Skin Diseases in Primary Immunodeficiencies
Primary immunodeficiencies are estimated to affect about 255,000 people in the United States, with at least 120 distinct primary immunodeficiencies described in the literature. They can generally be classified according to which arm of the immune system the defect targets (i.e., innate versus adaptive, humoral versus cellular). All of the primary immunodeficiencies are predisposed to recurrent and potentially severe infections but may also present with characteristic findings, which are not infectious in nature. The location of the defect within the immune system often correlates to the clinical presentation. However, many defects affect multiple functional components of immunity; hence considerable overlap exists.
KeywordsImmunodeficiency Innate Adaptive Humoral Cellular Complement
Primary immunodeficiencies are estimated to affect about 255,000 people in the United States, with at least 120 distinct primary immunodeficiencies described in the literature. They can generally be classified according to which arm of the immune system the defect targets (i.e., innate versus adaptive, humoral versus cellular). All of the primary immunodeficiencies are predisposed to recurrent and potentially severe infections but may also present with characteristic findings, which are not infectious in nature. The location of the defect within the immune system often correlates to the clinical presentation. However many defects affect multiple functional components of immunity; hence considerable overlap exists.
2.1 Innate Immunity
Primary immunodeficiencies with characteristic dermatologic findings
Leukocyte adhesion deficiency
Delayed separation of the umbilical cord
Chronic granulomatous disease
GI and GU granulomas
Autoimmune disease (i.e., lupus erythematosus)
Absence of lymph nodes
Dysmorphic facies (low-set ears, shortened philtrum, micrognathia)
Chronic mucocutaneous candidiasis
Diffuse eczema, retention of primary teeth, scoliosis, joint hyperextensibility, coarse facies
CD40 ligand deficiency
18.104.22.168 WHIM Syndrome
The syndrome of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) is a rare disease of the innate immune system caused by mutations in the gene encoding the chemokine receptor type 4 (CXCR4). CXCR4 is necessary for the development of myeloid cells and B lymphocytes. In affected individuals, mature myeloid cells are present in large quantities in the bone marrow but fail to exit. This results in a peripheral neutropenia, termed myelokathexis . The retained neutrophils have a characteristic apoptotic appearance, while the morphology of the other cells in the marrow remains normal . Lymphopenia, specifically of B lymphocytes, is another frequent finding, which may lead to mild to moderate hypogammaglobulinemia . The inheritance pattern is autosomal dominant, but sporadic and autosomal recessive cases have also been described .
Bacterial infections associated with WHIM syndrome are commonly caused by encapsulated organisms, such as Haemophilus influenzae, Staphylococcus aureus, and Proteus mirabilis. Frequent sites of infection are the aerodigestive tract (otitis media, sinusitis, and periodontal disease), lungs (pneumonia), and skin (cellulitis) . More severe infections, such as deep soft tissue infections and meningitis, have also been described, but most of the bacterial infections tend to have a milder course . Patients with WHIM syndrome may have other congenital anomalies, i ncluding tetralogy of Fallot, double aortic arch, radius hypoplasia, phalangeal agenesis, or other skeletal abnormalities .
Diagnosis of WHIM syndrome should be considered in all patients with a history of immunodeficiency and warts, particularly if neutropenia can be demonstrated . Bone marrow biopsy is helpful to establish the diag nosis . Obtaining the family history is also important, as younger patients may not yet have acquired HPV infection . Early diagnosis is essential in order to improve prognosis through the use of antibiotics, vaccinations, and cancer surveillance .
Various treatments have been reported to target the immune deficiency, including IVIG and GM-CSF. However, these treatments are expensive and nonspecific. Plerixafor (1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]), a CXCR4 antagonist, may also be a promising new treatment for WHIM syn drome, as it increases the release of the mature neutrophils from the bone marrow .
22.214.171.124 Leukocyte Adhesion Deficiency
The leukocyte adhesion deficiency (LAD) syndromes consist of three autosomal recessive disorders that impair the ability of leukocytes to adhere to blood vessel walls, thus preventing migration to sites of tissue infection and injury [5, 6]. The disorders are clinically discrete, but they all result in recurrent infections and leukocytosis . LAD-I is caused by a mutation in the gene encoding CD18, the β2 integrin found on leukocytes, which is responsible for high-affinity binding to intercellular adhesion molecule (ICAM-1 and ICAM-2) expressed on endothelial cells during leukocyte r ecruitment and extravasation [5, 8]. Less common is LAD-II, caused by a mutation in the gene encoding a GDP-fucose transporter necessary for the production of selectin ligands, which are needed for leukocyte rolling and tethering during the initial steps of recruitment [5, 8]. More recently, LAD-III was discovered, which is caused by mutations in the FERMT3 gene which encodes Kindlin-3, a protein involved in integrin activation .
Clinical features of LAD-I and LA D-III include recurrent severe bacterial and fungal infections localized to the skin and mucosal surfaces . The most common finding is gingivitis with periodontitis, leading to the loss of teeth . A frequent presenting symptom of LAD-I is delayed separation of the umbilical cord, often accompanied by omphalitis (infection of the umbilical cord stump) . Minor infections of the skin may quickly progress to necrotizing ulcerations with the appearance of pyoderma gangrenosum . The hallmark of LAD-I and LAD-III is the absence of pus formation i n infections caused by pyogenic bacteria. Greater than 75% of patients with severe LAD-I die within the first 5 years of life; nearly half of patients with moderate disease live to 30 years of age . These patients continue to experience recurrent otitis media, pneumonia, and cutaneous infections throughout life . LAD-III is also characterized by a bleeding tendency similar to Glanzmann’s thrombasthenia, increased bone density, and hepatosplenomegaly .
Patients with LAD-II likewise experience recurrent cutaneous infections. However, the degree of the infections is less severe and does not result in necrotic lesions. Furthermore, there is no delayed separation of the umbilical stump . Additional features include growth retardation, mental retardation, microcephaly, and coarse facies [5, 6].
The diagnosis of LAD should be suspected in any infant with recurrent non-purulent infections, as well as delayed umbilical cord separation. Diagnosis is confirmed by flow cytometry analysis . Antibiotics are the cornerstone of treatment for patients with LAD. Stem cell transplant is curative in LAD-I and LAD-III and is the preferred treatment for patients with severe LAD-I. Patients with LAD-III may require blood transfusions, while patients with LAD-II may benefit from oral supplementation with fucose .
126.96.36.199 Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) results from inherited mutations in genes encoding subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase is required to produce reactive oxygen species necessary for the intracellular killing of bacteria and fungi by phagocytic cells of the innate immune system [11, 12]. The most common subgroup of the disorder is X-linked CGD, which is caused by mutations in the gene encoding gp91phox. X-linked CGD affects mostly males, although female carriers can also display a C GD phenotype. Less common is autosomal recessive CGD, which is caused by mutations in the genes encoding p22phox and p47phox. These patients often have a less severe phenotype and present later in life than patients with X-linked CGD .
The primary manifestations of CGD include infections of the skin, lungs, lymph nodes, and liver . Infections are most frequently caused by catalase-positive organisms . In North America, the most common organisms to infect patients with CGD are Staphylococcus aureus, Nocardia spp., Burkholderia cepacia, Serratia marcescens, and Aspergillus species [6, 12]. The most common form of infection in patients with CGD is pneumonia . Recurrent bacterial skin infections include cellulitis, paronychia, impetigo, suppurative lymphadenopathy, abscesses, and pyoderma [13, 14]. Purulent reactions may occur around minor skin lesions or abrasions, and abscesses may develop at sites of immunizations [6, 13]. Scarring can occur as a result of slow healing and tissue necrosis . Less common skin manifestations of CGD include discoid lupus erythematosus, aphthous stoma titis, Raynaud’s phenomenon, arcuate dermal erythema, and Jessner’s lymphocytic infiltrate [6, 14]. These manifestations are more commonly observed in female carriers of X-linked CGD [6, 13].
In addition to recurrent infections, patients with CGD are predisposed to developing granulomas in the gastrointestinal and genitourinary tracts. Gastrointestinal involvement may mimic Crohn’s disease or lead to gastric outlet obstruction. Genitourinary manifestations include ureteral obstruction and urinary tract infections .
CGD can be diagnosed by direct meas urement of superoxide production, ferricytochrome c reduction, chemiluminescence, nitroblue tetrazolium (NBT) reduction, or dihydrorhodamine oxidation (DHR) . The NBT reduction assay is commonly used as a screening test. DHR oxidation or ferricytochrome c reduction assays can be used to verify the diagnosis [6, 12].
Long-term treatment for CGD is largely based on antibiotics and antifungals, as well as interferon (IFN)-γ. Chronic prophylaxis with trimethoprim-sulfamethoxazole reduces the occurrence of bacterial infections witho ut increasing the incidence of serious fungal infections. Aspergillus spp. infections can be reduced by the use of itraconazole prophylaxis. Additionally, administration of IFN-γ reduces the amount and severity of infections in patients with CGD, regardless of inheritance pattern, sex, or use of antibiotics [6, 12]. Patients with acute infections should be treated empirically with broad-spectrum antibiotics that cover S. aureus and Gram-negative bacteria until culture results are available . For deep tissue infection, surgical interventions such as debridement, irrigation, and drainage may be necessary . Bone marrow transplantation provides a potential cure for CGD; however, there is similar survival without bone marrow transplant .
188.8.131.52 Chédiak–Higashi Syndrome
Chédiak–Higashi syndrome (CHS) is an autosomal recessive syndrome caused by a mutation in gene encoding the CHS1/LYST protein, which is involved in intracellular vesicle formation. Subsequently, lysosomes and phagosomes fail to fuse properly [15, 16]. Cells of patients with CHS have characteristically enlarged granules containing lysosomes, melanosomes, cytolytic granules, and platelet-dense bodies . Several cell types are affected, including melanocytes, phagocytes, and neurons, which is reflected by the phenotypic characteristics of patients with CHS . Patients with CHS classically present with severe immunodeficiency with frequent bacterial infections, variable oculocutaneous al binism, bleeding tendencies, lymphoproliferation, and neurologic defects [15, 17, 18].
Patients with CHS suffer from recurrent, and sometimes fatal, pyogenic infections due to impairments in T cell function, NK cell function, and neutrophil and monocyte migration. The most frequent sites of infection in patients with CHS are the skin and respiratory tract . Infections are predominantly caused by Staphylococcus aureus, β-hemolytic streptococci, and fungi . Skin infections are typically superfici al pyodermas . Long-term and prophylactic antibiotic therapy is used for infection control [15, 18]. Patients who survive the early infections progress to the development of an uncontrolled lymphocyte and macrophage activation and proliferation, termed the “accelerated phase.” As a result, lymphocytic infiltrates collect in the major organs of the body, leading to multiorgan failure [15, 17, 18]. Death usually results from infection or hemorrhage [6, 18].
In addition to frequent infections, patients with CHS exhibit characteristic cutaneous findings, with varying degrees of hypopigmentation of the skin, hair, and eyes. The skin may take on a bronze to slate-gray tint with hypopigmen ted macules in sun-exposed sites . Alterations of ocular pigmentation may result in photosensitivity, nystagmus, and strabismus . Hair color can range from gray to white with a metallic sheen, and clumping of melanin in the hair shaft is characteristic [15, 18]. Platelets in CHS patients are found in normal quantities, but they are dysfunctional in the process of coagulation. This impairment in coagulation leads to bruising, mucosal bleeding, and petechiae .
The treatment of choice for CHS is bone marrow transplantation, which is effective for the hematologic and immunologic consequences of the disease. However, patients who live long enough will eventually develop neurologic defi ciencies. These include weakness, sensory deficits, ataxia, and progressive neurodegeneration [15, 17].
2.1.2 Toll-Like Receptors
The innate immune system has the ability to recognize invading pathogens through pattern recognition receptors (PRRs) on host cells. Toll-like receptors (TLRs) are one class of PRRs that signal a cascade in response to microbial components, leading to the transcription and translation of genes involved in the inflammatory and immune responses . TLR-4 is perhaps the most complex and versatile TLR so far elucidated, and to date, three major targets of mutations in the TLR4 signaling pathway have been identified in humans. These include mutations within TLR4 itself, as well as mutations in interleukin-1 receptor-associated kinase 4 (IRAK4) and NF-κB essential modulator (NEMO) . TLR4 mutations are positively associated with increased susceptibility to Gram-negative bacteremia and septic shock . There is als o a higher association with severe RSV disease in children, as well as increased risk of prematurity, which may be related to intrauterine infections [22, 23]. Interestingly, TLR4 mutations seem to be protective against inflammatory diseases such as atherogenesis and rheumatoid arthritis, reflecting the immune systems’ precarious balancing act between response to infection and over-exuberant inflammatory response .
184.108.40.206 IRAK4 Deficiency
Interleukin-1 (IL-1) is an essential pro-inflammatory cytokine of the innate immune system that is highly induced by the classical TLR signaling cascade. IRAK-4 is one of the necessary molecules involved in the TLR to IL-1 expression signaling pathway, and all human TLRs other than TLR3 use IRAK4 in their signaling [25, 26]. Patients with IRAK4 deficiency show increased susceptibility to both invasive and noninvasive bacterial infections. Invasive infections include meningitis, sepsis, arthritis, osteomyelitis, and deep organ abscess formation. Noninvasive bacterial infections most commonly involve the skin and include recurrent cellulitis , furunculosis, and folliculitis. Patients may also present with adenitis, omphalitis, maxillary sinusitis, tonsillar abscesses, recurrent otitis media, and orbital cellulitis or endophthalmitis. The most common pathogens that cause infections in these patients are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Infections tend to be acute in nature with weak inflammatory signs that appear late. Thus, it is critical to begin empiric intravenous antibiotic treatment as soon as infection is suspected. Of note, patients with IRAK4 deficiency do not show increased susceptibility to common viruses, parasites, and fungi. Patients typically experience their first bacterial infec tion before the age of 2 years, with some patients presenting in the neonatal period. Interestingly, IRAK4-deficient patients tend to suffer from fewer infections after the age of 14 years . Patients should receive prophyl actic antibiotics and be immunized against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. IgG injections until the age of 10 years may also be beneficial .
220.127.116.11 X-Linked Recessive Anhidrotic Ectodermal Dysplasia with Immunodeficiency
NEMO is a regulatory subunit of the IκB kinase (IKK) complex, which is involved in the degradation of IκBs and subsequent activation of NF-κB. Hypomorphic mutations in NEMO lead to X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XR-EDA-ID) . Patients with XR-EDA-ID display anhidrotic ectodermal dysplasia (EDA), which is marked by partial or total absence of teeth, conical teeth, dry skin, and sparse hair. These patients also present with severe bacterial infections, usually caused by encapsulated organisms (Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae). There have also been several reports of patients with mycobacterial disease and rare cases of patients with fungal or viral disease. The presentation and severity of disease vary by patient. However, patients typically pre sent early in childhood with multiple and severe infections of the respiratory and gastrointestinal tracts, skin, soft tissues, and bones. Meningitis and septicemia may also result. Patients frequently display poor inflammatory responses to the infections. All patients with XR-EDA-ID thus far show a decreased or absent amount of polysaccharide-specific antibodies . Patients with XR-EDA-ID should receive antibiotic prophylaxis and intravenous or subcutaneous IgG if B cell function is impaired. Those with functional B cell activity should be immunized against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae . Empiric antibiotic therapy should be initiated rapidly if infection is suspected, as patients may not show robust clinical signs of infection [20, 28].
2.1.3 Complement Deficiency
The complement system is an important part of the innate immune system and also acts as a bridge to adaptive immunity. It is composed of more than 30 components, both soluble and membrane bound, that act through an enzymatically triggered cascade on the surface of pathogens [16, 29]. Complement components can be activated through three pathways (classical, mannose-binding lectin, and alternative), but they converge in a final common pathway with the generation of various effector proteins . The complement system plays an important role in protection against bacterial pathogens, specifically Gram-negative and encapsulated organisms, through cell lysis and opsonization leading to phagocytosis . In addition to immunity, complement plays a role in modulating inflammatory responses, gene regulation, and recognition of self .
Various deficiencies of complement components are associated with greater susceptibility to bacterial infections and recurrent bacterial infections, particularly with encapsulated organisms . Because of the large number of proteins and pathways involved, there is considerable variation within the spectrum of infections . Common causes of infection include Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae [29, 31].
Complement deficiencies are also associated with several autoimmune disorders, including systemic lupus erythematosus (SLE), lupus-like syndromes, and glomerulonephritis . Patients with C1q deficiency have the highest incidence of autoimmune disease with the most severe manifestations . Compared to other causes of SLE, symptoms occur at a younger age, and the male-to-female ratio is equal . C2 deficiency is the most common deficiency of complement and is associated with a lower prevalence of SLE with a female predominance . Patients with SLE and lupus-like syndromes linked to complement deficiencies tend to have a high prevalence of cutaneous findings, including chronic cutaneous lupus erythematosus and subacute cutaneous lupus erythematosus, with photosensitivity . Interestingly, SLE associated with complement deficiency is marked by higher levels of anti-Ro antibodies and low levels of anti-nuclear antibodies [31, 32]. Antimalarials remain the treatment of choice with use of thalidomide when there is resistance to antimalarials .
18.104.22.168 Hereditary Angioedema
Hereditary angioedema is an autosomal dominant condition caused by a deficiency of C1-inhibitor, which leads to increased production of bradykinin . Hereditary angioedema presents as recurring attacks of localized, circumscribed swelling of the skin and mucous membranes. There may also be an erythema marginatum-like cutaneous presentation . Unlike typical urticaria, the lesions do not itch and are not painful [29, 32]. The condition can be life-threatening if it occurs in the upper airway, in which case the patient should be admitted to an intensive care unit . It may also cause abdominal pain and watery diarrhea if it occurs in t he gastrointestinal tract [29, 32]. Attacks may occur in response to trauma, menstruation, oral contraceptives, stressful situations, and other insults . Screening is based on low levels of C4, while low C1-inhibitor activity confirms the diagnosis . Purified C1-inhibitor is available for the tr eatment of severe cases .
2.2 Adaptive Immunity
The humoral arm of the adaptive immune system relies on B cell response and antibody production. Deficiencies in this arm of the immune system lead to increased susceptibility to multiple infections, most notably with encapsulated bacteria, parasites, enteroviruses, and papillomaviruses. Affected children may also demonstrate poor growth, recurrent sinopulmonary and GI infections, as well as the development of autoimmune disorders. Atopic-like dermatitis and noninfectious granulomas are also features of many of these diseases.
22.214.171.124 X-Linked Agammaglobulinemia
Agammaglobulinemia , also called Bruton syndrome, is a rare hereditary immunologic condition that usually appears between 4 and 12 months, since neonates receive adequate immunoglobulins for protection from their mother in early stages of infancy. Inheritance is X-linked recessive in 90% of cases and autosomal recessive in the remaining 10% . Serum levels show a decrease in all levels of immunoglobulins, which are virtually absent although IgG may be present in minimal quantities . There is a profound decrease in B cells, and plasma cells are absent from the bone marrow, spleen, lymph node, and connective tissues. Germinal centers are absent from the lymph nodes and spleen. Over 500 distinct mutations have been ident ified in the BTK (Bruton tyrosine kinase) gene, which is essential for the appropriate development of B lymphocytes and pre-B cell receptor signaling .
Patients present with recurrent bacterial infections of the skin, joints, central nervous system, gastrointestinal, and upper/lower respiratory tracts in the first few years of life. Classic infectious organisms include Staphylococcus, Streptococcus, Pneumococcus, Pseudomonas, and Haemophilus spp. Other systemic manifestations include lymphomas in approximately 5% of patients, rheumatoid-like arthritis, hepatitis B, rotavirus, and enteroviral infections. A characteristic feature is the absence of palpable lymph nodes. Dermatologic characteristics include eczematous atopic-like dermatitis, noninfectious granulomas, papular dermatitis due to lymphohistiocytic infiltration, and dermatomyositis-like disorder associated with chronic echoviral meningoencephalitis . The skin is the most common site of infection for these patients, with infections ranging from furuncles and cellulitis to ecthyma gangrenosum; recurrent staphylococcal infections may be prominent .
Management of this condition with high-dose gam ma globulin has permitted survival into adulthood for many patients. The lack of IgA leads to problems from chronic sinopulmonary infections, and chronic lung disease affects more than three quarters of patients over the age of 20 .
126.96.36.199 Selective IgA Deficiency
Selective or isolated IgA deficiency is the most common immunodeficiency state occurring in approximately 1:500 persons with an equal gender distribution. The immunodeficiency is usually asymptomatic with clinical symptoms manifesting in only 10–15% of individuals. Inheritance is autosomal dominant, autosomal recessive, or sporadic. The genetic cause is unknown; however, a few cases have been found to have a mutation in the TNF receptor family member, TACI .
In symptomatic patients, clinical manifestations include recurrent gastrointestinal and sinopulmonary infections in half of affected patients and autoimmune disorders in approximately one quarter. Dermatologic manifestations include eczematous dermatitis, mucocutaneous candidiasis, and cutaneous autoimmune conditions such as vitiligo, systemic lupus erythematosus, dermatomyositis, scleroderma, dermatitis herpetiformis, and lipodystrophia centrifugalis abdominalis . Patients have a tend ency to develop other systemic conditions such as inflammatory bowel disease, rheumatoid arthritis, celiac disease, Sjögren’s syndrome, asthma, vasculitis, and allergic reactions, such as anaphylaxis . There are an increased risk of malignancy and a development of common variable immunodeficiency in these patients, so long-term monitoring is crucial . Specific medications that appear to induce sele ctive IgA deficiency are cyclosporine, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, phenytoin, and sulfasalazine .
188.8.131.52 Selective IgM Deficiency
Low levels of IgM and normal amount of B cells characterize selective IgM deficiency. Infectious manifestations include recurrent ba cterial infections, and systemic manifestations include autoimmune diseases. Cutaneous manifestations range from extensive verrucae and eczematous atopic-like dermatitis to systemic lupus erythematosus. Management includes IVIg in patients with defective antigen-specific IgG responses and prophylactic/therapeutic antibiotics as appropriate; fresh frozen plasma can be considered for severe infections. IgM cannot be replaced, as it is not a significant component of therapeutic IVIg .
184.108.40.206 Common Variable Immunodeficiency
Common variable immunodeficiency (CVID), also called acquired hypogammaglobulinemia, is a heterogeneous group of disorders with defects in both humoral and cell-mediated immunities. It is the most common immunodeficiency syndrome after IgA deficiency and has variable severity of autoimmune and infectious complications . Patients have low levels of IgA and IgG, and approximately half also have low levels of IgM. The disorder may manifest in childhood or adulthood, with the average age of onset at 30 years old. The genetic defect is unknown .
Treatment options include replacement of hypogammaglobulinemia with IVIg or subcutaneous immunoglobulins to help with infections. Noninfectious granulomas are typically treated with corticosteroids (topical, intralesional, or systemic) or TNF-α inhibitors such as infliximab and etanercept in recalcitrant, steroid-refractory cases .
220.127.116.11 Class-Switch Recombination Defects
Class-switch recombination defects (formerly known as immunodeficiency with hyper-IgM or hyper-IgM syndromes) usually have an X-linked pattern, although autosomal recessive patterns also exist . Patients have high levels of IgM and isohemagglutinins and low levels of IgA, IgE, and IgG . B cells are at normal levels. The X-linked subtype is characterized by a defect in the CD40 ligand on T cells. The autosomal recessive subtypes are characterized by a defect in CD40 on B cells, activation-induced cytidi ne deaminase (AICDA), or uracil-DNA glycosylase (UNG) [50, 51].
Clinical manifestations include recurrent gastrointestinal and sinopulmonary infections with pyogenic bacteria and opportunistic organisms, e.g., Pneumocystis . Cutaneous manifestations in the X-linked form and the autosomal recessive form with CD40 malfunction include pyodermas, extensive verrucae, oral and anogenital ulcerations, noninfectious granulomas, and autoimmune conditions such as systemic lupus erythematosus . Systemic manifestations in these patients also include neutropenia, small lymph nodes, and autoimmune diseases, particularly hemolytic anemia and thyroiditis. Patients with AICDA and UNG defects typically manifest with pyodermas and similar infectious and systemic characteristics as the other immunodeficiencies with class-switch recombination defects but with massive lymphadenopathy with germinal centers, hepatosplenomegaly, and no opportun istic infections .
18.104.22.168 Thymoma with Immunodeficiency
Thymoma with immunodeficiency occurs in adults in whom benign thymoma and severe hypogammaglobulinemia appear nearly simultaneously. It is primarily a disorder of humoral immunity and antibody deficiency, which manifests as profound deficiency of B and pre-B cells .
Pure red cell aplasia and myelodysplasia can occur . Patients are at risk for fatal, opportunistic lung infections with Pneumocystis carinii and fungal organisms and have increased susceptibility to viral and bacterial infections . Thymectomy does not prevent development of lymphoreticular or infec tious complications. Supportive treatment with GM-CSF, IVIg, and transfusions may be necessary .
22.214.171.124 Transient Hypogammaglobulinemia of Infancy
Transient hypogammaglobulinemia of infancy (THI) is a common primary immunodeficiency disorder affecting infants and young children. THI is characterized by decreased serum IgG with or without decreased IgA and IgM levels with normal antibody responses to protein immunizations . The prevalence is estimated to be 0.6–1.1 cases per 1000 live births with a male preponderance of 2:1. There is variation per geographic region; for example, in Japan, THI comprises 18.5% of primary immunodeficiencies. Patients frequently have a history of THI and other immunodeficiencies. It is a congenital disorder that manifests by 6 months of age, though most children outgrow it by 2 years of age when serum immunoglobulin concentrations of IgG, IgA, and IgM and antibody responses normalize; however, some children may take longer to outgrow the condition .
Patients may be asymptomatic. Clinical manifestations include frequent and recurrent otitis media, sinusitis, and pulmonary infections . Life-threatening infections with encapsulated bacteria are uncommon but may occur. Allergies and autoimmune manifestations (e.g., hemolytic anemia and neutropenia) h ave been reported . Persistent oral candidiasis, severe varicella, and sepsis are infrequent.
Management is conservative and depends on the severity of complications and response to treatment. Appropriate antibiotics for infections and prophylactic use are common. A trial of IVIg is indicated in patients who develop severe life-threatening or recurrent infections despite appropriate antibiotic coverage, and past results have shown a significant decrease in infections. Subcutaneous gamma globulin is available as an alternative to IVIg .
2.2.2 Cellular (T Cell) Deficiencies
Disorders of the cellular arm of the adaptive immune system affect either T or B cell lineages or, very rarely, a combination of both B and T cells. They demonstrate an increased susceptibility to a number of infections, including those caused by Mycobacterium spp., Pneumocystis carinii, Candida albicans, and Epstein-Barr virus.
126.96.36.199 DiGeorge Syndrome
DiGeorge syndrome , also known as congenital thymic hypoplasia and velocardiofacial syndrome, is an autosomal dominant disorder due to hemizygous deletion of 22q11 in 50% of cases and, more rarely, due to deletions in 10p. Many cases are actually sporadic.
Most patients have congenital anomalies and minor thymic anomalies and present with congenital heart disease or hypocalcemia. Th e syndrome includes absent parathyroid glands and aortic anomalies. The most common causes of death are aortic and cardiac defects. Characteristic facies include micrognathia, hypertelorism, shortened philtrum, and notched, low-set ears.
“Complete DiGeorge syndrome” refers to an absent thymus along with these congenital malformations. There is absent or decreased cell-mediated immunity, and few T lymphocytes are found in peripheral tissues or blood. In contrast, “atypical DiGeorge syndrome” refers to eczematous dermatitis, lymphadenopathy, and oligoclonal T cell proliferation. The eczema ranges from atopic dermatitis, seborrheic dermatitis, or erythroderma . Opportunistic infections are common in spite of normal immunoglobulin levels, and maternally derived GVHD may occur in p atients with the “complete” form. Thymic transplantation is the treatment of choice for complete DiGeorge syndrome .
188.8.131.52 Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency disorder consisting of the classic triad: recurrent sinopulmonary infections, chronic eczematous dermatitis, and bleeding tendency attributed to microthrombocytopenia and platelet dysfunction . There are elevated levels of IgA and IgE, yet levels of IgG and IgM are normal. T cells decline in amount and function. WAS is caused by loss-of-function mutations in the WASP gene, which is universally expressed in h ematopoietic cell lineages . The WASP gene is important in reorganization of the cytoskeleton in these cells regarding polarization and migration in response to external physiologic stimuli, accounting for its protean clinical features . Most patients with this syndrome are male, and the incidence is 1:250,000 live births in European populations. The disorder is less common in Asians, blacks, and women; however, occasionally females are affected in the setting of homozygosity for a mild mutation or nonrandom X-chromosome inactivation.
The first clinical signs are petec hiae and ecchymoses due to platelet dysfunction and thrombocytopenia from birth. Platelet abnormalities represent the most common feature, while the classic triad develops in a minority of patients. Spontaneous bleeding, melena, hematuria, epistaxis, hematemesis, bloody diarrhea, and intracranial hemorrhage can also be observed . The onset of bacterial infections occurs early on, while development of viral and Pneumocystis infections occur later. Atopic dermatitis usually develops during the first few months of life and commonly involves the face, scalp, and flexural areas, although involvement may be widespread with progressive lichenification .
Secondary bacterial infections, eczema h erpeticum, and molluscum contagiosum commonly occur. Recurrent bacterial infections (particularly encapsulated organisms) including pneumonia, sinusitis, meningitis, otitis media, and septicemia begin during the first 3 months of life, which coincides with decreasing levels of maternal antibodies. With advancing age, there is increased susceptibility to viral infections such as herpes simplex virus, Pneumocystis carinii, and human papillomavirus . Lymphadenopathy, hepatosplenomegaly, and autoimmune diseases often develop. The majori ty of children develop at least one autoimmune disease, most commonly cutaneous small vessel vasculitis, arthritis, inflammatory bowel disease, cerebral vasculitis, and autoimmune hemoglobinopathies . Lymphadenopathy and hepatosplenomegaly are additional features with development of lymphoma in up to 25% of patients older than 20 years . The most common lymphoma is the non-Hodgkin type such as diffuse large B cell with brain and extranodal involvement.
Management includes antibiotics, platelet transfusions, and IVIg if necessary to prevent infections or improve dermatitis . Hema topoietic stem cell transplant is the treatment of choice. If performed early, the stem cell transplant provides complete reversal of immune and platelet dysfunction and improvement or resolution of the eczematous dermatitis. Patients with a matched related donor transplant have survival rates at 7 years of age that exceed 80%, in contrast to an untreated life expectancy of about 15 years, with death resulting from bleeding, infection, or lymphoma . Topical steroids hel p improve the eczematous dermatitis. Splenectomy is often performed to reduce bleeding complications; however, this leads to increased risk of sepsis with encapsulated organisms and thus is not routinely recommended. Platelet transfusions are given as required to control bleeding or in the setting of surgical procedures. Immunosuppressants and/or rituximab may be used to manage autoimmune complications . Prophylactic antibiotics and antivirals have been used as appropriate to decrease the risk of fatal infections. Gene therapy using autologous CD34 cells has been performed with success . Genetic counseling is paramount for female relatives of the patient, as female carriers can be detected, and prenatal diagnosis th rough direct mutational analysis is possible .
184.108.40.206 Chronic Mucocutaneous Candidiasis
Chronic mucocutaneous candidiasis (CMC) encompasses a heterogeneous group of disorders characterized by progressive and recurrent Candida albicans infections of the mucosa, skin, and nails. The condition usually manifests by 6 years of age, and its onset in adulthood may indicate an occult thymoma . Cases may be sporadic or inherited, which may be associated with endocrinopathy. Patients with APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome) often have a family history of similarly affected relatives .
Clinical severity ranges from rec urrent, recalcitrant thrush to a few scaly plaques and thickened, dystrophic nails that may be associated with paronychia to hyperkeratotic, crusted granulomatous plaques . Hyperkeratotic, crusted granulomatous plaques are more frequent on the scalp, periorificial, and intertriginous areas. Recurrent scalp infections may result in cicatricial alopecia. Mucosal involvement ranges from diffuse oral lesions, perleche, and lip fissures to chronic lesions on esophageal, genital, and laryngeal mucosae that can form strictures. Approxi mately 80% of patients with childhood onset CMC develop severe infections with organisms other than Candida albicans, including bacterial and/or dermatophyte infections . Systemic candidiasis is rare.
Patients typically do not respond well to topical medications; thus systemic antifungal agents such as fluconazole, ketoconazole, terbinafine, and itraconazole are necessary to control their disease . Courses are typically long-term, repeated, and given at higher doses than typical. Cimetidine has been reported to restore deficient cell-mediated immunity at a dose of 300 mg four times daily. Bone marrow transplant, leukocyte infusions, and fetal thymus grafts have been used in patients with severe im munodeficiency. Transfer factor administration may be beneficial to some patients with defective cell-mediated immunity .
220.127.116.11 Hyper-IgE Syndrome
Hyperimmunoglobulinemia E syndrome (HIES) comes in two varieties—autosomal dominant or autosomal recessive—which are clinically different . The autosomal dominant form is caused by a mutation in STAT3, while the autosomal recessive type was recently determined to be caused by biallelic mutations in the dedicator of cytokinesis 8 protein (DOCK8) gene . The autosomal dominant form is also known as “Job’s syndrome” and is characterized by the classic triad of high serum IgE, recurrent cutaneous and pulmonary infections, and eczema that evolves to resemble atopic dermatitis [75, 77, 78].
Skin disease is the first manifestation and is initially noted on the face or scalp; it then quickly spreads to the face, scalp, and body, favoring the shoulders, arms, chest, and buttocks . The newborn rash starts as pink papules that rapidly develop into pustules, coalescing into crusted plaques . Recurrent pyogenic pneumonia beginning in childhood is very common. Although antibiotic treatment helps clear the infection, the abnormal healing process leads to formation of pneumatoceles and bronchiectasis. Musculoskeletal abnormalities including scoliosis, osteopenia, hyperextensibility, and fractures with minimal trauma are common, and retention of primary teeth is characteristic. Mucocutaneous candidiases, usually thrush, onychomycosis, and vaginal candidiasis, are also common. Other oral manifestations include a high-arched palate, prominent mucosal wrinkles, and median rhomboid glossitis . Arterial aneurysms are common, and coronary artery aneurysms can lead to myocardial infarction . Characteristic facies including facial asymmetry, deep-set eyes, broad nose, and forehead prominence develop during childhood and adolescence .
Treatment includes bleach baths and chronic antibiotic prophylaxis to suppress infections, antifungals for Candida infections of the skin and nails, topical anti-inflammatories to manage eczema, and consideration of cyclosporine in severe cases .
18.104.22.168 DOCK8 Deficiency
Biallelic mutations in the dedicator of cytokinesis 8 protein (DOCK8 ) gene cause a combined primary immunodeficiency characterized by elevated levels of serum IgE, decreased IgM, sinopulmonary infections, lymphopenia, cutaneous viral infections, and eosinophilia. These patients were previously thought to have a variant form of Job’s syndrome given similar clinical presentations, and distinguishing these two etiologies is challenging. However, the recent discovery of the DOCK8 gene, a member of the DOCK180-related family of atypical guanine nucleotide exchange factors, and its mutation in this condition has helped differentiate different dermatologic manifestations of these hyper-IgE syndromes . The DOCK8 protein is believed to regulate cytoskeletal rearrangements that are important in immune functions including antibody responses and T cell expansion .
2.2.3 Combined B and T Cell Deficiencies
22.214.171.124 Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is a heterogeneous group of conditions that share clinical signs related to defective cell-mediated and humoral immunity. About three of four patients are male, and the condition occurs in 1:30,000 to 1:100,000 persons . The inheritance pattern varies from autosomal recessive to X-linked (more than 40% of cases), mostly due to a deficiency of the common γ-chain of the IL-2 receptor . Adenosine deaminase (ADA) deficiency and JAK3 mutations are responsible for 20% and 6% of cases, respectively .
The treatment of choice is hematopoietic stem cell transplant during infancy, ideally before 3 months of age. Improvement in immune function can be observed in patients with ADA deficiency after enzyme replacement via injection of polyethylene glycol-conjugated ADA. Gene therapy via retroviral-mediated ex vivo gene transfer into CD34 cells has also been successful in patients with X-linked SCID or ADA deficiency; however, activation of proto-oncogenes by the retroviral vector and the development of T cell leukemias in a number of patients with X-linked SCID have raised serious concerns regarding the safety of this experimental treatment modality [90, 91]. Prenatal diagnosis through fetal DNA analysis, ADA assays, and carrier detection through examination of maternal chromosome inactivation are possible for many forms of SCID .
Ataxia-telangiectasia (AT) is an autosomal recessive disorder caused by mutations in the ATM gene on chromosome 11, which encodes the ATM protein. The frequency of this disorder is approximately 1:40,000 to 1:100,000, with carriers approximating 1% of the population . Chromosomal instability due to absent ATM leads to persistent damage and an inability to repair breaks in DNA after exposure to ionizing radiation, resulting in an increased risk for malignancy and variable immunodeficiency .
AT is characterized by oculocutaneous telangiectasias, progressive cerebellar ataxia starting in infancy, and frequent sinopul monary infections . Characteristic skin changes include loss of subcutaneous fat, premature graying, vitiligo, seborrheic and/or atopic dermatitis, recurrent impetigo, acanthosis nigricans, nevoid hyper- or hypopigmentation (large segmental café au lait spots), warts, hirsutism, keratosis pilaris, and noninfectious granulomas . In late stages, tightening of the skin resembling acral sclerosis can occur .
Management is largely supportive, including antibiotics for infections, IVIg replacement in patients with severe immunodeficiency and recurrent infections, aggressive use of sunscreens, chest physiotherapy for patients with bronchiectasis, and possible systemic steroid therapy for interstitial lung disease. Prophylactic therapy incl udes antibiotics when warranted, avoidance of sun and radiation exposure, physical therapy for prevention of contractures, and high vigilance for infection and malignancy.
126.96.36.199 CD40 Ligand Deficiency
CD40 ligand deficiency , also known as X-linked immunodeficiency with hyper-immunoglobulin M (XHIGM), is a rare primary immunodeficiency syndrome caused by a mutation in the gene coding for CD40 ligand . CD40 is a surface antigen expressed on B cells, while CD40 ligand is expressed on activated T cells; CD40 ligand is necessary for T cells to induce B cells to undergo Ig class-switching from different immunoglobulins (i.e., IgM to IgG, IgE, or IgA) . Therefore, affected individuals have profoundly decreased levels of IgG, IgA, and IgE but normal or elevated levels of IgM. CD40 ligand is required for the maturation of T lymphocytes and macrophages; thus affected patients have a varia ble defect in their function .
This results in increased susceptibility to infection with fungi, bacteria, viruses, and parasites, in addition to an increased risk for malignancies and autoimmune disorders. There is inadequate data to give an accurate frequency of epidemiologic representation for the condition. Most patients are diagnosed by 4 years of age when nearly all patients develop symptoms. Over half develop symptoms of immunodeficiency by 1 year of age. Physical findings include lymphadenopathy, hepatomegaly, chronic diarrhea, f ailure to thrive, and sinopulmonary infections . Cutaneous manifestations include oral mucosal and anogenital ulcerations, particularly in patients with coexisting neutropenia.
Management is focused on treatment and prevention of infectious complications. Immunoglobulin and Pneumocystis prophylaxis help prevent infection . Neutropenic patients may benefit from GM-CSF. Bone marrow transplant and cord blood stem cell transplantation have been tried with varying levels of success. IVIg is the gold standard of therapy  Recombinant CD40 ligand has be en attempted with variable outcomes. Further research into treatment options is warranted .
Primary immunodeficiencies are a rare group of diseases in which there is an inherited deficiency of the immune system. They can be broadly classified as disorders of innate or adaptive immunity (Table 2.1). The clinical manifestations of this diverse group of immunodeficiencies are commonly infectious complications but can also include dysmorphisms as well as inflammatory, autoimmune, and even neoplastic events. Recognition of these diseases is important to optimize therapy for best patient outcome and to direct the attention of relatives of the patient to available genetic counseling resources.
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