will fail, and (3) the risk of graft versus host disease (GVHD). Although successful complete immune reconstitution from bone marrow transplantation is reported using fully matched related and unrelated donors or haploidentical parents, the graft may fail or patients may develop GVHD posttransplant. Other forms of stem cell reconstitution that can be offered include stem cell transplantation. Gene therapy is expected to become an option.
• The following organizations are among those providing educational services and support for families:
• • Immune Deficiency Foundation
    40 W Chesapeake Avenue. Suite 308
    Towson, MD 21204
    Telephone: (800) 296-4433
    Email: idf@primaryimmune.org
    This organization is an important resource for education and for support for patients and families with any primary immunodeficiency disease. Some states have local chapters.
  • The Jeffrey Modell Foundation
    747 Third Avenue
    34th Floor
    New York, NY 10017
    Telephone: 800-JEFF-844
    Email: info@jmfworld.org
    This organization provides support and raises funds.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Assess cell-mediated immunity with appropriate laboratory studies whenever unusually frequent or severe infections and autoimmune phenomena occur in infants or young children. A clinical history of consanguinity and other family members with similar clinical infections must be sought.
• Offer mutation analysis testing in patients in whom T-cell defects are suspected, and use these results as opportunities for prenatal diagnosis discussions with families.
• Please see Chromosomal Breakage Syndromes for an excellent discussion of ataxia telangiectasia.

Special Concerns

• Administration of the live oral poliovirus vaccine is contraindicated. Other live viral vaccines have been administered without complication but are contraindicated in individual patients with more global T-cell dysfunction.
• Adverse reactions to IVIG and RSV-IVIG must be discussed in detail with patients and families. Infection transmission is a potential but proven risk. Patients with DGS who have congenital cardiac anomalies and others with chronic pulmonary or cardiac disease may not tolerate the increased protein load on the cardiovascular system.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  This patient was diagnosed with ataxia telangiectasia when she presented at age 6 years. The family was concerned about the increased frequency of sinusitis during the past winter, and she was noted to have poor balance. Findings in her eyes had been explained as conjunctivitis since age 4 years.
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Media file 2:  A prominent site for telangiectasia in classic ataxia telangiectasia is the pinna.
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Media file 3:  Malformation of the pinna
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Media file 4:  Giant lysosomes.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

• Bacigalupo A. Antithymocyte globulin for prevention of graft-versus-host disease. Curr Opin Hematol. Nov 2005;12(6):457-62. [Medline].
• Bennett CL, Yoshioka R, Kiyosawa H, et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3. Am J Hum Genet. Feb 2000;66(2):461-8.