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Hyper-IgM Syndrome

The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome disorders characterized by low or absent serum levels of IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis, and IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions and normal or elevated levels of IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions. Hyper-IgM syndrome is most commonly caused by 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) mutations in the CD40 ligand 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, which results in abnormal signaling between B and T 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. Because of the pattern of inheritance, male individuals are most commonly affected. Typically, CD40 is involved in the generation of 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 with high-affinity immunoglobulin. CD40 is also involved in the maturation 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. The disease has a wide range of severity, ranging from 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 in early infancy to autoimmune conditions and malignancies. Management includes immunoglobulin replacement and administration of prophylactic antimicrobial agents. The only curative approach is hematopoietic cell transplantation.

Last updated: 27 May, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Epidemiology

  • Very rare group of diseases
  • 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: approximately 2 in every 1 million newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn boys

Pathophysiology

  • CD40 ligand is found on the surface 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 attaches to its receptor Receptor 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 on the membrane of 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, which produce antibodies Antibodies 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
  • Defective CD40 leads to a defective interaction between 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 and a humoral immune response.
  • 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 are incapable of class switching, resulting in an overproduction of IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions antibodies Antibodies 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 and an underproduction of IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis, and IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions.
  • Leads to vulnerability to encapsulated Encapsulated Klebsiella bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology and toxins

Classification

There are various conditions that belong to hyper-IgM syndrome. Because of the rareness of the syndrome, only the most common causes are mentioned below.

CD40 ligand (CD40L) deficiency

  • Combined immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome
  • Most common form of hyper-IgM syndrome
  • X-linked inheritance X-linked inheritance 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. Alport Syndrome
  • Impaired interaction between activated CD4+ 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 expressing CD40L and cells expressing CD40

Activation-induced cytidine deaminase Activation-induced cytidine deaminase B cells: Types and Functions (AID) deficiency

CD40 deficiency

Clinical Presentation

The median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion age at onset for hyper-IgM syndrome is approximately 2 years. It often takes a few more years for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship to be diagnosed with the condition. Possible signs and symptoms include:

  • Recurrent sinopulmonary 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 infancy
  • 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, especially:
    • Pneumocystis jirovecii 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 ( 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))
    • Histoplasma Histoplasma Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Histoplasma/Histoplasmosis lung infection Lung infection 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
    • Cryptosporidium gastroenteritis Gastroenteritis Gastroenteritis is inflammation of the stomach and intestines, commonly caused by infections from bacteria, viruses, or parasites. Transmission may be foodborne, fecal-oral, or through animal contact. Common clinical features include abdominal pain, diarrhea, vomiting, fever, and dehydration. Gastroenteritis
    • GI infection GI infection Microsporidia/Microsporidiosis with Giardia Giardia A genus of flagellate intestinal eukaryotes parasitic in various vertebrates, including humans. Characteristics include the presence of four pairs of flagella arising from a complicated system of axonemes and cysts that are ellipsoidal to ovoidal in shape. Nitroimidazoles lamblia
    • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus
  • Malignancies
  • 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
  • Autoimmune disorders
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
  • Encephalopathy (degenerative)

Diagnosis

Laboratory abnormalities

  • Low levels of IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis, IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, and IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions in serum
  • Normal or elevated levels of IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions in serum
  • Insufficient or missing antibody response to certain protein ( tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus, diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria, and Haemophilus influenzae Haemophilus Influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through viii. Haemophilus) and polysaccharide ( Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae) antigens

Confirmatory tests

  • 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 analysis to confirm 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 of CD40
  • 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 showing absent or decreased expression of CD40 ligand protein on the surface 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

Management and Prognosis

Management

  • CD40L and CD40 deficiency: 
    • Immunoglobulin replacement therapy → reduces risk of bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis and 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
    • Allogeneic hematopoietic cell transplantation (HCT): curative approach
    • Monitoring: regular Regular Insulin assessment of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy parameters plus ultrasound
  • AID deficiency: 
    • Immunoglobulin replacement therapy → reduces risk of bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis and 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
    • HCT: curative approach
    • Monitoring: regular Regular Insulin checkups to monitor for bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis and lymphoproliferative diseases

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

  • CD40L and CD40 deficiency: 
    • Most common causes of death are 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, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease, and malignancies.
    • Life expectation is most impacted by the presence and severity of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease.
    • About 60% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship live until 20 years of age.
    • Hematopoietic cell transplantation increases survival to 90% at 20 years of age.
  • AID deficiency: 
    • Better 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 than CD40L and CD40 deficiency
    • Regular Regular Insulin immunoglobulin replacement therapy and early treatment of 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 improve outcome significantly.

Differential Diagnosis

  • Agammaglobulinemia or hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency: condition with absent or extremely low 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. The 3 major types that have been described are 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), early-onset, and late-onset. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with 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 have no tonsils Tonsils Tonsillitis and adenoids. Diagnosis is made by measuring reduced serum 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 and by 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 replacement 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.
  • 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)): One of the most common primary immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome diseases caused by defective B-cell maturation and immunoglobulin production. The cause of 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) remains unknown in most cases. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may present with 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, lymphoid hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, and malignancies. Diagnosis includes measurement of serum 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 and poor response to vaccines. 

References

  1. Qamar N, Fuleihan RL. (2014). The hyper IgM syndromes. Retrieved March 22, 2021, from https://pubmed.ncbi.nlm.nih.gov/23797640/
  2. Karaca NE, Durandy A, Gulez N, Aksu G, Kutukculer N. (2011). Study of patients with hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature. European Journal of Pediatrics 170:1039–1047. https://doi.org/10.1007/s00431-011-1400-2
  3. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. (2009). Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunological Reviews 229:152–172. https://doi.org/10.1111/j.1600-065X.2009.00782.x 
  4. Levy J, et al. (1997). Clinical spectrum of X-linked hyper-IgM syndrome. Journal of Pediatrics 131(1 Pt 1):47–54. https://doi.org/10.1016/s0022-3476(97)70123-9

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