Sandbox: wdx

Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency

Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:

Disorder	Mechanism	Characteristic Features	Clinical Presentation	Laboratory Findings
Wiskott-Aldrich Syndrome	Mutation in WAS gene T cells unable to reorganize actin microfilaments (microfilament defect)	X-linked recessive pattern of inheritance Increased risk of autoimmune disease and malignancy	Thrombocytopenic purpura Eczema Recurrent infections	Decreased to normal IgG and IgM Increased IgE and IgA Fewer and smaller platelets
X-Linked (Bruton) Agammaglobulinemia	Defect in tyrosine kinase gene (BTK) B cells fail to mature	X-linked recessive pattern of inheritance Increased prevalence in males	Recurrent bacterial and enteroviral infections after 6 months of age Pre-disposition to development of infections by encapsulated organisms Pre-disposition to development of Giardia infections Absent lymph nodes and tonsils	Normal CD19+ B cell count Decreased pro-B cells Increased pre-B cells Decreased immunoglobulins of all classes
Selective IgA Deficiency	Stem cell defect (Transferrable with marrow transplant) Lack of IL-4, IL-6, IL-7, IL-10, TGF-β, and IL-21 Mutations in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI, TNFRSF13B)	Most common primary immune deficiency	Majority of the cases are asymptomatic Respiratory and gastrointestinal infections (mucosal infections) Associated with autoimmune diseases Atopy Anaphylaxis to IgA containing products	Serum IgA < 7 mg/dl Normal IgG and IgM levels
Common Variable Immunodeficiency	Defective B cell differentiation	May be acquired in 20-30 years of age	May present with other autoimmune diseases Associated with bronchiectasis Associated with lymphoma Associated with sinopulmonary infections (Bacterial, enteroviral and parasitic such as Giardia)	Decreased plasma cells Decreased immunoglobulins
Autosomal dominant hype IgE syndrome (Job's Syndrome)	Defieciency of Th17 cells due to STAT3 mutation Impaired neutrophils to sites of infection	Distinctive coarse facies Cold (non-inflammatory) Staphylococcal abscesses Retained primary teeth Eczema		Increased levels of IgE Decreased levels of interferon gamma (IFN-gamma)
Severe combined immunodeficiency (SCID)	Defective interleukin-2 receptor gamma chain Adenosine deaminase deficiency Reg 1 and Reg 2 nonsense mutations	IL-2R disease is X-linked ADA deficiency and reg mutations are typically autosomal recessive	Failure to thrive Chronic diarrhea Thrush Recurrent bacterial, viral and protozoal infections Treatment is bone marrow transplant	Decreased T cell receptor excision circles (TRECs) Abscence of thymic shadow on chest X-Ray Absent germinal centers of lymph node biopsy Absent T cells on flow cytometry
Ataxia Telangiectasia	Defect in ATM gene DNA double stranded breaks leading to cell cycle arrest	Hypersensitivity to X-Rays	Triad of: Ataxia Spider angiomas (Nests of distended capillaries) IgA deficiency	Increased alpha fetoprotein (AFP) Decreased IgA, IgG and IgE Lymphopenia Cerebellar atrophy
Hyper IgM Syndrome	Defective CD40L (CD40 ligand) on Th cells leading to class switching defect	X-linked recessive pattern of inheritance	Severe pyogenic infections in early life Opportunistic infection with: Pneumocystis jiroveci Cryptosporidium Cytomegalovirus (CMV)	Increased IgM Decreased IgG, IgA and IgE No germinal centers

• Malignancy: can cause the reduction in the immunoglobulin production.

• Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
• Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
• Other causes of primary humoral immunodeficiencies.
• Smoking: may cause IgG2 subclass deficiency.
• Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

An ECG in a person with a potassium level of 1.1 showing the classical ECG changes of ST segment depression, inverted T waves, large U waves, and a slightly prolonged PR interval. By James Heilman, MD - Own work, CC BY-SA 3.0

An ECG in a person with a potassium level of 1.1 showing the classical ECG changes of ST segment depression, inverted T waves, large U waves, and a slightly prolonged PR interval. By James Heilman, MD - Own work, CC BY-SA 3.0

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Table

Complications	Polymyositis	Dermatomyositis
Malignancy	Lung	Lung