Pathology Notes

Practice questions answers Primary immunodeficiency disorders © Jun Wang, MD, PhD 1. C. When patients present with recurrent infections, always consider immunodeficiency . Lymphocytopenia is suggestive of lymphocytic defects, so that phenotyping of lymphocytes, as well as immunoglobulin profiles would be critical screening test. Blood culture is helpful if sepsis is suspected. Chest CT and MRI may help finding thoracic abnormalities. Monospot is for infectious mononucleosis , or other EBV infections. Oral plaque biopsy may determine the underlying pathology. All four have limited value in investigating the immune functions of this patient. 2. E. With markedly reduced T cells and low levels of B cells, and clinical presentation of recurrent infections, failure to thrive, this is most likely severe combined immunodeficiency , a condition all immunoglobulin, especially IgM, levels are reduced. Elevated IgG and normal IgM and IgA is either reactive (polyclonal), or due to plas

Practice questions Primary immunodeficiency disorders © Jun Wang, MD, PhD 1. Use this case for next four questions . A nine-month-old boy presents with recurrent oral ulcers, thrush, fever and failure to thrive since 5 months. He had been hospitalized for pneumonia three times. He has two cousins from the maternal side died before age 1, with unknown diagnosis. Physical examination reveal general pallor. Oral cavity examination reveal a few whitish plaques. No tonsil is seen. Laboratory test results include: hemoglobin 9 mg/dL (normal 10.3–12.4 mg/dL), white count 17 x 10 9 /L (normal 4.5-11 x 10 9 /ml) and absolute lymphocytes 0.2 x 10 9 /L (normal 1.4-22 x 10 9 /L). Peripheral blood smear reveals no significant morphological abnormalities. His platelet, renal and liver function tests are within normal range. HIV ELISA is negative. What additional tests should be performed? A. Blood culture B. Chest CT and MRI C. Lymphocyte phenotyping and serum immunoglobulin profile

X-Linked Lymphoproliferative Syndrome Updated: 08/17/2020 © Jun Wang, MD, PhD General features Rare X-linked Predilection for Epstein-Barr virus infections   Markedly increased risk for B-cell lymphoma Clinical presentations Median age of onset: 3-5 years Variable, including Hemophagocytic lymphohistiocytosis   Fatal fulminant infectious mononucleosis Lymphoma Hypogammaglobulinemia Fulminant hepatitis with massive hepatic necrosis Hepatic encephalopathy Genetic abnormality Mutation of SH2D1A Pathogenesis Defective lymphocytic activation Sustained T cell proliferation Inability to eliminate EBV-infected B-cells Morphological features Hemophagocytic lymphohistiocytosis Managements Stem cell transplantation Immunoglobulin replacement Back to primary immunodeficiency disorders Back to contents

Wiskott-Aldrich Syndrome    Updated: 08/17/2020 © Jun Wang, MD, PhD General features X-linked recessive Clinical presentations Triad : recurrent b acterial sinopulmonary infections , eczema and bleeding diathesis Genetic abnormality Mutation of WASp Pathogenesis Actin polymerization defects in hematopoietic cells, resulting in defective antibody production, T cell response and platelet production Laboratory findings Thrombocytopenia Platelet dysfunction Managements Treat infections Transfusion Bone marrow transplantation Back to primary immunodeficiency disorders Back to contents

Transient Hypogammaglobulinemia of Infancy   Updated: 08/17/2020 © Jun Wang, MD, PhD General features Relatively common, with male preponderance Affects infants and young children Clinical presentations Can be asymptomatic Symptoms developed 6 month after birth Recurrent infections, including sinusitis, otitis media, bronchial infections Usually intact T cell function, no opportunistic infections Allegic or autoimmune disorders Frequencies of infection markedly reduced after 3 years of age Genetic abnormalities Variable Intrinsic B cell defect Dysfunction of Th cell and suppressor T cells Abnormality in the cytokines, such as IL-4, Il-6 etc Pathogenesis Unclear Key Laboratory findings Low serum IgG, with or without decreased IgA and IgM Usually normal levels of lymphocyte subpopulations  Normal response to immunizations Managements Continue routine immunization Treat infections Back to primary immunodeficiency disorders Back to

Isolated IgA Deficiency Updated: 06/02/2020 © Jun Wang, MD, PhD Definition Decreased or absent levels of IgA in the presence of normal levels of IgG and IgM , in a patient older than 4 years old , in whom NO other causes of hypogamamaglobulinemia General features Most common primary immunodeficiency disorder Common in whites Usually inherited without distinct inheritance pattern Sporadic cases associated with drug usages have been reported Total (undetectable IgA) or partial (reduced IgA) Risk of lymphoid and GI origins malignancies May progress to common variable immunodeficiency Clinical presentations Usually asymptomatic Symptoms developed in later life Recurrent mucosa associated infections, including sinopulmonary and GI tract Allegic disorders: atopic dermatitis, respiratory allergies, etc Autoimmune disorders, ITP most common Anaphylaxis following transfusion of blood or immunoglobulins Genetic abnormalities Variable Intrinsic B cell de

Hyper IgM syndrome   Updated: 08/15/2022 © Jun Wang, MD, PhD General features Commonly X-linked, may be autosomal recessive Commonly have positive family history of male lateral relatives Relatively poor prognosis Clinical presentations Recurrent infections including pneumonia, and opportunistic pathogens, such as pneumocystis jiroveci etc Genetic abnormalities Loss of function mutation of CD40 ligand on CD4+ T cells May be caused by CD40 deficiency on B cells Pathogenesis Defective interaction between helper T cell and developing B cells/macrophages Impaired immunoglobulin isotype switch Impaired CD40L-mediated macrophage activation Key Laboratory findings Neutropenia, probably due to myeloid maturation arrest High IgM Low IgA, IgG, and IgE Diagnosis Male patient with serum IgG concentration at least 2 SD below normal for age and one of the following: Mutation of CD40L Maternal cousins, uncles, or nephews with confirmed diagnosis of XHIM

Common Variable Immunodeficiency   Updated: 08/17/2020 © Jun Wang, MD, PhD General features Heterogeneous group with no clearly understood etiology Hereditary or sporadic No recognizable inheritance pattern High risk of autoimmune, inflammatory and malignant disorders Increased risk of gastric carcinoma, melanoma and EB virus associated B cell lymphoma Diagnosis of exclusion Clinical presentations 5 distinct clinical phenotypes No complications Antoimmunity Polyclonal lymphocytic infiltrate Enteropathy Lymphoid malignancy Recurrent infections including diarrhea, pneumonia, otitis media, sinusitis etc Splenomegaly and generalized lymphadenopathy Autoimmune disorders Skin manifestations: Alopecia, etc Genetic abnormalities Variable Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) Inducible co-stimulator of activated T cells (ICOS) Others Pathogenesis Defects in immunoglobulin production due to either in

DiGeorge syndrome Updated: 08/17/2020 © Jun Wang, MD, PhD General features Inherited or sporadic Multiple organ/tissue defects Complete (absence) or partial (underdeveloped) thymus Congenital heart disease most common cause of death Clinical presentations Facial appearance: Elongated face , retrognathia or micrognathia, cleft palate etc Congenital heart defects Neonatal hypocalcemia T-cell dysfunction, although infections are not the first manifestation Recurrent infections associated with T cell dysfunction: fungal, Pneumocystis jiroveci, viral, etc Genetic abnormality Deletion of 22q11.2 Pathogenesis Failure of 3 rd and 4 th pharyngeal pouches Heart involvement: Congenital heart diseases Parathyroid defects: hypocalcemia Thymus defect: No or deficient T-cell proliferation in response to mitogen Key Laboratory findings Reduced levels of T cells in peripheral blood Hypocalcemia Genetic studies (FISH) for 22q11.2 Key morphological feature

Ataxia telangiectasia Updated: 08/17/2020 © Jun Wang, MD, PhD General features Autosomal recessive Clinical presentations Progressive impairment of neurological deficits, vascular malformation and immunodeficiency affecting both B and T cells Recurrent sinopulmonary infections Development defects Genetic abnormality Mutation of ATM Pathogenesis Defected DNA repair, abnormal function of p53 Laboratory findings Thrombocytopenia Platelet dysfunction Managements Treat infections Treat correlated abnormalities Back to primary immunodeficiency disorders Back to contents

X-linked agammaglobulinemia Updated: 08/17/2020 © Jun Wang, MD, PhD General features AKA Bruton's disease Impaired B cell differentiation and immunoglobulin production X-linked Almost exclusively in boys Clinical presentations Recurrent infections, especially encapsulated pyogenic bacteria, such as Streptococcus Pneumoniae Commonly pneumonia, otitis media, diarrhea, etc Presentations starts 4-6 months after birth Genetic abnormality Bruton tyrosine kinase mutation Pathogenesis B cell development arrest Key Laboratory findings Low levels of Ig after 6 months, IgM and IgA typically undetectable Markedly reduced or absent CD19+ B cells in circulation Circulating T cells may be increased Key morphological features Underdeveloped or absent lymphoid tissue, such as lymph nodes, tonsils, etc. Absent plasma cells Diagnosis Low or absent number of mature B cells Low or absent expression of m heavy chain on surface of lymphocytes Molecular t

Severe combined immunodeficiency   Updated: 07/19/2022 © Jun Wang, MD, PhD General features Heterogeneous group Variable genetic abnormalities T-cell defects with associated B-cell dysfunction May develop non-Hodgkin lymphoma Death may occur within first year of life unless stem cell transplantation Clinical presentations Usually have positive family history Presentation shortly after birth Severe and often life threatening infections Opportunistic infections Failure to thrive Mucocutaneous candidiasis resistant to treatment Autoimmune disorders Genetic abnormalities and associated pathogenesis X-linked : most common type, mutations of common gamma-chain of interleukin receptors , causing defective lymphocytic proliferative (IL-2), B-cell class switch (IL-4), T-cell selection in thymus (IL-7), and NK-cell development (IL-15) Autosomal recessive : mutation of adenosine deaminase , etc, causing accumulation of cytotoxic DNA byproducts (Deoxy-ATP, etc) and s

Primary immunodeficiency disorders   Updated: 07/14/2023 © Jun Wang, MD, PhD General features Preferred term: Inborn errors of immunity   Deficiency in immune system function due to intrinsic defects Poor or absent function of one or more components of the immune system Rare condition except IgA deficiency Early diagnosis and treatment critical for outcomes Clinical presentations Recurrent infections Opportunistic infections Unusual infections Autoimmune disorders Key Laboratory findings Lymphocytopenia Neutropenia Abnormal levels of immunoglobulin Screening tests: immunodeficiency unlikely if normal results CBC and differential: neutrophils, lymphocytes Quantitative serum immunoglobulin levels IgA, IgE, IgG and IgM Levels of specific antibodies to vaccines Skin testing for delayed hypersensitivity Additional tests Lymphocytopenia : Flow cytometry/immunophenotyping, antibodies to T, B or NK cells Cellular immunity dysfunction : T-cell receptor e

Practice questions answers Coagulopathy  © Jun Wang, MD, PhD 1. E. Bleeding disorders with normal platelet counts are commonly associated with coagulation factor abnormalities, either due to factor deficiency or presence of inhibitors. Correction of PT or PTT by mixing studies rules out presence of inhibitors, usually antibodies against coagulation factors. Liver disease associated coagulopathy usually have prolonged PT and PTT. Renal function abnormality can be seen in thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome and atypical hemolytic-uremic syndrome . Vitamin B12 and folate deficiencies are associated with megaloblastic anemia. These are less likely due to normal CBC. 2. B. Factor VIII is low in patients with von Willebrand disease , since von Willebrand factors are carriers of factor VIII. Lacking of von Willebrand factors will influence stabilization of factor VIII. This is less likely to be either Hemophilia A or Hemophilia B since the later tw