MedGen

Autoinflammation, immune dysregulation, and eosinophilia (AIIDE) is an autosomal dominant disorder characterized by onset of severe atopic dermatitis and chronic gastrointestinal inflammation, mainly involving the colon, in infancy or early childhood. Affected individuals tend to have asthma and food or environmental allergies, as well as poor overall growth with short stature. Severe liver involvement has also been reported (Takeichi et al., 2021). Laboratory studies show increased eosinophils with normal or increased IgE levels, as well as evidence of a hyperactive immune state, including increased erythrocyte sedimentation rate and C-reactive protein. Treatment with JAK inhibitors, such as ruxolitinib and tofacitinib, results in dramatic clinical improvement (summary by Gruber et al., 2020). [from OMIM]

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency. [from GeneReviews]

Crohn's disease is a complex, long-lasting (chronic) disorder that primarily affects the digestive system. This condition involves an abnormal immune response that causes excess inflammation. It most often affects the intestinal walls, particularly in the lower part of the small intestine (the ileum) and portions of the large intestine (the colon). However, inflammation can occur in any part of the digestive system, from the mouth to the anus. The inflamed tissues become thick and swollen, and the inner surfaces of the digestive system may develop open sores (ulcers).

Crohn's disease most commonly appears in a person's late teens or twenties, although the disease can begin at any age. Signs and symptoms tend to flare up multiple times throughout life. The most common features of this condition are persistent diarrhea, abdominal pain and cramping, loss of appetite, weight loss, and fever. Some people with Crohn's disease have blood in the stool from inflamed tissues in the intestine; over time, chronic bleeding can lead to a low number of red blood cells (anemia). In some cases, Crohn's disease can also cause inflammation affecting the joints, eyes, or skin.

Intestinal blockage is a common complication of Crohn's disease. Blockages are caused by swelling or a buildup of scar tissue in the intestinal walls. Some affected individuals also develop fistulae, which are abnormal connections between the intestine and other tissues. Fistulae occur when ulcers break through the intestinal wall and passages form between loops of the intestine or between the intestine and nearby structures (such as the bladder, vagina, or skin).

Crohn's disease is one common form of inflammatory bowel disease (IBD). Another type of IBD, ulcerative colitis, also causes chronic inflammation of the intestinal lining. Unlike Crohn's disease, which can affect any part of the digestive system, ulcerative colitis typically causes inflammation only in the colon. [from MedlinePlus Genetics]

An inherited susceptibility or predisposition to developing allergic rhinitis. [from MONDO]

Infantile-onset multisystem autoimmune disease-1 is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. Common manifestations include insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease, and autoimmune hematologic disorders. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. Some patients may show recurrent infections. The disorder results from an inborn error of cytokine signaling (summary by Flanagan et al., 2014 and Milner et al., 2015). Genetic Heterogeneity of Infantile-Onset Multisystem Autoimmune Disease See also ADMIO2 (617006), caused by mutation in the ZAP70 gene (176947) on chromosome 2q12, and ADMIO3 (620430), caused by mutation in the CBLB gene (604491) on chromosome 3q13. [from OMIM]

IMD29 results from autosomal recessive IL12B deficiency and is characterized by undetectable IL12B secretion from leukocytes. IL12B-deficient patients generally present with bacillus Calmette-Guerin (BCG) disease after vaccination in childhood, and at least half also have Salmonella infection. Infections with Mycobacterium tuberculosis and environmental mycobacteria have also been reported in IL12B-deficient patients. The phenotype is relatively mild, and patients have a good prognosis (review by Al-Muhsen and Casanova, 2008). [from OMIM]

Multiple sclerosis-5 (MS5) is a chronic inflammatory disease of the central nervous system characterized by damage to axonal myelin sheaths and axons, commonly resulting in progressive neurologic disability beginning in early adulthood (summary by Xu et al., 2001). For a discussion of genetic heterogeneity of multiple sclerosis (MS), see MS1 (126200). [from OMIM]

Polycystic lung disease (PCLUD) is an autosomal recessive disorder characterized by childhood-onset exertional dyspnea and cough due to progressive airflow obstruction in the lungs. Pulmonary imaging shows diffuse lung disease with pleural and subpleural cysts and peripheral consolidations, and lung biopsy shows bronchiolitis and lymphocytosis of the terminal bronchioles, often with features of pulmonary alveolar proteinosis (PAP). Most affected individuals have recurrent respiratory infections; some have an adverse response to BCG vaccination. Additional features may include digital clubbing, allergies, and atopic dermatitis (et al., 2024). [from OMIM]

Transplantation of hematopoietic stem cells is a successful therapy for some tumors derived from bone marrow precursors, such as certain leukemias and lymphomas, and it can be used to cure some primary immunodeficiencies and inherited hematopoietic stem-cell diseases. One of the major complications of allogeneic bone marrow transplantation is graft-versus-host disease (GVHD), in which mature donor T cells that contaminate the allogeneic bone marrow recognize the tissues of the recipient as foreign, causing a severe inflammatory disease characterized by rashes, diarrhea, and liver disease. GVHD is particularly virulent when there is a mismatch of a major major histocompatibility complex (MHC) class I or class II antigen. Most transplants are therefore undertaken only when the donor and recipient are HLA-matched sibs or, less frequently, when there is an HLA-matched unrelated donor. However, GVHD also occurs in the context of disparities between minor histocompatibility antigens, and immunosuppression must be used in every stem-cell transplant (summary by Janeway et al., 2005). At the core of the immunogenetic basis for GVHD is the diversity of HLA, killer immunoglobulin-like receptors (KIRs; see 604936), and cytokine genes. HLA class I molecules function as ligands for natural killer cell inhibitory KIRs, indicating that GVHD results from a complex interplay between innate and adaptive immune responses. Cytokines may modulate the intensity of tissue injury and inflammation in GVHD, and therefore cytokine polymorphisms in either patient or donor or both may explain individual risks of GVHD (review by Petersdorf and Malkki, 2006). [from OMIM]

Maraviroc is a chemokine receptor antagonist that is used in combination with other antiretroviral agents to treat human immunodeficiency virus type 1 (HIV-1) infection. Maraviroc exerts its therapeutic activity by blocking entry of the HIV-1 virus into immune cells—specifically the CD4-expressing T-helper cells, which play a major role in protecting the body from infection—precursor cells, and dendritic cells. HIV-1 infection is classified in two major forms according to the co-receptor it employs to gain entry in to the cell, namely the chemokine receptor 5 (CCR5) or the CXC chemokine receptor 4 (CXCR4). These co-receptors are expressed on different types of cells, and HIV tropism refers to the types of cells and tissues in which the virus infects and replicates. A tropism assay is conducted to determine which co-receptor the HIV-1 virus uses, i.e., whether the virus is CCR5-tropic, CXCR4-tropic, dual tropic (i.e., HIV-1 virus that is able to use both receptors), or mixed tropic (i.e., a mixture of HIV-1 viruses, some of which use CCR5 and others that use CXCR4). Maraviroc is only indicated for treatment of adults with CCR5 tropic HIV-1 and is not recommended when the CXCR4-tropic virus has been detected. The FDA-approved drug label for maraviroc states that “prior to initiation of maraviroc, test all patients for CCR5 tropism using a highly sensitive tropism assay”. [from Medical Genetics Summaries]

An autosomal recessive condition caused by mutation(s) in the IL10RA gene, encoding interleukin-10 receptor subunit alpha. It is characterized by early-onset chronic relapsing intestinal inflammation. [from NCI]

Chronic recurrent multifocal osteomyelitis-2 with periostitis and pustulosis (CRMO2) is an autosomal recessive multisystemic autoinflammatory disorder characterized by onset of symptoms in early infancy. Affected individuals present with joint swelling and pain, pustular rash, oral mucosal lesions, and fetal distress. The disorder progresses in severity to generalized severe pustulosis or ichthyosiform lesions and diffuse bone lesions. Radiographic studies show widening of the anterior rib ends, periosteal elevation along multiple long bones, multifocal osteolytic lesions, heterotopic ossification, and metaphyseal erosions of the long bones. Laboratory studies show elevation of inflammatory markers. The disorder results from unopposed activation of the IL1 inflammatory signaling pathway. Treatment with the interleukin-1 receptor antagonist anakinra may result in clinical improvement (Aksentijevich et al., 2009). For a discussion of genetic heterogeneity of CRMO, see 609628. [from OMIM]

Immunodeficiency-35 (IMD35) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by Kreins et al., 2015). [from OMIM]

HBV is a DNA virus that enters the liver via the bloodstream, and replication occurs only in liver tissue. Transmission occurs by percutaneous or mucosal exposure to infected blood or other body fluids. Approximately one third of all cases of cirrhosis and half of all cases of hepatocellular carcinoma (HCC; 114550) can be attributed to chronic HBV infection. Worldwide, 2 billion people have been infected with HBV, 360 million have chronic infection, and 600,000 die each year from HBV-related liver disease or HCC. However, there is marked geographic variability in HBV prevalence, with chronic infection affecting less than 2% of the populations of North America and western and northern Europe; between 2 and 7% of the populations of eastern and central Europe, the Amazon basin, the Middle East, and the Indian subcontinent; and more than 8% of the populations of Asia, sub-Saharan Africa, and the Pacific (Seeff and Hoofnagle, 2006; Shepard et al., 2006). [from OMIM]

Any inflammatory bowel disease in which the cause of the disease is a mutation in the IL10RB gene. [from MONDO]

Uncontrolled type 1 diabetes can lead to a life-threatening complication called diabetic ketoacidosis. Without insulin, cells cannot take in glucose. A lack of glucose in cells prompts the liver to try to compensate by releasing more glucose into the blood, and blood glucose can become extremely high. The cells, unable to use the glucose in the blood for energy, respond by using fats instead. Breaking down fats to obtain energy produces waste products called ketones, which can build up to toxic levels in people with type 1 diabetes, resulting in diabetic ketoacidosis. Affected individuals may begin breathing rapidly; develop a fruity odor in the breath; and experience nausea, vomiting, facial flushing, stomach pain, and dryness of the mouth (xerostomia). In severe cases, diabetic ketoacidosis can lead to coma and death.

Over many years, the chronic high blood glucose associated with diabetes may cause damage to blood vessels and nerves, leading to complications affecting many organs and tissues. The retina, which is the light-sensitive tissue at the back of the eye, can be damaged (diabetic retinopathy), leading to vision loss and eventual blindness. Kidney damage (diabetic nephropathy) may also occur and can lead to kidney failure and end-stage renal disease (ESRD). Pain, tingling, and loss of normal sensation (diabetic neuropathy) often occur, especially in the feet. Impaired circulation and absence of the normal sensations that prompt reaction to injury can result in permanent damage to the feet; in severe cases, the damage can lead to amputation. People with type 1 diabetes are also at increased risk of heart attacks, strokes, and problems with urinary and sexual function.

Type 1 diabetes can occur at any age, from early childhood to late adulthood. The first signs and symptoms of the disorder are caused by high blood glucose and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet, and weight loss. These symptoms may recur during the course of the disorder if blood glucose is not well controlled by insulin replacement therapy. Improper control can also cause blood glucose levels to become too low (hypoglycemia). This may occur when the body's needs change, such as during exercise or if eating is delayed. Hypoglycemia can cause headache, dizziness, hunger, shaking, sweating, weakness, and agitation.

Type 1 diabetes is a disorder characterized by abnormally high levels of blood glucose, also called blood sugar. In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of glucose in the blood. [from MedlinePlus Genetics]

Any microvascular complications of diabetes, susceptibility in which the cause of the disease is a mutation in the IL1RN gene. [from MONDO]

WNV is an enveloped, neurotropic, single-stranded sense RNA flavivirus that is naturally maintained in a zoonotic cycle between avian hosts and mosquito vectors. The virus was first isolated from a Ugandan woman in 1937 and subsequently emerged in Europe and, in 1999, in New York, with eventual spread throughout North America. WNV causes a spectrum of disease ranging from acute fever to lethal encephalitis. Susceptibility to WNV is increased in the elderly and in immunocompromised individuals (summary by Diamond and Klein (2006) and Glass et al. (2005)). [from OMIM]

Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (603903), thalassemia (see 141800), glucose-6-phosphatase deficiency (300908), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (Kwiatkowski, 2005; Campino et al., 2006). [from OMIM]

Bronchial asthma is the most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al., 2001; Illig and Wjst, 2002; Pillai et al., 2006). See 147050 for information on the asthma-associated phenotype atopy. [from OMIM]