Hypogammaglobulinemia is a problem with the immune system in which not enough
gamma globulin
Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis. The most significant gamma globulins are immunoglobulins (antibodies), although some immunoglobulins are not gamma globulins, and some g ...
s are produced in the blood (thus ''
hypo-'' + ''gamma'' + ''
globulin'' + ''
-emia''). This results in a lower
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
count, which impairs the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as
common variable immunodeficiency
Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign ...
, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria.
Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of
live vaccines, and take precautionary measures when traveling to regions with
endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.
Types
The following lists types of "agammaglobulinemia" catalogued in the OMIM. Hypogammaglobulinemia can have other types; see sections "Causes" and "Etymology" below.
Symptoms and signs
The presenting feature of hypogammaglobulinemia is usually a clinical history of recurrent, chronic, or atypical infections. These infections include but are not limited to:
bronchitis
Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...
,
ear infections,
meningitis
Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...
,
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
,
sinus infections
Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, headac ...
, and
skin infections Skin and skin structure infections (SSSIs), also referred to as skin and soft tissue infections (SSTIs), or acute bacterial skin and skin structure infections (ABSSSIs), are infections of skin and associated soft tissues (such as loose connective ti ...
. Such infections can potentially damage organs, leading to severe complications. Other symptoms of hypogammaglobulinemia include chronic
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
and complications from receiving live vaccines. Certain symptoms of chronic damage may be related to recurrent infection. For example,
shortness of breath
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, chronic cough, and sputum production may indicate the presence of
bronchiectasis
Bronchiectasis is a disease in which there is permanent enlargement of parts of the airways of the lung. Symptoms typically include a chronic cough with mucus production. Other symptoms include shortness of breath, coughing up blood, and chest ...
. Sinus pain, nasal discharge, and
postnasal drip
Post-nasal drip (PND), also known as upper airway cough syndrome (UACS), occurs when excessive mucus is produced by the nasal mucosa. The excess mucus accumulates in the back of the nose, and eventually in the throat once it drips down the back ...
may indicate the presence of
chronic sinusitis
Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, heada ...
. Diarrhea and
steatorrhea
Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may o ...
may indicate
malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
.
Another sign or symptom that may occur in patients is blotchiness of the skin color, especially noticed above the waist, on the arms, neck, and upper chest areas, however, it may occur anywhere on the skin.
Babies with transient hypogammaglobulinemia (THI) usually become symptomatic 6 to 12 months after birth, with the symptoms usually consisting of frequent ear, sinus, and lung infections. Other symptoms include
respiratory tract infections,
food allergies,
eczema
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...
,
urinary tract infection
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...
s, and intestinal infections.
Causes
Hypogammaglobulinemia can be caused by either a
primary
Primary or primaries may refer to:
Arts, entertainment, and media Music Groups and labels
* Primary (band), from Australia
* Primary (musician), hip hop musician and record producer from South Korea
* Primary Music, Israeli record label
Works
...
or
secondary
Secondary may refer to: Science and nature
* Secondary emission, of particles
** Secondary electrons, electrons generated as ionization products
* The secondary winding, or the electrical or electronic circuit connected to the secondary winding i ...
immunodeficiency. Primary immunodeficiencies are caused by a
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
or series of mutations to the genome.
For example, a study from 2012 found that a compound
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
...
deleterious mutation in the
CD21 gene is associated with hypogammaglobulinemia. Genetic analysis revealed the patient was heterozygous for CD21, with the paternally inherited
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chrom ...
(also shared with one sister) having a disrupted splicing donor site at exon 6, while the maternally inherited allele had a mutation resulting in a
premature stop codon
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produ ...
in exon 13. Neither mutation was found in 100 healthy control subjects, showing the rarity of the mutations. Around 300 different genes in total have been identified which account for different forms of
primary immunodeficiency (PID). These different forms can affect different parts of the immune system, including immunoglobulin production. Primary immunodeficiencies usually have a delay of several years between initial clinical presentation and diagnosis. Some primary immune deficiencies include
ataxia-telangiectasia (A-T),
autosomal recessive agammaglobulinemia (ARA),
common variable immunodeficiency
Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign ...
(CVID),
hyper-IgM syndromes
Hyper IgM syndrome describes a group of primary immune deficiency disorders characterized by defective CD40 signaling; ''via'' B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch reco ...
, IgG subclass deficiency, isolated non-IgG immunoglobulin deficiencies,
severe combined immunodeficiency (SCID), specific antibody deficiency (SAD),
Wiskott-Aldrich syndrome, or
X-linked agammaglobulinemia
X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the whit ...
. CVID is the most common form of primary immunodeficiency. SCID is considered a medical emergency and suspected cases require immediate specialist center referral for diagnosis and treatment. It is more often that hypogammaglobulinemia develops as a result of another condition, which are called secondary or acquired immune deficiencies. These include blood cancers such as
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever ...
(CLL),
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
, or
myeloma,
HIV,
nephrotic syndrome
Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy ...
, poor nutrition,
protein-losing enteropathy, getting an
organ transplant
Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpor ...
, or
radiation therapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
. This also includes medications which can cause hypogammaglobulinemia such as
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are inv ...
s,
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
drugs, or
antiseizure medication.
Screening
Screening of immunoglobulin levels in relatives of CVID and IgA patients finds a familial inheritance rate of 10% to 20%. In cases where a carrier of such a mutation would like to have children,
preimplantation genetic diagnosis (PGD) has been offered.
PGD is defined as the testing of pre-implantation stage embryos or oocytes for genetic defects. It requires
in vitro fertilization, embryo biopsy, and either
fluorescent in situ hybridization
Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by ...
or
polymerase chain reaction
The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
on a singular cell, making it a complex procedure. While some question the ethicality of such artificial selection, it is generally seen as an important alternative to prenatal diagnosis. Prevention of secondary immunodeficiency involves monitoring patients carefully with high risk of developing hypogammaglobulinemia. This entails measuring immunoglobulin levels in patients with hematologic malignancy, or those receiving chemotherapy or immunosuppressive therapy such as
rituximab.
Treatment
Protocols for different forms of primary immunodeficiency vary significantly. The aim of treatments implemented by specialist centers is usually to reduce the risk of complications. One method of treatment is by
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
administration of gamma globulins, either monthly
intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
,
subcutaneously, or more recently, by weekly self-administered
hypodermoclysis. In either case, mild allergic reactions are common, and are usually manageable with oral
diphenhydramine
Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into ...
. Evidence comparing immunoglobulin replacement with no treatment is limited, and guidelines for treatment are therefore mainly derived from
observational studies.
Antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s are also frequently used as treatment. Other standard forms of treatment include a form of
enzyme replacement therapy
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is availa ...
called PEG-ADA, and antibiotic treatment given for the prevention of
Pneumocystis pneumonia
''Pneumocystis'' pneumonia (PCP), also known as ''Pneumocystis jirovecii'' pneumonia (PJP), is a form of pneumonia that is caused by the yeast-like fungus ''Pneumocystis jirovecii''.
''Pneumocystis'' specimens are commonly found in the lungs of ...
.
One emerging therapy is
hematopoietic stem cell transplantation, which has been considered standard treatment for many combined primary immunodeficiencies including SCID, CD40 deficiency, CD40 ligand deficiency, and Wiskott-Aldrich syndrome, but has been extended to secondary immunodeficiencies over the last two decades. Another emerging therapy is
gene therapy
Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...
, which has been used to treat X-linked SCID, SCID due to
adenosine deaminase deficiency
Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immuno ...
, and
chronic granulomatous disease
Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reacti ...
.
Prognosis
Early detection and treatment of hypogammaglobulinemia is known to reduce rates of
morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
and the chance of long-term pulmonary complications. Evidence shows that there is an association between achieving higher IgG levels and reduced infection frequency. If hypogammaglobulinemia remains undetected and untreated, outcomes are generally poor, especially if chronic lung damage or bronchiectasis has occurred. Unfortunately, the diagnosis of hypogammaglobulinemia is often significantly delayed.
Research
In 2015, a journal article by McDermott et al. reported on a case in which
chromothripsis, normally a catastrophic event in which chromosomes undergo massive deletion and rearrangement within a single stem cell's DNA, cured a patient with
WHIM syndrome, a primary immunodeficiency disease. WHIM is
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
and is caused by a
gain-of-function mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
of the
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
receptor CXCR4. The mutation in CXCR4 increases signaling because it disrupts negative regulatory elements usually present, creating exaggerated functions of the receptor. The term "WHIM" is an acronym for the main manifestations of the disease: warts, hypogammaglobulinemia, recurrent infections, and
myelokathexis. Myelokathexis is impaired escape of mature
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s from bone marrow, causing
neutropenia
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
. Patients with WHIM syndrome have severely reduced peripheral blood B cells and some reduction in peripheral blood T cells and
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s (McDermott). The cured patient, designated WHIM-09, is a white female presented at age 58. She also presented with her two daughters, WHIM-10 (age 21) and WHIM-11 (age 23). Both daughters fulfilled all of the clinical criteria for WHIM syndrome, while WHIM-09 did not. She reported that she had had many serious infections from childhood until age 38 but had had none in the past 20 years. She has fulfilled none of the criteria for WHIM syndrome except for mild hypogammaglobulinemia since then. WHIM-09 was the first patient ever described with myelokathexis, the "M" in WHIM syndrome, and her parents and siblings showed no sign of the syndrome. Therefore, the evidence is compatible with a WHIM mutation occurring de novo in patient WHIM-09, an autosomal dominant transition to two of her three daughters, and a spontaneous and complete remission in WHIM-09. This provides the first evidence that chromothripsis may result in clinical benefit, in particular, the cure of a genetic disease. If a cell with chromothripsis dies, it is clinically undetectable, making the true frequency of its occurrence hard to determine. Therefore, it is only detected if it acquires a strong selective advantage creating a clinically apparent clonal population harboring the same pattern of deletions and arrangements. This results in either cancer, or if the location is fortuitous, the cure of a genetic condition as occurred in patient WHIM-09.
Effect on viral evolution
One study of the genomic variation in the
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...
virus in patients with and without hypogammaglobulinemia found that patients with hypogammaglobulinemia had fewer
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
substitutions per year than the control patients, suggesting that in the absence of selective pressure caused by the immune system, the frequency of the occurrence of genetic variation in the major viral species is reduced. They used five control patients and four patients with CVID, a particularly severe form of hypogammaglobulinemia. The control patients had a mean nucleotide
rate-of-change of 6.954 nucleotide substitutions per year while the patients with CVID had 0.415 nucleotide substitutions per year. While the mutations still occur in the patients with CVID, they tend to remain as a minor species in the absence of immune selection.
Terminology
"Hypogammaglobulinemia" is largely synonymous with "agammaglobulinemia". When the latter term is used (as in "
X-linked agammaglobulinemia
X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the whit ...
") it implies that gamma globulins are not merely reduced, but completely absent. Modern assays have allowed most agammaglobulinemias to be more precisely defined as hypogammaglobulinemias, but the distinction is not usually clinically relevant.
"Hypogammaglobulinemia" is distinguished from
dysgammaglobulinemia
Dysgammaglobulinemia is a type of immune disorder characterized by a reduction in some types of gamma globulins, resulting in heightened susceptibility to some infectious diseases where primary immunity is antibody based.
It is distinguished from ...
, which is a reduction in some types of
gamma globulin
Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis. The most significant gamma globulins are immunoglobulins (antibodies), although some immunoglobulins are not gamma globulins, and some g ...
s, but not others.
References
Further reading
*
*
External links
{{Cell surface receptor deficiencies
Lymphocytic immune system disorders