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Combined immunodeficiency due to DOCK8 deficiency(HIES2)

MedGen UID:
1648410
Concept ID:
C4722305
Disease or Syndrome
Synonyms: DOCK8 Deficiency; HIES autosomal recessive; HIES2; HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE; Hyper-IgE recurrent infection syndrome, autosomal recessive; HYPER-IgE SYNDROME 2, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS
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

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. 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). [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.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Pulmonary pneumatocele
MedGen UID:
1386848
Concept ID:
C1504436
Disease or Syndrome
A pneumatocele is a thin walled, gas-filled space in the lung. It is most frequently caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluid and is usually transient. The mechanism is believed to be a combination of parenchymal necrosis and check-valve airway obstruction. A pneumatocele appears as an approximately round, thin-walled airspace in the lung.
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.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory 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.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
Sclerosing cholangitis
MedGen UID:
3036
Concept ID:
C0008313
Disease or Syndrome
Cholangitis associated with evident ductal fibrosis that develops as a consequence of long-standing bile duct inflammatory, obstruction, or ischemic injury; it can be obliterative or nonobliterative.
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.
Drug allergy
MedGen UID:
41663
Concept ID:
C0013182
Pathologic Function
Hypersensitivity in form of an adverse immune reaction against drugs.
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.
Molluscum contagiosum
MedGen UID:
10081
Concept ID:
C0026393
Disease or Syndrome
Molluscum contagiosum is a cutaneous viral infection that is commonly observed in both healthy and immunocompromised children. The infection is caused by a member of the Poxviridae family, the molluscum contagiosum virus. Molluscum contagiosum presents as single or multiple small white or flesh-colored papules that typically have a central umbilication. The central umbilication may be difficult to observe in young children and, instead, may bear an appearance similar to an acneiform eruption. The lesions vary in size (from 1 mm to 1 cm in diameter) and are painless, although a subset of patients report pruritus in the area of infection. On average, 11-20 papules appear on the body during the course of infection and generally remains a self-limiting disease. However, in immunosuppressed patients, molluscum contagiosum can be a severe infection with hundreds of lesions developing on the body. Extensive eruption is indicative of an advanced immunodeficiency state.
Osteomyelitis
MedGen UID:
10497
Concept ID:
C0029443
Disease or Syndrome
Osteomyelitis is an inflammatory process accompanied by bone destruction and caused by an infecting microorganism.
Sepsis
MedGen UID:
48626
Concept ID:
C0036690
Disease or Syndrome
Systemic inflammatory response to infection.
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.
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.
Allergic rhinitis
MedGen UID:
382012
Concept ID:
C2607914
Disease or Syndrome
It is characterized by one or more symptoms including sneezing, itching, nasal congestion, and rhinorrhea.
Severe viral infection
MedGen UID:
479058
Concept ID:
C3277428
Finding
An unusually severe viral infection.
Anaphylactic shock
MedGen UID:
1373755
Concept ID:
C4316895
Pathologic Function
An acute hypersensitivity reaction due to exposure to a previously encountered antigen.
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 presence 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

Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
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
Lee WI, Huang JL, Yeh KW, Jaing TH, Lin TY, Huang YC, Chiu CH
J Formos Med Assoc 2011 Dec;110(12):750-8. Epub 2011 Dec 23 doi: 10.1016/j.jfma.2011.11.004. PMID: 22248828
Al-Herz W, Nanda A
Pediatr Dermatol 2011 Sep-Oct;28(5):494-501. Epub 2011 Mar 31 doi: 10.1111/j.1525-1470.2011.01409.x. PMID: 21453308

Diagnosis

Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
Mogensen TH
Int Rev Immunol 2016;35(1):39-56. Epub 2015 May 13 doi: 10.3109/08830185.2015.1027820. PMID: 25970001
Worth AJ, Booth C, Veys P
Curr Opin Hematol 2013 Nov;20(6):501-8. doi: 10.1097/MOH.0b013e328365a13b. PMID: 24104410
van der Valk P, Herman CJ
Lab Invest 1987 Feb;56(2):127-37. PMID: 3543488
Bennett JA
Am J Nurs 1985 Oct;85(10):1086-9. PMID: 2996353

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
Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ
Immunol Rev 2008 Jun;223:132-42. doi: 10.1111/j.1600-065X.2008.00644.x. PMID: 18613833Free PMC Article
DeWitt CA, Bishop AB, Buescher LS, Stone SP
J Am Acad Dermatol 2006 May;54(5):855-65. doi: 10.1016/j.jaad.2005.10.022. PMID: 16635666
Andronikou S, Eimany A, Robinson PJ, Kemp A
S Afr Med J 2004 Mar;94(3):166-7. PMID: 15098273

Prognosis

Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
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
Al-Herz W, Nanda A
Pediatr Dermatol 2011 Sep-Oct;28(5):494-501. Epub 2011 Mar 31 doi: 10.1111/j.1525-1470.2011.01409.x. PMID: 21453308
Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker EO, Pietrogrande MC, Cossu F, Franco JL, Matamoros N, Pietrucha B, Heropolitańska-Pliszka E, Yeganeh M, Moin M, Español T, Ehl S, Gennery AR, Abinun M, Breborowicz A, Niehues T, Kilic SS, Junker A, Turvey SE, Plebani A, Sánchez B, Garty BZ, Pignata C, Cancrini C, Litzman J, Sanal O, Baumann U, Bacchetta R, Hsu AP, Davis JN, Hammarström L, Davies EG, Eren E, Arkwright PD, Moilanen JS, Viemann D, Khan S, Maródi L, Cant AJ, Freeman AF, Puck JM, Holland SM, Grimbacher B
J Allergy Clin Immunol 2010 Feb;125(2):424-432.e8. doi: 10.1016/j.jaci.2009.10.059. PMID: 20159255Free PMC Article
Andronikou S, Eimany A, Robinson PJ, Kemp A
S Afr Med J 2004 Mar;94(3):166-7. PMID: 15098273

Clinical prediction guides

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
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
Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, Atkinson TP, Uzel G, Matthews HF, Mustillo PJ, Lewis DB, Kavadas FD, Hanson IC, Kumar AR, Geha RS, Douek DC, Holland SM, Freeman AF, Su HC
J Allergy Clin Immunol 2014 Jun;133(6):1667-75. Epub 2014 May 3 doi: 10.1016/j.jaci.2014.03.025. PMID: 24797421Free PMC Article
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
Al-Herz W, Nanda A
Pediatr Dermatol 2011 Sep-Oct;28(5):494-501. Epub 2011 Mar 31 doi: 10.1111/j.1525-1470.2011.01409.x. PMID: 21453308

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