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Immunodeficiency Disorders By Melissa Pugliano-Mauro, MD, and Wendy Myers, MD. (Updated July 2015*)

DISEASE INHERITANCE/GENE KEY IMMUNOLOGIC MALIGNANCY CLINICAL TREATMENT FEATURES MANIFESTATIONS

X-linked Agamma- • X-linked Gram-positive • Absent IgM, A, D, E Lympho-reticular Atopic dermatitis, vasculitis, IVIG globulinemia (Bruton recessive (90%) pyogenic infections • Small amount of IgG malignancies, urticaria, no palpable lymph Syndrome) • AR (10%) • B cells lacking especially nodes (no geminal centers), • Bruton tyrosine kinase • CMI intact and growth failure (Btk): maturation block in pre-B cell to B-cell differentiation

Isolated IgA • AD or AR: TNFRSF13B One half have • Absent or low IgA Risk is • 1 out of 600 white deficiency gene repeated infections • One half have Anti-IgA increased persons • Acquired (phenytoin or antibodies • Most common chemotherapy) disorder • Defect in maturation • Anaphylaxis to IVIG of B-cell as it develops or transfusions into IgA-producing • Asthma, (increase plasma cell collagen vascular disease [SLE], celiac, UC, vitiligo) • Atopic dermatitis

Common Variable • Acquired Recurrent sinopul- • Most Ig classes low with • Lympho-reticular • Second most common Immuno-deficiency • HLA B8 & DR3 monary infections no antibodies to bacterial malignancies: immunodeficiency disorder (after (CVID) antigens (400-fold) IgA deficiency) • B cells are present but • Increase risk of • Eczematous dermatitis, abnormal differentiation cancer (10-fold pyoderma, moniliasis , verruca, overall) dermatophyte infections • Autoimmunity (vitiligo, alopecia areata, hemolytic anemia, ITP, vasculitis), GI abnormalities • Cutaneous and visceral non- infectious granulomas

Immuno-deficiency • X-linked: CD40LG Respiratory • Normal or elevated • Autoimmunity (thyroiditis and IVIG, allogenic BMT with Hyper IgM (CD40 ligand on T cells) infections, otitis IgM, D hemolytic anemia) • AR: CD40 (on B cells) media • Low or absent • Painful oral and anogenital IgG, A, E ulcers, diarrhea, widespread • Recurrent -resistant warts neutropenia Melissa Pugliano- Mauro, MD is a

resident at the Cartilage-hair • AR: RMRP gene Severe varicella • Defective CMI Non-Hodgkin’s • Short-limbed dwarfism, fine University of Vermont/ Hypoplasia encodes RNA component zoster and HSV • Minority of patients lymphoma and BCC sparse hypopigmented hair, Syndrome of ribonucleoprotein infections with defective humoral doughy skin with abnormal elastic Fletcher Allen Health endoribonuclease immunity tissue • Commonly in • Hypoplastic • Hirschsprung disease, impaired Care Amish and Finns anemia spermatogenesis

Omenn • AR: RAG-1 and Recurrent • Hypogamma- • Mimics GVHD Syndrome RAG-2 infections globulinemia with elevated • Exfoliative erythroderma • Form of SCID IgE (starting at a few weeks old) with • Antibody production and alopecia CMI impaired • Diarrhea, HSM, LAD, • Eosinophilia early death • TcR rearrangements restricted with inefficient and/or abnormal generation of TcR

Severe Combined • X-linked Rec: deficiency Pseudomonas, Staph, • Impaired humoral • Thymus is small or absent BMT, antibiotics, Wendy Myers, MD, Immuno-deficiency of γ chain of IL-2 receptor Enterobac- teriaceae, and CMI • Triad: moniliasis of oropharynx irradiated blood is a resident at the (SCID) (most common); IL2RG and Candida • Deficiency or total and skin, intractable diarrhea and products, • AR: adenosine absence of circulating pneumonia gene therapy, University of Vermont/ deaminase or JAK3 Viral ; usual lymphocytes • Recurrent infections, failure to recombinant IL-2 cause of death • Mature T cells absent thrive and intractable diarrhea infusion Fletcher Allen Health • B cells normal or apparent within first few months Care. decreased of life • Ig’s low • Morbilliform eruption/ • Lack NK cells seborrheic dermatitis- like/LP- like/sclero-dermatous—GVHD secondary to in utero maternal lymphocytes, nonirradiated transfusions

irectionsin D­Residency p. 1 • Summer 2008 boards’ fodder

Immunodeficiency Disorders By Melissa Pugliano-Mauro, MD, and Wendy Myers, MD. (Updated July 2015*)

DISEASE INHERITANCE/ GENE INFECTIONS KEY IMMUNOLOGIC MALIGNANCY CLINICAL TREATMENT Abbreviations: FEATURES MANIFESTATIONS AD: autosomal dominant AR: autosomal recessive Wiskott- Aldrich • X-linked recessive: • Pyoderma, • Elevated IgA, D, E Lymphoreticular • Triad: chronic eczematous Platelet BCC: basal cell carcinoma Syndrome WASP gene encodes recurrent • Decreased IgM malignancy dermatitis, infections, transfusions, WASP protein, which sinopulmonary • Low or NL IgG (up to ¼ of survivors thrombocytopenia with splenectomy, IVIG, BMT: bone marrow is important in lymphocyte infections (e.g. • Impaired humoral develop lymphoma) and purpura BMT transplant and megakaryocyte suppurative otitis and CMI • Bloody diarrhea may CM: cell mediated signal trans- duction and media), infections distinguish this from SCID actin filament assembly; with encapsulated • Molluscum, HSV immunity • Impairs T cell activation organisms (e.g. GVHD: graft versus host and NK cell function. pneumonia and • Important in meningitis) disease regulation of high affinity • Increased HSM: IgE receptor on mast susceptibility to HSV hepatosplenomegaly cells (eczema herpeticum) HSV: herpes simplex virus Ig: immunoglobulin ITP: idiopathic Chronic Granuloma- X-linked recessive: gp91- Staph aureus, • Deficiency of NADPH- • Eczema of the scalp, backs of • BMT/ stem cell thrombocytopenic tous Disease phox (phagocyte oxidase) Aspergillus fumigatus, oxidase complex with ears, face transplantaion purpura gene; CYBB gene which Burkholderia cepacia, defective ability • Purulent and granulomatous • Prophylaxis with leads to absence Candida to generate hydro- infections of long bones, lym- trime- thoprim- LAD: lymphadenopathy of NADPH oxidase spp., atypical gen peroxide and phatic tissue, , skin sulfametho- xazole LN: lymph nodes activity mycobacteria inability to kill intracellular and lungs and itraconazole NCF: neutrophil cytosol factors AR (24%): p47 and p67- organisms • Ulcerative stomatitis, • IFN-γ to phox genes; CYBA, NCF • Elevated IgG, M, A furunculosis, subcutaneous NL: normal reduce 1 and 2 • Neutrophil abscesses OM: otitis media frequency of leukocytosis and suppurative LAD TcR: T cell receptor • Nitro-blue tetrazolium (NBT) is infections low/no blue color change • Female carriers: increased infections, arcuate dermal and DLE-like skin lesions, and aphthous stomatitis

Chediak-Higashi AR: LYST (lysosomal Enteric bacterial • Neutropenia • Lymphoma • Light blond hair with silver BMT is treatment of Syndrome trafficking regulator) gene organisms, bacterial • Neutrophils do not or other cancers sheen (small regularly spaced choice and should which leads to defective sinusitis & pneumonia phagocytose normally usually cause early clumps of melanin on light be performed early vesicular transport to (S. pyrogenes, and there is defective death microscopy), pigmented nevi, (before accelerated and from the lysosome, S. pneumoniae), chemotaxis • 85% with slate-gray skin color, bruises phase) causing giant perinuclear superficial • Ig’s normal accelerated phase: • Ocular albinism with nystagmus vesicles in neutrophils pyodermas • Melanocytes— lympho- histiocytic and photophobia (leukocytes with pigmentary dilution proliferation • Pancytopenia large azurophilic giant • Neurons— progressive with infiltration of liver, • HSM granules), melanocytes deterioration and LNs • Platelet storage pool and neurons deficiency—petechiae, gingival bleeding, ecchymoses, epistaxis

Griscelli AR: Myosin-Va or RAB27A Pyogenic systemic Accelerated phase • Neutropenia, BMT Syndrome genes play a role in infections as well thrombocytopenia membrane transport and • Silver-gray hair, eyebrows and organelle trafficking, eyelashes (uneven clusters of e.g. transfer of melanin in the medulla on light melanosomes microscopy) • Pigment dilution of the skin • HSM

Hyperimmuno- AD: STAT3 gene (signal Furunculosis, • High IgE, D and IgE anti- • Eczema, coarse facies, papular globulinemia E transducer and activator sinopulmonary staph antibodies prurigo, keratoderma of palms Syndrome (including of transcription 3) infections, cold • Eosinophilia and soles Job Syndrome) is critical to IL-6 pathway abscesses • Chemotaxis of • Recurrent OM, bronchitis/ (acute phase response) neutrophils and monocytes pneumonia, chronic AR: DOK8 gene S. aureus, Candida impaired mucocutaneous candidiasis, spp., Strep furuncles, carbuncles and abscesses • Osteopenia with fractures, scoliosis and dental abnormalities (retention of primary teeth) • Job Syndrome: females with red hair, freckles, blue eyes and hyper-extensible joints with cold abscesses

References: www.accessmedicine.com (photo, Bolognia JL and Orlow SJ. Melanocyte Biology in: Bolognia JL, Jorizzo JL, Rapini RP. , 2nd edition. Mosby Elsevier. 2008:905. James WD, Berger TG, Elston DM. Andrew’s Diseases of the Skin Clinical Dermatology, 10th edition. Saunders Elsevier. 2006: 83-90.Schaffer. JV and Paller AS. Primary in: Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, 2nd edition. Mosby Else- vier. 2008:801-823.Spitz JL and Levy M. Disorders with Immunodeficiency in: Genodermatoses A clinical Guide to Genetic Skin Disorders, 2nd edition. Lippincott Williams and Wilkins. 2005:255-271.

*Reviewed and updated July 2015 by: Alina Goldenberg, MD, Emily deGolian, MD, and Sharon Jacob, MD.

irectionsin www.aad.org/DIR Summer 2008 • p. 2 D­Residency