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Combined immunodeficiency due to DOCK8 deficiency(HIES2)

MedGen UID:
1648410
Concept ID:
C4722305
Disease or Syndrome
Synonyms: AR hyperimmunoglobulin E syndrome; Autosomal Recessive Hyper IgE Syndrome; HIES autosomal recessive; HIES2; Hyper Ig E syndrome, autosomal recessive; HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE; Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): DOCK8 (9p24.3)
 
Monarch Initiative: MONDO:0009478
OMIM®: 243700
Orphanet: ORPHA217390

Definition

Autosomal dominant hyper-IgE recurrent infection syndrome-1 (HIES1; 147060) is a primary immunodeficiency disorder characterized by recurrent Staphylococcus aureus skin abscesses, increased serum IgE, and abnormalities of the connective tissue, skeleton, and dentition (Buckley et al., 1972; Grimbacher et al., 1999). Autosomal recessive HIES2 shares hyper-IgE, eosinophilia, and recurrent Staphylococcal infections, but is distinguished from autosomal dominant HIES1 by the lack of connective tissue and skeletal involvement (Renner et al., 2004). See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006). For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see 147060. [from OMIM]

Additional description

From MedlinePlus Genetics
DOCK8 immunodeficiency syndrome is a disorder of the immune system. The condition is characterized by recurrent infections that are severe and can be life-threatening. The infections can be caused by bacteria, viruses, or fungi. Skin infections cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling. People with DOCK8 immunodeficiency syndrome also tend to have frequent bouts of pneumonia and other respiratory tract infections. Other immune system-related problems in people with DOCK8 immunodeficiency syndrome include an inflammatory skin disorder called eczema, food or environmental allergies, and asthma.

DOCK8 immunodeficiency syndrome is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood; the levels can be more than 10 times higher than normal for no known reason. IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and plays a role in allergies. It is unclear why people with DOCK8 immunodeficiency syndrome have such high levels of this protein. People with DOCK8 immunodeficiency syndrome also have highly elevated numbers of certain white blood cells called eosinophils (hypereosinophilia). Eosinophils aid in the immune response and are involved in allergic reactions.

Some people with DOCK8 immunodeficiency syndrome have neurological problems, such as paralysis that affects the face or one side of the body (hemiplegia). Blockage of blood flow in the brain or abnormal bleeding in the brain, both of which can lead to stroke, can also occur in DOCK8 immunodeficiency syndrome.

People with DOCK8 immunodeficiency syndrome have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin.

DOCK8 immunodeficiency syndrome is also commonly called autosomal recessive hyper-IgE syndrome. However, researchers have identified several conditions that feature elevated levels of IgE and that follow an autosomal recessive pattern of inheritance. Each of these conditions has its own set of additional signs and symptoms and a different genetic cause. Some doctors consider these conditions forms of hyper-IgE syndrome, while others consider them independent disorders.  https://medlineplus.gov/genetics/condition/dock8-immunodeficiency-syndrome

Clinical features

From HPO
Squamous cell carcinoma
MedGen UID:
2874
Concept ID:
C0007137
Neoplastic Process
The presence of squamous cell carcinoma of the skin.
Cerebral vasculitis
MedGen UID:
68652
Concept ID:
C0238051
Disease or Syndrome
Inflammation of the blood vessels within the brain.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Eosinophilic infiltration of the esophagus
MedGen UID:
1637185
Concept ID:
C4703646
Finding
Infiltration of numerous eosinophils (usually greater than 15 per high power field) into the squamous epithelium of the esophagus, and layering of eosinophils on the surface layer of the esophagus.
Hemiplegia
MedGen UID:
9196
Concept ID:
C0018991
Sign or Symptom
Paralysis (complete loss of muscle function) in the arm, leg, and in some cases the face on one side of the body.
Subarachnoid hemorrhage
MedGen UID:
11625
Concept ID:
C0038525
Disease or Syndrome
Hemorrhage occurring between the arachnoid mater and the pia mater.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
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.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
Asthma is characterized by increased responsiveness of the tracheobronchial tree to multiple stimuli, leading to narrowing of the air passages with resultant dyspnea, cough, and wheezing.
Atopic eczema
MedGen UID:
41502
Concept ID:
C0011615
Disease or Syndrome
Atopic dermatitis (ATOD), also known as eczema, is a common chronic pruritic inflammatory skin disease with a strong genetic component. Onset typically occurs during the first 2 years of life (review by Soderhall et al., 2007). Genetic Heterogeneity of Atopic Dermatitis Many inflammatory diseases, such as atopic eczema, are genetically complex, with multiple alleles at several loci thought to be involved in their pathogenesis. Several susceptibility loci for atopic dermatitis have been identified: ATOD1 on chromosome 3q21, ATOD2 (605803) on chromosome 1q21, ATOD3 (605804) on chromosome 20p, ATOD4 (605805) on chromosome 17q25.3, ATOD5 (603165) on chromosome 13q12-q14, ATOD6 (605845) on chromosome 5q31-q33, ATOD7 (613064) on chromosome 11q13.5, ATOD8 (613518) on chromosome 4q22.1, and ATOD9 (613519) on chromosome 3p24.
Eczema
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis. The term eczema is broadly applied to a range of persistent skin conditions and can be related to a number of underlying conditions. Manifestations of eczema can include dryness and recurring skin rashes with redness, skin edema, itching and dryness, crusting, flaking, blistering, cracking, oozing, or bleeding.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Increased count of eosinophils in the blood.
Increased circulating IgE level
MedGen UID:
116018
Concept ID:
C0236175
Finding
An abnormally increased overall level of immunoglobulin E in blood.
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
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.
Recurrent viral infections
MedGen UID:
332357
Concept ID:
C1837066
Finding
Increased susceptibility to viral infections, as manifested by recurrent episodes of viral infection.
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
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.
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.
Increased circulating IgG level
MedGen UID:
347032
Concept ID:
C1858977
Finding
An abnormally increased level of immunoglobulin G in blood.
Food allergy
MedGen UID:
1635115
Concept ID:
C4554344
Disease or Syndrome
Primary food allergies primarily occur as a result (most likely) of gastrointestinal sensitization to predominantly stable food allergens (glycoproteins). A secondary food allergy develops after primary sensitization to airborne allergens (e. g., pollen allergens) with subsequent reactions (due to cross-reactivity) to structurally related often labile allergens in (plant) foods.
Disseminated molluscum contagiosum
MedGen UID:
1693458
Concept ID:
C5139182
Disease or Syndrome
The presense of molluscum contagiosum lesions across multiple areas of the body.
Decreased proportion of CD4-positive helper T cells
MedGen UID:
1719772
Concept ID:
C5235140
Finding
A decreased proportion of circulating CD4-positive helper T cells relative to total T cell count.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCombined immunodeficiency due to DOCK8 deficiency

Professional guidelines

PubMed

Ollech A, Mashiah J, Lev A, Simon AJ, Somech R, Adam E, Barzilai A, Hagin D, Greenberger S
J Dermatol 2021 Sep;48(9):1386-1393. Epub 2021 May 27 doi: 10.1111/1346-8138.15955. PMID: 34043252
Freeman AF
J Pediatric Infect Dis Soc 2018 Dec 26;7(suppl_2):S79-S82. doi: 10.1093/jpids/piy114. PMID: 30590619Free PMC Article
Biggs CM, Keles S, Chatila TA
Clin Immunol 2017 Aug;181:75-82. Epub 2017 Jun 15 doi: 10.1016/j.clim.2017.06.003. PMID: 28625885Free PMC Article

Recent clinical studies

Etiology

Durkee-Shock J, Zhang A, Liang H, Wright H, Magnusson J, Garabedian E, Marsh RA, Sullivan KE, Keller MD; USIDNET Consortium
J Allergy Clin Immunol Pract 2022 May;10(5):1334-1341.e6. Epub 2022 Feb 13 doi: 10.1016/j.jaip.2022.01.042. PMID: 35172220
Raedler J, Magg T, Rohlfs M, Klein C, Vallée T, Hauck F, Albert MH
J Clin Immunol 2021 Oct;41(7):1536-1548. Epub 2021 Jun 2 doi: 10.1007/s10875-021-01069-5. PMID: 34080085Free PMC Article
Zhang Q, Jing H, Su HC
J Clin Immunol 2016 Jul;36(5):441-9. Epub 2016 May 20 doi: 10.1007/s10875-016-0296-z. PMID: 27207373Free 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
Su HC
Curr Opin Allergy Clin Immunol 2010 Dec;10(6):515-20. doi: 10.1097/ACI.0b013e32833fd718. PMID: 20864884Free PMC Article

Diagnosis

Durkee-Shock J, Zhang A, Liang H, Wright H, Magnusson J, Garabedian E, Marsh RA, Sullivan KE, Keller MD; USIDNET Consortium
J Allergy Clin Immunol Pract 2022 May;10(5):1334-1341.e6. Epub 2022 Feb 13 doi: 10.1016/j.jaip.2022.01.042. PMID: 35172220
Tangye SG, Gray PE, Pillay BA, Yap JY, Figgett WA, Reeves J, Kummerfeld SK, Stoddard J, Uzel G, Jing H, Su HC, Campbell DE, Sullivan A, Burnett L, Peake J, Ma CS
J Clin Immunol 2022 Jan;42(1):119-129. Epub 2021 Oct 17 doi: 10.1007/s10875-021-01152-x. PMID: 34657245Free 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
Zhang Q, Jing H, Su HC
J Clin Immunol 2016 Jul;36(5):441-9. Epub 2016 May 20 doi: 10.1007/s10875-016-0296-z. PMID: 27207373Free PMC Article
van der Valk P, Herman CJ
Lab Invest 1987 Feb;56(2):127-37. PMID: 3543488

Therapy

Durkee-Shock J, Zhang A, Liang H, Wright H, Magnusson J, Garabedian E, Marsh RA, Sullivan KE, Keller MD; USIDNET Consortium
J Allergy Clin Immunol Pract 2022 May;10(5):1334-1341.e6. Epub 2022 Feb 13 doi: 10.1016/j.jaip.2022.01.042. PMID: 35172220
Mogensen TH
Int Rev Immunol 2016;35(1):39-56. Epub 2015 May 13 doi: 10.3109/08830185.2015.1027820. PMID: 25970001
Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, Shah N, Bollard C, Kong HH, Moutsopoulos N, Stone K, Gea-Banacloche J, Holland SM, Hickstein DD
Biol Blood Marrow Transplant 2015 Jun;21(6):1037-45. Epub 2015 Jan 27 doi: 10.1016/j.bbmt.2015.01.022. PMID: 25636378Free PMC Article
Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, Khalak HG, Wakil S, Eldali AM, Arnaout R, Al-Ghonaium A, Al-Muhsen S, Al-Dhekri H, Al-Saud B, Al-Mousa H
J Clin Immunol 2013 Jan;33(1):55-67. Epub 2012 Sep 12 doi: 10.1007/s10875-012-9769-x. PMID: 22968740
Broun SN
AIDS Patient Care STDS 1998 Jun;12(6):481-8. doi: 10.1089/apc.1998.12.481. PMID: 11361996

Prognosis

Ollech A, Mashiah J, Lev A, Simon AJ, Somech R, Adam E, Barzilai A, Hagin D, Greenberger S
J Dermatol 2021 Sep;48(9):1386-1393. Epub 2021 May 27 doi: 10.1111/1346-8138.15955. PMID: 34043252
Ponsford MJ, Klocperk A, Pulvirenti F, Dalm VASH, Milota T, Cinetto F, Chovancova Z, Rial MJ, Sediva A, Litzman J, Agostini C, van Hagen M, Quinti I, Jolles S
Allergy 2018 Nov;73(11):2122-2136. Epub 2018 Oct 2 doi: 10.1111/all.13578. PMID: 30043993
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT
J Clin Immunol 2015 Feb;35(2):189-98. Epub 2015 Jan 28 doi: 10.1007/s10875-014-0126-0. PMID: 25627830
Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, Khalak HG, Wakil S, Eldali AM, Arnaout R, Al-Ghonaium A, Al-Muhsen S, Al-Dhekri H, Al-Saud B, Al-Mousa H
J Clin Immunol 2013 Jan;33(1):55-67. Epub 2012 Sep 12 doi: 10.1007/s10875-012-9769-x. PMID: 22968740
Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC
N Engl J Med 2009 Nov 19;361(21):2046-55. Epub 2009 Sep 23 doi: 10.1056/NEJMoa0905506. PMID: 19776401Free 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: 37080116
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT
J Clin Immunol 2015 Feb;35(2):189-98. Epub 2015 Jan 28 doi: 10.1007/s10875-014-0126-0. PMID: 25627830
Alsum Z, Hawwari A, Alsmadi O, Al-Hissi S, Borrero E, Abu-Staiteh A, Khalak HG, Wakil S, Eldali AM, Arnaout R, Al-Ghonaium A, Al-Muhsen S, Al-Dhekri H, Al-Saud B, Al-Mousa H
J Clin Immunol 2013 Jan;33(1):55-67. Epub 2012 Sep 12 doi: 10.1007/s10875-012-9769-x. PMID: 22968740
Su HC, Jing H, Zhang Q
Ann N Y Acad Sci 2011 Dec;1246:26-33. doi: 10.1111/j.1749-6632.2011.06295.x. PMID: 22236427
Su HC
Curr Opin Allergy Clin Immunol 2010 Dec;10(6):515-20. doi: 10.1097/ACI.0b013e32833fd718. PMID: 20864884Free PMC Article

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