Types of PI

Activated PI3K delta syndrome (APDS) is a rare primary immunodeficiency (PI) that is often misdiagnosed as CVID or another antibody deficiency.

 

People with agammaglobulinemia can't produce antibodies, which are an important part of the body's defense against germs.

Some individuals who have recurrent or severe infections have normal or high immunoglobulin levels but do not produce antibodies to either protein or polysaccharide vaccine antigens.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1) or polyglandular autoimmune (PGA) syndrome type-1, is a primary immunodeficiency disease caused by variants in the autoimmune regulator (AIRE) gene.

 

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder that causes neurological symptoms (like unsteady gait), dilated corkscrew-shaped blood vessels in the white of the eyes and on sun-exposed skin, combined immune deficiency, and high risk of cancer.

ALPS is a rare genetic disorder in which lymphocytes, a type of white blood cell, increase and accumulate in the spleen and lymph nodes. This is due to the failure of the mechanism that normally causes lymphocytes to die naturally.

Bare lymphocyte syndrome type 1 and 2 are forms of combined immune deficiencies (CIDs) characterized by a shortage of major histocompatibility complex (MHC) proteins.

Deficiency of BCL10 is a rare combined immunodeficiency (CID) associated with severe recurrent infections and autoimmunity.

BCL11A deficiency is a rare combined immunodeficiency (CID) that causes a profound lack of T cells and risk of invasive infections akin to severe combined immunodeficiency (SCID). Other features include neonatal teeth, umbilical hernia, and skeletal and brain abnormalities.

Bloom syndrome is a type of combined immunodeficiency (CID) caused by a DNA repair defect and primarily described in the Ashkenazi Jewish population.

Variants in CARD11 are associated with a spectrum of primary immunodeficiencies. Complete absence of CARD11, which is a rare autosomal recessive condition, causes hypogammaglobulinemia and T cell dysfunction in spite of normal T cell numbers.

Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia sometimes also referred to as immunodeficiency with short-limbed dwarfism. It is caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene.

Individuals with CD3 gamma deficiency have clinical phenotypes ranging from immune deficiency to immune dysregulation with autoimmunity.

CD70 deficiency is a rare form of combined immunodeficiency with hypogammaglobulinemia and low CD8+ T cells. Individuals are particularly susceptible to chronic Epstein-Barr virus (EBV) and at high risk of EBV-associated lymphoma.

CD8 deficiency is an extremely rare autosomal recessive disorder due to homozygous mutation of CD8 gene.

CHARGE syndrome is a genetic syndrome with a known pattern of features: coloboma of the eye, heart defects, atresia of the choanae, restriction of growth and development, and ear abnormalities and deafness.

Chronic granulomatous disease (CGD) is an inherited disease in which the body’s cells that eat invaders (also called phagocytes) do not make hydrogen peroxide and other chemicals. These chemicals are needed to kill certain bacteria and fungi.

Chronic mucocutaneous candidiasis (CMC) is characterized by persistent Candida (fungus) infections of the mucous membranes, scalp, skin, and nails.

People with chronic neutropenia have low levels of white blood cells called neutrophils, and the condition is both a rare blood disorder and a rare type of primary immunodeficiency (PI).

Combined immune deficiencies (CID) are a group of primary immunodeficiencies in which both T cells and B cells of the adaptive immune system are either low or function poorly.

Combined immunodeficiency with intestinal atresias (CID-IA) is a rare, severe disorder in which parts of the small intestine fail to develop properly.

Comel-Netherton syndrome is a type of hyper IgE syndrome that affects the skin, hair, and immune system.

Common variable immune deficiency (CVID), previously known as adult-onset hypogammaglobulinemia, is one of the most frequently diagnosed primary immunodeficiencies. It is characterized by low levels of serum antibodies, which cause an increased susceptibility to infection.

Individuals with a complement deficiency can have clinical problems that are a result of the role that the specific complement protein plays in the normal function of the human body.

Congenital athymia is an ultra-rare condition in which children are born without a thymus, causing severe immunodeficiency and immune dysregulation.

Constitutional mismatch repair deficiency (CMMRD) describes several disorders that lead to childhood-onset cancer. CMMRD caused by variants in the PMS2 gene also leads to immune deficiency.

Coronin 1A deficiency is associated with a very low number of T cells with impaired function, similar to severe combined immunodeficiency (SCID).

Variants in the genes encoding cytotoxic T lymphocytic antigen-4 (CTLA4) and lipopolysaccharide responsive beige-like anchor (LRBA) can cause immune dysregulation. This means the components of the immune system regulating inflammation, autoimmunity, and cancer lose their proper function, leading to an array of autoimmune disorders and infections.

DiGeorge syndrome, most frequently caused by a deletion at 22q11.2, is a PI caused by abnormal migration and development of certain cells and tissues during fetal development.

DOCK2 deficiency is an autosomal recessive disorder associated with early-onset invasive bacterial and viral infections, lymphopenia, and defective T, B, and NK cell function.

Individuals with this condition can present with severe T cell defects that may mimic severe combined immunodeficiency (SCID) at birth. Additionally, they present with significant bone deformities, such as early fused cranial bones (craniosynostosis) with a small cervical canal, short stature, and abnormally shaped digits.

Also known as nude/severe combined immunodeficiency (SCID), this rare primary immunodeficiency disrupts adaptive immunity and is characterized by congenital athymia, congenital alopecia totalis, and nail dystrophy.

Good's syndrome is a rare primary immunodeficiency in adults that results in recurrent infections, low immunoglobulins, and thymic tumors.

Hemophagocytic lymphohistiocytosis (HLH) occurs when histiocytes and lymphocytes become overactive and attack the body rather than just microorganisms. Familial HLH is a type of PI.

This syndrome is a severe form of dyskeratosis congenita with poor growth inside the womb, microcephaly (small head), and pancytopenia (low numbers of all blood cells).

Hyper IgE syndromes (HIES) are rare forms of primary immunodeficiencies (PI) characterized by recurrent eczema, skin abscesses, lung infections, eosinophilia (high numbers of eosinophils in the blood), and high serum levels of immunoglobulin E (IgE). 

Hyper IgM syndromes (HIGM) are characterized by decreased levels of immunoglobulin G (IgG) in the blood and normal or elevated levels of immunoglobulin M (IgM). 

Patients with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.

Deficiencies of the cytokine, IL-21, and IL21 receptor has been described in children with very early onset inflammatory bowel disease, liver disease, and immunodeficiency with T cell and B cell defects.

Short for immunodeficiency-centromeric instability facial anomalies syndrome, ICF syndrome is an autosomal recessive disorder that may be due to variants in the ZBTB24, DNMT3B, CDCA7, or HELLS genes.

People with deletions of multiple genes in the immunoglobulin heavy chain region can be asymptomatic or can exhibit susceptibility to infections.

Innate immune disorders include Myd88 and IRAK-4 deficiencies, TLR3 deficiency, NF-kappa-B essential modulator (NEMO) deficiency syndrome, natural killer (NK) cell deficiency, and disorders in interferon-γ (IFN-γ) and interleukin (IL)-12/23 signaling pathways. 

IPEX is an X-linked disorder in which affected boys develop severe autoimmunity that can target any organ. The gut, skin, and endocrine organs—particularly the pancreas and thyroid gland—are the most common targets.

Kabuki syndrome is a multisystem genetic disorder involving characteristic facial features, growth and developmental delay, and skeletal abnormalities.

Kappa light chain deficiency is a rare autosomal recessive antibody deficiency.

Autosomal recessive disorder due to deficiency of lymphocyte-specific protein-tyrosine kinase (Lck or p56lck), one of the proteins activated upon engagement of the TCR/CD3 complex. Depending on the mutation, individuals may present within the first year of life with variable features.

Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency that causes individuals to be abnormally susceptible to developing frequent soft-tissue infections, gum inflammation, and tooth loss.

Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS) causes severe, early lung disease.

Individuals with ligase 1 deficiency have high sensitivity to sunlight, stunted growth, developmental delay, and a high predisposition for cancer.

MALT1 deficiency is a combined immunodeficiency that can cause severe eczema, recurrent bacterial and viral infections, inflammatory gastrointestinal disease, long bone fractures, and severe periodontal disease.

Moesin deficiency is an X-linked immunodeficiency associated with lymphopenia, neutropenia, and recurrent bacterial infections.

NEMO deficiency syndrome is a complex disease caused by genetic variants in the X-linked NEMO gene (also known as IKK gamma or IKKG).

Variants in the gene that codes for a protein called nibrin cause Nijmegen breakage syndrome (NBS). Affected individuals are highly sensitive to the effects of sunlight and radiation, or any substance that can cause breaks in DNA.

NIK deficiency is a rare immunodeficiency resulting in impaired function of T cells, B cells, and natural killer (NK) cells. Affected individuals are susceptible to a wide range of infections.

OX40 deficiency is a rare immunodeficiency. CD4+ T cells appear to be dysfunctional in this disorder, whereas antibody production is still intact.

"Leaky" variants in RAG1 or RAG2 with residual protein function and T cell production can have a variable presentation, including Omenn syndrome, granulomatous disease, and/or autoimmunity.

PolE/PolE2 deficiency is inherited in an autosomal recessive manner. Affected individuals have a high predisposition for infections and decreased numbers of both T and B cells.

Primary immune regulatory disorders (PIRD) are characterized by a disturbance of immune tolerance and excessive inflammation.

Purine nucleotide phosphorylase (PNP) deficiency is a rare recessive disorder resulting in moderate to severe immunodeficiency, with reduced T cell numbers and risk of recurrent infections, as well as autoimmune disease.

RelB deficiency has been found in a small number of individuals with poor T cell and B cell function in spite of normal lymphocyte numbers.

RHOH deficiency is an autosomal recessive disorder caused by variants in the Ras homolog gene family member H (RHOH) gene leading to a defect of T cell function.

RIDDLE is short for radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties. It is an autosomal recessive disorder, in which individuals have difficulty repairing DNA damage sustained by the cells.

Schimke’s immuno-osseous dysplasia, an autosomal recessive disorder, is caused by a variant in a gene responsible for chromatin remodeling (SMARCAL1).

Selective IgA deficiency is a primary immunodeficiency characterized by an undetectable level of immunoglobulin A (IgA) in the blood and secretions but no other immunoglobulin deficiencies.

Individuals with selective IgM deficiency have low levels or lack immunoglobulin M (IgM) but have normal levels of IgA, and IgG. These individuals may have no illness, whereas others develop a variety of illnesses, including infections, allergies, and autoimmunity. 

Severe combined immune deficiency (SCID) is a life-threatening primary immunodeficiency (PI), with a combined absence of T cell and B cell function. There are at least 20 different genetic variants that can cause SCID.

Individuals with specific antibody deficiency have normal levels of antibodies (immunoglobulins) but cannot produce antibodies to specific types of microorganisms that cause respiratory infections.

STAT1 and STAT3 gain of function are autosomal dominant primary immunodeficiencies with significant autoimmunity as a result of immune dysregulation.

The clinical phenotype for STK4 deficiency includes persistent viral infections and bacterial infections. Other reported features include fungal infections, mild eczema, autoimmune cytopenias, and lymphopenia.

TCRa deficiency causes susceptibility to recurrent respiratory tract infections, candidiasis, gastroenteritis, and herpesvirus infections, as well as autoimmune symptoms.

Deficiency of transferrin receptor 1 (TFR1) is a rare, recessive immunodeficiency that causes hypogammaglobulinemia, defective T cell function, intermittent neutropenia and thrombocytopenia, and mild anemia.

Transcobalamin II deficiency is a rare autosomal recessive type of primary immunodeficiency.

When it takes longer than expected for a baby to make their own IgG antibodies, they may have transient hypogammaglobulinemia of infancy (THI).

Tricho-hepato-enteric syndrome (THES) is a rare, recessive disorder characterized by chronic diarrhea with poor growth, liver disease, hair and facial abnormalities, and immunodeficiency with impaired antibody function and lymphopenia.

Unspecified hypogammaglobulinemia refers to individuals who have low serum immunoglobulins but do not fit the diagnostic criteria of defined antibody deficiencies like common variable immune deficiency (CVID).

Patients with veno-occlusive disease with immunodeficiency (VODI) have a predisposition to fungal infections, low platelet counts, and enlarged livers.

Warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome is an ultra-rare and difficult-to-diagnose primary immunodeficiency (PI) in which individuals are susceptible to life-threatening bacterial infections and to human papillomavirus (HPV) infections.

Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency (PI) that causes bleeding problems and eczema in addition to susceptibility to infections. It is inherited in an X-linked recessive manner.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) is seen in boys and is characterized by low CD4 T cells, chronic Epstein-Barr virus (EBV) infections, and lymphoproliferative disorders related to the EBV.

XLP is characterized by life-long vulnerability to Epstein-Barr virus (EBV) infection, which can lead to severe and fatal infectious mononucleosis, lymph node cancers (lymphomas), and combined immunodeficiency.

ZAP-70 deficiency is a rare autosomal recessive combined immunodeficiency. Peripheral T cells from individuals with ZAP-70 deficiency demonstrate defective T cell signaling and have an autoreactive phenotype. Indeed, several individuals have presented with autoimmune disorders.