B-Cell and T-Cell Combined Disorders 

Updated: Dec 11, 2018
Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

The immune system's lymphocyte component is divided into B cells and T cells. Traditionally, B cells have been believed to be the lymphocytes responsible for antibody production via maturation into plasma cells (ie, humoral immunity), and T cells have been believed to be the lymphocytes responsible for killing other cells or organisms (ie, cellular immunity). Currently, 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/cytotoxic cells) possess the killing function and also inhibit B-cell development. Therefore, any T-cell disorder theoretically has the potential to cause defective B-cell function.

Pathophysiology

Because a major loss or dysfunction of T cells can cause secondary B-cell deficiency, numerous disorders have clinical manifestations of combined B-cell and T-cell deficiency, although 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-cell 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). RAG1 and RAG2 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.[1] Deoxyguanosine and deoxyadenosine 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-cell 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 can also 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 involving DNA repair indicate some interaction between the immune system and neurologic function. Ataxia-telangiectasia (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 cells and B cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in circulating T cells 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.

Two syndromes indicate close interaction between the immune and endocrine systems: chronic mucocutaneous candidiasis (CMC) and immune dysregulation with polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.[2]

CMC is a complex disorder in which patients have persistent or recurrent infections of the skin, nails, and mucous membranes by Candida species. It can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or autosomal recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Two other familial subtypes include 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).[3] This disease has been mapped to chromosome 21q22.3 and the gene identified as the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 60 different disease-causing mutations in AIRE have been discovered and the role in various manifestations of CMC and APECED/APS I are under investigation.

IPEX syndrome is associated with mutations in the FOXP3 gene at Xp11.23. Affected males have diarrhea (enteropathy) and autoimmune phenomena primarily involving the endocrine system, such as diabetes or thyroid disease. Other autoimmune processes may include hemolytic anemia and collagen-vascular disease. The typical triad consists of enteropathy, dermatitis, and endocrine abnormalities. Most individuals with this condition do not live beyond age 3 years.

Epidemiology

Frequency

United States

Stiehm estimated that combined cellular and antibody deficiencies account for approximately 20% of primary immunodeficiencies.[4] AT is a rare disease with an estimated prevalence of less than 1 case per 100,000 population; the incidence of CMC is similar at 1 case per 103,000 population. Some report an increased frequency of approximately 1 case of AT per 40,000 births in the United States.

Newborn screening in California established the incidence of SCID as 1 case in 66,250 live births. According to the Centers for Disease Control and Prevention (CDC), only 16 states in the United States currently include SCID on newborn screening. Testing uses quantification of T-cell receptor excision circles (TRECs) to evaluate T-cell production by the thymus. TRECs are also used for evaluation of other T-cell immunodeficiency disorders, both acquired and congenital.[#IntroductionFrequencyInternational]

A study of data from a spectrum of 11 newborn screening programs determined that SCID, leaky SCID, and Omenn syndrome affected 1 in 58,000 infants. The survival rate was 92% for infants who received transplantation, enzyme replacement, and/or gene therapy.[5]

International

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

The birth frequency of AT in the United Kingdom is approximately 1 case per 300,000 population. 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). Indeed, the Finnish series of patients is the largest internationally.[6]

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

Sex

No differences have been reported based on sex except in IPEX syndrome.

Age

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

 

Presentation

History

Clinical manifestations of many combined B-cell and T-cell deficiencies derive from associated organ involvement, thus eliciting variable onsets for the different symptoms. Neurologic and cutaneous symptoms predominate in ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Autoimmune endocrinopathies and cutaneous manifestations are seen in patients with chronic mucocutaneous candidiasis (CMC) and immune dysregulation with polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. In other combined B-cell and T-cell deficiencies, the presence of unusual organisms in certain infections, the chronic nature of infectious processes, and autoimmune phenomena may indicate the presence of an underlying immunodeficiency.[7]

AT is an obvious diagnosis when both ataxia and telangiectasia are present. A diagnosis of AT can also be made upon onset of ataxia and before telangiectasia appears, if confirmed by laboratory test results. In most patients, a misdiagnosis of cerebral palsy is usually made 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, mean age of ataxia onset was 15 months; mean age of telangiectasia onset was 72 months.[8] This study by confirmed that a misdiagnosis of cerebral palsy was made in most patients (29 of 48). To alleviate this problem, the study recommends routine serum alpha-fetoprotein (AFP) testing for all children with persistent ataxia.

Ataxia is initially 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, less often, a dysconjugate gaze is noted. Muscle weakness may appear late in the course, with subsequent muscle atrophy. Mental function can be affected.

AT has increased alpha fetoprotein levels, whereas NBS has microcephaly and mental retardation.

Telangiectasia usually occurs on the bulbar conjunctivae in patients younger than 5-6 years and becomes more 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. See the images below.

Telangiectasia. Telangiectasia.
Telangiectasia of conjunctivae. Telangiectasia of conjunctivae.

Bloom syndrome may also have telangiectasias, especially 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 more variable. Therefore, the resulting predisposition to infection can vary. Recurrent sinopulmonary infections may be a complaint before ataxia or telangiectasia develops. An increase in lower respiratory tract infections is observed with age with subsequent chronic lung disease. Impaired oropharyngeal swallowing mechanisms may contribute with chronic aspiration. Infections can be caused by viral and bacterial pathogens, although typically not by opportunistic agents.

In a review of 100 patients with AT, recurrent upper and lower tract infections were common, including otitis media 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 states that no offspring of AT homozygotes are known.[4] Patients may also 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.

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 cessation of antibiotics or inhaled corticosteroid therapy and when T-cell deficiency has been excluded. Esophageal or tracheal candidiasis is uncommon and may simply represent colonization of mucous membranes after a course of systemic antibiotic therapy. See the image below.

A 5-year-old boy with thrush. A 5-year-old boy with thrush.

More extensive cutaneous infections with skin, nail, and mucous membrane involvement may develop in late childhood or during adolescence (CMC type 4). These patients apparently are less likely to develop endocrinopathies.

According to Stiehm, "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..."[4] According to one study, the most commonly affected organs 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, usually in adult or middle-aged patients. These patients may also 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 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, red blood cell [RBC], white blood cell [WBC], platelets), chronic active hepatitis, and juvenile rheumatoid arthritis for CMC.

The combination of dermatitis and thrombocytopenia (as an autoimmune process) in males may confuse IPEX with patients with Wiskott-Aldrich syndrome. Indeed, IPEX was originally thought to be a Wiskott-Aldrich syndrome variant because the gene that encodes WASP also lies in the same region as FOXP3 gene. The dermatitis in IPEX is also eczematous in nature.

Enteropathy with failure to thrive is almost always present in IPEX. It usually presents with watery diarrhea and villous atrophy is commonly found on intestinal biopsy.

Endocrinopathy is commonly present but may not appear initially. The most common endocrine dysfunction is early onset insulin-dependent diabetes mellitus. Thyroid disease (either hypothyroidism or hyperthyroidism) is also common.

Examples of autoimmune phenomena include immune hemolytic anemia, immune thrombocytopenia, autoimmune neutropenia, lymphadenopathy, splenomegaly, tubular nephropathy, or alopecia.

Patients with IPEX usually present in early infancy and may die within the first 2 years of life due to either metabolic derangements or sepsis. The most common pathogens were Staphylococcus, cytomegalovirus (CMV), and Candida.

Neoplastic diseases other than thymomas can occur, which emphasizes the importance of T cells in immune surveillance. However, a greater incidence of malignancy is observed in AT, especially lymphoid tumors, which has been attributed to their increased sensitivity to radiation. Occasionally, leukemia has been a presenting finding of AT. On the other hand, CMC with squamous cell carcinoma of the oral cavity or esophagus has also been described.[9]

Physical

Depending on the specific combined immunodeficiency syndromes, physical examination may yield varying 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 manifest progressive cerebellar ataxia. However, the classic form has onset in infancy, and steady progression to milder forms in which the progression may be slower or the onset may be later have been noted. 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 later.

In CMC, almost all patients have skin or nail findings.[10] 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 more extensive forms, nails and extremities may develop severe hyperkeratosis with nail deformities.

In IPEX, the typical rash is eczematoid.

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 patients with AT, some of whom may not have symptoms until adulthood.

Mutations in the ATM gene are probably 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.

Immunological studies indicate that dendritic maturation may be impaired in both CMC and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Subsequent altered regulation of pattern recognition receptors may be responsible for the disease manifestations.[11]

Other studies show that these patients have an inability to clear Candida. This may be due to a defect in the immune response of interleukin (IL)-17-producing T cells.[12]

CMC is included as part of the APECED disorder, which is also known as autoimmune polyglandular syndrome type I (APS I). This disease has been mapped to chromosome 21q22.3, and the gene is identified as the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 60 different disease-causing mutations in AIRE have been discovered, and the role in various manifestations of CMC and APECED/APS I are under investigation. AIRE may be involved in thymocyte negative selection, which 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 autosomal recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Therefore, determining whether the AIRE gene markers (and autoantibodies) segregate with disease in a family in whom the diagnosis of CMC is possible is important.

Two other familial subtypes include an autosomal dominant form with nail candidiasis and intercellular adhesion molecule-1 (ICAM-1) deficiency and an autosomal recessive form with hyperimmunoglobulinemia E. Chronic localized CMC has no apparent genetic component.

 

DDx

 

Workup

Laboratory Studies

Laboratory findings in the measurement of immune function are heterogeneous in patients with ataxia-telangiectasia (AT). Findings widely vary.

Decreased or absent levels of serum immunoglobulin A (IgA), immunoglobulin G (IgG)2, and immunoglobulin E (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, although the vaccination may need to be repeated.[13]

Researchers recently observed hypergammaglobulinemia in 39% of 90 patients with AT. An isolated increase in immunoglobulin M (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. Lymphopenia is typically present. In one 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 (interleukin [IL]-2, interferon [IFN]-gamma) and Th2 (IL-10, IL-4) cells.[14]

A laboratory finding unique to AT is an elevated serum alpha-fetoprotein protein (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 Nijmegen breakage syndrome (NBS), and helicase gene defect defines Bloom syndrome.

Studies of the immune function in patients with chronic mucocutaneous candidiasis (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, IL-2 and IFN-gamma) and increased levels of IL-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.

Autoantibodies against type I IFNs have been proposed as an additional diagnostic criterion for autoimmune polyglandular syndrome type I (APS I).[15]

Imaging Studies

MRI is the preferred method for radiologic evaluation in patients with AT; however, exaggerated radiographic changes are not usually visible until age 10 years. Imaging may then 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.

In particularly, antibodies against interferon appear to be especially common in APS I and CMC.[16, 15]

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

Medical Care

As with other immunodeficiencies, aggressive antibiotic administration and supportive care may prolong the patient's survival, though no current therapy cures ataxia-telangiectasia (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 chronic mucocutaneous candidiasis (CMC).

Unlike other combined immunodeficiency syndromes, AT and CMC do 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 immunoglobulin G (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.

The Primary Immune Deficiency Treatment Consortium analyzed the results of hematopoietic stem cell transplantation in children with SCID.[17] Researchers collected data from 240 infants who had received transplants at 25 centers from 2000-2009 and concluded that transplants from donors other than matched siblings resulted in high survival rates if the infants were identified before infection developed. Asymptomatic infants responded well to all graft sources.[18]

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 and Nijmegen breakage syndrome (NBS) have an increased risk of developing malignancy, careful monitoring is required by a hematologist-oncologist. Because patients with CMC may be at risk of developing various endocrinopathies, careful monitoring is required by an endocrinologist. Thymoma may also develop in adulthood. Regular screening by a gastroenterologist has been suggested for patients with CMC with a history of recurrent candidal esophagus or a family history positive for esophageal or oral carcinoma.

Primary care physicians who are less experienced in interpreting results of immune function tests should refer patients to an immunologist.

Refer parents of children with AT and CMC to a genetic counselor because they are at risk for affected additional offspring.

Diet

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

Activity

Because of the increased sensitivity to radiation in patients with AT or NBS, advise these patients to avoid excessive sun exposure and to use sunscreens when outdoors.

The typical patient with AT usually requires a wheelchair for mobility by early teenage years.

For patients with CMC, good oral hygiene and aggressive treatment of oral and esophageal candidiasis are needed.

Avoidance of additional risk factors for oral and esophageal cancer such as cigarette smoking and excessive alcohol consumption may also be warranted.

 

Medication

Medication Summary

Unlike in other combined immunodeficiency syndromes, gamma-globulin replacement therapy does not appear to be beneficial in patients with ataxia-telangiectasia (AT) because of marked variation of humoral immunodeficiency with concomitant variable susceptibility to infections; however, individual patients may benefit. A study by Claret Teruel et al indicated that 7 out of 12 patients with AT received gamma-globulin due to immunoglobulin G (IgG) deficiency. Similarly, Kalfa et al described 9 patients with chronic mucocutaneous candidiasis (CMC) with selective antibody deficiency.[19] All 9 had IgG2 deficiency with IgG4 deficiency in 8 patients and immunoglobulin A (IgA) deficiency in 3 patients. All 9 had recurrent severe lung infections and may have benefited from intravenous immunoglobulin (IVIG) therapy.

Replacement therapy using IVIG in patients with primary immunodeficiencies

Overall consensus among clinical immunologists is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels at greater than 500 mg/dL is desirable. Patients (X-linked agammaglobulinemia) with meningoencephalitis require much higher doses (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 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 dosages or shorter intervals may be required.

For replacement therapy in patients with primary immunodeficiency, all brands of IVIG are probably equivalent, although differences in the viral inactivation processes (eg, solvent-detergent treatment versus pasteurization, liquid versus lyophilized powder) may be noted. The choice of brands may depend on the hospital or home care formulary and local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial.

Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, also is recommended. The Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, patients with preexisting renal insufficiency, diabetes, volume depletion, sepsis, or paraproteinemia; patients aged >65 y; and patients who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

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 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 reference range serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include 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 thought 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 every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before 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 acute renal failure. 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 treatment and prior to each infusion is necessary. If renal function deteriorates, discontinue the product.

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 IVIG treatment. However, in actual experience, this reaction is very rare. In addition, anaphylaxis is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Exercise caution 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.

Table. Intravenous Immunoglobulin Therapy [20, 21, 22, 23] (Open Table in a new window)

Brand(Manufacturer)

Manufacturing Process

pH

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

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(ZLB Behring)

Kistler-Nitschmann fractionation, pH 4, nanofiltration

6.4-6.8

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

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

Trace

Flebogamma

(Grifols USA)

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

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

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

4.6-5.1

0.25 M 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

4-4.5

Contains no sugar, contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

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

4.8-5.1

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

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III, ultrafiltration, pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

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

6.4-7.2

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

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

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

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

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

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

6.6

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

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

720

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-cell 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 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.[24] 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.

Antibodies

Class Summary

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

RSV-IVIG (RespiGam)

Polyclonal human immunoglobulin made by selecting donors with high titers of anti-RSV antibody. With monthly infusion, protects high-risk infants against severe RSV disease. In clinical trials, RSV-IVIG reduced hospitalization for non-RSV infections lower respiratory tract and rates of otitis media compared with placebo.

Palivizumab (Synagis)

Humanized mouse monoclonal IgG preparation specifically directed toward RSV.

Anti-infective Agents

Class Summary

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.

Trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Administration on Mondays, Wednesdays, and Fridays instead of 3 consecutive days also effective. This regimen may be especially necessary if physician must desensitize patient because of drug allergy; spreading dose throughout the week allows for continued attachment of drug to IgE on mast cells without degranulation.

Pentamidine (Pentam-300, Pentacarinat, NebuPent)

Antiprotozoal agent used for prophylaxis and treatment of P carinii infection. Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, inhibiting protein and phospholipid synthesis.

 

Follow-up

Prognosis

Because the underlying immunodeficiency in patients with ataxia-telangiectasia (AT) widely varies, overall prognosis can vary. Approximately 10-15% develop malignancy in childhood, usually lymphoid tumors. However, other tumors, including brain tumors and certain carcinomas have also been seen in patients with AT. The role of ATM mutations in breast cancer is currently under intense investigation.[25] Similarly, the degree and extent of any associated autoimmune endocrinopathies in patients with chronic mucocutaneous candidiasis (CMC) widely varies and affects the prognosis.

Early detection of malignancy and aggressive treatment for sinopulmonary infections prolong survival. In AT, their chronic lung disease appear to be primarily interstitial and responsive only to systemic corticosteroids given early in the course. One case report detailed improvement of neurologic symptoms with systemic corticosteroids.[26]

The use of the conjugated pneumococcal vaccine may be of benefit because infections with Streptococcus pneumoniae is common. Some patients may benefit from intravenous immunoglobulin (IVIG). Some patients survive into adulthood. A 31-year-old individual is the oldest reported patient.

The median survival in two large cohorts of patients with AT is age 25 and 19 years, with a wide range. Life expectancy does not correlate well with severity of neurologic impairment.[27]

In CMC, survival into adulthood is common. However, early detection of associated endocrinopathies is critical. In addition, aggressive treatment for lower respiratory tract infections prevents morbidity due to the development of chronic lung disease. CMC has been associated with squamous cell carcinoma of the oral cavity or esophagus; endoscopic screening has been suggested for patients that develop symptoms of esophageal candidiasis and in those with a positive family history.[9]

Delayed diagnosis of AT or CMC may compromise the patient and family member care. Early diagnosis of AT alerts the physician to a possible immunodeficiency and the need to limit patients' exposure to ultraviolet light and diagnostic radiographs. Similarly, early diagnosis of CMC 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 routinely testing serum alpha-fetoprotein (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.