By definition, primary immune deficiencies are due to genetic causes. They may result from a single genetic defect, but most are multifactorial. They may be caused by recessive or dominant inheritance. Some are latent, and require a certain environmental trigger to become manifest, like the presence in the environment of a reactive allergen. Other problems become apparent due to aging of bodily and cellular maintenance processes.

A survey of 10,000 American households revealed that the prevalence of diagnosed primary immunodeficiency approaches 1 in 1200. This figure does not take into account people with mild immune system defects who have not received a formal diagnosis.

Milder forms of primary immunodeficiency, such as selective immunoglobulin A deficiency, are fairly common, with random groups of people (such as otherwise healthy blood donors) having a rate of 1:600. Other disorders are distinctly more uncommon, with incidences between 1:100,000 and 1:2,000,000 being reported.

WHIM Syndrome (or Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Neutropenia is usually detected shortly after birth, affecting 6% to 8% of all newborns in neonatal intensive care units (NICUs). Out of the approximately 600,000 neonates annually treated in NICUs in the United States, 48,000 may be diagnosed as neutropenic. The incidence of neutropenia is greater in premature infants. Six to fifty-eight percent of preterm neonates are diagnosed with this auto-immune disease. The incidence of neutropenia correlates with decreasing birth weight. The disorder is seen up to 38% in infants that weigh less than 1000g, 13% in infants weighing less than 2500g, and 3% of term infants weighing more than 2500 g. Neutropenia is often temporary, affecting most newborns in only first few days after birth. In others, it becomes more severe and chronic indicating a deficiency in innate immunity.

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

Cyclic neutropenia (or cyclical neutropenia) is a form of neutropenia, a white blood cell deficiency, that tends to occur every three weeks and lasts three to six days at a time due to changing rates of cell production by the bone marrow.

Cyclic neutropenia is the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase,

and is estimated to occur in 1 in 1 million individuals worldwide. Treatment includes G-CSF and usually improves after puberty.

Kostmann syndrome is a group of diseases that affect myelopoiesis, causing a congenital form of neutropenia (severe congenital neutropenia [SCN]), usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections.

Most cases of SCN respond to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count and decreases the severity and frequency of infections. Although this treatment has significantly improved survival, people with SCN are at risk of long-term complications such as hematopoietic clonal disorders (myelodysplastic syndrome, acute myeloid leukemia).

Kostmann disease (SCN3), the initial subtype recognized, was clinically described in 1956. This type has an autosomal recessive inheritance pattern, whereas the most common subtype of Kostmann syndrome, SCN1, shows autosomal dominant inheritance.

The various mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease.

The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. No geographical factor is present.

This form usually lessens in severity within two years of diagnosis.

The use of prophylactic antibiotics has been proposed.

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Recent studies have found that the life expectancy of males with XLT is not significantly affected. Individuals with XLT typically experience milder symptoms than those with other "WAS"-related disorders. For this reason, the long term prognosis for individuals with XLT is generally positive as long as symptoms are managed appropriately. Enhanced treatment methods in the past two decades have significantly improved the prognosis as well.

Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The disorder is believed to be inherited in an autosomal dominant manner. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). The disorder shows prominent neutrophil morphologic abnormalities.

Myelokathexis is amongst the diseases treated with bone marrow transplantation and cord blood stem cells.

WHIM syndrome is a very rare variant of severe congenital neutropenia that presents with warts, hypogammaglobunemia, infections, and myelokathexis. A gain in function mutation resulting in a truncated form of CXCR4 is believe to be its cause.

WHIM syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, CXCR4, resulting in a carboxy-terminus truncation of the receptor of between ten and 19 residues. The gene mutant is located on 2q21. The truncation of the receptor protein results in the inability of downregulation after stimulation. Thus, the receptor remain in an activated state. WHIM syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking.

An association with "GRK3" has also been observed.

The pathophysiology of neutropenia can be divided into "congenital" and "acquired". In congenital neutropenia (cyclic neutropenia) is autosomal dominant, mutations in the ELA2 gene (neutrophil elastase), is the genetic reason for this condition.

Acquired neutropenia (immune-associated neutropenia) is due to anti-neutrophil antibodies that work against neutrophil-specific antigens, ultimately altering neutrophil function.

Neutropenia fever can complicate the treatment of cancers. Observations of pediatric patients have noted that fungal infections are more likely to develop in patients with neutropenia. Mortality increases during cancer treatments if neutropenia is also present.

Congenital neutropenia is determined by blood neutrophil counts (absolute neutrophil counts or ANC) < 0.5 × 10/L and recurrent bacterial infections beginning very early in childhood.

Congenital neutropenia is related to alloimmunization, sepsis, maternal hypertension, twin-to-twin transfusion syndrome, and Rh hemolytic disease.

Autoimmune neutropenia is a form of neutropenia which is most common in infants and young children where the body identifies the neutrophils as enemies and makes antibody to destroy them.

Primary autoimmune neutropenia (AIN) is an autoimmune disease first reported in 1975 that primarily occurs in infancy. In autoimmune neutropenia, the immune system produces autoantibodies directed against the neutrophilic protein antigens in white blood cells known as granulocytic neutrophils (granulocytes, segmented neutrophils, segs, polysegmented neutrophils, polys). These antibodies destroy granulocytic neutrophils. Consequently, patients with autoimmune neutropenia have low levels of granulocytic neutrophilic white blood cells causing a condition of neutropenia. Neutropenia causes an increased risk of infection from organisms that the body could normally fight easily.

Who is Affected?

Primary autoimmune neutropenia has been reported as early as the second month of life although most cases are diagnosed in children between 5 and 15 months of age. Girls have a slightly higher risk of developing AIN than boys. In neutropenia discovered at birth or shortly after birth, a diagnosis of allo-immune neutropenia (from maternal white blood cell antibodies passively transferred to the infant) is more likely.

Neutropenia

In infants neutropenia is defined by absolute neutrophil counts less than 1000/uL. After the first year of life neutropenia is defined by absolute counts less than 1500/uL. Neutropenia may be primary in which it is the only blood abnormality seen. In secondary neutropenia, other primary conditions occur, including other autoimmune diseases, infections, and malignancies. Neutropenia is considered chronic when it persists for more than 6 months.

Symptoms and Disease Course

Neutropenia, which may be discovered on routine blood tests, typically causes benign infections even when the condition is severe. Ear infections (otitis media) are the most common infection seen in autoimmune neutropenia and typically infection responds to antibiotic treatment alone. Infections associated with primary AIN are usually mild and limited, including skin infections such as impetigo, gastroenteritis, upper respiratory tract infections, and ear infections. Rarely, cellulitis and abscesses may occur.

Studies of children studied for up to six years showed that most cases of autoimmune neutropenia resolved spontaneously after a median of 17 months. In 80 percent of patients, neutropenia persisted for 7 to 24 months.

Diagnosis

Patients with autoimmune neutropenia are diagnosed on the basis of blood tests showing neutropenia and the presence of granulocyte-specific antibodies. In some cases, tests for granulocyte-specific antibodies need to be repeated several times before a positive result is seen. Bone marrow aspiration, if performed, is typically normal or it can show increased cell production with a variably diminished number of segmented granulocytes.

s association with prior parvovirus B19 has been made, but this hasn’t been confirmed. Similar to the platelet deficiency idiopathic thrombocytopenic purpura, vaccines are suspected of triggering this disorder.

Treatment

Treatment consists of corticosteroids to reduce autoantibody production, antibiotics to prevent infection and granulocyte colony-stimulating factor (G-CSF) to temporarily increase neutrophil counts. In cases of severe infection or the need for surgery, intravenous immunoglobulin therapy may be used.

Cyclic neutropenia is a disorder that causes frequent infections and other health problems in affected individuals. People with this condition have recurrent episodes of neutropenia during which there is a shortage (deficiency) of neutrophils. Neutrophils are a type of white blood cell that plays a role in inflammation and in fighting infection. The episodes of neutropenia are apparent at birth or soon afterward. For most affected individuals, neutropenia recurs every 21 days and lasts about 3 to 5 days.

Neutropenia makes it more difficult for the body to fight off pathogens such as bacteria and viruses, so people with cyclic neutropenia typically develop recurrent infections of the sinuses, respiratory tract, and skin. Additionally, people with this condition often develop open sores (ulcers) in the mouth and colon, inflammation of the throat (pharyngitis) and gums (gingivitis), recurrent fever, or abdominal pain. People with cyclic neutropenia have these health problems only during episodes of neutropenia. At times when their neutrophil levels are normal, they are not at an increased risk of infection and inflammation.

XMEN disease is a rare genetic disorder of the immune system that illustrates the role of Mg2+ in cell signaling. XMEN stands for “X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia.” It is characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Investigators in the laboratory of Dr. Michael Lenardo, National Institute of Allergy and Infectious Diseases at the National Institutes of Health first described this condition in 2011.

X-linked thrombocytopenia, also referred to as XLT or thrombocytopenia 1, is an inherited clotting disorder that primarily affects males. It is a "WAS"-related disorder, meaning it is caused by a mutation in the Wiskott-Aldrich Syndrome ("WAS") gene, which is located on the short arm of the X chromosome. "WAS"-related disorders include Wiskott-Aldrich syndrome, XLT, and X-linked congenital neutropenia (XLN). Of the "WAS"-related disorders, X-linked thrombocytopenia is considered to be the milder phenotype. Between 1 and 10 per million males worldwide are affected with this disorder. Females may be affected with this disorder but this is very rare since females have two X chromosomes and are therefore typically carriers of the mutation.

It is thought to have an estimated incidence of 1 in 75,000 people.

Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop "in utero". However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.

The five subtypes of FHL are each associated with a specific gene:

- FHL1: "HPLH1"

- FHL2: "PRF1" (Perforin)

- FHL3: "UNC13D" (Munc13-4)

- FHL4: "STX11" (Syntaxin 11)

- FHL5: "STXBP2" (Syntaxin binding protein 2)/UNC18-2

Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.

Monocytopenia is a form of leukopenia associated with a deficiency of monocytes. The causes of monocytopenia include: acute infections, stress, treatment with glucocorticoids, aplastic anemia, hairy cell leukemia, acute myeloid leukemia, treatment with myelotoxic drugs and genetic syndromes, as for example MonoMAC syndrome.

It has been proposed as a measure to predict neutropenia, though some research indicates that it is less effective than lymphopenia.

XMEN patients have splenomegaly, chronic Epstein Barr Virus (EBV) infection, and are developmentally normal. They have an increased susceptibility for developing EBV+ lymphoma. Additionally, XMEN patients have excessive infections consistent with the underlying immunodeficiency. These infections included recurrent otitis media, sinusitis, viral pneumonia, diarrhea, upper respiratory infections, epiglottitis, and pertussis. Although autoimmune symptoms do not feature prominently in XMEN autoimmune cytopenias were observed in two unrelated patients.

In the figure to the left, major features are present in all XMEN patients, while minor features are found only in some.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Macrophage-activation syndrome (MAS) is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic-onset juvenile idiopathic arthritis (SoJIA). In addition, MAS has been described in association with systemic lupus erythematosus (SLE), Kawasaki disease, and adult-onset Still's disease. It is thought to be closely related and pathophysiologically very similar to reactive (secondary) hemophagocytic lymphohistiocytosis (HLH). The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized.

The most common cause of temporary lymphocytopenia is a recent infection, such as the common cold.

Lymphocytopenia, but not idiopathic CD4+ lymphocytopenia, is associated with corticosteroid use, infections with HIV and other viral, bacterial, and fungal agents, malnutrition, systemic lupus erythematosus, severe stress, intense or prolonged physical exercise (due to cortisol release), rheumatoid arthritis, sarcoidosis, and iatrogenic (caused by other medical treatments) conditions.

Lymphocytopenia is a frequent, temporary result from many types of chemotherapy, such as with cytotoxic agents or immunosuppressive drugs. Some malignancies that have spread to involve the bone marrow, such as leukemia or advanced Hodgkin's disease, also cause lymphocytopenia.

Another cause is infection with Influenza A virus subtype H1N1 (and other subtypes of the Influenza A virus) and is then often associated with Monocytosis; H1N1 was responsible for the Spanish flu, the 2009 flu pandemic and in 2016 for the Influenza-epidemic in Brazil.

Large doses of radiation, such as those involved with nuclear accidents or medical whole body radiation, may cause lymphocytopenia.