Immunodeficiency Disorders

Question 1

Cause: Defects in T-cell function and/or number with or without B and NK cell lymphopenia
Presentation: Recurrent bacterial, fungal, viral, and opportunistic infections within first 6 months of life, failure to thrive, often fatal if untreated by 1 year of age
Types: Classical/typical: <300 T-cells/mm3, Variant/atypical: 300-1500
Treatment: Infection prevention and HSCT

Answer 1

Severe Combined Immune Deficiency (SCID)

Question 2

AKA CD40L deficiency
Cause: Inability to class switch from IgM to other Igs, T-cell immunodeficiency from impaired activation, X-linked
Presentation: bacterial and opportunistic infections

Answer 2

Hyper IgM Syndrome

Question 3

Cause: Defect in neural crest cell migration of 3rd and 4th pharyngeal pouches, AD
Presentation: CATCH 22, triad of hypocalcemia, conotruncal heart defects, and thymic hypoplasia
Treatment: monitor for autoimmune disease, thymus transplantation

Answer 3

DiGeorge Syndrome

Question 4

Cause: AR, neurocutaneous syndrome
Presentation: Progressive neurodegeneration with cerebellar ataxia, oculocutaneous telangiectasia, T-cell immunodeficiency, radiosensitivity and malignancy, fatal by 3rd decade of life due to respiratory failure

Answer 4

Ataxia Telangiectasia

Question 5

Cause: X-linked disorder due to mutations in WAS, impaired regulation of actin polymerization in hematopoietic cells
Presentation: Triad of thrombocytopenia, eczema, and recurrent infections (bacterial and opportunistic)
Treatment: prophylaxis for infections, immunosuppression for autoimmune disease, HSCT or gene therapy

Answer 5

Wiskott-Aldrich Syndrome

Question 6

Cause: AD mutation in STAT3, decreased to absent Th17 cells, abnormal Th1 signaling
Presentation:Triad of cold abscesses, bacterial and fungal pneumonia with pneumatoceles, elevated IgE; early onset eczema and mucocutaneous candidiasis, skeletal/dental/vascular abnormalities

Answer 6

STAT3 Loss of Function (AKA Autosomal Dominant Hyper IgE Syndrome or Job’s Syndrome)

Question 7

Cause: X-linked and autosomal recessive, maturational arrest of B cells, presents after 6 months of age
Presentation: Bacterial infections, enteroviral meningitis, chronic norovirus, gastroenteritis, cryptococcal meningitis
Treatment: antimicrobials, immunoglobin

Answer 7

Agammaglobulinemia

Question 8

Cause: Low IgG, IgA, and IgM, poor IgG production to vaccines, > 2 years of age
Presentation: recurrent infections, autoimmunity, lymphoproliferative disease (can cause lymphoma)

Answer 8

Common Variable Immune Deficiency

Question 9

Cause: AR deficiency of AIRE causes loss of negative selection and central tolerance
Presentation: autoantibodies causing chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency

Answer 9

APECED

Question 10

Cause: Over 60 monogenic conditions described
Presentation: Onset < 6 years of age, 25% have an underlying immune deficiency, diarrhea, poor weight gain, blood in bowel movements
Treatment: Respond poorly to standard therapy

Answer 10

VEOIBD (Very early onset inflammatory bowel disease)

Question 11

Cause: Absent Treg cells due to mutation in FOXP3, X linked
Presentation: in infancy with diabetes mellitus, intractable diarrhea, eczema and autoimmune cytopenias
Treatment: Immunosuppression, HSCT

Answer 11

IPEX ( immune dysfunction, polyendocrinopathy, enteropathy, X linked)

Question 12

Cause: pathological CD8+ T-cell and macrophage activation
Presentation: Fever, Splenomegaly, cytopenias, hypertriglyceridemia, hyperfibrinogenemia, hemophagocytosis, low NK activity, Ferritin > 500 ng/ml, elevated soluble CD25 (Mortality 50%)

Answer 12

Hemophagocytic Lymphohistiocytosis (HLH)

Question 13

Cause: Inability to maintain lymphocyte homeostasis due to defects in FAS-mediated apoptosis
Presentation: chronic splenomegaly or lymphadenopathy, autoimmune cytopenias, EBV-related lymphoma, family history, increased double negative CD3+ T-cells

Answer 13

Autoimmune Lymphoproliferative Syndrome

Question 14

Cause: Mutations in NADPH oxidase pathway resulting in an inability of phagocytes to kill ingested microbes, can be X-linked or AR
Presentation: Recurrent infections with catalase-positive organisms, non-caseating granulomas, autoimmune disease, inflammatory disorders
Diagnostics: Nitroblue Tetrazolium Test (NBT) used to assess neutrophil oxidative burst
Treatment: Antibiotic, antifungal, or interferon-gamma prophylaxis, consideration for HSCT or gene therapy

Answer 14

Chronic Granulomatous Disease

Question 15

Cause: Mutations affecting leukocyte margination and migration (neutrophils remain in circulation)
Presentation: Mucocutaneous bacterial infections, periodontitis, poor wound healing, delayed umbilical separation, absent pus formation
(See notes for three different types)

Answer 15

Leukocyte Adhesion Deficiency