Chapter 51: Primary Immunodeficiency Syndrome

• Primary immune deficiency diseases (PIDDs) are characterized by increased susceptibility to infections and are determined by the failure of either the humoral or cellular arms of the immune system or both.

• The clinical features of PIDDs are listed in Table 51–1.

  — Characterized, principally by recurrent pyogenic bacterial infections, including sinusitis, furunculosis, and recurrent or chronic pneumonias that often terminate in bronchiectasis. These infections are initially responsive to antibiotics but soon relapse.

• Evaluation of serum immunoglobulin (Ig) levels and specific antibody responses in patients with recurring infections without an apparent predisposing cause should be made.

  — Baseline Ig levels are often low or virtually absent.

  — Antibody response to immunization is often inadequate.

• Abnormality of cellular immunity causes:

  — Susceptibility to viral, protozoal, and fungal infections.

  — Patients are often anergic. Rejection or clearance of allogeneic cells may be impaired.

  — There may be a secondary defect in humoral immunity because of T-cell dysfunction and loss of B-cell helper activity.

• Autoimmune diseases such as immune-mediated hemolytic anemia, thrombocytopenia, or rheumatoid arthritis-like conditions occur at a higher frequency in certain primary immunodeficiency states.

• The more severe primary immune deficiencies are usually present in infancy, although common variable immunodeficiency (CVID) often presents later in life.

• In Ig-deficient patients, treatment with intravenous immunoglobulin (IVIG) may decrease infectious events.

• The autosomal recessive syndromes are frequently the result of consanguineous marriages.

X-Linked and Autosomal Recessive Agammaglobulinemia

Definition and Genetic Features

• Caused by maturation defect in B-cell development.

• X-linked agammaglobulinemia is the result of a mutation in the Bruton tyrosine kinase (BTK) gene.

• Autosomal recessive agammaglobulinemia is the result of mutations in genes relevant to immunoglobulin heavy or light chains, i.e., IGHM, IGLL1, CD79a, CD79b or the B-cell adaptor molecule, BLINK.

Clinical Features

• X-linked and autosomal recessive agammaglobulinemia have similar clinical features: low Ig levels, decreased B cells, and recurrent infections.

• Normal levels of IgG at birth as a result of transfer from maternal circulation. Thus, usually asymptomatic for the first few months of life.

• Symptoms and signs vary and may be mild or severe (see Table 51–1). First develop between 4 and 12 months of age. First signs of the disease may not be apparent for several years in some patients.

• Otitis media, sinusitis, pyoderma, diarrhea are most frequent presenting findings.

• Pneumonia, meningitis, septicemia, osteomyelitis, and septic arthritis may occur later.

• Neutropenia may accompany X-linked agammaglobulinemia and increase the risk of recurrent or chronic infections.

• Most common pathogens: Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus.

• The response to many viral infections is often normal but usually susceptible to echovirus and coxsackie virus presenting as meningoencephalitis, dermatomyositis, or hepatitis. They are also unusually susceptible to poliovirus. Attenuated live polio vaccine can cause severe morbidity and mortality once maternal antibodies have disappeared.

• Gastroenteritis caused by Giardia lamblia, Campylobacter species, or rotavirus is common and may be associated with malabsorption.

• Patients have an increased incidence of aggressive rectosigmoid carcinoma.

Laboratory Features

• Reduced level of serum Ig is the hallmark; B cells are less than 1 percent of normal (tonsils are absent).

• B cell maturation arrest prevents plasma cell development and these cells are absent from marrow, gastrointestinal tract, and lymph nodes.

• Specific antibodies are also reduced or absent (Table 51–2).

• Flow cytometry can be used to measure the BTK protein in normal monocytes or platelets and female carriers can be identified.

• Analysis of mutations in the BTK gene can be used to make the diagnosis and to identify affected males in utero.

Treatment

• Treatment with intravenous IVIG: pooled plasma-derived preparation that contains IgG and IgA.

• Individualized doses that usually start at 400 to 600 mg/kg intravenously every 4 weeks.

• Prophylactic antibiotic therapy may be useful in certain circumstances, such as patients with chronic lung disease.

Course

• Treatment with IVIG markedly decreases enteroviral infections but some patients develop neurodegenerative disease or chronic ileitis (Crohn-like disease) despite treatment and without evidence of an infectious etiology.

Hyperimmunoglobulin M Syndromes

Definition and Genetics Abnormalities

• Characterized by recurrent infections associated with low serum levels of IgG, IgA, and IgE but normal or increased levels of IgM.

• Mutations affect genes involved in B-cell activation, class switch recombination (CSR), and somatic hypermutation (SHM).

• Mutations occur in genes encoding enzymes intrinsic to B cells, i.e., AID, UNG, and the NEMO gene, the latter crucial for nuclear factor-κB activation.

X-Linked Hyper-IgM as a Result of CD40L Deficiency

• Caused by mutations in CD40L distributed throughout the gene resulting in nonfunctional CD40L protein.

• Normally, CD40L on surface of CD4+ T lymphocytes interacts with CD40 expressed constituently on B lymphocytes.

Clinical Features

• Characterized by recurrent bacterial infections in infants. Often presents with interstitial pneumonia caused by Pneumocystis jiroveci.

• Fifty percent of affected males also develop neutropenia.

• High risk of developing chronic Cryptosporidium infections complicated by ascending cholangiolitis and chronic liver disease.

• Progressive neurodegeneration, as in X-linked agammaglobulinemia, can occur.

Laboratory Features

• Normal blood B cell subsets but B cells are naïve.

• Defective lymph node germinal center development and severe deficiency in follicular dendritic cells.

• Response to specific antigens reduced (see Table 51–2).

• Mild cases left untreated can lead to red cell aplasia as a result of chronic parvovirus B19 infection.

Treatment

• During infancy, treat with trimethoprim-sulfamethoxazole to prevent P. jiroveci pneumonia.

• IVIG doses are similar to X-linked agammaglobulinemia to prevent chronic infections including parvovirus.

• Allogeneic hematopoietic stem cell transplantation should be considered if an appropriate donor can be identified.

• Treat severe and persistent neutropenia with G-CSF.

Autosomal Recessive Hyper-IgM with CD40 Mutations

• Similar clinical features to those with CD40L mutations.

Autosomal Recessive Hyper-IgM Syndrome Caused by an Intrinsic Defect

• Mutations of the activation-induced cytidine deaminase gene (AID).

• Because of mild phenotype, often discovered later in life.

Clinical Features

• Recurrent bacterial infections that affect upper and lower respiratory tract.

• Enlarged tonsils and lymph nodes from marked follicular hyperplasia.

• T- and B-cell subset are normal but all CD27⁺ memory B cells fail to switch isotypes and express IgM and IgD.

• Treatment with IVIG prophylaxis often associated with excellent long-term prognosis.

X-linked Anhydrotic Ectodermal Dysplasia with Immunodeficiency Caused by Mutations of NEMO

• Characterized by partial or complete absence of sweat glands, sparse hair growth, and abnormal dentition.

• Most patients present with bacterial infections, especially S. pneumoniae S. aureus, and atypical mycobacteria; 20 percent of infections are caused by viral infections.

• Approximately 20 percent of patients develop inflammatory bowel disease.

• Treatment with IVIG is useful but does not prevent the occurrence of serious complications.

Common Variable Immunodeficiency and Selective IgA Deficiency

• CVID is heterogeneous and may present at any age but usually occurs during adulthood.

• Characterized by hypogammaglobulinemia, impaired antibody responses, and recurrent bacterial infections.

• In conjunction with selective IgA deficiency, most common primary immunodeficiency syndrome.

• Selective IgA deficiency may be the initial presenting finding in later CVID.

• Familial concordance in approximately 20 percent of cases and CVID and IgA deficiency can occur in the same family.

Clinical Features and Treatment of CVID

• Characterized by recurring sinopulmonary infections and bacterial pneumonia.

• If untreated, may lead to bronchiectasis and chronic lung disease.

• Lymphadenopathy and splenomegaly are common.

• Caseating granuloma of lung, spleen, liver, skin, and other tissues are damaging to organ function.

• Frequent gastrointestinal complaints. Lymphoid hyperplasia of the small bowel results in a syndrome mimicking chronic inflammatory bowel disease.

• Bowel disease associated with G. lambia or Campylobacter infections.

• Autoimmune disorders are common and may resemble rheumatoid arthritis, dermatomyositis, or scleroderma.

• May develop autoimmune hemolytic anemia, autoimmune thrombocytopenia purpura, autoimmune neutropenia, pernicious anemia, and chronic active hepatitis.

• Despite normal B-lymphocyte levels and lymph node cortical follicles, patients have agammaglobulinemia that may be profound.

• Uncommonly, patients may have an associated thymoma.

Treatment and Course

• IVIG infusions and prophylactic antibiotics are beneficial but often insufficient to prevent serious complications.

• There is a marked increase in the risk of lymphoma, gastrointestinal cancers, and a variety of other cancers.

• Allogeneic hematopoietic stem cell transplantation is not recommended unless used to treat a secondary lymphoma.

Clinical Features and Treatment of Selective IgA Deficiency

• Characterized by less than 10 mg/dL of IgA.

• Differs greatly between ethnic groups: Highest frequency in Scandinavia and lowest in Asian populations.

• Fundamental defect is the failure of IgA-bearing B lymphocytes to mature into IgA-secreting plasma cells.

• Most persons remain healthy.

• If disease signs occur, they include recurrent sinopulmonary infections and atopic symptoms including allergic conjunctivitis, rhinitis, and eczema. Food allergies are common, and asthma is more refractory to symptomatic treatment.

• Symptomatic individuals have concomitant deficiency in IgG₂ and IgG₃ and poor responses to polysaccharide antigens.

• Chronic giardiasis, malabsorption, celiac disease, primary biliary cirrhosis, and pernicious anemia can occur.

• Higher incidence of rheumatoid arthritis, myasthenia gravis, thyroiditis, and systemic lupus erythematosus.

• No specific treatment is available.

• In patients with chronic pulmonary disease, selective prophylactic antibiotic therapy may be useful and where a defect in response to polysaccharide antigens is suspected or measured, prophylactic IVIG can be beneficial.

Definition and History

• Heterogeneous group of genetic disorders that is characterized invariably by a severe impairment of T-lymphocyte development and function and a variable defect in either B or NK cells or both (see Fig. 51–1).

• Severe combined immunodeficiency (SCID) can be classified into four groups based on the associated immune cell deficiencies:

  — T–B+NK– SCID (Most common type)

  — T–B+NK+ SCID

  — T–B–NK+ SCID

  — T–B–NK– SCID

• Incidence rate is 1 in 50,000 births.

• Most common form is inherited as an X-linked trait.

• Reconstitution of a functioning immune system by transplantation of histocompatible allogeneic lymphohematopoietic stem cells may be lifesaving.

Molecular Defects and Pathogenesis of SCID

Resulting from Increased Apoptosis of Lymphocyte Progenitors

• Adenosine deaminase (ADA) deficiency:

  — Inherited as an autosomal recessive trait.

  — Characterized by the virtual absence of T lymphocytes as a result of absence of ADA resultant high intracellular levels of adenosine and deoxyadenosine and phosphorylated metabolites result in T-cell progenitor apoptosis.

  — Reduction in number of B cells, also.

• Purine nucleoside phosphorylase (PNP) deficiency

  — High levels of deoxyguanosine triphosphate cause destruction of immature thymocytes and neuronal toxicity.

  — Characterized by decreased T-cell counts. B and NK cells unaffected.

• Adenylate kinase 2 deficiency

  — Originally termed reticular dysgenesis. So named because absence of cells in lymphohematopoietic organs left a background of reticular cells and fibers and the inference was drawn, erroneously, that this stroma could not support immune and blood cell development.

  — Autosomal recessive SCID characterized by extreme lymphopenia, absence of neutrophils (loss of G-CSF responsiveness), and sensorineural deafness.

  — Severe sepsis early in infancy.

  — Successful treatment with allogeneic stem cell transplantation indicates it is a cellular and not stromal (reticular cell) disorder.

Result of defective signaling through the T-cell receptor (TCR)

• Defects of IL-7 receptor(R)-mediated signaling abrogate development of T cells and defects in IL-15R signaling affect development of NK cells resulting in SCID type T-B+NK-.

• X-linked IL2Rγ gene mutations account for 40 percent of all SCID cases and result in lack of T and NK cells (T-B+NK-). However, B-cell function is impaired by failure of T helper function and a non-functional common gamma chain shared by several other key interleukin receptors (e.g., 2R, 4R, 9R,15R, and 21R).

• JAK3 deficiency is an autosomal recessive disorder with a phenotype identical to X-linked SCID type T-B+NK-.

• Defects in V(D) J recombination affect both T and B cell development and causes T-B-NK+ SCID.

• RAG1 and RAG2 deficiencies causes T-B-NK+ SCID and account for 10 percent of all SCID cases.

• Defects of the CD3, δ, ε, or ζ chains affect signaling through the TCR and cause T-B+NK+ SCID.

Clinical Features of SCID

• Characterized by P. jiroveci pneumonia, cytomegalovirus (CMV), adenovirus, parainfluenza 2 virus, respiratory syncytial virus, chronic diarrhea, failure to thrive, and persistent candidiasis.

• Infections develop in first months of life.

• Hypoplastic lymphoid tissue (atrophic tonsils and lymph nodes).

• Absence of thymic shadow on chest radiograph.

Laboratory Features of SCID

• Lymphocyte count usually less than 2.0 × 10⁹/L.

• In infants, marked blood T-cell deficiency. Blood CD3+ cells should be determined.

• Maternal T-cell engraftment and "leaky" SCID characterized by expression of CD45RA+ whereas infants T cells are CD45RA naïve and fail to respond to mitogens in vitro.

• Ig levels low in infants.

• Eosinophilia and elevated levels of IgE.

• Marrow abnormalities observed in ADA, PNP, XLF, and LIG4 deficiencies.

• ADA and PNP deficiency-related SCID, elevated levels of deoxyadenosine triphosphate, and deoxyguanosine triphosphate, respectively in red cells.

Therapy, Course, and Prognosis of SCID

• Fatal if untreated.

• High-dose intravenous sulfamethoxazole/trimethoprim (20 mg/kg) is effective in treating P. jiroveci pneumonia.

• CMV should be treated with ganciclovir.

• Adenoviral infections should be treated with cidofovir.

• IVIG and antimicrobial prophylaxis should be administered to reduce risk of infections.

• Survival is dependent on immune reconstitution by allogeneic hematopoietic stem cell transplantation.

• Enzyme replacement has benefited SCID patients with ADA deficiency and gene therapy has been successful in that variant of SCID without adverse events (e.g., acute leukemia from insertional mutagenesis).

Omenn Syndrome

• Mutations in RAG1 and RAG2 most common, which restrict T-cell maturation and function. For example, negative selection of autoreactive T cells is reduced and regulator T cell development is impaired.

Clinical Findings

• Severe infections.

• Early onset, diffuse rash, or generalized erythroderma.

• Alopecia.

• Lymphadenopathy and hepatosplenomegaly.

• A pattern of congenital anomalies occurs together more frequently than one would expect on the basis of chance.

Laboratory Findings

• Leukocytosis with eosinophilia.

• Hypoproteinemia with edema.

• Oligoclonal expansion of anergic, activated T lymphocytes that infiltrate and damage target tissues.

• Decreased serum IgG, M, and A levels, but elevated IgE.

• Distribution of blood CD4 and CD8 lymphocyte subsets are skewed.

• Lymphocyte production of IL-4 and IL-5 increased.

• Lymphocyte response to antigens nonexistent and response to mitogens is varied.

• Blood B and NK cell counts are abnormal in some patients.

Treatment

• Optimal approach is allogeneic hematopoietic stem cell transplantation.

• Patients require aggressive nutritional support, correction of hypoproteinemia, and treatment or prevention of infections with antibiotics, antifungals, and serum immunoglobulin replacement.

• Careful use of immunosuppression with glucocorticoids or cyclosporine A may mitigate T-cell induced tissue damage.

ZAP-70 Deficiency

• Form of SCID resulting from the inability to support positive selection of CD8+ lymphocytes in the thymus.

Clinical Features

• Severe infections.

• Palpable lymph nodes and thymic shadow is visible on the chest radiograph.

• CD8+ T cells reduced, but absolute lymphocyte count is normal.

• Response to mitogens in vitro reduced indicating CD4+ lymphocytes defective.

• Some, but not all patients, have severe hypogammaglobulinemia.

Treatment

• Optimal approach is allogeneic hematopoietic stem cell transplantation.

MHC Class I Deficiency

• Characterized by reduced expression of MHC class I molecules at the cell surface.

• Autosomal recessive trait, may be caused by mutations in TAP1, TAP2, or Tapasin genes, which defects interfere with intracellular transport of antigens and their loading onto MHC class I molecules and cell surface expression of the MHC complex.

Clinical Findings

• Low levels of CB8+ T cells and Ig levels are variable.

• Recurrent respiratory infections in children.

• Chronic inflammatory lung disease and skin lesions in patients with TAP1 and TAP2 deficiencies.

• Chronic lung disease is usually the cause of death.

Treatment

• Prophylactic and therapeutic measures used for cystic fibrosis are beneficial. Maintaining liquid pulmonary secretions, appropriate antibiotic use.

MHC Class II Deficiency

• Autosomal recessive inheritance.

• Characterized by lack of MHC class II expression.

• Found in North African populations.

• Four gene mutations are known: CIITA, RFXANK, RFX5, and RFXAP.

• These mutations encode defective transcription factors that normally control MHC class II antigen expression by binding to the proximal promoters of the MHC class II gene.

Clinical Features

• Blood CD4+ T cell count is reduced.

• Severe lung infections.

• Chronic diarrhea.

• Sclerosing cholangitis, often secondary to Cryptosporidium or CMV infection.

Treatment and Course

• Poor prognosis.

• Respiratory infections are predominant cause of death.

• Nutritional support is often needed and antibiotic prophylaxis and immunoglobulin replacement therapy are required, but with marginal impact on long-term prognosis.

• May be treated with allogeneic hematopoietic stem cell transplantation but overall results are unsatisfactory. Severe graft-versus-host disease is common.

Coronin-1A Deficiency

• Characterized by mutations affecting both alleles of the CORO1A gene, an actin regulator expressed principally in hematopoietic cells.

• Regulates release of T lymphocytes from thymus and trafficking of naïve T cells.

• Characteristic finding is T-cell lymphopenia with normal numbers of B and NK cells.

• Treatment by allogeneic hematopoietic stem cell transplantation is best approach if a donor available.

Signal Transducers and Activator 5b (STAT5b) Deficiency

• Autosomal recessive disease characterized by the association of growth hormone insensitivity and a highly variable degree of immune deficiency.

• Results in impaired transcriptions of genes involved in immune system function and other non-immune related genes.

Clinical Features

• Short stature in the face of normal or elevated levels of growth hormone but insulin growth factor is very low.

• Pulmonary infections including P. jiroveci pneumonia.

• Increased susceptibility to severe viral diseases.

• Lung fibrosis.

• Failure to respond to growth hormone replacement therapy.

• Glucocorticoids may be beneficial if there is evidence of lung fibrosis.

Ca²⁺ Entry Channel Deficiency

• Autosomal recessive disorder.

• Mutations of both ORAI1 and STIM1 genes, the products of which regulate the function of calcium channels in the cell membrane and endoplasmic reticulum, respectively.

• Clinical features resemble SCID.

• Additional features include nonprogressive myopathy, ectodermal dysplasia, hepatosplenomegaly, hemolytic anemia, and thrombocytopenia.

• In spite of hypergammaglobulinemia, specific antibody responses are defective and T cells do not respond to mitogens in part as a result of failure of calcium influx after stimulation.

• Allogeneic hematopoietic stem cell transplantation can correct the defect.

DiGeorge Syndrome

• Developmental disorder caused by abnormal cephalic neural crest migration and differentiation in the third and fourth pharyngeal arches during embryonic development.

• Approximately 75 percent of persons with this phenotype have a deletion at band q11.2 on chromosome 22 (referred to as 22q11.2 deletion syndrome).

Clinical and Laboratory Features

• Phenotype varies but classically has the triad of (1) congenital cardiac defects, (2) hypocalcemia as a result of parathyroid insufficiency, and (3) immune deficiency as a consequence of aplasia or hypoplasia of the thymus.

• Fifty to 80 percent develop cardiac defects; 50 to 60 percent develop hypocalcemia.

• Mild to moderate immune deficiency involving T-cell maturation and function with T-cell numbers often less than 1.5 × 10⁹/L.

• High incidence of autoimmune diseases, such as rheumatoid arthritis and thyroiditis.

• As young adults, develop social, behavioral, and psychiatric problems.

• Those with profound T-cell deficiency may develop B-cell lymphomas.

• If suspected, fluorescence in situ hybridization can be used to detect 22q11.2 deletion.

Treatment

• Cardiac defects and hypocalcemia require immediate attention.

• Patients may require antibiotic prophylaxis, IVIG therapy, and if T-cell function is absent, immune reconstitution by allogeneic hematopoietic stem cell transplantation if a donor is available.

• The concept of a link between immune dysregulation and autoimmunity has been strengthened by the discovery of distinct single gene defects resulting in unusual susceptibility to autoimmune diseases.

IPEX Syndrome

• The acronym IPEX derives from the presence of immune dysregulation, polyendocrinopathy, enteropathy, and an X-linked inheritance.

• Characterized by early onset diarrhea secondary to autoimmune enteropathy.

• Multiple endocrinopathies including type 1 diabetes mellitus, thyroiditis, and, rarely, adrenal insufficiency.

• Autoimmune hemolytic anemia, thrombocytopenia, and neutropenia are common complications.

• Eczema or other chronic dermatitis may occur.

• Elevated serum IgA and IgE. Absence of CD4+CD25+FOXP3+regulatory T cells

• Cyclosporine A, tacrolimus, sirolimus, or glucocorticoids can provide temporary amelioration.

APECED Syndrome

• The acronym APECED derives from the presence of autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy.

• Autosomal recessive disorder also known as autoimmune polygrandular syndrome (APS) type I.

• Results from mutations in the AIRE gene, which causes a decrease in the expression of tissue restricted antigens, failure of negative selection of autoreactive T cells in the thymus, and a resultant release of autoreactive T cell clones to peripheral lymphatic tissues.

• Found in isolated populations such as Finns, Iranian Jews, and Sardinians.

• Patients present with chronic mucocutaneous candidiasis and endocrinopathies, predominantly involving the parathyroid and adrenal glands, less frequently the thyroid and the pancreas.

• Associated with ectodermal manifestations, such as dystrophic finger nails and dental enamel.

Autoimmune Lymphoproliferative Syndrome

• The acronym ALPS derives from the autoimmune lymphoproliferative syndrome.

• Mutations are found in the genes required for "programmed cell death." Fas-mediated apoptosis pathway mutations account for about 85 percent of cases:

  — Mutations in CD95 (ALPS type Ia)

  — Mutations in CD95L (ALPS type Ib)

  — Mutations in caspase 10 or caspase 8 (ALPS type II) (approximately 5% of cases)

  — No mutations of Fas, FasL, or caspases (ALPS type III) (approximately 10% of cases)

• Phenotype caused by defective apoptosis of lymphocytes, resulting in polyclonal lymphadenopathy, hepatosplenomegaly, and autoimmune disorders, which most commonly include autoimmune hemolytic anemia, thrombocytopenia, and neutropenia.

• Spleen and lymph nodes show pronounced hyperplasia and the T-cell population includes a large proportion of TCRα/β+ CD4-CD8- cells.

• Treatment options include immunosuppressive therapy.

• Splenectomy is recommended in patients with large spleens.

• Long-term prognosis is poor.

• Lymphoma develops in about one of ten patients.

Wiskott-Aldrich Syndrome (WAS)

Definition

• X-linked disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, immunodeficiency, and a high incidence of autoimmune diseases and malignancies (see Chap. 76).

• Phenotype is associated with null-mutations of the gene that encodes the WAS protein (WASP).

• Milder phenotype is called X-linked thrombocytopenia (XLT).

• Characterized by mild eczema and few problems.

Clinical and Laboratory Features

• Thrombocytopenia in the range of 20 to 60 × 10⁹/L and microplatelets, but normal numbers of marrow megakaryocytes.

• Hemorrhagic manifestations may be mild.

• Classic WAS is characterized by bacterial, fungal, and viral infections.

Treatment

• May require antibiotic prophylaxis and IVIG.

• If autoimmune symptoms arise, immunosuppressive therapy may be required.

• Early allogeneic hematopoietic stem cell transplantation is treatment of choice; outcome is excellent if a matched-related or unrelated donor can be identified.

• Splenectomy ameliorates the bleeding tendency by increasing the number of blood platelets.

• XLT patients often have an excellent prognosis, but may develop complications, including serious bleeding, autoimmune diseases, and malignancies.

• Standard-conditioning for myeloablative transplantation (busulfan, cyclophosphamide, with or without antithymocyte globulin) is required.

The Hyperimmunoglobulin E Syndromes

Autosomal Dominant Hyper-IgE Syndrome (HIES)

• Autosomal dominant or sporadic multisystem immunodeficiency.

• Characterized by eczema, S. aureus-induced skin abscesses, recurrent pneumonia with abscess and pneumatocele formation, Candida infections, and skeletal and connective tissue abnormalities.

• Serum IgE levels greater than 2000 IU/mL and often much greater.

• Eosinophilia, neutrophil chemotactic defects and decreased lymphocyte proliferation to specific antigens.

• Treatment includes prophylactic antibiotic therapy to decrease the frequency of S. aureus pulmonary infections.

• Antifungal therapy is indicated to prevent recurrent Candida infections.

• Allogeneic hematopoietic stem cell transplantation has not been of clear benefit in the cases so treated.

Autosomal Recessive Hyper IgE Syndromes

• Characterized by elevated serum levels of IgE, recurrent bacterial, fungal, and viral infections including herpes simplex, therapy-resistant molluscum contagiosum, and recurrent varicella zoster.

Immunoosseous Dysplasias

Cartilage-Hair Hypoplasia

• Autosomal recessive characterized by short-limbed dwarfism, light colored hypoplasic hair, marrow cell dysplasia, Hirschsprung disease, and a variable degree of immunodeficiency from normal to severe, and increased susceptibility to malignancies.

• In the severe cases, allogeneic hematopoietic stem cell can correct the immune abnormalities.

Schimke Syndrome

• The disease is caused by a gene that encodes for a chromatin remodeling protein.

• Autosomal recessive condition characterized by dwarfism, microcephaly, cognitive and motor abnormalities, renal impairment leading to renal failure, facial dimorphisms, marrow failure, premature atherosclerosis, and immunodeficiency ranging from T-cell lymphopenia to SCID.

• Recurrent bacterial, fungal, and viral infections, including with opportunistic organisms occur in over half the patients.

• Combined allogeneic hematopoietic stem cell and renal transplantation has been used with success.

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome (WHIMS)

• Autosomal dominant disorder caused by a mutation in CXCL4 that disrupts the chemokine CXCL12 receptor involved in leukocyte trafficking.

• Retention and apoptosis of neutrophils in marrow (myelokathexis) causes severe neutropenia.

• Early onset of recurrent bacterial infections is common.

• Warts resulting from papillomavirus infection develop in second decade of life.

• Hypogammaglobulinemia, lymphopenia, and low B-cell counts are common.

• IVIG replacement therapy and antibiotics as required. Recombinant G-CSF can increase neutrophil count.

• Warts are resistant to local therapy and should be monitored for neoplastic transformation.

• Characterized by increased spontaneous or induced DNA breaks, susceptibility to infections secondary to immune deficiency, and an increased risk of malignancies.

• Genes responsible for these diseases protect human genome integrity by contributing to the complex task of double-strand break repair

Ataxia-Telangiectasia (AT)

• A multisystem disorder, characterized by immunodeficiency, progressive neurologic impairment, and ocular and cutaneous telangiectasia.

• Immune deficiency is variable and may include cellular and humoral immunity.

• Thymus is small.

• Mutation in ATM gene results in inability to repair double-stranded DNA breaks.

• Common to have recurrent respiratory infections that result in chronic lung disease.

• Phenotype is low or absent IgA and IgE and is often combined with IgG₂ and IgG₄ deficiency.

• Clinical manifestations include cerebellar ataxia, which becomes evident when a child begins to walk. Involuntary movements become a handicap and most are wheelchair bound by age 10 years.

• Children do not develop normal speech patterns.

• Cortical cerebellar degeneration involves primarily Purkinje and granular cells; progressive changes to the central nervous system also occur.

• Cytogenetic abnormalities include chromosomal breaks, translocations, rearrangements, and inversions; these defects increase following in vitro exposure of cells to radiation.

• Elevation of serum α-fetoprotein is a very common and characteristic laboratory finding.

• Infections and cancer (lymphomas, usually T-cell type (50%), leukemias (25%), and solid tumors (25%) are the most common causes of death.

Ataxia-Telangiectasia-Like Disorder (ATLD)

• Similar clinical features to AT with progressive ataxia but a slower progression of disease.

• Characterized by mutations in the gene encoding the hMre11 protein, part of the DNA repair complex.

Nijmegen Breakage Syndrome (NBS)

• Characterized by short stature, microcephaly, a bird-like face, immunodeficiency, chromosomal instability, increased sensitivity to radiation and radiomimetic drugs (e.g., alkylating agents), and a high likelihood of developing malignancies.

• Absence of telangiectasia formation and of neurodegeneration.

• Development of respiratory infections is common.

• Humoral and cellular immunity is defective.

• Characterized by increased chromatid and chromosome breaks, rearrangements/translocations involving chromosomes 7 and 14, telomere fusions, radio-resistant DNA synthesis, and hypersensitivity to radiation.

• High incidence of lymphoid malignancies and certain solid tumors (e.g., rhabdomyosarcoma).

• Prophylactic antibiotics and IVIG for patients with recurrent infections.

• Allogeneic hematopoietic stem cell transplantation has been successful.

Bloom Syndrome (BS)

• Caused by mutation in BMS gene that encodes a protein involved in sensing DNA damage and contributes to maintenance of genomic integrity during DNA replication or repair.

• Characterized by short stature, hypersensitivity to sunlight, increased susceptibility to infections, and a predisposition to early development of cancer, e.g., lymphoma and leukemia in first two decades of life and cancer of colon, skin, and breast at a later age.

• Fifty percent of patients develop cancer before the age of 25.

• Confirmed by demonstrating excessive numbers of sister-chromatid exchanges, increased chromatid gaps and breaks, and the presence of quadriradial configuration composed of two homologous chromosomes.

• Patients may benefit from antibiotic prophylaxis and IVIG therapy, if immune deficiency is documented. Because of increased radiation sensitivity, exposure to any form of irradiation should be restricted.

Familial Hemophagocytic Lymphohistiocytosis (FHL)

• Characterized by uncontrolled proliferation of activated lymphocytes and histiocytes that secrete large amounts of proinflammatory cytokines (see Chap. 33).

Clinical and Laboratory Features

• Signs and symptoms appear within first year of life.

• Symptoms include high fever, severe hepatosplenomegaly, lymphadenopathy, hemorrhagic manifestations from thrombocytopenia, and edema. Also may have neurologic symptoms.

• Immunologic findings include persistently impaired cytolytic activity of NK cells and elevated levels of inflammatory cytokines (IFN-γ, IL-1, IL-6, tumor necrosis factor-γ) in the blood.

• The diagnosis of FHL forms that are characterized by reduced NK cell degranulation (such as UNC13D and STX11 defects) may be facilitated by the analysis of membrane expression of the lysosomal marker CD107a.

• Without treatment FHL is fatal.

• If disease is active, treatments include antimicrobials, etoposide, immune suppression (antithymocyte globulin), cyclosporine A, and dexamethasone.

• Cure can be achieved by allogeneic hematopoietic stem cell transplantation.

X-Linked Lymphoproliferative Disease (XLP1 and XLP2)

• XLP1 is characterized by mutations in the SH2D1A gene that encodes the SLAM-associated protein (SAP) involved in T and NK cell signaling and impair T and NK cell cytotoxicity capability.

• XLP2 is characterized by mutations in the XIAP gene and also lack NK and T cells.

Clinical and Laboratory Features

• Fulminant Epstein-Barr virus (EBV) infectious mononucleosis in 60 percent of cases.

• Hypogammaglobulinemia can follow primary EBV infection.

• EBV-related lymphoma in 30 percent of cases (esp. Burkitt lymphoma).

• Flow cytometry can be used to detect lack of SAP protein expression in circulating T and NK lymphocytes.

Treatment and Prognosis

• If untreated, approximately 70 percent of patients die within 10 years of onset.

• Mortality rate is higher (approaches 100%) in patients who have fulminant infectious mononucleosis.

• Treatment of choice is allogeneic hematopoietic stem cell transplantation when performed early in life before EBV infection.

• Nonmyeloablative allogeneic hematopoietic stem cell transplantation may be useful after EBV infection supervenes in patients with severe organ toxicity.

• Use of anti-CD20 monoclonal antibody can reduce EBV load and improve clinical status.

• Igs can be used to reduce the risk of infections in patients with hypogammaglobulinemia.

• Anti-tumor necrosis factor-α therapy or etoposide may be useful in patients with active EBV infection and a severe systemic inflammatory response.

Chediak-Higashi Syndrome

• Autosomal recessive disorder characterized by immune dysregulation with impaired cellular cytotoxicity, partial oculocutaneous albinism, platelet functional abnormalities, and neurologic involvement (see Chap. 33).

• Caused by mutations in the LYST gene the encoded protein of which contributes to sorting lysosomal proteins and fusing lysosomal vesicles.

• Common features include bruises and bacterial and viral infections.

• "Accelerated phase" of syndrome is characterized by high fever, hepatosplenomegaly, coagulation abnormalities, increase of liver enzymes and bilirubin (with possible jaundice), edema, and neurologic symptoms.

• Morphologic hallmark of disease: abnormally large granules in lymphocytes, neutrophils, platelets, melanocytes, and neurons.

• Examination of the blood film permits detection of the enlarged and abnormal granules in blood cells.

• Allogeneic hematopoietic stem cell transplantation can ameliorate immune and cellular abnormalities but does not prevent progressive neurologic involvement.

Griscelli Syndrome Type 2 (GS2)

• Autosomal recessive syndrome characterized by immunodeficiency and hypopigmentation. Variable degree of neurologic involvement is also present.

• Caused by mutations in the RAB27A gene, which encodes a guanosine triphosphate involved in intracellular transport of granules.

• Susceptible to pyogenic infections.

• "Accelerated phase" of syndrome is characterized by high fever, hepatosplenomegaly, neutropenia, and thrombocytopenia.

• Hypopigmentation is a result of large clumps of melanin in the hair shafts.

• Allogeneic hematopoietic stem cell transplantation can ameliorate the manifestations of the disorder.

Hermansky-Pudlak Type 2

• Caused by mutations of the AP3B1 gene, which encodes a protein that regulates sorting of lysosomal membrane proteins to the granules.

• Characterized by oculocutaneous albinism, bleeding tendency, recurrent infections, and moderate to severe neutropenia (see Chaps. 32 and 33).

• The bleeding tendency results from decreased platelet dense granules and faulty degranulation.

• Missorting of tyrosinase in melanocytes accounts for albinism.

• Bony anomalies (with dysplastic acetabulae), facial dysmorphism and development of pulmonary fibrosis are features.

• Control of infections is important to manage disease.

• G-CSF may improve chronic neutropenia.

Toll-Like Receptor (TLR)-Signaling Defects

• Deficiencies of IRAK-4. MyD88, TLR3, and UNC-93B proteins occur.

• Two phenotypes have been identified.

• TLR-signaling defects result in increased susceptibility to herpes simplex virus encephalitis (HSE) associated with mutations have been identified in the UNC-93B1 gene.

• TLR-signaling defects with increased susceptibility to recurrent, invasive pyogenic infections associated with mutations in IRAK-4 and MyD88.

• Diagnosis can be suspected based on the history of infection associated with poor inflammatory responses.

• Defects involving other microbial pattern-recognition signaling pathways with increased susceptibility to fungal infections.

Mendelian Susceptibility to Mycobacterial Disease

• Defects occur along the JAK-STAT4 pathway.

• IL-12p40 deficiency is characterized increased risk of severe infections due to Calmette-Guerin and environmental mycobacteria.

  — Only genetically-determined cytokine deficiency known in humans.

  — Treatment with antibiotics and interferon-γ.

• IL-12Rβ₁ deficiency is characterized by infections with mycobacteria of low virulence and Salmonella species.

  — Treatment with antibiotics and IFN-γ is effective and prognosis is good.

• IFN- γR1 and IFN- γR2 deficiencies produce variable susceptibilities.

  — Persons with complete deficiencies develop severe infections with mycobacteria early in life with lack of granuloma formation.

  — Complete STAT1 deficiency causes increased susceptibility to mycobacterial disease with a severe clinical course.

  — Dominant partial STAT1 deficiency is caused by a heterozygous mutation that allows formation of the IFN-α/β-dependent ISGF3 transcription factor, but abrogates expression of the γ-activating factor, composed of STAT1 homodimers. Affected individuals have either a mild clinical course, characterized by selective susceptibility to mycobacterial infections or are asymptomatic.

• Mutations in the classic pathways (C1q, C1r/C1s, C4, C2, and C3) result in pyogenic infections and autoimmune diseases.

• Mutations in the alternative pathway (factors B, D, h, properidin) result in meningococcal and pneumococcal sepsis.

• Mutations in the terminal complement components (C5-C9) result in increased susceptibility to Neisseria species infections.

• Mutations in C1 esterase inhibitor (C1-INH) gene is the cause of hereditary angioedema.

• Diagnosis of a deficiency assesses the hemolytic function of CH50 and AH50.

  — If CH50 absent and AH50 normal, may be a C1, C4, or C2 defect.

  — If CH50 normal and AH50 absent, may be a properdin or factor D defect.

  — If CH50 and AH50 abnormal, may be a C3 to C8 defect.

  — CH50 usually at half normal in the case of C9 defects.

• Treatment is determined by the type of deficiency.