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Hyper-IgE recurrent infection syndrome 1, autosomal dominant(HIES1)

MedGen UID:
1648470
Concept ID:
C4721531
Disease or Syndrome
Synonyms: AD hyperimmunoglobulin E syndrome; Autosomal Dominant Hyper IgE Syndrome; HIES autosomal dominant; Hyper Ig E syndrome, autosomal dominant; Hyper-IgE recurrent infection syndrome 1; HYPER-IgE SYNDROME 1, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant; Job syndrome; Job's Syndrome
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): STAT3 (17q21.2)
 
Monarch Initiative: MONDO:0007818
OMIM®: 147060
Orphanet: ORPHA2314

Disease characteristics

Excerpted from the GeneReview: STAT3 Hyper IgE Syndrome
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. [from GeneReviews]
Authors:
Amy P Hsu  |  Joie Davis  |  Jennifer M Puck, et. al.   view full author information

Additional descriptions

From OMIM
Hyper-IgE syndrome-1 with recurrent infections (HIES1) is an autosomal dominant immunologic disorder characterized by chronic eczema (atopy), recurrent Staphylococcal infections, increased serum IgE, and eosinophilia. Other more variable immunologic abnormalities include defective granulocyte chemotaxis, abnormalities in T-lymphocyte subgroups, impaired antibody production, and decreased production of or response to certain cytokines. Importantly, the same immune system defects are not found in all patients. Some patients may have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures (Buckley et al., 1972; Grimbacher et al., 1999). Genetic Heterogeneity of Hyper-IgE Syndrome See also HIES2 (243700), caused by mutation in the DOCK8 gene (611432); HIES3 (618282), caused by mutation in the ZNF341 gene (618269); HIES4A (619752) and HIES4B (618523), both caused by mutation in the IL6ST gene (600694); HIES5 (618944), caused by mutation in the IL6R gene (147880); and HIES6 (620532), caused by mutation in the STAT6 gene (601512).  http://www.omim.org/entry/147060
From MedlinePlus Genetics
Autosomal dominant hyper-IgE syndrome (AD-HIES), formerly known as Job syndrome, is a condition that affects several body systems, particularly the immune system. Recurrent infections are common in people with this condition. Affected individuals tend to have frequent bouts of pneumonia, which are caused by certain kinds of bacteria that infect the lungs and cause inflammation. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, excessive inflammation can damage body tissues. Recurring pneumonia often results in the formation of air-filled cysts (pneumatoceles) in the lungs. Frequent skin infections and an inflammatory skin disorder called eczema are also very common in AD-HIES. These skin problems cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling.

For unknown reasons, people with AD-HIES have abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood. IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and is involved in allergies. However, IgE is not needed for these roles in people with AD-HIES, and it is unclear why affected individuals have such high levels of the protein without having allergies.

AD-HIES also affects other parts of the body, including the bones and teeth. Many people with AD-HIES have skeletal abnormalities such as an unusually large range of joint movement (hyperextensibility), an abnormal curvature of the spine (scoliosis), reduced bone density (osteopenia), and a tendency for bones to fracture easily. A common dental abnormality in this condition is that the primary (baby) teeth do not fall out at the usual time during childhood but are retained as the adult teeth grow in. Other signs and symptoms of AD-HIES can include abnormalities of the arteries that supply blood to the heart muscle (coronary arteries), distinctive facial features, and structural abnormalities of the brain, which do not affect a person's intelligence.  https://medlineplus.gov/genetics/condition/autosomal-dominant-hyper-ige-syndrome

Clinical features

From HPO
Craniosynostosis syndrome
MedGen UID:
1163
Concept ID:
C0010278
Disease or Syndrome
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
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.
Chronic mucocutaneous candidiasis
MedGen UID:
2426
Concept ID:
C0006845
Disease or Syndrome
Recurrent or persistent superficial Candida infections of the skin, mucous membranes, and nails.
Eczema
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.
Cutaneous abscess
MedGen UID:
450991
Concept ID:
C0149777
Pathologic Function
A circumscribed area of pus or necrotic debris in the skin.
Increased circulating IgE level
MedGen UID:
116018
Concept ID:
C0236175
Finding
An abnormally increased overall level of immunoglobulin E in blood.
Recurrent fungal infections
MedGen UID:
336166
Concept ID:
C1844384
Disease or Syndrome
Increased susceptibility to fungal infections, as manifested by multiple episodes of fungal infection.
Recurrent Staphylococcus aureus infections
MedGen UID:
392925
Concept ID:
C2673462
Finding
Increased susceptibility to Staphylococcus aureus infections, as manifested by recurrent episodes of Staphylococcus aureus infection.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Persistence of primary teeth
MedGen UID:
75597
Concept ID:
C0266050
Disease or Syndrome
Persistence of the primary teeth beyond the age by which they normally are shed and replaced by the permanent teeth.
Wide nose
MedGen UID:
140869
Concept ID:
C0426421
Finding
Interalar distance more than two standard deviations above the mean for age, i.e., an apparently increased width of the nasal base and alae.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Erythema
MedGen UID:
11999
Concept ID:
C0041834
Disease or Syndrome
Redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyper-IgE recurrent infection syndrome 1, autosomal dominant

Professional guidelines

PubMed

Heimall J, Davis J, Shaw PA, Hsu AP, Gu W, Welch P, Holland SM, Freeman AF
Clin Immunol 2011 Apr;139(1):75-84. Epub 2011 Jan 14 doi: 10.1016/j.clim.2011.01.001. PMID: 21288777Free PMC Article

Recent clinical studies

Etiology

Mohammadi T, Azizi G, Rafiemanesh H, Farahani P, Nirouei M, Tavakol M
Clin Exp Med 2023 Dec;23(8):4835-4859. Epub 2023 Nov 4 doi: 10.1007/s10238-023-01228-5. PMID: 37924455
Mahdaviani SA, Ghadimi S, Fallahi M, Hashemi-Moghaddam SA, Chavoshzadeh Z, Puel A, Rezaei N, Rekabi M, Daneshmandi Z, Sheikhy K, Kakhki AD, Saghebi SR, Pejhan S, Jamee M
BMC Surg 2023 Sep 23;23(1):289. doi: 10.1186/s12893-023-02193-2. PMID: 37741967Free PMC Article
Shamriz O, Rubin L, Simon AJ, Lev A, Barel O, Somech R, Korem M, Matza Porges S, Freund T, Hagin D, Garty BZ, Nahum A, Molho Pessach V, Tal Y
Front Immunol 2022;13:1044933. Epub 2022 Dec 20 doi: 10.3389/fimmu.2022.1044933. PMID: 36605204Free PMC Article
Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K, Buckley R, Haddad E, Ochs HD, Fuleihan R, Routes J, Muskat M, Lugar P, Mancini J, Cunningham-Rundles C
J Allergy Clin Immunol Pract 2018 May-Jun;6(3):996-1001. Epub 2017 Sep 19 doi: 10.1016/j.jaip.2017.06.041. PMID: 28939137Free PMC Article
D'Assante R, Fusco A, Palamaro L, Giardino G, Gallo V, Cirillo E, Pignata C
Int Rev Immunol 2016;35(1):25-38. Epub 2015 Mar 16 doi: 10.3109/08830185.2015.1010724. PMID: 25774666

Diagnosis

Kasap N, Kara A, Celik V, Bilgic Eltan S, Akay Haci I, Kose H, Aygun A, Akkelle E, Yakici N, Guner SN, Reisli I, Keles S, Cekic S, Kilic SS, Karaca NE, Gulez N, Genel F, Ozen A, Yucelten AD, Karakoc-Aydiner E, Schmitz-Abe K, Baris S
J Clin Immunol 2023 Nov;43(8):1882-1890. Epub 2023 Jul 29 doi: 10.1007/s10875-023-01554-z. PMID: 37507632
Shamriz O, Rubin L, Simon AJ, Lev A, Barel O, Somech R, Korem M, Matza Porges S, Freund T, Hagin D, Garty BZ, Nahum A, Molho Pessach V, Tal Y
Front Immunol 2022;13:1044933. Epub 2022 Dec 20 doi: 10.3389/fimmu.2022.1044933. PMID: 36605204Free PMC Article
Bergerson JRE, Freeman AF
Immunol Allergy Clin North Am 2019 Feb;39(1):49-61. doi: 10.1016/j.iac.2018.08.007. PMID: 30466772
Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K, Buckley R, Haddad E, Ochs HD, Fuleihan R, Routes J, Muskat M, Lugar P, Mancini J, Cunningham-Rundles C
J Allergy Clin Immunol Pract 2018 May-Jun;6(3):996-1001. Epub 2017 Sep 19 doi: 10.1016/j.jaip.2017.06.041. PMID: 28939137Free PMC Article
Grimbacher B, Holland SM, Puck JM
Immunol Rev 2005 Feb;203:244-50. doi: 10.1111/j.0105-2896.2005.00228.x. PMID: 15661034

Therapy

Staudacher O, Krüger R, Kölsch U, Thee S, Gratopp A, Wahn V, Lau S, von Bernuth H
J Allergy Clin Immunol Pract 2022 Jan;10(1):349-351.e1. Epub 2021 Sep 16 doi: 10.1016/j.jaip.2021.08.042. PMID: 34536614
Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O'Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M
J Clin Invest 2020 Aug 3;130(8):4167-4181. doi: 10.1172/JCI135490. PMID: 32369445Free PMC Article
Ling Y, Puel A
Actas Dermosifiliogr 2014 Oct;105 Suppl 1:34-40. doi: 10.1016/S0001-7310(14)70016-X. PMID: 25398490
Ma H, Kuang L, Lv G, Wang B, Lian Z
Clin Vaccine Immunol 2014 Jan;21(1):107-9. Epub 2013 Nov 6 doi: 10.1128/CVI.00529-13. PMID: 24197892Free PMC Article
Patteri P, Serru A, Chessa ML, Loi M, Pinna A
Int Ophthalmol 2009 Oct;29(5):415-7. Epub 2008 Jun 5 doi: 10.1007/s10792-008-9238-y. PMID: 18528638

Prognosis

Kasap N, Kara A, Celik V, Bilgic Eltan S, Akay Haci I, Kose H, Aygun A, Akkelle E, Yakici N, Guner SN, Reisli I, Keles S, Cekic S, Kilic SS, Karaca NE, Gulez N, Genel F, Ozen A, Yucelten AD, Karakoc-Aydiner E, Schmitz-Abe K, Baris S
J Clin Immunol 2023 Nov;43(8):1882-1890. Epub 2023 Jul 29 doi: 10.1007/s10875-023-01554-z. PMID: 37507632
Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O'Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M
J Clin Invest 2020 Aug 3;130(8):4167-4181. doi: 10.1172/JCI135490. PMID: 32369445Free PMC Article
Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K, Buckley R, Haddad E, Ochs HD, Fuleihan R, Routes J, Muskat M, Lugar P, Mancini J, Cunningham-Rundles C
J Allergy Clin Immunol Pract 2018 May-Jun;6(3):996-1001. Epub 2017 Sep 19 doi: 10.1016/j.jaip.2017.06.041. PMID: 28939137Free PMC Article
Bocchini CE, Nahmod K, Katsonis P, Kim S, Kasembeli MM, Freeman A, Lichtarge O, Makedonas G, Tweardy DJ
Blood 2016 Dec 29;128(26):3061-3072. Epub 2016 Oct 31 doi: 10.1182/blood-2016-02-702373. PMID: 27799162Free PMC Article
Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L, Thumerelle C, Oksenhendler E, Boutboul D, Thomas C, Hoarau C, Lebranchu Y, Stephan JL, Cazorla C, Aladjidi N, Micheau M, Tron F, Baruchel A, Barlogis V, Palenzuela G, Mathey C, Dominique S, Body G, Munzer M, Fouyssac F, Jaussaud R, Bader-Meunier B, Mahlaoui N, Blanche S, Debré M, Le Bourgeois M, Gandemer V, Lambert N, Grandin V, Ndaga S, Jacques C, Harre C, Forveille M, Alyanakian MA, Durandy A, Bodemer C, Suarez F, Hermine O, Lortholary O, Casanova JL, Fischer A, Picard C
Medicine (Baltimore) 2012 Jul;91(4):e1-e19. doi: 10.1097/MD.0b013e31825f95b9. PMID: 22751495Free PMC Article

Clinical prediction guides

Béziat V, Fieschi C, Momenilandi M, Migaud M, Belaid B, Djidjik R, Puel A
Curr Opin Immunol 2023 Jun;82:102326. Epub 2023 Apr 18 doi: 10.1016/j.coi.2023.102326. PMID: 37080116Free PMC Article
Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O'Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M
J Clin Invest 2020 Aug 3;130(8):4167-4181. doi: 10.1172/JCI135490. PMID: 32369445Free PMC Article
Gernez Y, Freeman AF, Holland SM, Garabedian E, Patel NC, Puck JM, Sullivan KE, Akhter J, Secord E, Chen K, Buckley R, Haddad E, Ochs HD, Fuleihan R, Routes J, Muskat M, Lugar P, Mancini J, Cunningham-Rundles C
J Allergy Clin Immunol Pract 2018 May-Jun;6(3):996-1001. Epub 2017 Sep 19 doi: 10.1016/j.jaip.2017.06.041. PMID: 28939137Free PMC Article
Ling Y, Puel A
Actas Dermosifiliogr 2014 Oct;105 Suppl 1:34-40. doi: 10.1016/S0001-7310(14)70016-X. PMID: 25398490
Minegishi Y
Curr Opin Immunol 2009 Oct;21(5):487-92. Epub 2009 Aug 28 doi: 10.1016/j.coi.2009.07.013. PMID: 19717292

Recent systematic reviews

Mohammadi T, Azizi G, Rafiemanesh H, Farahani P, Nirouei M, Tavakol M
Clin Exp Med 2023 Dec;23(8):4835-4859. Epub 2023 Nov 4 doi: 10.1007/s10238-023-01228-5. PMID: 37924455

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