MedGen

Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. [from OMIM]

A form of hereditary angioedema characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway. [from ORDO]

Periodontal Ehlers-Danlos syndrome (pEDS) is characterized by distinct oral manifestations. Periodontal tissue breakdown beginning in the teens results in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. Since the first descriptions of pEDS in the 1970s, 148 individuals have been reported in the literature; however, future in-depth descriptions of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features. [from GeneReviews]

Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family. Classification of the Enchondromatoses In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978). Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas). [from OMIM]

RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by Oliveira, 2013 and Niemela et al., 2010). The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; 601859) and was originally designated ALPS IV. [from OMIM]

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006). [from OMIM]

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]

Immunodeficiency-36 with lymphoproliferation (IMD36) is an autosomal dominant primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016). [from OMIM]

Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (summary by Stepensky et al., 2011; Linka et al., 2012). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240). [from OMIM]

C1q deficiency (C1QD) is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; see 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (summary by Topaloglu et al., 1996 and Vassallo et al., 2007). Genetic Heterogeneity of C1q Deficiency See also C1q deficiency-2 (C1QD2; 620321), caused by mutation in the C1QB gene (120570), and C1q deficiency-3 (C1QD3; 620322), caused by mutation in the C1QC gene (120575). [from OMIM]

Immunoglobulin (Ig) A deficiency (IGAD) is characterized by decreased or absent levels of serum IgA in the presence of normal serum levels of IgG and IgM in a patient older than 4 years of age in whom other causes of hypogammaglobulinemia have been excluded. IgA in the dimeric form is the dominant immunoglobulin in luminal secretions, such as saliva, tears, bronchial secretions, nasal mucosal secretions, and mucous secretions of the small intestine. Individuals with selective IgA deficiency may be asymptomatic or have recurrent sinopulmonary and gastrointestinal infections, allergic disorders, and autoimmune disorders. The diagnosis of IgA deficiency depends on the measurement of monomeric IgA concentrations in serum; thus individuals with IgA deficiency may have IgA in mucosal systems, which may offer some protection (review by Yel, 2010). Genetic Heterogeneity of IgA Deficiency The IGAD1 locus maps to chromosome 6p21. See also IGAD2 (609529), which is caused by mutation in the TNFRSF13B gene (604907) on chromosome 17p11. [from OMIM]

Myasthenia gravis is an autoimmune disease in which antibodies bind to acetylcholine receptors or to functionally related molecules in the postsynaptic membrane at the neuromuscular junction. The antibodies induce weakness of skeletal muscles, which is the sole disease manifestation. The weakness can be generalized or localized, is more proximal than distal, and nearly always includes eye muscles, with diplopia and ptosis. The pattern of involvement is usually symmetric, apart from the eye involvement, which is often markedly asymmetric and involves several eye muscles. The weakness typically increases with exercise and repetitive muscle use (fatigue) and varies over the course of a day and from day to day, often with nearly normal muscle strength in the morning (summary by Gilhus, 2016). [from OMIM]

Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013). For a general description and a discussion of genetic heterogeneity of ALPS, see 601859. [from OMIM]

Gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1) is characterized by multiple intestinal atresia, in which atresia occurs at various levels throughout the small and large intestines. Surgical outcomes are poor, and the condition is usually fatal within the first month of life. Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency (Samuels et al., 2013; Avitzur et al., 2014; Lemoine et al., 2014). Genetic Heterogeneity of GIDID See also GIDID2 (619708), caused by mutation in the PI4KA gene (600286) on chromosome 22q11. [from OMIM]

In addition to classic type 1 (see 222100) and type 2 (see 125853) diabetes mellitus, atypical presentations are seen, particularly in populations of African ancestry. Ketosis-prone diabetes, the most common atypical form, is characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding, and association with type 1 susceptibility HLA alleles is variable (Sobngwi et al., 2002). [from OMIM]

The stiff-person syndrome (SPS) is most often an adult-onset sporadic acquired disorder characterized by progressive muscle stiffness with superimposed painful muscle spasms accompanied by electromyographic evidence of continuous motor activity at rest. SPS has been associated with autoimmune disorders, diabetes mellitus, thyrotoxicosis, and hypopituitarism with adrenal insufficiency (George et al., 1984). Approximately 60% of patients with SPS have antibodies to glutamic acid decarboxylase (GAD2, or GAD65; 138275), the rate-limiting enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), suggesting an immune-mediated pathogenesis (Folli et al., 1993). Approximately 10% of patients develop SPS as a paraneoplastic neurologic disorder associated with antibodies to amphiphysin (AMPH; 600418), an intracellular protein associated with neuronal synaptic vesicle endocytosis (Burns, 2005). See also congenital stiff-man syndrome, or hereditary hyperexplexia (149400), which is caused by mutations in subunits of the glycine receptor gene (GLRA1, 138491; GLRB, 138492). Meinck and Thompson (2002) provided a detailed review of stiff-person syndrome. They also discussed 2 possibly related conditions, progressive encephalomyelitis with rigidity (PERM), a more severe disorder with other neurologic features, and stiff-limb or stiff-leg syndrome, a focal disorder. [from OMIM]

Any selective IgA deficiency disease in which the cause of the disease is a mutation in the TNFRSF13B gene. [from MONDO]

A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own tissue constituents. It may be systemic (e.g., systemic lupus erythematosus), or organ specific, (e.g., thyroiditis). [from NCI]

Alopecia areata is a genetically determined, immune-mediated disorder of the hair follicle with an estimated lifetime risk of approximately 2%, making it one of the most common human autoimmune diseases. It shows a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body (Gilhar and Kalish, 2006). [from OMIM]