Leukocyte Adhesion Deficiency Type 1

Epidemiology and Etiology

Epidemiology

• < 400 cases in the United States
• All races are affected.
• Mortality Mortality All deaths reported in a given population. Measures of Health Status:
  • Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with the severe form (< 1% expression of CD18) die within the 1st 2 years of life.
  • Those with 1%–30% expression of CD18 may survive to adulthood.

Etiology

• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics: Leukocyte adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies deficiency type 1 Type 1 Spinal Muscular Atrophy (LAD1) is caused by mutations in the ITGB2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. 
• Mode of inheritance: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance 
• Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis encoded: CD18, the beta-2 subunit of 3 integrins:
  • Lymphocyte function–associated antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 1 (LFA-1)
  • Macrophage antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 1 (Mac-1)
  • Glycoprotein (GP) 150/95

Pathophysiology and Clinical Presentation

Pathophysiology

• Integrins are important for: 
  • Leukocyte adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies to endothelial cells during migration
  • Interacting with antigen-presenting cells Antigen-presenting cells A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors. Adaptive Immune Response
  • Cytotoxic Cytotoxic Parvovirus B19 killing
• A deficiency or mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in these integrins interferes with:
  • Leukocyte adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies
  • Transmigration
  • Chemotaxis
  • Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation
  • Respiratory burst 
• Result: The immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs is unable to properly respond to an infection.

Clinical presentation

• Recurrent bacterial or fungal soft tissue Soft Tissue Soft Tissue Abscess infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Omphalitis (infection of the umbilical cord stump Umbilical Cord Stump Physical Examination of the Newborn) is common shortly after birth. 
• Other signs include:
  • Delayed separation of the umbilical cord Umbilical cord The flexible rope-like structure that connects a developing fetus to the placenta in mammals. The cord contains blood vessels which carry oxygen and nutrients from the mother to the fetus and waste products away from the fetus. Placenta, Umbilical Cord, and Amniotic Cavity
  • Periodontal disease
  • Elevated neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation
  • Impaired wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing
  • Fevers

Diagnosis and Management

Diagnosis

• Involves several preliminary tests of immune function, including basic evaluation of the humoral immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs and the cell-mediated immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs
• WBC differential will reveal extremely elevated levels of neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation.
• Confirmation with flow cytometry Flow cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. X-linked Agammaglobulinemia to evaluate for CD18 deficiency

Management

• Currently, the only curative therapy is hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation.
• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics therapy is a potential treatment.

Differential Diagnosis

• Bare lymphocyte syndrome Bare lymphocyte syndrome Severe Combined Immunodeficiency (SCID): form of SCID SCID Severe combined immunodeficiency (SCID), also called “bubble boy disease,” is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. Severe Combined Immunodeficiency (SCID) in which MHC molecules are affected. Bare lymphocyte syndrome Bare lymphocyte syndrome Severe Combined Immunodeficiency (SCID) is notable for having normal levels of B and T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions. The functionality of these cells, not their development, is impaired. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can have recurrent bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, particularly of the respiratory tract. Management includes allogeneic stem cell transplantation Allogeneic Stem Cell Transplantation Acute Lymphoblastic Leukemia.
• Chronic granulomatous disease Granulomatous disease A defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. When chronic granulomatous disease is caused by mutations in the cybb gene, the condition is inherited in an X-linked recessive pattern. When chronic granulomatous disease is caused by cyba, ncf1, ncf2, or ncf4 gene mutations, the condition is inherited in an autosomal recessive pattern. Common Variable Immunodeficiency (CVID): consequence of defective phagocytic cells. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will have recurrent infections Recurrent infections Common Variable Immunodeficiency (CVID), abscesses, and granulomatous lesions of multiple organs. The diagnosis is made with neutrophil function testing for superoxide production. Antimicrobial prophylaxis Prophylaxis Cephalosporins, interferon-gamma, granulocyte transfusion Granulocyte transfusion Severe Congenital Neutropenia, and hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation are potential management options.
• Chediak-Higashi syndrome ( CHS CHS Cannabinoids): autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder caused by mutations affecting a lysosomal trafficking regulator Lysosomal trafficking regulator Chédiak-Higashi Syndrome protein. This protein plays a crucial role in the inability of neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation to kill phagocytosed microbes. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with CHS CHS Cannabinoids exhibit recurrent pyogenic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, easy bleeding and bruising, and neurologic manifestations. This syndrome is also associated with oculocutaneous albinism Oculocutaneous albinism Heterogeneous group of autosomal recessive disorders comprising at least four recognized types, all having in common varying degrees of hypopigmentation of the skin, hair, and eyes. The two most common are the tyrosinase-positive and tyrosinase-negative types. Albinism. The diagnosis is made based on analysis of the patient’s blood or bone marrow smear Bone marrow smear Chédiak-Higashi Syndrome and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. The treatment of choice is allogeneic hematopoietic cell transplantation.
• Hyper-IgE syndrome: hereditary primary immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome disease characterized by recurrent skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions abscesses, pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia with pneumatoceles Pneumatoceles Pneumocystis jirovecii/Pneumocystis Pneumonia (PCP), and eczematous dermatitis Dermatitis Any inflammation of the skin. Atopic Dermatitis (Eczema). The diagnosis is made with elevated serum IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions levels and can be confirmed with genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management includes prophylactic antibiotics and interferon-gamma for severe infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.
• Severe congenital neutropenia Congenital neutropenia Severe Congenital Neutropenia: rare disease resulting from genetic mutations Genetic Mutations Carcinogenesis that affect myelopoiesis Myelopoiesis Formation of myeloid cells from the pluripotent hematopoietic stem cells in the bone marrow via myeloid stem cells. Myelopoiesis generally refers to the production of leukocytes in blood, such as monocytes and granulocytes. This process also produces precursor cells for macrophage and dendritic cells found in the lymphoid tissue. White Myeloid Cells: Histology. Severe congenital neutropenia Congenital neutropenia Severe Congenital Neutropenia manifests in infancy with life-threatening bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia is found on laboratory evaluation, often with an elevated monocyte count. A bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma will also aid in the diagnosis. Management includes granulocyte colony-stimulating factor Granulocyte colony-stimulating factor A glycoprotein of mw 25 kda containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. White Myeloid Cells: Histology and hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation.
• Myeloperoxidase Myeloperoxidase Acute Myeloid Leukemia deficiency: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder that causes impaired microbial killing by phagocytes. The majority of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with myeloperoxidase Myeloperoxidase Acute Myeloid Leukemia deficiency are asymptomatic, while others can have recurrent, severe fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. The diagnosis is made with histochemical staining Histochemical staining Myeloperoxidase Deficiency for myeloperoxidase Myeloperoxidase Acute Myeloid Leukemia in neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation. There is no specific management for this condition, but patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be treated for any infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.