Crouzon syndrome is an autosomal dominant disorder characterized by craniosynostosis causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism (Reardon et al., 1994; Glaser et al., 2000).

Dystrophic epidermolysis bullosa (DEB) is a genetic skin disorder affecting skin and nails that usually presents at birth. DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). Each type is further divided into multiple clinical subtypes. Absence of a known family history of DEB does not preclude the diagnosis. Clinical findings in severe generalized RDEB include skin fragility manifest by blistering with minimal trauma that heals with milia and scarring. Blistering and erosions affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Consequently, malnutrition and vitamin and mineral deficiency may lead to growth restriction in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, with contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma is higher than 90%. In contrast, the blistering in the less severe forms of RDEB may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without the mutilating scarring seen in severe generalized RDEB. In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB.

Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this GeneReview) is characterized by a triad of major clinical features including partial-to-complete alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Sweating is preserved and there are usually no dental anomalies. Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is fine, sparse, and brittle. Progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. Associated features may include cutaneous hyperpigmentation (particularly over the joints) and finger clubbing. The clinical manifestations are highly variable even within the same family.

Congenital erythropoietic porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink-to-dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from nonimmune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.

If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics.

A rare autosomal recessive inherited syndrome. It is characterized by xeroderma pigmentosum, mental retardation, dwarfism, hypogonadism, and neurologic abnormalities.

Lymphedema-distichiasis syndrome (referred to as LDS in this GeneReview) is characterized by lower-limb lymphedema, and distichiasis (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair). Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs with or without involvement of the external genitalia, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis than females. Distichiasis, which may be present at birth, is observed in 94% of affected individuals. About 75% of affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include varicose veins and ptosis.

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Muckle-Wells syndrome (MWS) is characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis (Dode et al., 2002).

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

IGHD3 is characterized by agammaglobulinemia and markedly reduced numbers of B cells, short stature, delayed bone age, and good response to treatment with growth hormone (summary by Conley et al., 1991). For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400.

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.

Autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR) is characterized by neonatal-onset ichthyotic erythroderma and profound sensorineural deafness, with failure to thrive and developmental delay in childhood. Severe corneal scarring with vision loss has been observed in adulthood. Low plasma copper and ceruloplasmin levels have been reported in some patients (Alsaif et al., 2019; Boyden et al., 2019). An autosomal dominant form of KID syndrome (KIDAD; 148210) is caused by mutation in the GJB2 gene (121011) on chromosome 13q12. Mutation in the AP1S1 gene (603531) causes a disorder with overlapping features (MEDNIK; 609313).

Familial periodic fever (FPF) is an autoinflammatory disorder characterized by recurrent fever with localized myalgia and painful erythema. Febrile attacks may last 1 or 2 days but often last longer than 1 week. Arthralgia of large joints, abdominal pain, conjunctivitis, and periorbital edema are common features. During attacks, painless cutaneous lesions may develop on the trunk or extremities and may migrate distally (review by Drenth and van der Meer, 2001).

Severe combined immunodeficiency refers to a genetically and clinically heterogeneous group of disorders with defective cellular and humoral immune function. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms, including Candida albicans, Pneumocystis carinii, and cytomegalovirus, among many others. Laboratory analysis shows profound lymphopenia with diminished or absent immunoglobulins. The common characteristic of all types of SCID is absence of T cell-mediated cellular immunity due to a defect in T-cell development. Without treatment, patients usually die within the first year of life. The overall prevalence of all types of SCID is approximately 1 in 75,000 births (Fischer et al., 1997; Buckley, 2004). Genetic Heterogeneity of SCID SCID can be divided into 2 main classes: those with B lymphocytes (B+ SCID) and those without (B- SCID). Presence or absence of NK cells is variable within these groups. The most common form of SCID is X-linked T-, B+, NK- SCID (SCIDX1; 300400) caused by mutation in the IL2RG gene (308380) on chromosome Xq13.1. Autosomal recessive SCID includes T-, B-, NK+ SCID, caused by mutation in the RAG1 and RAG2 genes on 11p13; T-, B+, NK- SCID (600802), caused by mutation in the JAK3 gene (600173) on 19p13; T-, B+, NK+ SCID (IMD104; 608971), caused by mutation in the IL7R gene (146661) on 5p13; T-, B+, NK+ SCID (IMD105; 619924), caused by mutation in the CD45 gene (PTPRC; 151460) on 1q31-q32; T-, B+, NK+ SCID (IMD19; 615617), caused by mutation in the CD3D gene (186790) on 11q23; T-, B-, NK- SCID (102700) caused by mutation in the ADA (608958) gene on 20q13; and T-, B-, NK+ SCID with sensitivity to ionizing radiation (602450), caused by mutation in the Artemis gene (DCLRE1C; 605988) on 10p13 (Kalman et al., 2004); and T-, B-, NK+ SCID with microcephaly, growth retardation, and sensitivity to ionizing radiation (611291), caused by mutation in the NHEJ1 gene (611290) on 2q35. Approximately 20 to 30% of all SCID patients are T-, B-, NK+, and approximately half of these patients have mutations in the RAG1 or RAG2 genes (Schwarz et al., 1996; Fischer et al., 1997).

Congenital nasolacrimal drainage system impatency is relatively common, occurring in approximately 20% of children within the first year of life. Such infants typically manifest persistent epiphora and/or recurrent infections of the lacrimal pathway such as conjunctivitis. The most frequent site of such obstruction occurs at the distal intranasal segment of the nasolacrimal drainage system at the valve of Hasner (summary by Wang and Cunningham, 2011). Congenital dacryocystocele, an uncommon variant of nasolacrimal duct obstruction, characterized by the appearance of a cystic blue mass over the area of the lacrimal duct soon after birth. Dacryocystoceles are thought to result from a persistent membrane at the valve of Hasner and a functional obstruction of the common canaliculus or valve of Rosenmuller. The resulting lacrimal sac distention has been reported to be more common in female and non-Hispanic white patients, and familial cases have been described only sporadically. Common presenting signs include dacryocystitis, facial cellulitis, and respiratory distress; the development of astigmatism in association with dacryocystocele has only rarely been observed (summary by Shekunov et al., 2010).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (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 and, rarely, acute myelogenous leukemia. Other ectodermal findings include 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.

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

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.

Mandibulofacial dysostosis-macroblepharon-macrostomia syndrome is a rare developmental defect during embryogenesis disorder characterized by macroblepharon, ectropion, and facial dysmorphism which includes severe hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, broad nasal bridge, long and smooth philtrum, and macrostomia with thin upper lip vermilion border. Other features may include large fontanelles, prominent metopic ridge, thick eyebrows, mild synophrys, increased density of upper eyelashes, anterverted nares, abnormal dentition and capillary hemangioma.

Congenital plasminogen deficiency is a rare autosomal recessive disorder characterized clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. A slightly increased female:male ratio has been observed (1.4:1 to 2:1) (Schuster and Seregard, 2003; Tefs et al., 2006). Type I plasminogen deficiency is characterized by decreased serum plasminogen activity, decreased plasminogen antigen levels, and clinical symptoms, whereas type II plasminogen deficiency, also known as 'dysplasminogenemia,' is characterized by decreased plasminogen activity with normal or slightly reduced antigen levels. Patients with type II deficiency are usually asymptomatic. Ligneous conjunctivitis and pseudomembranous formation has only been associated with type I plasminogen deficiency. Presumably, normal amounts of plasminogen antigen with decreased activity, as seen in type II, is sufficient for normal wound healing (Schuster and Seregard, 2003).

Keratosis follicularis spinulosa decalvans (KFSD) is an uncommon genodermatosis characterized by follicular hyperkeratosis, progressive cicatricial alopecia, and photophobia. Most reported cases show X-linked inheritance (KFSDX; 308800) (Castori et al., 2009).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous group of disorders characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections, and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B cells are usually in the normal range, but can be low. Most individuals with CVID have onset of infections after age 10 years. CVID represents the most common form of primary immunodeficiency disorders and is the most common form of primary antibody deficiency. Approximately 10 to 20% of patients with a diagnosis of CVID have a family history of the disorder (reviews by Chapel et al., 2008, Conley et al., 2009, and Yong et al., 2009). Genetic Heterogeneity of Common Variable Immunodeficiency Common variable immunodeficiency is a genetically heterogeneous disorder. See also CVID2 (240500), caused by mutation in the TACI gene (TNFRSF13B; 604907); CVID3 (613493), caused by mutation in the CD19 gene (107265); CVID4 (613494), caused by mutation in the BAFFR gene (TNFRSF13C; 606269); CVID5 (613495), caused by mutation in the CD20 gene (112210); CVID6 (613496), caused by mutation in the CD81 gene (186845); CVID7 (614699), caused by mutation in the CD21 gene (CR2; 120650); CVID8 (614700), caused by mutation in the LRBA gene (606453); CVID10 (615577), caused by mutation in the NFKB2 gene (164012); CVID11 (615767), caused by mutation in the IL21 gene (605384); CVID12 (616576), caused by mutation in the NFKB1 gene (164011); CVID13 (616873), caused by mutation in the IKZF1 gene (603023); CVID14 (617765), caused by mutation in the IRF2BP2 gene (615332); and CVID15 (620670), caused by heterozygous mutation in the SEC61A1 gene (609213). The disorder formerly designated CVID9 has been found to be a form of autoimmune lymphoproliferative disorder; see ALPS3 (615559).

Any autosomal agammaglobulinemia in which the cause of the disease is a mutation in the CD79B gene.

Agammaglobulinemia is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The most common form of agammaglobulinemia is X-linked agammaglobulinemia (AGMX1, XLA; 300755), also known as Bruton disease, which is caused by mutation in the BTK gene (300300). AGMX1 accounts for anywhere from 85 to 95% of males who have the characteristic findings (Lopez Granados et al., 2002; Ferrari et al., 2007). Autosomal recessive inheritance of agammaglobulinemia, which has a similar phenotype to that of the X-linked form, has been observed in a small number of families, and accounts for up to 15% of patients with agammaglobulinemia (Ferrari et al., 2007). Conley (1999) gave a comprehensive review of autosomal recessive agammaglobulinemia. Genetic Heterogeneity of Autosomal Agammaglobulinemia Autosomal agammaglobulinemia is a genetically heterogeneous disorder: see also AGM2 (613500), caused by mutation in the IGLL1 gene (146770); AGM3 (613501), caused by mutation in the CD79A gene (112205); AGM4 (613502), caused by mutation in the BLNK gene (604515); AGM5 (613506), caused by disruption of the LRRC8 gene (608360); AGM6 (612692), caused by mutation in the CD79B gene (147245); AGM7 (615214), caused by mutation in the PIK3R1 gene (171833); AGM8 (616941), caused by mutation in the TCF3 gene (147141); AGM9 (619693), caused by mutation in the SLC39A7 gene (601416); and AGM10 (619707), caused by mutation in the SPI1 gene (165170).

Granulomatosis with polyangiitis, formerly termed Wegener granulomatosis, is a systemic disease with a complex genetic background. It is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, vasculitis, and the presence of antineutrophil cytoplasmatic autoantibodies (ANCAs) in patient sera. These ANCAs are antibodies to a defined target antigen, proteinase-3 (PR3, PRTN3; 177020), which is present within primary azurophil granules of neutrophils (PMNs) and lysozymes of monocytes. On cytokine priming of PMNs, PR3 translocates to the cell surface, where PR3-ANCAs can interact with their antigens and activate PMNs. PMNs from patients with active GPA express PR3 on their surface, produce respiratory burst, and release proteolytic enzymes after activation with PR3-ANCAs. The consequence is a self-sustaining inflammatory process (Jagiello et al., 2004).

Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Keratosis follicularis spinulosa decalvans is an uncommon genodermatosis chiefly characterized by widespread keratosis pilaris, progressive cicatricial alopecia of the scalp, eyebrows, and eyelashes, and an excess of affected males. Photophobia, blepharitis/conjunctivitis, and corneal dystrophy are characteristic ancillary findings. It is most often inherited as an X-linked trait (summary by Castori et al., 2009). Autosomal dominant inheritance has also been reported (KFSD; 612843). The term 'cum ophiasi' means 'with ophiasis,' i.e., baldness in 1 or more winding streaks about the head, which comes from the Greek for snake. Decalvans refers to the loss of hair.

Arboleda-Tham syndrome (ARTHS) is an autosomal dominant disorder with the core features of impaired intellectual development, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications (summary by Kennedy et al., 2019).

DFNA34 is an autosomal dominant form of postlingual, slowly progressive sensorineural hearing loss with variable severity and variable additional features. Some patients have pure hearing loss without significant additional features, whereas some patients have features of an autoinflammatory disorder with systemic manifestations, including periodic fevers, arthralgias, and episodic urticaria. The disorder results from abnormally increased activation of the inflammatory pathway, and treatment with an IL1 receptor antagonist (see 147679) may be effective if started early (summary by Nakanishi et al., 2017).

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\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\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\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).

This autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; and PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22.

Proteasome-associated autoinflammatory syndrome-3 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).

Otofaciocervical syndrome-2 with T-cell deficiency (OTFCS2) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies including vertebral defects, low-set clavicles, winged scapulae, sloping shoulders, and mild intellectual disability (summary by Pohl et al., 2013). Patients have been reported who also exhibit altered thymus development with T-cell immunodeficiency and recurrent, sometimes fatal, infections (Paganini et al., 2017; Yamazaki et al., 2020). For a discussion of genetic heterogeneity of otofaciocervical syndrome, see OTFCS1 (166780).

A rare genetic combined T and B cell immunodeficiency characterised by life-threatening infections due to disrupted transferrin receptor 1 endocytosis, resulting in defective cellular iron transport and impaired T and B cell function. Patients present with early-onset chronic diarrhoea, severe recurrent infections and failure to thrive. Laboratory studies reveal hypo or agammaglobulinaemia, normal lymphocyte counts but decreased numbers of memory B cells, intermittent neutropenia and thrombocytopenia, and mild anaemia (resistant to iron supplementation) with low mean corpuscular volume.

Lacrimoauriculodentodigital syndrome-2 (LADD2) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006).

Lacrimoauriculodentodigital syndrome-1 (LADD1) is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006). Genetic Heterogeneity of Lacrimoauriculodentodigital Syndrome LADD syndrome-2 (LADD2; 620192) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16, and LADD syndrome-3 (LADD3; 620193) is caused by mutation in the FGF10 gene, an FGFR ligand, on chromosome 5p12.