AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

The lymphocyte component of the immune system is divided into B cells and T cells. B cells have traditionally been believed to be the lymphocytes responsible for antibody production by means of their maturation into plasma cells (ie, humoral immunity). T cells have been believed to be the lymphocytes responsible for killing other cells or organisms (ie, cellular immunity). At present, certain T lymphocytes (ie, T-helper cells) are known to be responsible for helping immature B cells develop into mature B cells. Other T lymphocytes (ie, T-suppressor or cytotoxic cells) possess the killing function and also inhibit B-cell development. Therefore, any T-cell disorder can theoretically cause defective B-cell function.

Because ataxia telangiectasia (AT) and chronic mucocutaneous candidiasis (CMC) are not discussed in separate pediatric articles, this article emphasizes their clinical presentation and management.

Pathophysiology

Because a major loss or dysfunction of T cells can cause secondary B-cell deficiency, a number of disorders show clinical manifestations of combined B- and T-cell deficiency, though the only pathology is in the T cell. In converse, some diseases appear to primarily involve the T cells and do not appear to affect antibody production. Those diseases are discussed in T-Cell Disorders.

Development of mature functioning B and T cells involves a complex series of steps, each of which may be defective, resulting in B- and T-cell deficiency. When T-cell deficiency is especially severe or involves the T-helper cell function, the deficiency causes an antibody deficiency. The most severe manifestations occur within the first 2 years of life as various types of severe combined immunodeficiency (SCID). See Omenn Syndrome and Purine Nucleoside Phosphorylase Deficiency for a discussion of other forms of SCID.

Omenn syndrome is the result of mutations in the genes coding for recombinases (recombination activating genes), ie, RAG1 and RAG2, that cause a defect in the variable diversity joining (VDJ) rearrangement needed for mature T and B cells to develop. Deficiency of purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) elevates intracellular levels of deoxyguanosine and deoxyadenosine, respectively, which are more toxic in lymphocytes than in other cell types. Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic symptoms of SCID. Symptoms in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and nonself.

In other B- and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Recognize that patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia also can have either a T-cell or combined defect. (See Cartilage-Hair Hypoplasia.)

Male patients with thrombocytopenia and eczema may have Wiskott-Aldrich syndrome with defective T-cell function and resultant recurrent infections. They have poor antibody responses to polysaccharide antigens but elevated levels of serum immunoglobulin A (IgA) and immunoglobulin E (IgE) with low levels of immunoglobulin M (IgM). (See Wiskott-Aldrich Syndrome.)

Two autosomal recessive syndromes indicate some interaction of the immune system with neurologic function. AT is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is obvious when both ataxia and telangiectasia are present. Multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and a combined immunodeficiency that can be quite variable. This is discussed in additional detail in this article.

Nijmegen breakage syndrome (NBS) is also an autosomal recessive chromosomal instability syndrome. NBS is characterized by microcephaly with growth retardation, normal or impaired intelligence, birdlike facies, increased susceptibility to infection, humoral and cellular immunodeficiency, and high risk for lymphatic tumor development. Nearly all patients with NBS are homozygous for the same founder mutation, ie, deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin. Because most patients with NBS are of Slavonic origin, this frameshift mutation came to be called the Slavonic mutation.

These 2 syndromes, AT and NBS, are part of a family of mutations involving proteins involved in DNA repair. Ataxialike disorder (ATLD) syndrome involves a mutation in meiotic recombination 11 homolog (MRE11). These 3 syndromes are associated with decrease circulating levels of T cells (but circulating levels of B cells are normal) and often decreased levels of IgA, IgE, and IgG subclasses. Artemis deficiency (with mutations in the Artemis protein resulting in defective VDJ recombination) decreases both T and B cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in circulating T and B cells and serum immunoglobulins. Finally, Bloom syndrome results from a mutation in the helicase enzyme called BLM RecQ. All of these defects in DNA repair are characterized by an increased risk of malignancy and radiation sensitivity.

CMC is a complex disorder in which patients have persistent or recurrent infections of the skin, nails, and mucous membranes due to infection by Candida species. CMC can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Two other familial subtypes are an autosomal dominant form with nail candidiasis and intercellular adhesion molecule-1 (ICAM-1) deficiency and an autosomal recessive form with hyperimmunoglobulin E.

CMC is included as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disorder, which is also known as autoimmune polyglandular syndrome type I (APS I). The genetic basis of the disease has been mapped to chromosome 21q22.3, and the gene identified is the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 45 different disease-causing mutations in AIRE have been discovered, and its role in various manifestations of CMC and APECED or APS I are being examined.

Frequency

United States

Stiehm (1996) estimated that combined cellular and antibody deficiencies account for approximately 20% of primary immunodeficiencies. AT is a rare disease with an estimated prevalence of <1 per 100,000 population; the incidence of CMC is similar at 1 per 103,000. Some report an increased frequency of approximately 1 case of AT per 40,000 births in the United States.

International

In Brazil, combined immunodeficiency defects accounted for 16 (9.6%) of 166 primary immunodeficiencies in children examined over 15 years. Spain's Registry for Primary Immunodeficiency Diseases included 14.7% T-cell and combined deficiencies, similar to the European registry report of 20.2%. In a survey of 201 Swedish patients from 1974-1979, 20.8% had combined T- and B-cell disorders.

The birth frequency of AT in the United Kingdom is approximately 1 in 300,000. In the Slavonic population, the prevalence of AT appears higher (1:40,000-100,000) than the prevalence of NBS (1:60,000-120,000). CMC with APECED is inherited as an autosomal recessive trait and appears to be prevalent in genetically isolated populations of the Finns, the Iranian Jews, and the Sardinians (with prevalences of 1:25,000, 1:9000, and 1:14,500, respectively).

Mortality/Morbidity

Similar to patients with B-cell deficiency, a major cause of mortality and morbidity is recurrent upper and lower respiratory infections because patients cannot mount an adequate immune reaction. Patients' increased susceptibility to development of malignancy also indicates the importance of T cells in immune surveillance and the role of cellular immunity in the protection against tumor cells. Abnormal immune systems in patients can produce autoimmune reactions in which an inappropriate exaggerated reaction can occur toward self-antigens.

Race

Although combined B- and T-cell disorders are rare, they are described in all races.

Sex

No sex-based differences have been reported.

Age

The disorders almost always occur in young infants, and the syndrome can often be recognized on the basis of its nonimmunologic manifestations.

CLINICAL

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History

Clinical manifestations of many combined B- and T-cell deficiencies derive from associated organ involvement, eliciting variable onsets for the different symptoms. Neurologic and cutaneous symptoms predominate in AT and NBS. Autoimmune endocrinopathies and cutaneous candidal infections are seen in patients with CMC. In other combined B- and T-cell deficiencies, the presence of unusual organisms in certain infections or the chronic nature of infectious processes may indicate an underlying immunodeficiency.

• AT is an obvious diagnosis when both ataxia and telangiectasia are present. AT also can be diagnosed at the onset of ataxia and before telangiectasia appears, if laboratory results confirm AT. In most patients, cerebral palsy is usually misdiagnosed because ataxia most often occurs during infancy. Telangiectasia usually does not appear until patients are aged 5 years.
• • In a review of 48 patients with AT, the mean age at the onset of ataxia was 15 months. The mean age at the onset of telangiectasia was 72 months (Cabana, 1998). The data confirmed that a misdiagnosis of cerebral palsy was made in 29 of 48 patients. To alleviate this problem, they recommend routine serum alpha-fetoprotein (AFP) testing for all children with persistent ataxia.
  • Ataxia initially is cerebellar with associated posture and gait problems. Speech may become slurred. Movement disorders also occur and may be choreoathetoid or ticlike. Oculomotor apraxia is usually present, and a dysconjugate gaze is sometimes noted. Muscle weakness may appear late in the course of disease, with subsequent muscle atrophy. Mental function can be affected.

  • AT should be distinguishable from NBS without problems. AT results in increased AFP levels, whereas NBS causes microcephaly and mental retardation.
  • Telangiectasia usually occurs on the bulbar conjunctivae in patients younger than 5-6 years and becomes most prominent in other areas, especially the pinna. Other cutaneous manifestations include progressive cutaneous atrophy, areas of hypopigmentation or hyperpigmentation, hypertrichosis, atopic dermatitis, and cutaneous malignancies.

  • Bloom syndrome also may have telangiectasias, especially in sun-exposed areas. However, patients have short stature and birdlike facies.
  • All patients have a deficiency of cell-mediated immunity. However, deficiency in humoral immunity is most variable. Therefore, the resulting predisposition to infection can vary. Recurrent sinopulmonary infections may be a complaint before ataxia or telangiectasia develops. Rates of lower respiratory tract infections appear to increase with age with subsequent chronic lung disease. Impaired oropharyngeal swallowing mechanisms may contribute with chronic aspiration. Viral and bacterial pathogens, though typically not opportunistic agents, can cause infections.
  • In a review of 100 patients with AT, recurrent upper and lower tract infections were frequent. Otitis media occurred in 46%; sinusitis, in 27%; bronchitis, in 19%; and pneumonia, in 15%. Systemic bacterial and severe viral or opportunistic infections were uncommon.
  • Although endocrine abnormalities are uncommon, they may include failure to develop secondary sex characteristics. Stiehm (1996) states that no offspring of AT homozygotes are known. Patients also may have growth failure.

• Patients with CMC have persistent or recurrent candidal infections of the skin, nails, and mucous membranes. The extent and location of infections, genetic factors, and associated autoimmune disorders delineate 6 clinical syndromes (Stiehm, 1996).
• • Candidiasis is almost always observed in patients with CMC. Infants with CMC type 3 usually present with persistent diaper rash or other localized lesions involving the extremities. Extreme hyperkeratosis may occur. Persistent or recurrent thrush is also common. Consider CMC in patients when chronic oral candidiasis (CMC type 1) continues after antibiotic or inhaled corticosteroid therapy is stopped and when T-cell deficiency is excluded. Esophageal or tracheal candidiasis is uncommon and may simply represent colonization of mucous membranes after a course of systemic antibiotic therapy.
  • Relatively extensive cutaneous infections involving the skin, nail, and mucous membrane may develop in late childhood or during adolescence (CMC type 4). Patients with these findings are apparently less likely than others to develop endocrinopathies.
  • According to Stiehm (1996), "It is important to appreciate that the endocrinopathies may develop any time from childhood through adulthood and that patients may have sequential loss of functions of various endocrine organs." According to 1 study, the organs most commonly affected are the parathyroid glands (54 of 68 patients), adrenal glands (49 of 68 patients), and thyroid gland (2 of 68 patients). Gonadal failure commonly causes infertility. Insulin-dependent diabetes occurs in approximately 10% of patients. Overall, CMC is associated with autoimmune endocrinopathies in about 40% of patients.
  • An association of CMC with thymomas (CMC type 5) has been described and usually occurs in adult or middle-aged patients. These patients also may have other autoimmune disorders, such as myasthenia gravis, aplastic anemia, and hypogammaglobulinemia.
  • An association of chronic keratitis with CMC has been noted and appears to be an autosomal dominant trait.

• Patients with CMC are susceptible to frequent infections caused by viruses and bacteria in the skin and in the upper and lower respiratory tracts.
• Other autoimmune disorders are common and include various autoimmune hematologic disorders (eg, those involving RBCs, WBCs, and/or platelets), chronic active hepatitis, and juvenile rheumatoid arthritis.
• Neoplastic diseases other than thymomas can occur. This observation again emphasizes the importance of T cells in immune surveillance. However, there appeared to be a greater incidence of malignancy in AT, especially lymphoid tumors, which has been attributed to their increased sensitivity to radiation. Occasionally, leukemia has been a presenting finding of AT.

Physical

Depending on the specific combined immunodeficiency syndromes, physical examination may yield various signs, as follows:

• In patients with AT, gait abnormalities occur at a median age of 15 months. Deterioration of the newly acquired developmental milestone of walking signals a problem.
• • All patients have progressive cerebellar ataxia. However, there is heterogeneity with the classic form showing onset in infancy and steady progression to milder forms where the progression may be slower or onset later.
  • Other neurologic signs include dystonia and oculomotor apraxia.
  • Drooling, strabismus, and a masklike facies may be seen.
  • In addition to cerebellar signs, extrapyramidal and posterior-column signs may be present.
  • Reflexes are decreased, and muscle weakness may be present.
  • Sensory involvement is uncommon.
  • Telangiectasia is commonly observed on the bulbar conjunctivae and may occur in children aged 1-6 years. Other areas, such as the lateral aspect of the nose, the ears, the antecubital and popliteal areas, and the dorsa of the hands and feet, may be affected late.

• In CMC, mucous membranes in the oral cavity may be covered with a patchy pseudomembrane composed of mycelial Candida albicans (ie, thrush). Infants may have a persistent diaper rash with fungal infection. In extensive forms, nails and extremities may develop severe hyperkeratosis with nail deformities.

Causes

• The gene responsible for AT, designated ATM (ie, AT, mutated), encodes for a protein that belongs to a family of phosphatidylinositol 3-kinase (PI3-K)–related kinases (PIKK). Members of this family are involved in mitogenic signal transduction, intracellular protein transport, and control of the cell cycle. In biologic terms, cells have an extreme sensitivity to radiation and an increased predisposition to become cancerous.
• • ATM is located on the long arm of chromosome 11 at subband q22.3. ATM is a large gene, with over 300 mutations described in 66 exons and no common, predominant mutation.
  • In contrast, the NBS1 gene involved in NBS is located on chromosomal band 8q21. Seven mutations are reported worldwide, with a high predominance of the founder mutation 567del5 in the Slavonic population.
  • Most patients with the classic AT phenotype are homozygous or compound heterozygous for ATM mutations that result in a truncated or unstable protein with total loss of ATM function. Some patients have mild forms of the disease, termed AT variants, and are either homozygous for mild mutations or compound heterozygotes for mild mutations. These mutations are leaky splice or missense mutations. Preservation of neurologic function is correlated with the degree of ATM protein kinase activity. About 10% of normal ATM kinase activity is apparently adequate to moderate the phenotype but not to prevent it.
  • The additional recognition of many ATM substrates involved in the recognition and repair of DNA double-strand breaks may also allow for the heterologous symptoms among AT patients, some of whom may not have symptoms until adulthood.
  • Mutations in the ATM gene probably are not a common cause for cerebellar ataxia other than AT.
  • With the aid of molecular testing, AT can be distinguished from other autosomal recessive cerebellar ataxias, such as Friedrich ataxia, Mre11 deficiency (AT-like disease), and the oculomotor apraxias 1 (aprataxin deficiency) and 2 (senataxin deficiency). In addition, NBS1 deficiency defines NBS syndrome, and helicase gene defect defines Bloom syndrome.

• Heterogeneous manifestations of CMC may indicate numerous causes and a heterogeneous pattern of inheritance.
• • CMC is included as part of the APECED disorder, also known as APS I. This disease has been mapped to chromosomal subband 21q22.3, and the gene is identified as the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 45 disease-causing mutations in AIRE have been discovered, and the role in various manifestations of CMC and APECED or APS I are being examined. Some suggest that AIRE is involved in thymocyte negative selection and that it may partially account for autoimmunity.
  • CMC can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or recessive and are associated with or without various degrees of autoimmune endocrinopathy. Therefore, it is important to determine whether AIRE genetic markers (and autoantibodies) segregate with disease in a family in whom the diagnosis of CMC is being considered.
  • Two other familial subtypes are an autosomal dominant form with nail candidiasis and ICAM-1 deficiency and an autosomal recessive form with hyperimmunoglobulin E. Chronic localized CMC has no apparent genetic component.

DIFFERENTIALS

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WORKUP

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Lab Studies

• Laboratory findings in the measurement of immune function are heterogeneous in patients with AT. Akha et al reported, "While a single AT patient can potentially manifest all the cited abnormalities, it is necessary to emphasize that characteristically, the disease will show considerable variation both from 1 patient to another and in a single patient over the course of time."
  
  
  • Decreased or absent levels of serum IgA, IgG2, and IgE are the most common antibody abnormalities reported. In a review of 100 patients with AT, immunoglobulin deficiencies were common, affecting IgG4 in 65%, IgA in 63%, IgG2 in 48%, IgE in 23%, and IgG in 18%. All patients with AT produced IgG antibody to tetanus toxoid, whereas 76% did not respond to any of the pneumococcal polysaccharide serotypes. On the contrary, patients with AT do have increased pneumococcal antibody titers (levels lower than those of control subjects) after conjugated pneumococcal vaccination (Stray-Pedersen, 2005), although the vaccination may need to be repeated.
  
  
  
  • Researchers recently observed hypergammaglobulinemia in 39% of 90 patients with AT. An isolated increase in IgM levels was the most common finding (23%). Elevated IgG levels were recorded in 2%.
  
  
  
  • The most common cellular deficiencies are absent or delayed skin-hypersensitivity reactions to tetanus and candidal antigens, depressed lymphocyte responses to mitogens, and reduced numbers of CD4⁺ (helper) T lymphocytes (Regueiro et al, 2000). Lymphopenia is typically present. In 1 study, lymphopenia affected 71% of patients with AT, with decreased B cells in 75%, CD4 T lymphocytes in 69% and CD8 T lymphocytes in 51%. The lymphocytic response to mitogens, such as phytohemagglutinin (PHA), may be in reference range or decreased. Natural killer (NK)–cell activity is in the reference range.
  
  
  
  • Despite laboratory evidence of significant immune abnormalities, opportunistic infections are uncommon. More sophisticated immune studies show normal-to-increased levels of cytokine production in both Th1 (IL-2, IFN-gamma) and Th2 (IL-10, IL-4) cells (Pashankar et al, 2006).
  
  
  
  • A laboratory finding unique to AT is an elevated serum AFP level. The karyotype reveals little or no evidence of hepatic fibrosis or hepatitis to explain the elevated AFP levels.
  
  
  
  • With the aid of molecular testing, AT can be distinguished from other autosomal recessive cerebellar ataxias, such as Friedrich ataxia, Mre11 deficiency (AT-like disease), and the oculomotor apraxias 1 (aprataxin deficiency) and 2 (senataxin deficiency). In addition, NBS1 deficiency defines NBS syndrome, and helicase gene defect defines Bloom syndrome.
     
• Studies of the immune function in patients with CMC demonstrated considerable heterogeneity, with as many as 7 groups of cellular immune responses. All patients had a defective response to candidal antigen. In some patients, defective B-cell function was also documented.
  
  
  • Patients with CMC do not have a delayed hypersensitivity reaction to candidal species. Patients had a normal response to other antigens, or they were anergic. In vitro tests confirmed the inability of patients' lymphocytes to proliferate or to produce certain cytokines in response to candidal antigens.
  
  
  
  • Some patients are clinically identical to other patients with CMC except that they have normal lymphocyte responses to candidal species in terms of proliferation or cytokine production. However, these same patients (with chronic localized candidiasis) do not have a delayed hypersensitivity reaction to candidal species.
  
  
  
  • Some patients have depressed levels of the IgG2 and IgG4 subclasses yet normal absolute values of IgG, IgA, and IgM. These patients appear to be unable to mount a good response to polysaccharide antigens. Hypogammaglobulinemia was reported in several other patients.
  
  
  
  • Immunoregulatory abnormalities were observed in studies of lymphocytes in vitro. Abnormal patterns of cytokine production in response to stimulation with Candida species were noted. Decreased production of some but not all type 1 cytokines (eg, interleukin-2 and interferon-gamma) and increased levels of interleukin-10 were specifically observed.
  
  
  
  • Decreased levels of NK cells were documented in 55% of 51 patients in 1 series and in 18 of 23 cases in another series. Impaired NK-cell activity against K562 target cells was seen in half of the patients described in one paper.
     
• Whether B-cell abnormalities contribute to increased susceptibility to bacterial infections is uncertain. Deficient chemotactic activity of both neutrophils and monocytes has been described, as has abnormal antigen presentation by monocytes.

Imaging Studies

• MRI studies in patients with AT show ventricular dilation with diffuse cerebral atrophy. Cerebellar atrophy is marked. This finding is correlated with pathologic results showing a loss of Purkinje and granular cell layers in the cerebellum. Normal numbers of Purkinje cells at birth apparently undergo progressive degeneration.
• Efforts to correlate the degree of cerebellar atrophy and the patient's ability to walk have not yielded conclusive results. This lack may be because, though the cerebellum is almost universally affected, other structures, such as anterior horn cells, dorsal columns, and peripheral nerves, may be affected to different degrees.

Other Tests

• Electromyograms of patients with AT show potentials indicating disease of the anterior horn cell and correlating pathologic findings of anterior horn cell degeneration and posterior column demyelination.
• Personnel in cytogenetics laboratories perform chromosomal instability tests to confirm AT and NBS to assess spontaneous and induced breakage. Chromosomal karyotyping should reveal reciprocal translocations between chromosomes 7 and 14 in AT. Absence or dysfunction of the ATM protein and mutations in the ATM gene are diagnostic findings.
• Gammopathies observed in patients with AT are detected by means of immunoelectrophoresis, but they should be suspected when quantitative levels of immunoglobulin, usually IgM, are isolated.
• Measurements of autoantibodies are important in patients with CMC so that the various types of CMC can be classified. Of importance, CMC can be the initial manifestation of APECED in 93% of patients. Subsequent hypoparathyroidism or adrenal insufficiency occur in these patients; mean ages of onset are 9.2 or 13.6 years, respectively.

Histologic Findings

In patients with AT, the thymus is poorly developed, with few thymocytes, absent Hassall corpuscles, and little corticomedullary demarcation.

Staging

The lifetime cancer risk for patients with AT is 10-38%. Non-Hodgkin and Hodgkin lymphomas are staged by using conventional guidelines.

TREATMENT

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Medical Care

As with other immunodeficiencies, aggressive antibiotic administration and supportive care may prolong the patient's survival, though no current therapy cures AT. Careful observation for the early development of AT is indicated because patients with T-cell deficiency have an increased susceptibility to develop malignancies. Likewise, regular determination of serum autoantibody level and constant clinical evaluation for endocrinopathy (eg, hypoparathyroidism, hypoadrenalism, diabetes) is needed in patients with CMC.

• Unlike other combined immunodeficiency syndromes, AT and CMC does not generally warrant gamma-globulin replacement therapy because of the marked variation in humoral immunodeficiency with the concomitant variable susceptibility to infections. On the other hand, an individual patient may benefit from such treatment. If a trial of intravenous immunoglobulin (IVIG) is considered in these patients, the dosage is 400-600 mg/kg every 2-4 weeks for 6 months. A high dosage is indicated in those with bronchiectasis. Monitor the patient's clinical response rather than specific serum IgG levels.
• Bone marrow transplantation is difficult to justify because of potential adverse effects of cellular radiosensitivity in patients with AT. Transplantation is also unlikely to alter the progressive neurologic symptoms of the disease. The present authors know of no report of successful bone marrow transplantation in a patient with CMC.
• Use of thymic hormones (eg, thymosin) offers promise, but, to the author's knowledge, no clinical studies have been conducted.
• Irradiation of cellular blood products is indicated in patients with AT and CMC to prevent transfusion-associated graft versus host disease.
• Treatment of patients with AT who also have malignancies requires extremely careful planning and caution in the use of chemotherapy because of their increased chemosensitivity.

Consultations

• Because patients with AT or NBS have increased risk of developing malignancy, careful monitoring by a hematologist-oncologist is required. Because patients with CMC may be at risk of developing various endocrinopathies, careful monitoring by an endocrinologist is required. Thymoma may also develop in adulthood.
• Primary care physicians who are inexperienced in interpreting the results of immune function tests should refer patients to an immunologist.
• Refer parents of children with AT and CMC to a genetic counselor because the parents are at risk of having affected additional offspring.

Diet

The poor growth in patients with AT and NBS has not been shown to respond to nutritional intervention.

Activity

In recognition of the increased sensitivity to radiation of patients with AT or NBS, advise them to avoid excessive sun exposure and to use sunscreens when outdoors. The typical patient with AT usually requires the use of a wheelchair for mobility by their early teenage years.

MEDICATION

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Unlike in other combined immunodeficiency syndromes, AT does not seem to benefit from gamma-globulin replacement therapy because of the marked variation in humoral immunodeficiency with the concomitant variable susceptibility to infections. However, individual patients may benefit from such treatment. Claret Teruel et al (2005) recently indicated that 7 of 12 patients with AT received gammaglobulin because of IgG deficiency. Kalfa et al (2003) similarly described 9 patients with CMC and selective antibody deficiency. All 9 had IgG2 deficiency (IgG4 deficiency in 8 and IgA deficiency in 3). All 9 had recurrent severe lung infections and may have benefited from IVIG therapy.

The overall consensus among clinical immunologists is that an IVIG dosage of 400-600 mg/kg/mo or a dosage that maintains trough serum IgG levels >500 mg/dL is desirable. Patients with X-linked agammaglobulinemia and meningoencephalitis require doses of 1 g/kg and perhaps intrathecal therapy. Measurements 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 dosage of IVIG to achieve adequate serum levels. For persons who have high catabolism of infused IgG, frequent infusions (eg, q2-3wk) of small doses may maintain the serum level in the reference range. The rate of elimination of IgG may be heightened during active infection; measuring serum IgG levels and increasing the doses or shortening the intervals may be required.

For replacement therapy in patients with primary immunodeficiency, all brands of IVIG are probably equivalent, though they differ in their viral-inactivation processes (eg, solvent-detergent treatment vs pasteurization, liquid vs lyophilized powder). The choice of brand 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 in case they need to be reviewed to investigate adverse events or other consequences. Recording all adverse effects that occur during the infusion is crucial.

Also recommended is periodic monitoring of liver and renal function, approximately 3-4 times per year. The US Food and Drug Administration (FDA) recommends that, for patients at risk for renal failure, the recommended doses should not be exceeded and the infusion rates and concentrations should be the minimum levels that are practicable. Patient are risk include those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, or paraproteinemia; patients older than 65 years; and patients who use nephrotoxic drugs.

Initial treatment should be administered under close supervision by experienced personnel. The risk of adverse reactions during initial treatments is high, especially in patients with infections and in patients who form immune complexes. For patients with active infection, infusion rates may need to be slowed and the dose halved (ie, to 200-300 mg/kg), with the remaining portion administered the next day to achieve a full dose. Treatment should not be discontinued. After reference-range 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. Relatively serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with profound immunodeficiency or patients with active infections can have severe reactions.

Adverse reactions are thought be related to the anticomplementary activity of IgG aggregates in IVIG and the formation of immune complexes. 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 every 6-8 hours), acetaminophen 15 mg/kg/dose, diphenhydramine 1 mg/kg/dose, and/or hydrocortisone 6 mg/kg/dose (to a maximum of 100 mg) 1 hour before 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 clinically significant complication of IVIG treatment. Reports suggest that IVIG products containing sucrose as a stabilizer may be associated with an increased risk for acute renal failure. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest 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, blood urea nitrogen and creatinine levels should be monitored before treatment and before each infusion is administered. If renal function deteriorates, discontinue use of the product.

IgE antibodies to IgA are reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports describe true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after IVIG treatment. However, in actual experience, this reaction is rare. In addition, anaphylaxis is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or SCID. Exercise caution in patients with IgA deficiency ( <7 mg/dL) who need IVIG because of IgG-subclass deficiencies. Use of IVIG preparations with low concentrations of contaminating IgA is advised (see the Table below).

Immune Globulin, Intravenous

*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.

Although IVIG may improve the ability of some patients to handle infections, aggressive treatment of acute bacterial infections with specific antibiotics remains necessary. In patients with clinically significant T-cell deficiency, prophylaxis may be warranted against Pneumocystis carinii pneumonia, either in the form of oral trimethoprim-sulfamethoxazole (Bactrim or Septra) or pentamidine.

IVIG replacement therapy has not been effective in treating patients with AT and CMC. However, a trial of IVIG may be warranted in other patients with combined B- and T-cell deficiency who lack antibody production to specific antigens (eg, tetanus, diphtheria, or polysaccharide antigens to pathogens such as Haemophilus influenzae or Streptococcus pneumoniae).

Several reports describe subcutaneous infusion in children in whom IV access is difficult. Stiehm et al (1998) administered dosages of 100 mg/kg/wk (ie, 1 mL/kg of a 10% IV solution) or 250 mg/kg (ie, 2.5 mL/kg) every 3 weeks. Recently, the FDA approved a form of immunoglobulin for subcutaneous use. Exercise caution when treating patients with absent IgA serum levels because of the possibility of anaphylaxis. Some researchers urge screening these patients for serum anti-IgA antibody levels; others use Gammagard.

In patients younger than 2 years, use of passive immunization against respiratory syncytial virus (RSV) should be considered. Severe RSV bronchiolitis and pneumonitis may contribute to the development of chronic lung disease.

Drug Category: Antibodies

Prevention of RSV in immunodeficient patients is possible with passive immunization with RSV-specific polyclonal IVIG or humanized mouse monoclonal IgG.

Drug Category: Anti-infective agents

In patients with clinically significant T-cell deficiency, prophylaxis against P carinii pneumonia may be warranted. Prophylaxis may be in the form of oral trimethoprim-sulfamethoxazole (Bactrim or Septra) or pentamidine.

In patients with CMC, topical antifungal therapies are usually not effective. Oral candidiasis can be treated with clotrimazole troches instead of oral nystatin solution. Systemic oral antifungal drugs are occasionally effective and can improve the quality of life for affected patients. However, relapse after cessation of the antifungal therapy is common. Reports described successful treatment with cimetidine and zinc sulphate in patients with CMC.

FOLLOW-UP

Section 8 of 12  

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

Prognosis

• Because the underlying immunodeficiency in patients with AT is so variable, their overall prognoses can vary.
  
  
  • Approximately 10-15% develop malignancy, usually lymphoid tumors, in childhood. However, other tumors, including brain tumors and certain carcinomas, have also been seen in patients with AT. The role of ATM mutations to breast cancer is currently under intense investigation but does appear to be breast cancer susceptibility alleles (Renwick et al, 2006). The degree and extent of any associated autoimmune endocrinopathies in patients with CMC is similarly variable and affects the prognosis.
  
  
  
  • Early detection of malignancy and aggressive treatment for sinopulmonary infections prolong survival. In AT, chronic lung disease appears to be primarily interstitial and responsive only to systemic corticosteroids given early in the course of disease. A recent case report documented improvement of neurologic symptoms with the use of systemic corticosteroids (Buoni, 2006).
  
  
  
  • The use of the conjugated pneumococcal vaccine may be of benefit because infections with S pneumoniae are common. Some patients may benefit from IVIG. Some patients survive into adulthood. A 31-year-old individual is the oldest reported patient.
  
  
  
  • The median survival in 2 large cohorts of patients with AT was 25 and 19 years, with a wide distribution. Life expectancy does not correlate well with severity of neurologic impairment (Crawford et al, 2006).

• In CMC, survival into adulthood is common. However, early detection of associated endocrinopathies is critical. In addition, aggressive treatment for lower respiratory tract infections helps prevent morbidity due to the development of chronic lung disease.



• Delayed diagnosis of AT and/or CMC may compromise the care of patients and their family members.
  
  
  • Early diagnosis of AT alerts the physician to a possible immunodeficiency and the need to limit the patient's exposure to ultraviolet light and diagnostic radiographs. Early diagnosis of CMC similarly indicates the need to use effective antifungal medications and monitor for autoimmune disorders.
  
  
  
  • Early diagnosis also provides an opportunity for requisite genetic counseling because of the genetic component of the disease.
  
  
  
  • Some recommend routine testing of serum AFP levels in all toddlers and children with undiagnosed chronic or progressive ataxia. CMC should be considered in any patient with persistent candidal infection.

Patient Education

• Families may benefit from social support organizations, such as the Immune Deficiency Foundation.

MISCELLANEOUS

Section 9 of 12  

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

Medical/Legal Pitfalls

• Do not administer attenuated or live virus vaccines in patients in whom immunodeficiency is being considered. In particular, do not administer live polio vaccine to the patient or any person living in the same household as the patient.
• Failure to explore a coexisting T-cell deficiency can be disastrous because these deficiencies warrant aggressive therapy.
• Failure to refer a patient to an immunologist can be problematic if the primary physician is uncomfortable in interpreting the results of various immune-function tests.

Special Concerns

• Children with AT can have a lifelong disease that affects their family.
• Families may benefit from social support organizations, such as the Immune Deficiency Foundation.

TEST QUESTIONS

Section 10 of 12  

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

MULTIMEDIA

Section 11 of 12  

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

Media file 1:  Radiograph shows an 8-month-old boy who required ventilatory support for bilateral pneumonia and who received intravenous antibiotics. The patient recovered and returned home.
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Media type:  X-RAY

Media file 2:  Chest radiograph in an 8-month-old boy 2 weeks after he was treated for bilateral pneumonia (same patient as in Image 1). The patient returned to the emergency department with a fever and breathing problems.
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Media type:  X-RAY

Media file 3:  Chest radiograph in a 9-month-old boy (same patient as in Images 1-2). The patient developed breathing problems 1 month after recovering from a second hospitalization for pneumonia. By this time, serum immunoglobulin levels from the second hospitalization were in the patient's record and showed an immunoglobulin G level of 156 mg/dL and undetectable immunoglobulin A and immunoglobulin M levels. Subsequent bronchoscopy showed the presence of Pneumocystis carinii and cytomegalovirus.
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Media type:  X-RAY

Media file 4:  Telangiectasia.
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Media type:  Photo

Media file 5:  Telangiectasia of conjunctivae.
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Media type:  Photo

REFERENCES

Section 12 of 12

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

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• Ruan Qc, She JX. Autoimmune polyglandular syndrome type 1 and the autoimmune regulator. Clin Lab Med. 2004;24:305-17. [Medline].
• Sadighi Akha AA, Humphrey RL, Winkelstein JA, et al. Oligo-/monoclonal gammopathy and hypergammaglobulinemia in ataxia- telangiectasia. A study of 90 patients. Medicine (Baltimore). Nov 1999;78(6):370-81. [Medline].
• Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol. 2005;39:537-43. [Medline].
• Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am. Dec 2000;47(6):1355-69. [Medline].
• Stiehm ER. Immunologic Disorders in Infants and Children. Philadelphia, Pa: WB Saunders:1996.
• Stray-Pedersen A, Aaberge IS, Fruh A et al. Pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine; immunogenicity in patients with ataxia-telangiectasia. Clin Exp Immunol. 2005;140:507-16. [Medline].
• Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. J Clin Pathol. Oct 2005;58(10):1009-15. [Medline].
• Thampakkul S, Ballow M. Replacement intravenous immunoglobulin: serum globulin therapy in patients with antibody immune deficiency. 21. 2001:165-84.
• Buoni S, Zannolli R, Sorrentino L, Fois A. Betamethasone and improvement of neurological symptoms in ataxia-telangiectasia. Arch Neurol. Oct 2006;63(10):1479-82. [Medline].
• Crawford TO, Skolasky RL, Fernandez R, Rosquist KJ, Lederman HM. Survival probability in ataxia telangiectasia. Arch Dis Child. Jul 2006;91(7):610-1. [Medline].
• Pashankar F, Singhal V, Akabogu I, Gatti RA, Goldman FD. Intact T cell responses in ataxia telangiectasia. Clin Immunol. Aug 2006;120(2):156-62. [Medline].
• Regueiro JR, Porras O, Lavin M. Ataxia-telangiectasia: a primary immunodeficiency revisted. Immunol Allergy Clin North Am. 2000;20:177-206.
• Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. Aug 2006;38(8):873-5. [Medline].
• Stiehm ER, Casillas AM, Finkelstein JZ, Gallagher KT, Groncy PM, Kobayashi RH. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol. Jun 1998;101(6 Pt 1):848-9. [Medline].

Article Last Updated: Apr 5, 2007