Pathology Notes

Chediak-Higashi syndrome Updated: 08/03/2020 © Jun Wang, MD, PhD General features Rare Autosomal recessive Lysosomal storage disorder Associated with primary immunodeficiency due to impaired phagocytosis Affects multiple systems Symptoms usually present soon after birth Most patients died before 10 as a result of infection or an accelerated lymphoma like phase Pathogenesis Abnormal intracellular protein transport and pigmentation Chediak-Higashi syndrome genes ( LYST/CHS1 ) mutation Abnormal organelle trafficking and fusion Defective lysosome functions Neutrophils and macrophages with normal phagocytic function but delayed fusion of phagosomes with lysosomes NK cell and T cell cytotoxicity markedly decreased due to defective exocytosis of granules Melanosome defects Clinical features Early presentations Nonpigmented skin , blonde hair, blue eyes (partial oculocutaneous albinism) Recurrent bacterial infections Coagulation defects, usually mild Aden

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