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1.

Wiskott-Aldrich syndrome

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities. [from GeneReviews]

MedGen UID:
21921
Concept ID:
C0043194
Disease or Syndrome
2.

Hyper-IgM syndrome type 1

X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection. [from GeneReviews]

MedGen UID:
96019
Concept ID:
C0398689
Disease or Syndrome
3.

Autoimmune lymphoproliferative syndrome type 1

Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published. [from GeneReviews]

MedGen UID:
231300
Concept ID:
C1328840
Disease or Syndrome
4.

Hyperimmunoglobulin D with periodic fever

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.

Mevalonate 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).

During 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.

People 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. [from MedlinePlus Genetics]

MedGen UID:
140768
Concept ID:
C0398691
Disease or Syndrome
5.

Thrombocytopenia 1

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities. [from GeneReviews]

MedGen UID:
326416
Concept ID:
C1839163
Disease or Syndrome
6.

Combined immunodeficiency due to STIM1 deficiency

Immunodeficiency-10 (IMD10) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016). [from OMIM]

MedGen UID:
440575
Concept ID:
C2748557
Disease or Syndrome
7.

Ectodermal dysplasia and immunodeficiency 1

Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by Doffinger et al., 2001, Orange et al., 2004, Roberts et al., 2010, Heller et al., 2020). Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency Also see EDAID2 (612132), caused by mutation in the NFKBIA gene (164008). [from OMIM]

MedGen UID:
375787
Concept ID:
C1846008
Disease or Syndrome
8.

Autoimmune lymphoproliferative syndrome type 2A

Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published. [from GeneReviews]

MedGen UID:
349065
Concept ID:
C1858968
Disease or Syndrome
9.

Immunodeficiency 33

Immunodeficiency-33 (IMD33) is an X-linked recessive disorder that affects only males. It is characterized by early-onset severe infections, usually due to pneumococcus, H. influenzae, and atypical mycobacteria, although other organisms have also been detected. Immunologic investigations may show variable abnormalities or may be normal. Disturbances include dysgammaglobulinemia with hypogammaglobulinemia, decreased IgG2, aberrant levels of IgM and IgA, and decreased class-switched memory B cells. There is often poor, but variable, response to vaccination; in particular, most patients do not develop antibodies to certain polysaccharide vaccines, notably pneumococcus. Other immunologic abnormalities may include impaired NK cytotoxic function, impaired cytokine production upon stimulation with IL1B (147720) or TNFA (191160), low IL6 (147620), low IL12 (see 161561), and decreased IFNG (147570). Patients do not have overt abnormalities of T-cell proliferation, although signaling pathways, such as CD40LG (300386)/CD40 (109535), may be disturbed. There is heterogeneity in the immunologic phenotype, resulting in highly variable clinical courses, most likely due to the different effects of hypomorphic mutations. Treatment with antibiotics and IVIg is usually beneficial; hematopoietic stem cell transplantation may not be necessary, but can be effective. Features of hypohidrotic ectodermal dysplasia are generally not present, although some patients may have conical teeth or hypodontia (summary by Orange et al., 2004, Filipe-Santos et al., 2006, Salt et al., 2008, Heller et al., 2020). [from OMIM]

MedGen UID:
370376
Concept ID:
C1970879
Disease or Syndrome
10.

Proteasome-associated autoinflammatory syndrome 1

Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder 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; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21. [from OMIM]

MedGen UID:
1648310
Concept ID:
C4746851
Disease or Syndrome
11.

Immunodeficiency 25

Any severe combined immunodeficiency in which the cause of the disease is a mutation in the CD247 gene. [from MONDO]

MedGen UID:
346666
Concept ID:
C1857798
Disease or Syndrome
12.

Trichothiodystrophy 3, photosensitive

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675. [from OMIM]

MedGen UID:
865608
Concept ID:
C4017171
Disease or Syndrome
13.

STING-associated vasculopathy with onset in infancy

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). [from OMIM]

MedGen UID:
863159
Concept ID:
C4014722
Disease or Syndrome
14.

Immunodeficiency 64

Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity (summary by Salzer et al., 2016, Mao et al., 2018, and Winter et al., 2018). [from OMIM]

MedGen UID:
1684716
Concept ID:
C5231402
Disease or Syndrome
15.

Proteasome-associated autoinflammatory syndrome 2

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). [from OMIM]

MedGen UID:
1648482
Concept ID:
C4747989
Disease or Syndrome
16.

Infantile-onset periodic fever-panniculitis-dermatosis syndrome

Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive 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), leukocytosis, and neutrophilia in the absence of any infection. Patients exhibit no overt primary immunodeficiency (Damgaard et al., 2016 and Zhou et al., 2016). [from OMIM]

MedGen UID:
934581
Concept ID:
C4310614
Disease or Syndrome
17.

Autoinflammation with arthritis and dyskeratosis

Autoinflammation with arthritis and dyskeratosis (AIADK) is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (summary by Grandemange et al., 2016). [from OMIM]

MedGen UID:
1380109
Concept ID:
C4479278
Disease or Syndrome
18.

Immunodeficiency 89 and autoimmunity

Immunodeficiency-89 and autoimmunity (IMD89) is an autosomal recessive immune disorder characterized by adult onset of recurrent infections, allergies, microcytic anemia, and Crohn disease (see 266600) (Yang et al., 2020). [from OMIM]

MedGen UID:
1794237
Concept ID:
C5562027
Disease or Syndrome
19.

Immunodeficiency 113 with autoimmunity and autoinflammation

Immunodeficiency-113 with autoimmunity and autoinflammation (IMD113) is an autosomal recessive complex immunologic disorder with onset of symptoms in infancy. Affected individuals have recurrent infections and usually show features of autoimmunity and autoinflammation, such as hemolytic anemia, thrombocytopenia, hepatosplenomegaly, leukocytosis, neutrophilia, and elevated acute phase reactants. More variable systemic features may include celiac disease or enteropathy, ileus, nephropathy, eczema, and dermatomyositis. Additional features include facial dysmorphism, scoliosis, and poor wound healing. One patient with neurodevelopmental abnormalities has been reported. The disorder results from dysregulation of the actin cytoskeleton that affects certain cell lineages (Nunes-Santos et al., 2023). [from OMIM]

MedGen UID:
1851770
Concept ID:
C5882711
Disease or Syndrome
20.

Asthma, short stature, and elevated IgA

MedGen UID:
395313
Concept ID:
C1859647
Disease or Syndrome
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