Disorders with Immunodeficiency

Moise Levy M.D.

Clinical Pearls

(ML)

Wiskott-Aldrich Syndrome

Inheritance

X-linked recessive; Wiskott-Aldrich Syndrome (WAS) gene on Xp11

Prenatal Diagnosis

DNA analysis

Fetal blood sample in male fetus—abnormally small platelets

Incidence

1:250,000; males only

Age at Presentation

First few months of life with bleeding problems

Pathogenesis

Mutation in WAS gene that encodes WASp, a protein important in lymphocyte and megakaryocyte signal transduction and actin filament assembly, impairs T-cell activation and natural killer cell function

Key Features

Skin

Atopic dermatitis with increased involvement on scalp, face, flexures; secondary bacterial infection, eczema herpeticum, molluscum contagiosum, lichenification

Blood

Thrombocytopenia with petechiae, purpura, epistaxis, bloody diarrhea, hematemesis, intracranial hemorrhage

Infectious Disease

Recurrent bacterial infections (especially encapsulated organisms) with otitis media, pneumonia, meningitis, septicemia

Increased susceptibility to HSV (eczema herpeticum), Pneumocystis carinii, human papilloma virus

Immunology

Increased immunoglobulin (Ig) A, IgD, IgE, and decreased IgM

Impaired cell-mediated and humoral immune response

Increased IgE-mediated urticaria, food allergies, asthma

Neoplasm

Lymphoreticular malignancy (20%)—non-Hodgkin’s lymphoma most common

Differential Diagnosis

Atopic dermatitis

Severe combined immunodeficiciency (SCID) (p. 264)

Hyper-IgE syndrome (p. 262)

Chronic granulomatous disease (p. 258)

Laboratory Data

Complete blood count (CBC) with differential, platelets, mean platelet volume (MPV)

Serum Ig levels

Immunoblot/fluorescence-activated cell sorter analysis (FACS): WASp protein expression in mononuclear cells from peripheral blood

DNA analysis

Management

Bone marrow transplant (BMT)

Splenectomy with long-term antibiotic prophylaxis

Appropriate antibiotics, intravenous immunoglobulin, plasma/platelet transfusions

Topical corticosteroids, moisturizers, prophylactic oral acyclovir

Referral to hematologist/oncologist, infectious disease specialist, and dermatologist

Prognosis

Frequently, premature death in first decade of life because of infection > hemorrhage > malignancy

Clinical Pearls

The bloody nature of the diarrhea may help distinguish from SCID… The big problem with platelet transfusions is that the patient may develop platelet antibodies, making subsequent transfusions less useful… Standard atopic care with vigorous use of moisturizers first and foremost… Defer topical steroids unless necessary… Crust with eczema can be hemorrhagic… Failure to thrive can be seen as with all primary immunodeficiencies in infancy. Often, early death without BMT although longer survival without BMT may occur… ML

9.1. Eczematous dermatitis accentuated in flexures. Note splenectomy scar. (1)

9.2. Eczema herpeticum on dorsum of patient’s hand.

Chronic Granulomatous Disease

Inheritance

X-linked recessive (76%)—gp91-phox (phagocyte oxidase) gene on Xp21.1; autosomal recessive (24%)—p47 (more common), p67-phox genes on 7q1 1, 1q respectively

Prenatal Diagnosis

DNA analysis

Fetal blood sample—nitroblue tetrazolium (NBT) reduction assay of fetal leukocytes

Incidence

Approximately 1:250,000 to 500,000; M:F=9:1

Age at Presentation

Birth to 1 year old

Pathogenesis

Genetically heterogeneous group of immunodeficiency disorders caused by phox mutations in the nicotinamide dehydrogenase phosphate (NADPH) oxidase enzyme complex leading to an inability to produce a respiratory burst and defective killing of catalase positive organisms within phagocytic leukocytes; (respiratory burst occurs when NADPH oxidase acts as a catalyst for the production of superoxides and ultimately microbicidal oxidants)

Key Features

Skin

Recurrent pyoderma (Staphyloccus aureus most common), periorificial dermatitis with purulent drainage and regional lymphadenopathy, abcesses (perianal most common), granulomas

Mucous Membranes

Ulcerative stomatitis, chronic gingivitis

Lymph Nodes

Suppurative lymphadenitis with abscesses and fistulas (cervical nodes most common)

Lungs

Pneumonia with abscesses, cavitations, empyema (Staphylococcus, Aspergillosis, Nocardia)

Gastrointestinal Tract

Hepatosplenomegaly with granulomas, abscesses, chronic diarrhea, malabsorption

Musculoskeletal

Osteomyelitis (serratia marcescens most common), short stature

Differential Diagnosis

Hyper-IgE syndrome (p. 262)

SCID (p. 264)

Chédiak-Higashi syndrome (p. 62)

B-lymphocyte disorders

Laboratory Data

NBT reduction assay: leukocytes unable to reduce dye—no blue color change

CBC, erythrocyte sedimentation rate (ESR), immunoglobulin levels, chest x-ray, delayed hypersensitivity—skin test normal

Lungs, liver, bone imaging—locate occult inflammation; bacterial cultures

Immunoblot analysis of defective NADPH enzymes; DNA analysis

Management

Referral to infectious disease specialist—antibiotics

Referral to surgery—debridement, drainage, access to deeper infections; systemic steroids for obstructive visceral granulomas

Referral to dermatologist—topical and oral antibiotics, topical corticosteroids, antibacterial cleansers

Leukocyte transfusions, subcutaneous gamma interferon, BMT

Gene therapy for p47-phox form has been attempted with some persistence of corrected leukocytes at 6 months

Identify carriers and evaluate for lupus-like syndrome

Prognosis

Variable life span depending on control of infections; most with normal life span but poor quality of life

Clinical Pearls

A couple of kids have had resistant bacterial scalp infections… I have never seen the periorificial dermatitis… NBT is a simple test to do… Can be done right in the doctor’s office… May pick up tender joints by observing the kid’s positioning of the arms and legs… One-quarter of a cup of clorox to a full bath of water is a useful, cheap way to keep up with recurrent skin infections… I tend to not restrict patient’s activity… Subcutaneous gamma interferon three times a week has provided clinical improvement… Patients with chronic granulomatous disease (CGD) tend to be better targets for prophylactic antibiotics… ML

9.3. Three-month-old boy with granulomatous scalp nodule which grew serratia marcescens. (96)

9.4. Left. Nitroblue tetrazolium (NBT) reduction assay with normal control demonstrating leukocytes’ ability to reduce dye and produce blue color change. Right. Abnormal leukocytes in affected patient unable to reduce dye. (97)

Hyper-Immunoglobulin E Syndrome

Synonym

Job syndrome thought to be a variant

Inheritance

Autosomal dominant with variable expressivity; chromosome 4q21-gene unknown

Prenatal Diagnosis

None

Incidence

Rare—approximately 150 patients described; M=F

Age at Presentation

First few months to first year of life

Pathogenesis

Impaired regulation of IgE function and deficient neutrophil chemotaxis may play a role in susceptibility to infection

Key Features

Skin

Excoriated papules, pustules, furuncles, cellulitis and abscesses (30% cold) on scalp, neck, axillae, groin, periorbital; paronychial infection; infected with S. aureus (most commonly); also Candida, Streptococcus

Eczematous dermatitis increased in flexures, postauricular, hairline

Sinopulmonary

Recurrent bronchitis, lung abscesses, pneumonia secondary to S. aureus, Haemophilus influenzae; pneumatoceles with bacterial/fungal superinfection, empyemas, recurrent otitis media, sinusitis

Craniofacial

Coarse facies with broad nasal bridge, prominent nose

Musculoskeletal

Osteopenia with secondary fractures (pelvis, long bones, ribs most common), scoliosis, hyperextensible joints

Dental

Retained primary teeth, lack of development of secondary teeth

Differential Diagnosis

Atopic dermatitis

Wiskott-Aldrich syndrome (p. 256)

DiGeorge syndrome

Laboratory Data

IgE level markedly increased, IgD increased