T cells are major effector cells of the adaptive immune response from influencing antibody production to maintaining tolerance. The defining marker of the T cell is the T-cell receptor (TCR), and 2 distinct T-cell subsets have been characterized based on the structure of the TCR: TCRα/β and TCRγδ. The specificity of the TCRα/β T-cell repertoire is established during fetal development of the thymus, which develops at week 6 of gestation. Immature thymic cells develop from fetal liver cells and, after birth, from hematopoetic stem cells (HSCS) in the bone marrow. T cells develop from common lymphoid progenitor cells derived from HSCs within the thymus and undergo stages of differentiation, expressing 1 or both of the cytodifferentiation (CD) antigens CD4 and CD8. T cells expressing the α/β TCR are divided into various subsets based on surface CD antigens and function. CD4+ T cells, or helper T cells (TH), make up approximately 70% of T cells in the peripheral blood. TH cells recognize foreign antigens processed and presented in major histocompatibility complex (MHC) class II molecules and can be divided into additional subsets. TH1 CD4+ T cells produce interferon gamma (IFN-γ) and IL-2, favor antibody class switching to immunoglobulin (Ig) G2, and mediate protection against intracellular pathogens. TH2 CD4+ T cells produce IL-4, IL-13, and IL-5, favor class switching to IgG1 and IgE, and participate in atopic diseases and immunity against parasites. More recently, additional subsets of CD4+ T cells have been described that have effector functions against extracellular microbes: TH9 cells produce the anti-inflammatory cytokine IL-10 and are involved in the host defense against nematodes, whereas TH17 cells secrete IL-17, IL-21, and IL-22 and promote protective immunity against extracellular bacteria and fungi at mucosal surfaces. CD8+ cytotoxic T lymphocytes (CTLs) recognize endogenous proteins bound to MHC class I molecules, such as viral and tumor antigens, and mediate cytotoxicity by lysing altered or nonself cells. A third class of T cells (typically CD4+) with immune suppressive function are denoted as regulatory T cells (Treg) and can be identified (albeit with some exception) by the expression of the transcription facto FOXP3 (forkhead box P3). Treg cells are produced directly from the thymus (natural Treg) or induced within the periphery (induced Treg) and play major roles in mediating chronic inflammation, allergic disease, and autoimmunity.1
T-cell dysfunction in neonates has implications for a variety of responses and disease states. Infants are more susceptible to infectious agents, and according to the World Health Organization (WHO) estimates, approximately 2.5 million infants under the age of 1 die annually of infection. Infants are also less responsive to vaccination. In vaccinated infants, immunity wanes around 6–9 months after vaccination, and multiple booster shots are needed to maintain immunological memory.2 Historically, the function of neonatal T cells has been considered impaired, mainly attributed to immaturity of the neonatal immune response. Neonatal antigen-presenting cells produce lower amounts of IL-12, required for IFN-γ responses. The overall bias of the neonatal immune response toward TH2 leads to delayed production of proinflammatory cytokines and IL-2 and subsequent delayed effective CD8+ CTLs until several months after birth. The TH2 dominance during early life also influences the class of IgG antibodies, leading to a predominance of IgG1 and IgG3 and low production of IgG2. However, in certain instances, such as BCG vaccination, a proper TH1 response is mounted in neonates. Thus, baseline normal neonatal adaptive responses range from nonresponsiveness to adult-level T-cell responses (Table 112-1). Genetic defects in neonatal T-cell function tend to increase susceptibility of the already-vulnerable newborn to disease (Table 112-2). Because optimal B-cell function requires T-cell help, a T-cell defect typically results in a B-cell deficiency as well (considered combined immunodeficiencies, such as Wiskott-Alrich syndrome [WAS]). Newborns with primary immunodeficiencies most commonly present with increased cases of infection; however, diagnosing the disease with known characteristics prior to infection is the goal and will typically lead to a better outcome for the patient.
Table 112-1Neonatal T-Cell Responses to Vaccines and Infectious Disease ||Download (.pdf) Table 112-1Neonatal T-Cell Responses to Vaccines and Infectious Disease
|Infectious Agent ||T-Cell Responsesa || |
|Bordetella pertussis ||TH1 response || |
|Human cytomegalovirus ||Mature CD8 T-cell response, defective CD4 T-cell response || |
|Human immunodeficiency virus ||Mature CD8 T-cell response, defective CD4 T-cell response || |
|Herpes simplex virus 1 and 2 ||Delayed IFN-γ and TNF-α response, defective CD4+ T-cell response || |
|Trypanosma cruzi ||Mature CD8 T-cell response, defective CD4+ T-cell response || |
|Vaccine || ||Doses Given < 12 Months of Ageb |
|Hepatitis B ||Predominantly TH2 response, decreased IFN-γ response ||3 |
|Measles, mumps, rubella ||Low TH1 response ||1 (≥ 12 months) |
|Mycobacterium bovis BCGc ||Mature TH1 response || |
|Inactivated poliovirus ||Low TH1 response, decreased IFN-γ response ||3 |
|Diptheria, tetanus, pertussis ||Mature TH1 response by 2 months of age ||3 |
|Haemophilus influenza type b ||Weak memory T-cell response ||2–3 |
|Pneumococcal ||Low TH1 response, decreased IFN-γ response ||3 |
Table 112-2Inherited T-Cell Immunodeficiencies and Disease ||Download (.pdf) Table 112-2Inherited T-Cell Immunodeficiencies and Disease
|Syndrome/Disease ||T-Cell Dysfunction ||Chromosome ||Altered Protein |
|ZAP70 deficiency ||CD8 lymphocytopenia ||2q12 ||ZAP70 |
|DiGeorge syndrome ||Absent T-cell function ||22q11.2 10p13 ||TBX1 and other |
|Wiskott-Aldrich syndrome ||Dysfunctional B- and T-cell iterations ||Xp11.23 ||WASP |
|IPEX ||Decreased regulatory T-cell function ||Xp11.2-q13.3 ||FOXP3 |
|Nezelof syndrome ||Absent T-cell function ||? ||CD44? |
|NTED ||Overactive TSST-1-specific T cells ||? ||? |
CONGENITAL T-CELL IMMUNODEFICIENCIES
DiGeorge syndrome,3 or 22q11.2 deletion syndrome, is caused by the deletion affecting the long arm of chromosome 22. It is a genetic recessive immunodeficiency (in rare cases autosomal dominant) usually inherited from the mother. DiGeorge syndrome has occurred in both males and females and has an estimated prevalence of 1:4000. Some cases of DiGeorge and velocardiofacial syndromes have defects in other chromosomes, notably a deletion in chromosome region 10p14. There is considerable variability in the phenotype, and severity is based on the extent of the microdeletion. Individuals with DiGeorge syndrome may suffer from congenital heart defects, palatal abnormalities, hypocalcemia caused by hypoparathyroidism, distinctive craniofacial features, renal anomalies, and thymic hyplasia.4 Additional clinical findings associated with the disease and useful evaluations following diagnosis with DiGeorge/22q11.2 deletion syndrome are summarized in Table 112-3.
Table 112-3Clinical Characteristics and Diagnosis of DiGeorge/22q11.2 Deletion Syndrome ||Download (.pdf) Table 112-3Clinical Characteristics and Diagnosis of DiGeorge/22q11.2 Deletion Syndrome
|Common Clinical Features ||DiGeorge Syndrome Work-up ||Less-Frequent Clinical Features |
|Congenital heart disease ||Echocardiogram ||Severe dysphagia |
|Palatal abnormalities ||Speech therapy ||Growth hormone deficiency |
|Hypocalcemia ||Calcium, phosphorus, PTH, creatinine ||Autoimmune disease |
|Immune deficiency ||Immunoglobulin levels, B and T cell subtypes ||Neoplasms |
|Learning difficulties ||Psychiatric and cognitive assessment ||– |
|Characteristic facial features ||– ||– |
|Lymphopenia ||CBC with differential ||– |
|Renal anomalies ||Ultrasound ||– |
|Absence of Thymic gland ||Chest x-ray to identify thoracic vertebral abnormalities ||– |
T-cell immunodeficiency in DiGeorge syndrome is attributed to failure of development of the thymus, and patients may be mildly to severely lymphopenic based on the degree of thymic deficiency. Laboratory evaluation typically reveals normal-to-decreased numbers of T lymphocytes with absent-to-normal T-cell function and normal B-cell function.5 Serum immunoglobulin levels tend to be within normal limits. However, in the rare patient, B-lymphocyte function and antibody production may be abnormal as well. A defect in the delayed-type hypersensitivity is observed by the failure of affected patients to develop a positive skin test to candidin. Because of defects in cell-mediated immunity, patients are highly susceptible to opportunistic infections and to graft-vs-host disease (GVHD) from nonirradiated blood transfusions.
Diagnosis of individuals with DiGeorge syndrome is confirmed for the microdeletion on chromosome 22 via fluorescence in situ hybridization (FISH) chromosomal analysis.6 The 2 probes commercially available for 22q11.2 FISH analysis are TUPLE1 and N25. Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. Fetuses at increased risk may be evaluated between 18 and 22 weeks’ gestation by high-resolution ultrasound examination for palatal and other associated anomalies, by echocardiography for cardiac anomalies, or by chromosomal analysis of fetal cells obtained through amniocentesis.
Treatment of the 22q11.2 deletion/DiGeorge syndrome is based on the severity of the disease and may require surgery for cardiac defects and vitamin D, calcium, or parathyroid hormone replacement to correct hypocalcemia and treat seizures. Most infants have a mild-to-moderate deficit in T-cell function that often improves with age and do not suffer from recurrent infections in adulthood. For patients with the complete form of the syndrome with absent T-cell immunity (<0.2%), thymic grafts have been used successfully. Human leukocyte antigen (HLA)-identical bone marrow transplants have been successful at developing T-cell function in these patients, but this treatment cannot correct the thymic defect. Of note, prior to giving live vaccines, T-cell numbers and function should be assessed, if not done earlier, to prevent vaccine-related side effects.
Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency disease caused by mutations in the gene that produces the Wiskott-Aldrich syndrome protein (WASP). Various mutations in the WASP gene have been identified in patients with WAS, each affected family typically carrying its own characteristic mutation. If the mutation interferes completely with the ability to produce the WASP, the patient has the classic and more severe form of WAS. Alternatively, if the mutation only results in lower production of WASP, a milder form of the disorder may result. WAS is characterized by defective interactions between B and T cells, resulting in decreased cell-mediated immunity. Patients with classic WAS present with thrombocytopenia, eczema, and recurrent infection. Common infections are typically caused by pneumococcal bacteria, resulting in pneumonia, meningitis, or sepsis, but may involve all classes of microorganisms. The initial clinical manifestations of WAS may be present soon after birth or develop in the first year of life, with prolonged bleeding from the circumcision site, bloody diarrhea, or excessive bruising. Survival to adulthood is rare; infection, vasculitis, and bleeding are major causes of death.
Diagnosis of WAS should be considered in any male presenting with unusual bleeding and bruises, congenital thrombocytopenia, and small platelets. Patients with WAS have alterations in the humoral response with increased IgA and IgE levels and diminished IgM levels. Patients usually have diminished antibody responses to polysaccharide antigens. Assessment of blood lymphocytes demonstrates a slight reduction of T-cell numbers and response to mitogens. Diagnosis of WAS is confirmed by demonstrating a decrease or absence of the WASP in blood cells or by the presence of a mutation within the WASP gene.
Because WAS is inherited as a X-linked disorder, only boys are affected, and there may be brothers or maternal uncles with similar findings. It is possible that the family history may be negative if the disease is caused by occurrence of a new mutation. Prenatal DNA diagnosis of WAS can be performed by amniocentesis or chronic villus sampling.
Treatment of WAS symptoms include iron supplementation for anemia, prophylactic administration of immunoglobulin replacement for bacterial infections, and steroid creams to control areas of chronic inflammation caused by eczema. HLA-identical sibling bone marrow transplantation (BMT) have been successful at correcting the platelet and immunologic abnormalities and is the treatment of choice for boys with significant clinical findings of WAS.7 Matched unrelated donor transplantations have shown promise, especially if they are performed while the patient is under the age of 5 and prior to acquiring a severe viral infection or cancer. In some cases, cord blood stem cells have been successfully used for immune reconstitution and correction of platelet abnormalities.
Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is associated with mutations that abrogate expression of functional FOXP3 protein that results in defective development of CD4+CD25+ Treg and subsequent severe dysregulation of the immune system. In rare cases, IPEX could be the result of regulatory or conditional mutations outside FOXP3 coding regions, resulting in reduction in FOXP3 messenger RNA (mRNA) expression. IPEX syndrome is inherited in an X-linked manner and typically affects males, whereas females remain asymptomatic. This syndrome is extremely rare, with fewer than 150 affected individuals identified worldwide.
Usually, IPEX syndrome presents in the first few months of life with eczema dermatitis, watery diarrhea, and endocrinopathy.8 Possible other symptoms include cachexia, growth retardation caused by autoimmune enteropathy, and chronic inflammation with excessive cytokine production. Patients with IPEX may also present with hypothyroidism, Coombs-positive anemia, autoimmune neutropenia, and recurrent infection. Several cases have also demonstrated renal insufficiency, arthritis, and ulcerative colitis. Finally, patients with IPEX tend to be immunocompromised as a result of the defect in immunoregulation, resulting in severe infectious complications and sepsis.
Conventional CD4+ and CD8+ T cells numbers and function in vitro appear normal. Typically, patients with IPEX syndrome have elevated levels of serum IgE and, in some cases, IgA. Histopathology shows the absence of normal mucosa of the small bowel and colon with diffuse infiltration of inflammatory cells in the lamina propria. Definitive diagnosis is based on clinical features and DNA analysis of mutations in the FOXP3 gene. Analysis of peripheral blood by flow cytometry will show decreased numbers of FOXP3-expressing T cells in patients with IPEX syndrome.
Without treatment, IPEX syndrome is fatal within the first 2 years of life because of sepsis or failure to thrive. Immunosuppressive therapy and BMT have shown efficacy for IPEX syndrome.9 Immunosuppressive medications, such as cyclosporin A, tacrolimus, methotrexate, infliximab, and rituzimab, are only partially effective and limited by toxicity. Prophylactic antibiotic therapy for patients with autoimmune neutropenia or recurrent infections can be used to prevent secondary complications. Patients with IPEX syndrome should undergo periodic evaluation of complete blood cell count, glucose tolerance, thyroid function, kidney function, and liver function for evidence of autoimmune disease.
Neonatal Toxic Shock Syndrome-like Exanthematous Disease
Neonatal toxic shock syndrome-like exanthematous disease (NTED) is caused by overactivation of toxic shock syndrome toxin 1 (TSST-1) reactive T cells. Patients develop systemic exanthema, fever, mildly elevated serum C-reactive protein values, and thrombocytopenia. The disease is induced when patients are colonized with methicillin-resistant Staphylococcus aureus (MRSA) that produces TSST-1, which has superantigenic activity. To date, there is no genetic link to the disease. Transfer of maternal anti-TSST-1 IgG through the placenta is effective in protecting against the development of NTED.
Nezelof syndrome (NS) is an extremely rare immune deficiency disorder affecting both male and female siblings, indicating that it may be transmitted as an autosomal recessive genetic disorder. NS is caused by thymic hypoplasia and is characterized by absent T-cell function and deficient B-cell function with fairly normal immunoglobulin levels, but little-to-no specific antibody production. Patients with NS present with recurrent pneumonia, otitis media, chronic fungal infections, upper respiratory tract infections, and diarrhea. The lymph nodes and tonsils may be enlarged or absent in infants with the disease.
Definitive diagnosis of the disease includes defective B-cell and T-cell immunity despite a normal number of circulating B cells, a moderate-to-high rise in the number of T cells, a deficiency or an increase in 1 or more classes of immunoglobulins, a non-reactive Schick test after DPT (diphtheria and tetanus toxoids and pertussis) immunization, a reduced or an absent antibody reaction after specific antigen immunization, no thymus shadow on a chest x-ray film, and a decrease in the number of lymphocytes in the blood.
Initial supportive treatment may include immunoglobulin injections and prophylactic use of antibiotics. T-cell function can be temporarily restored by injection of thymosin or fetal thymus transplant. Major histocompatibility-matched BMT is a possible treatment, but the effectiveness is not well documented.
Zeta-Chain-Associated Protein Deficiency
Zeta-chain-associated protein (ZAP70) deficiency is a rare autosomal recessive T-cell immunodeficiency that is caused by mutations in the ZAP70 gene on chromosome 2 at position q12, within the kinase domain, that encodes ZAP70. ZAP70 is a non-src family protein tyrosine kinase important in TCR signaling and has an essential role in positive and negative selection in the thymus. The deficiency results in a selective absence of CD8+ T cells and normal or elevated numbers of circulating CD4+ T cells. In vitro, CD4+ T cells do not respond to mitogens or allogeneic cells. The thymus tends to have normal architecture with normal levels of differentiating CD4/CD8-double-positive thymocytes. Serum immunoglobulin concentrations in patients may be normal, low, or elevated, with normal or elevated B-cell numbers. The condition presents during infancy with severe, recurrent, frequently fatal infection.10
ACQUIRED T-CELL IMMUNODEFICIENCIES
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS). This retrovirus has a tropism for human CD4+ T cells, bone-marrow-derived dendritic cells, megakaryocytes, cells of monocyte-macrophage lineage, and the macrophage-microglial and endothelial cells of the central nervous system. A characteristic depletion of CD4+ cell numbers is observed in HIV infections, after which there is a continuous but variable rate of decline of CD4 T cells. Because CD4+ T cells play a pivotal role in many immunoregulatory functions, the loss in these cells is responsible for a reduction in their helper-inducer function and a decrease in other T-cell, B-cell, and monocyte activities, resulting in wide-ranging functional defects in cellular and humoral immunity. Immune dysregulation and innate immune activation are features of HIV disease.
Perinatal transmission may occur in utero, at the time of delivery, or via breast-feeding. Infants infected perinatally usually are asymptomatic during the first few months of life, and size and physical features are not different from uninfected neonates. The level of viremia rises steeply, reaching a peak at age 1–2 months. Infants have a gradual decline in plasma viremia that extends beyond 2 years. Infants generally have plasma virus levels 10 times higher than those in adults.
Identification of the infected infant relies on identification of the infected mother, followed by careful clinical and laboratory monitoring of the infant throughout the first year of life. Diagnostic laboratory tests include serial HIV antibody testing (ie, enzyme-linked immunosorbent assay [ELISA] and immunoblot); serial P24 antigen testing; HIV culture; immunoglobulin levels; T-cell numbers and subsets (see Table 112-4), and 1 or more other diagnostic techniques (eg, polymerase chain reaction [PCR], HIV-IgA, immunoblot assay). Of note, maternal HIV-specific IgG is passively transferred across the placenta and may persist in infants until 18 months of age; thus, for infants under the age of 18 months, the viral PCR assay is preferred over HIV antibody testing. The goal for neonatal HIV infection is to diagnose infection before the onset of severe opportunistic infection.
Table 112-4CD4 Lymphocyte Count Analysis for AIDS Diagnosis in Infants ||Download (.pdf) Table 112-4CD4 Lymphocyte Count Analysis for AIDS Diagnosis in Infants
| ||CD4+ T Cells/μL ||% of Total Lymphocytes |
|No evidence of suppression ||>1500 ||>25% |
|Moderate suppression ||750–1499 ||15%–24% |
|Severe suppression ||<750 ||<15% |
There is currently no cure for HIV infection, and it is managed with antiretroviral (ARV) therapy drugs. Didanosine, lamivudine, stavudine, zidovudine, and nevirapine are used to treat infants under 3 months of age. Common side effects of ARV therapy include nausea, vomiting, diarrhea, headache, and malaise. The success of ARV therapy is measured by the suppression of HIV replication (as measured by plasma viral load) and maintenance of CD4+ T-cell counts with the least amount of drug toxicity. The treatment paradigm changes frequently; therefore, prior to initiating treatment, expert consultation should be obtained.
Human T-Cell Leukemia Virus Type 1
Human T-cell leukemia virus type 1 is a retrovirus that infects CD4+ T cells and produces adult T-cell leukemia (ATL) and tropical spastic paraparesis, also called HTLV-1-associated myelopathy (HAM). HTLV-1 may also play a role in infective dermatitis, arthritis, uveitis, and Sjögren syndrome. Generally, only T cells are productively infected, but infection of B cells and other cell types is occasionally detected. As HTLV-1 infection results in latent carriage of integrated provirus, does not contain an oncogene, and does not insert into a unique site within the genome, most infected cells do not express viral gene products. The virus can be transmitted vertically from mothers to infants. Maternal anti-HTLV-1 antibodies inhibit milk-borne infections of HTLV-1 in early life. However, neonatal infection with HTLV-1 is preventable through short-term breast-feeding (<3 months) or bottle feeding. Modes of prevention of ATL and HAM have not been described.
CHRONIC MUCOCUTANEOUS CANDIDIASIS
Chronic mucocutaneous candidiasis (CMC) is an infection of the skin, mucous membranes, and nails by Candida albicans and is associated with defective T-cell-mediated immunity that is specific to Candida. The T cells of patients with CMC fail to produce cytokines essential for anti-Candida cell-mediated immunity. This defect can be caused by an inherited deficiency or have no genetic basis (Table 112-5). In several patients, gene sequencing identified mutations in signal transducer and activator of transcription (STAT) 1, leading to defective immune responses in TH1 and TH17 T cells.11 CMC can also severely affect patients with STAT3 deficiency and lack of IL-17- and IL-22-producing T cells. B-cell function is normal; thus, anti-Candida antibodies can be identified in patients.
Table 112-5Classification of Infant Patients With Chronic Mucocutaneous Candidiasis (CMC) ||Download (.pdf) Table 112-5Classification of Infant Patients With Chronic Mucocutaneous Candidiasis (CMC)
|Type ||Gene Defect ||Onset ||Clinical Features ||Associated Disorders ||Noncandidal Infections |
|Familial CMC ||Autosomal recessive ||<2 years ||Oral candidiasis ||No endocrinopathies ||Yes |
|Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome ||Autosomal recessive, mutations in the AIRE gene || |
Endocrine abnormalities between 10 and 15 years of age
Oral and diaper area candidiasis
Endocrinopathies and autoimmune disorders
|Hypoparathyroidism, hypoadrenalism, thyroid disease, hepatitis, malabsorption, primary hypogonadism, pernicious anemia, alopecia areata ||Yes |
|Chronic localized candidiasis ||No known genetic basis ||<5 years ||Thick, adherent candidal crusts on the scalp and face, oral candidiasis ||None ||Yes |
|CMC with keratitis ||Autosomal dominant ||Early childhood ||Candidiasis of the oral cavity, diaper area ||Keratoconjunctivitis, alopecia, endocrine abnormalities ||Yes |
Neonatal candidiasis presents 3–7 days after birth with oral thrush and diaper dermatitis. More extensive scaling of skin lesions and thickened nails and red, swollen periungual tissues can follow these infections. Chronic mucocutaneous candidiasis may be classified based on its association with other conditions. The condition without endocrinopathy is typically not associated with autoimmune disorders; inheritance may be autosomal recessive or dominant. Chronic mucocutaneous candidiasis with endocrinopathy may occur as part of autoimmune polyendocrinopathy syndrome type 1, also known as APECED, or may also be observed in patients with other conditions, such as hyperimmunoglobulin IgE syndrome and HIV infection. Persistent and refractory candidal infections must be distinguished from the more common treatment-responsive overgrowth of Candida that occurs in the setting of systemic antibiotic therapy, local/systemic corticosteroid treatment, or hyperglycemia in persons with diabetes mellitus.
Chronic mucocutaneous candidiasis is not associated with a high degree of mortality because disseminated invasive candidal infections are rare. However, patients with APECED have significant morbidity from endocrinopathies or other autoimmune diseases associated with this condition. Orally and topically administered antifungal agents improve the condition of patients with CMC. Fluconasole and itraconazole are available as suspensions and can be used in pediatric populations. Of note, these drugs inhibit the cytochrome P-450 system, and treatment may alter catabolism of other drugs, such as coumadin; immunosuppressive drugs (tacrolimus, cyclosporin A); antimycobacterial drugs (rifampin); and anti-HIV protease inhibitors.12 In autoimmune disorders, reconstitution of the cell-mediated immune response with leukocyte transfer from healthy, related donors has proven beneficial.
Acute Lymphoblastic Leukemia
Acute leukemias make up a group of lymphopoietic stem cell disorders that are characterized by clonal expansion of immature lymphohematopoietic cells in the bone marrow. Lymphoblasts that are unable to differentiate accumulate in the bone marrow and suppress normal hemopoietic cells. Chromosomal abnormalities have been found in most cases of acute lymphoblastic leukemia (ALL).13 Around 20% of ALLs are of the T-cell type; the remaining are mainly of the B-cell type. Finally, ALL occurs more frequently among children than myeloid leukemias, reaching a peak at 3–4 years of age.
Patients with ALL develop a normochromic, normocytic anemia and may develop weakness, pallor, and malaise. In most cases, patients develop bleeding secondary to thrombocytopenia. Granulocytopenia is also common in patients with ALL and results in increased bacterial infections. Patients also experience bone pain and generalized lymphadenopathy.
Diagnosis of ALL is accomplished by demonstrating lymphoblasts in the bone marrow. Lymphoblasts can also be detected in peripheral blood and are usually accompanied by an elevated leukocyte count. A normal or decreased leukocyte count may appear in patients without peripheral blood lymphoblasts. The age at onset and initial total leukocyte count are valuable for prognosis. Allogeneic stem cell transplantation is only performed in cases with very high-risk ALL features.14 Aggressive nonablative chemotherapy has been successful in driving complete remission and is the treatment of choice for children with ALL.15
MA. Phenotypical and functional specialization of FOXP3+
regulatory T cells. Nat Rev Immunol
et al.. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol
BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet
et al.. Craniosynostosis: another feature of the 22q11.2 deletion syndrome. Am J Med Genet A
KE. The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Curr Opin Allergy Clin Immunol
et al.. Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization. Hum Genet
RM. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood
P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr
AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet
et al.. Oski’s Pediatrics: Principles And Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.
van de Veerdonk
et al.. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med
CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J
et al.. Chromosomal abnormalities in acute lymphoblastic leukemia. Cancer Res
et al.. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet
A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am
. 2009;23:1033–1042, vi.