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Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia presents with progressive ataxia, telangiectasias, extrapyramidal symptoms, dermatological manifestations, immune dysfunction, and progressive pulmonary disease. Diagnosis is based on clinical presentation and confirmed with neuroimaging and genetic testing. Management is supportive with symptom management. Prognosis is poor secondary to numerous complications.

Common Variable Immunodeficiency (CVID)

Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins G, A, and M. The underlying causes of CVID are largely unknown. Patients with this condition are prone to infections in the gastrointestinal tract and the upper and lower respiratory tracts. CVID is also associated with a higher risk of developing autoimmune disorders, granulomatous diseases, and malignancy.

Selective IgA Deficiency

Selective immunoglobulin A (IgA) deficiency is the most common type of primary immunodeficiency. The condition is a hypogammaglobulinemia characterized by a lack or reduced levels of IgA. This antibody mainly resides in the mucous membranes of the mouth, airways, and digestive tract. The exact cause is unknown. The disease is usually asymptomatic, although some patients can present with recurrent respiratory and gastrointestinal infections as well as autoimmune and malignant disorders. Diagnosis is made with a measure of exceptionally low IgA levels in the serum in the presence of normal IgG and IgM levels.

Autosomal Dominant Hyperimmunoglobulin E Syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES), also known as Job's syndrome, is a rare form of primary immunodeficiency disorder that affects various organs systems in addition to the immune system. Some cases of AD-HIES are caused by mutations in the STAT3 gene, resulting in abnormal neutrophil chemotaxis. In other cases, the cause is unknown. Patients with AD-HIES experience recurrent pneumonia, skin infections, rashes, blisters, and abscesses.

Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID), also called “bubble boy disease,” is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. It is the most severe form of primary immunodeficiency and is characterized by dysfunction in both humoral and cell-mediated immune responses. Multiple mutations can result in heterogeneous types of SCID. Patients present with severe and recurrent infections within the first months of life. Management includes IV immunoglobulins and bone marrow transplantation. If left untreated, SCID is usually fatal within the 1st year of life.

Hereditary Angioedema (C1 Esterase Inhibitor Deficiency)

Hereditary angioedema (HAE), also known as C1 esterase inhibitor (C1-INH) deficiency, is an autosomal dominant disorder characterized by recurrent episodes of severe swelling (angioedema). Hereditary angioedema commonly affects the limbs, face, intestinal tract, and upper airway. Swelling in the airway can restrict breathing and lead to a life-threatening airway obstruction. Hereditary angioedema has 3 subtypes distinguished by their underlying etiologies and levels of C1 inhibitor in the blood. Management includes treatment with danazol, kallikrein inhibitors, and C1-INHs. Hereditary angioedema is self-limiting, but may be fatal if the airway becomes compromised.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. The diagnosis is made by testing neutrophil function for superoxide production. Patients with CGD are at increased risk of life-threatening infections with fungi and catalase-positive bacteria. Inflammatory complications such as CGD colitis are also possible. The introduction of antimicrobial prophylaxis and the use of azole antifungals has increased the overall life expectancy of these patients.

Burkholderia

Burkholderia species are gram-negative bacilli with 2 clinically relevant pathogens: B. pseudomallei (causing melioidosis) and B. cepacia complex (causing opportunistic infections). Melioidosis is commonly seen in Asia and Australia. Infection is transmitted by contact with contaminated soil or water (via skin wounds). The disease affects multiple systems, and can present with pneumonia, encephalomyelitis, and skin abscesses. Diagnosis is by culture of specimen (depending on the organ involved). Treatment requires an initial intensive antibiotic therapy followed by prolonged eradication therapy. Burkholderia cepacia complex (BCC) generally affects immunocompromised individuals such as those with cystic fibrosis (CF). It can be transmitted from person to person or through contaminated devices. While BCC is a rare infection, it is important to diagnose, as BCC is multi-drug resistant and infection is a relative contraindication to lung transplantation.

Humoral Adaptive Immunity

Humoral adaptive immunity is an integral part of the adaptive immune system, which mounts a highly specific defense against pathogens but takes a longer time to respond (compared to the innate immune system). Humoral immunity is the arm of the immune system protecting the extracellular fluids of the lymphatics (lymph), interstitium, and circulatory system (plasma) from microbial contamination mediated through soluble molecules. The B cells play a major role, producing antibodies or immunoglobulins. Arising from the bone marrow, B cells originate from the common lymphoid progenitor and undergo stages to assemble the B cell receptor. To become fully functional, activation follows, and this can be T cell–dependent (which produces memory cells) or T cell–independent (producing a short-lived response). When activated, B cells go through processes enhancing antigen affinity, class switching, and differentiation to plasma cells and memory cells. Plasma cells produce the antibodies, while memory B cells respond to reinfection. There are different immunoglobulin isotypes, generally providing immune protection through complement activation, opsonization, neutralization of toxins or viruses, and induction of cell lysis.

DiGeorge Syndrome

DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). Conotruncal anomalies present as congenital heart defects. Other manifestations consist of characteristic facial features, frequent infections, and neuropsychiatric disorders.

Urticaria (Hives)

Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation resulting in the release of histamine and other vasoactive substances from mast cells and basophils in the dermis resulting in extravasation of plasma into the dermis. Urticaria can be caused by myriad inciting events, such as allergic reactions, infections, exposure, and many others. The diagnosis is made clinically. H1-antagonists are used as 1st-line treatment.

Angioedema

Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Clinically, angioedema presents with swelling around the eyes, lips, tongue, mouth, bowel wall, extremities, or genitalia. Angioedema may also compromise the airway. Urticaria will be present when the angioedema is mediated by mast cells, but not when it is due to increases in bradykinin. Diagnosis is usually clinical but additional testing may include skin/serum testing for specific antigens and C4 level assessment. Management depends on the underlying mechanism but may include treatment for anaphylaxis, removing any offending agents, antihistamines, glucocorticoids, and/or therapies that target bradykinin.

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich syndrome presents as a classic triad of eczema, bleeding diathesis, and recurrent opportunistic infections, but also carries a high risk of development of autoimmunity and malignancy. Management includes hematopoietic stem cell transplantation (HSCT), immunoglobulin replacement therapy, prophylactic and therapeutic antibiotics, and systemic steroids. Without HSCT, prognosis is poor and life expectancy is shortened.

Type I Hypersensitivity Reaction

Type I hypersensitivity reaction is an abnormal immune response triggered by exposure to specific antigens known as allergens. In this type of hypersensitivity reaction, the presentation of the antigen to the T-helper cells (Th cells) initiates a cascade of immunologic events leading to the production of antigen-specific IgE antibodies. Reexposure to the antigen promotes degranulation of the IgE-bound mast cells and basophils, releasing chemical mediators that cause various allergy symptoms. Manifestations can be local, depending on the route of entry of the antigen. In severe cases, systemic reaction leads to anaphylactic shock. To determine allergic etiology, skin testing as well as in vitro tests are available. Management includes avoidance of triggers to reduce exacerbation. Common treatment options are antihistamines and glucocorticoids to control the inflammatory response. Anaphylaxis, however, is a medical emergency that requires immediate airway access with administration of epinephrine and fluid resuscitation.

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Pediatric Allergy and Immunology

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Your Educators of course Pediatric Allergy and Immunology

Brian Alverson, MD

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