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Immunodeficiency 97 with autoinflammation(IMD97)

MedGen UID:
1802936
Concept ID:
C5676946
Disease or Syndrome
Synonym: IMD97
 
Gene (location): PIK3CG (7q22.3)
 
Monarch Initiative: MONDO:0030717
OMIM®: 619802

Definition

Immunodeficiency-97 with autoinflammation (IMD97) is an autosomal recessive complex immunologic disorder with variable features. Affected individuals present in the first decade of life with inflammatory interstitial lung disease or colitis due to abnormal tissue infiltration by activated T cells. Patients develop autoimmune cytopenias and may have lymphadenopathy; 1 reported patient had features of hemophagocytic lymphohistiocytosis (HLH; see FHL1, 267700). Some patients may have recurrent infections associated with mild lymphopenia, hypogammaglobulinemia, and NK cell dysfunction. Immunologic workup indicates signs of significant immune dysregulation with elevation of inflammatory serum markers, variable immune cell defects involving neutrophils, NK cells, and myeloid cells, and disrupted levels of T regulatory cells (Tregs). Two unrelated patients have been reported (summary by Takeda et al., 2019 and Thian et al., 2020). [from OMIM]

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Foam cells
MedGen UID:
924121
Concept ID:
C4281786
Finding
The presence of foam cells, a type of macrophage that localizes to fatty deposits on blood vessel walls, where they ingest low-density lipoproteins and become laden with lipids, giving them a foamy appearance.
Colitis
MedGen UID:
40385
Concept ID:
C0009319
Disease or Syndrome
Ulcerative colitis is a chronic disorder that affects the digestive system. This condition is characterized by abnormal inflammation of the inner surface (epithelium) of the rectum and colon. The rectum and colon make up most of the length of the large intestine. The inflammation usually causes open sores (ulcers) to develop in the large intestine. Ulcerative colitis usually appears between the age of 15 and 30, although it can develop at any age. The inflammation tends to flare up multiple times throughout a person's life, which causes recurring signs and symptoms.\n\nThe most common symptoms of ulcerative colitis are cramping abdominal pain and frequent diarrhea, often with blood, pus, or mucus in the stool. Other signs and symptoms include nausea, loss of appetite, bowel urgency, fatigue, and fevers. Chronic bleeding from the inflamed and ulcerated intestinal tissue can cause a shortage of red blood cells (anemia) in some affected individuals. People with this disorder have difficulty absorbing enough fluids and nutrients from their diet and often experience weight loss. Affected children usually grow more slowly than normal. Less commonly, ulcerative colitis causes problems with the skin, joints, eyes, kidneys, or liver, which are most likely due to abnormal inflammation.\n\nToxic megacolon is a rare complication of ulcerative colitis that can be life-threatening. Toxic megacolon involves a widening (dilation) of the colon and an overwhelming inflammatory response. Ulcerative colitis also increases the risk of developing colon cancer, especially in people whose entire colon is inflamed and in those who have had ulcerative colitis for 8 years or more.\n\nUlcerative colitis is one common form of inflammatory bowel disease (IBD). Another type of IBD, Crohn's disease, also causes chronic inflammation of the intestines. Unlike ulcerative colitis, which affects only the inner surface of the large intestine, Crohn's disease can cause inflammation in any part of the digestive system, and the inflammation extends deeper into the intestinal tissue.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Enterocolitis
MedGen UID:
4966
Concept ID:
C0014356
Disease or Syndrome
An inflammation of the colon and small intestine. However, most conditions are either categorized as Enteritis (inflammation of the small intestine) or Colitis (inflammation of the large intestine).
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Bronchiolitis obliterans organizing pneumonia
MedGen UID:
116663
Concept ID:
C0242770
Disease or Syndrome
Bronchiolitis obliterans organizing pneumonia (BOOP) is and interstitial lung abnormalitiy characterized histopathologically by plugs of granulation tissue lying within small airways, alveolar ducts, and alveoli and by chronic inflammatory cell infiltration in alveolar walls. Patients with BOOP generally present with subacute illness, including shortness of breath, fever, malaise, and weight loss.
Recurrent sinopulmonary infections
MedGen UID:
339549
Concept ID:
C1846546
Finding
An increased susceptibility to infections involving both the paranasal sinuses and the lungs, as manifested by a history of recurrent sinopulmonary infections.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
An autoimmune form of hemolytic anemia.
Eczematoid dermatitis
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Increased count of eosinophils in the blood.
Granuloma
MedGen UID:
5376
Concept ID:
C0018188
Pathologic Function
A compact, organized collection of mature mononuclear phagocytes, which may be but is not necessarily accompanied by accessory features such as necrosis.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Decreased circulating IgA level
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Neutropenia in presence of anti-neutropil antibodies
MedGen UID:
137947
Concept ID:
C0340971
Disease or Syndrome
A type of neutropenia that is observed in the presence of granulocyte-specific antibodies.
Monocytopenia
MedGen UID:
507013
Concept ID:
C0427544
Finding
An decreased number of circulating monocytes.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargment (swelling) of a lymph node.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Hemophagocytosis
MedGen UID:
163750
Concept ID:
C0876991
Disease or Syndrome
Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.
Decreased proportion of CD8-positive T cells
MedGen UID:
374188
Concept ID:
C1839305
Finding
A decreased proportion of circulating CD8-positive, alpha-beta T cells relative to total number of T cells.
Recurrent skin infections
MedGen UID:
377848
Concept ID:
C1853193
Disease or Syndrome
Infections of the skin that happen multiple times.
Reduced natural killer cell count
MedGen UID:
383765
Concept ID:
C1855767
Finding
Less than normal number of natural killer cells, a type of lymphocyte in the innate immune system with an ability to mediate cytotoxicity and produce cytokines after the ligation of a germline-encoded activation receptor.
Elevated proportion of CD4-negative, CD8-negative, alpha-beta regulatory T cells
MedGen UID:
395145
Concept ID:
C1858973
Finding
An abnormally increased proportion of CD4-negative, CD8-negative (double negative or DN) alpha-beta regulatory T cells (Tregs) as compared to total number of T cells.
Decreased circulating antibody level
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
Decreased proportion of CD4+CD25+ regulatory T cells
MedGen UID:
1688709
Concept ID:
C5139086
Finding
An abnormally decreased proportion of CD4-positive, CD25-positive, alpha-beta regulatory T cells in circulation, relative to another population of cells.
Decreased circulating IgG level
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Decreased proportion of CD8-positive, alpha-beta TEMRA T cells
MedGen UID:
1711089
Concept ID:
C5398016
Finding
An decreased proportion of CD8-positive, alpha-beta effector memory RA TEMRA T cells compared to the total number of T cells in the blood. These cells have the phenotype CD45RA-positive, CD45RO-negative, and CCR7-negative.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Nasal congestion
MedGen UID:
6523
Concept ID:
C0027424
Sign or Symptom
Reduced ability to pass air through the nasal cavity often leading to mouth breathing.
Mediastinal lymphadenopathy
MedGen UID:
451062
Concept ID:
C0520743
Disease or Syndrome
Swelling of lymph nodes within the mediastinum, the central compartment of the thoracic cavities that contains the heart and the great vessels, the esophagus, and trachea and other structures including lymph nodes.

Recent clinical studies

Etiology

Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520
Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, Taskinen M, Koskenvuo M, Saarela J, Dimitrova D, Hickstein DD, Hsu AP, Holland SM, Krance R, Sasa G, Kumar AR, Müller I, de Sousa MA, Delafontaine S, Moens L, Babor F, Barzaghi F, Cicalese MP, Bredius R, van Montfrans J, Baretta V, Cesaro S, Stepensky P, Benedicte N, Moshous D, Le Guenno G, Boutboul D, Dalal J, Brooks JP, Dokmeci E, Dara J, Lucas CL, Hambleton S, Wilson K, Jolles S, Koc Y, Güngör T, Schnider C, Candotti F, Steinmann S, Schulz A, Chambers C, Hershfield M, Ombrello A, Kanakry JA, Meyts I
J Clin Immunol 2021 Oct;41(7):1633-1647. Epub 2021 Jul 29 doi: 10.1007/s10875-021-01098-0. PMID: 34324127Free PMC Article
Goudouris ES
J Pediatr (Rio J) 2021 Mar-Apr;97 Suppl 1(Suppl 1):S24-S33. Epub 2020 Nov 8 doi: 10.1016/j.jped.2020.10.004. PMID: 33176164Free PMC Article
Mulders-Manders CM, Engwerda C, Simon A, van der Meer JWM, Bleeker-Rovers CP
Medicine (Baltimore) 2018 Jun;97(25):e11241. doi: 10.1097/MD.0000000000011241. PMID: 29924054Free PMC Article

Diagnosis

Mulders-Manders CM, Engwerda C, Simon A, van der Meer JWM, Bleeker-Rovers CP
Medicine (Baltimore) 2018 Jun;97(25):e11241. doi: 10.1097/MD.0000000000011241. PMID: 29924054Free PMC Article

Therapy

Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, Taskinen M, Koskenvuo M, Saarela J, Dimitrova D, Hickstein DD, Hsu AP, Holland SM, Krance R, Sasa G, Kumar AR, Müller I, de Sousa MA, Delafontaine S, Moens L, Babor F, Barzaghi F, Cicalese MP, Bredius R, van Montfrans J, Baretta V, Cesaro S, Stepensky P, Benedicte N, Moshous D, Le Guenno G, Boutboul D, Dalal J, Brooks JP, Dokmeci E, Dara J, Lucas CL, Hambleton S, Wilson K, Jolles S, Koc Y, Güngör T, Schnider C, Candotti F, Steinmann S, Schulz A, Chambers C, Hershfield M, Ombrello A, Kanakry JA, Meyts I
J Clin Immunol 2021 Oct;41(7):1633-1647. Epub 2021 Jul 29 doi: 10.1007/s10875-021-01098-0. PMID: 34324127Free PMC Article

Prognosis

Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520
Mulders-Manders CM, Engwerda C, Simon A, van der Meer JWM, Bleeker-Rovers CP
Medicine (Baltimore) 2018 Jun;97(25):e11241. doi: 10.1097/MD.0000000000011241. PMID: 29924054Free PMC Article

Clinical prediction guides

Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520

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