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Severe Combined Immunodeficiency (SCID)

Severe combined immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome (SCID), also called “bubble boy disease,” is a rare genetic disorder in which the development of functional 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 is disturbed due to several genetic mutations Genetic Mutations Carcinogenesis that result in reduced or absent immune function. It is the most severe form of primary immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome and is characterized by dysfunction in both humoral and cell-mediated immune responses. Multiple mutations can result in heterogeneous types of SCID. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with severe and recurrent 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 within the first months of life. Management includes IV immunoglobulins IV immunoglobulins Immunoglobulin preparations used in intravenous infusion, containing primarily immunoglobulin g. They are used to treat a variety of diseases associated with decreased or abnormal immunoglobulin levels including pediatric aids; primary hypergammaglobulinemia; scid; cytomegalovirus infections in transplant recipients, lymphocytic leukemia, chronic; kawasaki syndrome, infection in neonates, and idiopathic thrombocytopenic purpura. DiGeorge Syndrome and 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 transplantation. If left untreated, SCID is usually fatal within the 1st year of life.

Last updated: 10 Mar, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Etiology

Epidemiology

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: < 1 in 100,000 live births
  • Higher prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency rates are found in areas and cultures Cultures Klebsiella in which consanguineous mating is common.
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of 1 in 2,500 among Navajo and Apache children

Etiology

At least 12 genes Genes 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. DNA Types and Structure are known to cause severe combined immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome (SCID) if mutated, including those that encode for the following:

  • The common γ chain shared by the receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors for the cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IL-2, IL-4, IL-7, IL-9, and IL-15
    • IL-7 is the most important cytokine because it stimulates the survival and expansion of immature B- and T-cell precursors. 
  • Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs deaminase ( ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism)
  • Purine nucleoside phosphorylase Purine nucleoside phosphorylase An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. Purine and Pyrimidine Metabolism
  • Mitochondrial adenylate kinase 2
  • Janus kinase-3 (JAK3)
  • RAG-1 and RAG-2 genes Genes 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. DNA Types and Structure

The pattern of inheritance depends on the type of genetic 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 involved:

  • Approximately 50% of cases follow an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) recessive pattern of inheritance and are associated with mutations of the common γ chain.
  • Approximately 40%50% of cases follow an 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 pattern of inheritance and are often (50%) associated with mutations of ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism.

Pathophysiology

  • The 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 affected will determine which type of cell is lacking or deficient, with 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, B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, and NK cells NK cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology being the most commonly affected. 
  • All types of SCID are categorized by a low or absent level of 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.
  • Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors containing the common γ chain are located on the surface of immature cells in 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, which assist in forming lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology; regulate the growth and maturation of several subtypes of 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, B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, and natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology; and regulate the entire 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.
  • Mutations affecting these receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors lead to atrophic or hypoplastic lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs and lymphopenia.
  • Thus, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with SCID have extreme susceptibility to infection in infancy.
Table: Possible SCID phenotypes
Phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics Genetic defect Genetic Defect Ion Channel Myopathy
TB+NK γC, JAK3
TBNK+ RAG-1, RAG-2, Artemis, DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ligase IV, Cernunnos, DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure PKcs
TB+NK+ IL-7Rα, CD3δ, CD3ζ, Coronin-1A, ZAP-7O, CD45
TBNK ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism, AK2
Table: Types of SCID
Syndrome Defect
X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) severe combined immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome Mutations in the 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 encoding the common γ chain, a protein that is shared by the receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors for interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
Adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs deaminase deficiency
  • Caused by a defective enzyme, ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism, which is necessary for the breakdown of purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids
  • Leads to an accumulation of dATP, which inhibits the activity of ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism (enzyme that generates deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure)
Purine nucleoside phosphorylase Purine nucleoside phosphorylase An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. Purine and Pyrimidine Metabolism ( PNP PNP An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. Purine and Pyrimidine Metabolism) 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 involving mutations of the PNP PNP An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. Purine and Pyrimidine Metabolism 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
Reticular dysgenesis Inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 malfunction
Omenn syndrome Omenn syndrome An autosomal recessive form of severe combined immunodeficiency (SCID) caused by mutations in the RAG1 or RAG2 genes. IPEX Syndrome
  • Caused by a partial loss of RAG 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 function
  • Leads to loss or defective 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 recombination Recombination Production of new arrangements of DNA by various mechanisms such as assortment and segregation, crossing over; gene conversion; genetic transformation; genetic conjugation; genetic transduction; or mixed infection of viruses. Virology in T- and B-cell receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, which results in impaired pathogen recognition
Bare lymphocyte syndrome
  • 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 condition in which MHC molecules are affected
  • This type 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; their functionality is impaired, not their development.
JAK3 JAK3 is an enzyme that mediates transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology downstream of the γc signals.

Clinical Presentation

The disease typically presents in early childhood (26 months). Severe and recurrent opportunistic 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 are seen in affected individuals.

  • Chronic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Dermatitis Dermatitis Any inflammation of the skin. Atopic Dermatitis (Eczema)
  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive due to recurrent 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 and malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
  • Viral 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 (e.g., cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus [CMV] rotavirus Rotavirus A genus of Reoviridae, causing acute gastroenteritis in birds and mammals, including humans. Transmission is horizontal and by environmental contamination. Seven species (rotaviruses A through G) are recognized. Rotavirus, varicella)
  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
  • Candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
  • Mycobacterium avium Mycobacterium avium A bacterium causing tuberculosis in domestic fowl and other birds. In pigs, it may cause localized and sometimes disseminated disease. The organism occurs occasionally in sheep and cattle. It should be distinguished from the m. avium complex, which infects primarily humans. Mycobacterium complex (MAC) infection
  • Pneumocystis pneumonia Pneumocystis Pneumonia Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jirovecii/Pneumocystis Pneumonia (PCP) (common presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with no 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)
  • Lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy, thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, and tonsils Tonsils Tonsillitis are usually hypoplastic or absent in these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

Diagnosis

  • Early diagnosis is possible through newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care for SCID.
  • Symptoms that create suspicion of or support the diagnosis of SCID: 
    • Family history Family History Adult Health Maintenance of infant deaths
    • Presence of a chronic cough
    • Presence of hyperinflated lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
    • Recurrent and persistent 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 
  • To confirm the diagnosis:
    • Complete blood count: reduced levels of 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 and B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions or NK cells NK cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology (or both)
    • 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: T-cell subpopulation deficiency (definitive diagnosis)
  • Ancillary tests in SCID patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship (if needed):
    • Chest X-ray Chest X-ray X-ray visualization of the chest and organs of the thoracic cavity. It is not restricted to visualization of the lungs. Pulmonary Function Tests: absence of thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy
    • Lymph node biopsy Lymph Node Biopsy Lymphadenopathy: absence of germinal centers
Scid x-ray

Chest X-ray Chest X-ray X-ray visualization of the chest and organs of the thoracic cavity. It is not restricted to visualization of the lungs. Pulmonary Function Tests of a 5-month-old boy with SCID complicated by disseminated bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus Calmette-Guérin ( BCG BCG An active immunizing agent and a viable avirulent attenuated strain of Mycobacterium bovis, which confers immunity to mycobacterial infections. It is used also in immunotherapy of neoplasms due to its stimulation of antibodies and non-specific immunity. Cancer Immunotherapy) disease showing the absence of a thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy and bilateral areas of opacities

Image: “ Chest X-ray Chest X-ray X-ray visualization of the chest and organs of the thoracic cavity. It is not restricted to visualization of the lungs. Pulmonary Function Tests” by Pediatric Intensive Care Unit, Hospital Dona Estefânia, 1169-045 Lisboa, Portugal. License: CC BY 3.0

Management and Prognosis

  • 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 transplantation before 3 months of age
    • Avoid public exposure Exposure ABCDE Assessment prior to transplant.
    • The best donor is ideally a sibling with a close tissue match.
  • Intravenous immunoglobulin ( IVIG IVIG Dermatomyositis) infusion
    • Replaces missing immunoglobulin from B-cell dysfunction due to missing 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 results of IVIG IVIG Dermatomyositis last approximately 3 weeks.
  • Pneumocystis pneumonia Pneumocystis Pneumonia Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jirovecii/Pneumocystis Pneumonia (PCP) ( PCP PCP Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jirovecii/Pneumocystis Pneumonia (PCP)) prophylaxis Prophylaxis Cephalosporins with trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim sulfamethoxazole Sulfamethoxazole A bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. Its broad spectrum of activity has been limited by the development of resistance. Sulfonamides and Trimethoprim (TMP/SMX) starting at 1 month of age
  • Reverse isolation
  • Enzyme replacement for ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism deficiency
  • Investigational therapies include 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.
    • SCID is the first disease First disease Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. It is highly contagious and spreads by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Measles Virus in which 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 has successfully replaced the mutated 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.
    • Still considered experimental or investigational because some of the patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who received the treatment later developed leukemia
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
    • Highly fatal
    • Death results from repeated 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 before the age of 2

Differential Diagnosis

The following conditions are differential diagnoses for SCID:

  • DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome: a condition caused by a microdeletion at a location designated q11.2 of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22, due to defective development of the 3rd and 4th pharyngeal pouches Pharyngeal pouches Branchial Apparatus and Aortic Arches, leading to thymic and parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) (causing T-cell immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome and hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, respectively). Other manifestations include characteristic facial features, congenital Congenital Chorioretinitis heart defects, frequent 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, and neuropsychiatric disorders.
  • CHARGE syndrome CHARGE Syndrome CHARGE syndrome is a rare genetic condition with autosomal dominant inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genetic Abnormalities, and Ear abnormalities. CHARGE Syndrome: a rare genetic disorder in children affecting almost all body systems due to impaired 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 expression as a result of inherited mutations in the specific genes Genes 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. DNA Types and Structure. CHARGE stands for Coloboma, Heart defects, Atresia choanae, Growth retardation, Genital abnormalities, and E ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation abnormalities. The syndrome is usually associated with hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) or aplasia Aplasia Cranial Nerve Palsies of the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, leading to immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome.
  • Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich Syndrome: an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) mixed disorder of B- and T-cell deficiency. Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich Syndrome is caused by a WAS 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 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 that leads to impaired actin Actin Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or f-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or g-actin. In conjunction with myosins, actin is responsible for the contraction and relaxation of muscle. Skeletal Muscle Contraction cytoskeleton Cytoskeleton The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. The Cell: Cytosol and Cytoskeleton, 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 and chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1, impaired platelet development, and, in general, a loss of humoral and cellular responses. The syndrome presents as eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema), bleeding disorders Bleeding disorders Hypocoagulable conditions, also known as bleeding disorders or bleeding diathesis, are a diverse group of diseases that result in abnormal hemostasis. Physiologic hemostasis is dependent on the integrity of endothelial cells, subendothelial matrix, platelets, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding. Hypocoagulable Conditions, recurrent opportunistic 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, and autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity.
  • HIV HIV Anti-HIV Drugs infection and AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS: caused by a single-stranded RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology in the Retroviridae Retroviridae The human immunodeficiency virus (HIV) is a species of Lentivirus, a genus of the family Retroviridae, which causes HIV infections and acquired immunodeficiency syndrome (AIDS). The virus has high genetic variability and is divided into 2 major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). The human immunodeficiency virus is a single-stranded, positive-sense, enveloped RNA virus, which targets and destroys WBCs, leading to frequent opportunistic infections and, eventually, death. Human Immunodeficiency Virus (HIV) family; transmitted through the exchange of body fluids such as semen and blood. Presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor is marked by a deterioration of 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, beginning with constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis such as lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, and advancing into AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS-defining illnesses, such as opportunistic 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.
  • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome ( CVID CVID Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins g, a, and m. Common Variable Immunodeficiency (CVID)): a type of primary immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome characterized by reduced serum levels of immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions G, A, and M. The underlying causes are unknown. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with this condition are prone to 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 in the gastrointestinal tract and the upper and lower respiratory tracts and have a higher risk of developing autoimmune, granulomatous, and neoplastic diseases.

References

  1. National Institute of Allergy and Infectious Diseases (2019. https://www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid
  2. American Academy of Asthma Allergy & Immunology. Retrieved August 28, 2020, from https://www.aaaai.org/conditions-and-treatments/primary-immunodeficiency-disease/severe-combined-immunodeficiency#:~:text=Severe%20Combined%20Immunodeficiency%20(SCID)%20is,be%20the%20most%20serious%20PIDD.
  3. Le, T., & Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th anniversary edition) P. 117. New York: McGraw-Hill Medical.
  4. Kumar, V., Abbas, A. K., Aster, J. C., & Robbins, S. L. (2013). Robbins basic pathology, p. 142. Philadelphia, PA: Elsevier/Saunders.

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