Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient's inability to reutilize biotin, a necessary nutrient. Sweetman (1981) recognized that multiple carboxylase deficiency could be classified into early (see 253270) and late forms. The early form showed higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations. Sweetman (1981) proposed a defect in holocarboxylase synthetase and intestinal biotin absorption, respectively. Some patients with biotinidase deficiency present in infancy (Baumgartner et al., 1985; Kalayci et al., 1994), and some individuals with this deficiency are asymptomatic (Wolf et al., 1997).

Systemic amyloidosis is a rare protein misfolding and deposition disorder caused by extracellular deposition of amyloid and leading to progressive organ failure. Amyloid is composed of highly organized proteinaceous, insoluble, and degradation-resistant fibrils. Hereditary systemic amyloidosis-2 (AMYLD2), resulting from mutation in the FGA gene, is the most common form of hereditary renal amyloidosis. The kidneys are the major affected organ, presenting with proteinuria. Other less frequently involved organs include liver, heart, autonomic nerve, and, rarely, peripheral nerve. A strong family history of coronary or vascular disease is also frequently seen (summary by Muchtar et al., 2021). The various forms of hereditary systemic amyloidosis that do not have peripheral neuropathy as part of the clinical syndrome have been referred to as 'Ostertag type' in reference to a German family described by Benno Ostertag (1932) in which several members died with renal amyloidosis. Since the form of hereditary amyloidosis caused by mutation in the FGA gene is the most common in Europe and has a clinical presentation with hypertension and proteinuria, Benson (2005) considered it a very good candidate for being the original amyloidosis described by Ostertag. For a discussion of genetic heterogeneity of hereditary systemic amyloidosis, see AMYLD1 (105210).

Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005). Also see biotinidase deficiency (253260), another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981).

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.\n\nMevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).\n\nPeople with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.\n\nDuring episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.

Chronic infantile neurologic cutaneous and articular syndrome (CINCA) is an early-onset, severe, chronic inflammatory disease, characterized by cutaneous symptoms, central nervous system involvement, and arthropathy (Feldmann et al., 2002). See also familial cold autoinflammatory syndrome-1 (FCAS1, CAPS1; 120100), an allelic disorder with a less severe phenotype.

TNF receptor-associated periodic fever syndrome (TRAPS) is characterized by episodes of inflammation typically occurring every four to six weeks and lasting between five and 25 days. Flares may be prompted by stress, infection, trauma, hormonal changes, and vaccination. Symptoms may include fever, abdominal pain, arthralgia, myalgia, migratory rash, and eye inflammation, with variable severity. Symptoms often begin in early childhood (median age 4.3 years), though symptom onset can occur later in life. During a flare, acute-phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A are typically elevated. Generally, acute-phase reactants stabilize between flares but may remain somewhat elevated even in the absence of clinical symptoms. AA amyloidosis, the most severe sequela of TRAPS, can largely be avoided with adequate treatment. Proteinuria and kidney failure occur in 80%-90% of affected individuals with amyloidosis, while intestinal, thyroid, myocardium, liver, and spleen deposits are less common.

The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). Typical X-SCID. Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms. With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant. Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications.

Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. The age at onset is highly variable, ranging from infancy to adulthood. Disease progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013). Genetic Heterogeneity of Bethlem Myopathy See Bethlem myopathy-1B (BTHLM1B; 620725), caused by mutation in the COL6A2 gene (120240) on chromosome 21q22; Bethlem myopathy-1C (620726), caused by mutation the COL6A3 gene (120250) on chromosome 2q37; and Bethlem myopathy-2 (BTHLM2; 616471), caused by mutation in the COL12A1 gene (120320) on chromosome 6q13-q14.

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.

Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (appears at ages 6-12 months) followed by post-inflammatory poikiloderma (at age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome, acute myelogenous leukemia, and skin cancer. Other ectodermal findings include thickened nails, nail dystrophy, and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease, and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe "delayed" or "late-onset" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals). Some healthy individuals who are deficient in red blood cell ADA (termed "partial ADA deficiency") have been discovered by screening populations or relatives of individuals with ADA-SCID. Newborn screening (NBS) for SCID uses extracts from Guthrie card dried blood spots to measure T-cell receptor excision circle (TREC) DNA by polymerase chain reaction (PCR). Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS). Both techniques can identify ADA-SCID before affected infants become symptomatic. Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia. Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID. Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function. If immune function is not restored with enzyme replacement therapy (ERT), gene therapy, or hematopoietic stem cell transplantation (HSCT), children with ADA-SCID rarely survive beyond age one to two years. NBS for SCID does not identify individuals with the ADA-CID phenotype whose TREC numbers are above the threshold values of most screening laboratories. However, ADA-CID is identified by TMS NBS since the ADA substrates Ado and dAdo are increased. As TMS NBS for Ado/dAdo is not yet widely performed, individuals with ADA-CID are more often clinically diagnosed between ages one and ten years ("delayed" onset), or less often in the second to fourth decades ("late"/"adult" onset). Because the immunologic abnormalities are less pronounced than those of ADA-SCID, infections in ADA-CID may not be life-threatening and include recurrent otitis media, sinusitis, upper respiratory infections, and human papilloma viral infections. Untreated individuals with ADA-CID can develop over time chronic pulmonary disease, autoimmunity, atopic disease with elevated immunoglobulin E, and malignancy.

Familial hemophagocytic lymphohistiocytosis-2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon (IFNG; 147570) and TNF-alpha (191160), by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation (summary by Dufourcq-Lagelouse et al., 1999, Stepp et al., 1999, and Molleran Lee et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of FHL, see 267700.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder clinically diagnosed based on the fulfillment of 5 of 8 criteria, including fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK) cell activity, hyperferritinemia, and high soluble IL2 receptor levels (IL2R; 147730). The disorder typically presents in infancy or early childhood. Persistent remission is rarely achieved with chemo- or immunotherapy; hematopoietic stem cell transplantation is the only cure (summary by Muller et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL), see 267700.

Individuals with LPIN2-related Majeed syndrome typically experience multisystem inflammatory symptoms, including chronic sterile multifocal osteomyelitis, recurrent bone pain, recurrent fever, failure to thrive, dyserythropoietic anemia, and neutrophilic dermatosis. Recurrent bone pain is frequently localized near the joints, often of the long bones of the lower extremities. Recurrent osteomyelitis with joint swelling can lead to subsequent joint contractures. Congenital dyserythropoietic, microcytic anemia can range from mild to severe and sometimes requires blood transfusion. Neutrophilic dermatosis typically presents as transient painful erythematous plaques, pustules, or nodules with neutrophilic infiltrates. Other features of LPIN2-related Majeed syndrome include the development of hepatosplenomegaly and gastrointestinal symptoms, such as recurrent abdominal pain and/or recurrent diarrhea. As more families are being described, individuals with milder features are now being recognized.

Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia (AICZC) is characterized by chronic systemic inflammation, prominent skin inflammation, arthralgias/arthritis, hepatosplenomegaly, pancytopenia, and failure to thrive. A hallmark of the disease is the extreme increase in serum concentrations of zinc and the proinflammatory alarmins MRP8 (S100A8; 123885) and MRP14 (S100A9; 123886), which make up the heterodimeric calcium- and zinc-binding protein complex calprotectin. Severe anemia and neutropenia are accompanied by thrombocytopenia in most patients, and bone marrow aspirates show dysgranulopoiesis and dyserythropoiesis. Intrafamilial variable expressivity and incomplete penetrance have been observed (summary by Holzinger et al., 2015).

Mevalonic aciduria (MEVA), the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).

Familial cold autoinflammatory syndrome-2 (FCAS2) is an autosomal dominant autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable, ranging from the first year of life to middle age, and the severity and clinical manifestations are heterogeneous (summary by Shen et al., 2017). For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (120100).

This syndrome is characterized by exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis. It has been described in four children, three boys and one girl, from two consanguineous families. The disease is due to a mutation in the COX4I2 gene, encoding a mitochondrial cytochrome C oxidase sub-unit. Transmission is autosomal recessive.

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.

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.

A rare, heterogeneous group of rheumatologic diseases characterized by arthritis which has an onset before 16 years of age, persists for more than 6 weeks, and is of unknown origin.

Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.

Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.

Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

STING-associated vasculopathy with onset in infancy is an autoinflammatory vasculopathy causing severe skin lesions, particularly affecting the face, ears, nose, and digits, and resulting in ulceration, eschar formation, necrosis, and, in some cases, amputation. Many patients have interstitial lung disease. Tissue biopsy and laboratory findings show a hyperinflammatory state, with evidence of increased beta-interferon (IFNB1; 147640) signaling (summary by Liu et al., 2014).

Autoinflammation with infantile enterocolitis is an autosomal dominant disorder characterized by onset of recurrent flares of autoinflammation in early infancy. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy associated with laboratory evidence of activated inflammation. This initial presentation is followed by recurrent febrile episodes with splenomegaly and sometimes hematologic disturbances, arthralgias, or myalgias. The disorder results from overactivation of an arm of the immune response system (Romberg et al., 2014; Canna et al., 2014).

Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (i.e., inflammation and/or immune deficiency). The most common manifestations and their frequency include: (1) recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons); (2) recurrent fevers (~50%), typically lasting for three to seven days that can rarely progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis; (3) skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura, urticaria, lupus-like macular rashes, and eczematoid dermatitis; (4) gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis, ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation; and (5) arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or psoriatic-like erosions. Other less common but significant findings include lymphoproliferation, most often lymphadenopathy; liver involvement, including severe hepatitis that if untreated can progress to cirrhosis and liver failure; neurologic disease including central nervous system vasculitis/vasculopathy (manifesting as severe headaches and cognitive changes) and in some individuals transient ischemic attacks. Other findings include aseptic meningitis, mononeuritis multiplex, chronic inflammatory demyelinating polyradiculoneuropathy, and/or peripheral neuropathy. HA20 demonstrates both variable expressivity (i.e., different systems may be involved simultaneously and/or over time in an affected individual) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family).

Autosomal recessive autoinflammation, panniculitis, and dermatosis syndrome (AIPDSB) is an autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP; 123260), leukocytosis, and neutrophilia in the absence of any infection. Patients exhibit no overt primary immunodeficiency (Damgaard et al., 2016 and Zhou et al., 2016).

Yao syndrome (YAOS) is an autoinflammatory disease characterized by periodic fever, dermatitis, arthritis, and swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. The disorder is associated with specific NOD2 variants (and Shen, 2017).

Neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) is an autosomal recessive disorder comprising impaired intellectual development, speech delay, mild microcephaly, and midbrain-hindbrain malformation (Ravindran et al., 2017).

Immunodeficiency-71 with inflammatory disease and congenital thrombocytopenia (IMD71) is an autosomal recessive immunologic disorder characterized by the onset of recurrent infections and inflammatory features such as vasculitis and eczema in infancy or early childhood. Infectious agents include bacteria and viruses. Laboratory findings are variable, but usually show thrombocytopenia, sometimes with abnormal platelet morphology, increased serum IgE, IgA, or IgM, leukocytosis, decreased or increased T lymphocytes, and increased eosinophils. Detailed studies show impaired neutrophil and T-cell chemotaxis, as well as impaired T-cell activation due to defects in F-actin (see 102610) polymerization (summary by Brigida et al., 2018).

Cryopyrin-associated periodic syndromes (CAPS) are a group of conditions that have overlapping signs and symptoms and the same genetic cause. The group includes three conditions known as familial cold autoinflammatory syndrome type 1 (FCAS1), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID). These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. FCAS1 is the least severe form of CAPS, MWS is intermediate in severity, and NOMID is the most severe form.\n\nThe signs and symptoms of CAPS affect multiple body systems. Generally, CAPS are characterized by periodic episodes of skin rash, fever, and joint pain. These episodes can be triggered by exposure to cold temperatures, fatigue, other stressors, or they may arise spontaneously. Episodes can last from a few hours to several days. These episodes typically begin in infancy or early childhood and persist throughout life.\n\nWhile the CAPS spectrum shares similar signs and symptoms, the individual conditions tend to have distinct patterns of features. People with FCAS1 are particularly sensitive to the cold, and exposure to cold temperatures can trigger a painful or burning rash. The rash usually affects the torso and limbs but may spread to the rest of the body. In addition to fever and joint pain, other possible symptoms include muscle aches, chills, drowsiness, eye redness, headache, and nausea.\n\nIn people with NOMID, the signs and symptoms of the condition are usually present from birth and persists throughout life. In addition to skin rash and fever, affected individuals may have joint inflammation, swelling, and joint deformities called contractures that may restrict movement. People with NOMID typically have headaches, seizures, and cognitive impairment resulting from chronic meningitis, which is inflammation of the tissue that covers and protects the brain and spinal cord (meninges). Other features of NOMID include eye problems, short stature, distinctive facial features, and kidney damage caused by amyloidosis.\n\nIndividuals with MWS develop the typical periodic episodes of skin rash, fever, and joint pain after cold exposure, although episodes may occur spontaneously or all the time. Additionally, they can develop progressive hearing loss in their teenage years. Other features of MWS include skin lesions or kidney damage from abnormal deposits of a protein called amyloid (amyloidosis).

Proteasome-associated autoinflammatory syndrome-3 (PRAAS3) is an autosomal recessive syndrome with onset in early infancy. Affected individuals present with nodular dermatitis, recurrent fever, myositis, panniculitis-induced lipodystrophy, lymphadenopathy, and dysregulation of the immune response, particularly associated with abnormal type I interferon-induced gene expression patterns. Additional features are highly variable, but may include joint contractures, hepatosplenomegaly, anemia, thrombocytopenia, recurrent infections, autoantibodies, and hypergammaglobulinemia. Some patients may have intracranial calcifications (summary by Brehm et al., 2015). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).

Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is an autosomal dominant disorder with onset in early infancy. Affected individuals develop severe inflammatory neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (summary by Poli et al., 2018). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).

Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, and sometimes seizures, resulting in death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Van Bergen et al., 2019). For a discussion of genetic heterogeneity of PEBEL, see PEBEL1 (617186).

Immunodeficiency-69 (IMD69) is an autosomal recessive disorder characterized by increased susceptibility to disseminated mycobacterial infection, including after BCG (bacille Calmette-Guerin) vaccination. Affected individuals develop fever, hepatosplenomegaly, leukocytosis, and thrombocytosis during the acute infection. There appears to be normal immunologic function against other pathogens, including viruses and bacteria. Immunologic work-up shows normal parameters, but patient T and NK cells fail to produce gamma-interferon (IFNG) when stimulated in vitro (summary by Kerner et al., 2020). IMD69 is a form of mendelian susceptibility to mycobacterial disease (MSMD) (see, e.g., IMD27A; 209950).

Proteasome-associated autoinflammatory syndrome-5 (PRAAS5) is an autosomal recessive immunologic disorder characterized by the appearance of annular erythematous inflammatory skin lesions on the face and extremities in the first days of life. Additional features include failure to thrive, recurrent fever, microcytic anemia, elevated liver and muscle enzymes, and hypertriglyceridemia. Laboratory studies show leukocytosis with neutrophilia, elevated acute phase reactants, and activation of the type 1 interferon (IFN; see 147660) pathway, consistent with autoinflammation. Treatment with JAK1 (147795) inhibitors results in significant clinical improvement or even clinical remission (summary by Papendorf et al., 2023). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).

Immunodeficiency-81 (IMD81) is an autosomal recessive complex immunologic disorder with onset of symptoms in infancy. The phenotype is highly variable and may include both immunodeficiency with recurrent infections, including bacterial and fungal infections, as well as autoimmune features, including autoimmune hemolytic anemia, pancytopenia, thrombocytopenia, and inflammatory bowel disease. Immunologic workup shows immune dysregulation with abnormalities affecting multiple immune cell lineages, including T cells, B cells, NK cells, and neutrophils, which may be decreased or increased and demonstrate functional deficits. There is a wide range of hematologic abnormalities. Affected individuals may be susceptible to severe EBV infection. The disorder is caused by a defect in intracellular immune signaling pathways (summary by Lev et al., 2021; Edwards et al., 2023).

Immunodeficiency-82 with systemic inflammation (IMD82) is a complex autosomal dominant immunologic disorder characterized by recurrent infections with various organisms, as well as noninfectious inflammation manifest as lymphocytic organ infiltration with gastritis, colitis, and lung, liver, CNS, or skin disease. One of the more common features is inflammation of the stomach and bowel. Most patients develop symptoms in infancy or early childhood; the severity is variable. There may be accompanying fever, elevated white blood cell count, decreased B cells, hypogammaglobulinemia, increased C-reactive protein (CRP; 123260), and a generalized hyperinflammatory state. Immunologic workup shows variable B- and T-cell abnormalities such as skewed subgroups. Patients have a propensity for the development of lymphoma, usually in adulthood. At the molecular level, the disorder results from a gain-of-function mutation that leads to constitutive and enhanced activation of the intracellular inflammatory signaling pathway. Treatment with SYK inhibitors rescued human cell abnormalities and resulted in clinical improvement in mice (Wang et al., 2021).

X-linked familial Behcet-like autoinflammatory syndrome-2 (AIFBL2) is an X-linked recessive disorder characterized by the onset of inflammatory symptoms in the first decade of life in male patients. Affected males often present with oral mucosal ulceration and skin inflammation. More variable features may include gastrointestinal ulceration, arthritis, recurrent fevers, and iron deficiency anemia. Laboratory studies are consistent with immune dysregulation manifest as increased inflammatory markers and variable immune cell abnormalities, such as decreased NK cells and low memory B cells. One patient presented with recurrent infections and immunodeficiency in addition to autoinflammation. The disorder results from a defect in ELF4, which normally acts as a negative regulator of inflammatory disease. Symptoms may respond to blockade of IL1 (see 147760) or TNFA (191160) (summary by Tyler et al., 2021 and Sun et al., 2022). For a discussion of genetic heterogeneity of AIFBL, see AIFBL1 (616744).

Immunodeficiency-105 (IMD105) is an autosomal recessive disorder characterized by onset of recurrent infections in early infancy. Manifestations may include pneumonia, dermatitis, and lymphadenopathy. B-cell lymphoma was reported in 1 patient. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, hypogammaglobulinemia, and normal or low NK cells. The disorder is caused by a deficiency of transmembrane protein CD45 (PTPRC) on leukocytes, which plays an important role in T- and B-cell development (Cale et al., 1997; Kung et al., 2000). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.

Proteasome-associated autoinflammatory syndrome-6 (PRAAS6) is characterized by a proteasome-associated autoinflammatory syndrome with immunodeficiency (Kanazawa et al., 2021).