Combined Immunodeficiency Due To DOCK8 Deficiency

Mendelian MONDO:0009478 Pathograph 40 Show in embeddings browser Combined immunodeficiency Primary Immunodeficiency

Combined immunodeficiency due to DOCK8 deficiency is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in DOCK8, and is the principal genetic cause of the autosomal recessive form of hyper-IgE syndrome (AR-HIES). DOCK8 is an atypical guanine nucleotide exchange factor that activates the Rho-family GTPase CDC42 at the leading-edge membrane of migrating and synapsing leukocytes. Without it, lymphocytes cannot coordinate the cortical actin cytoskeleton: CD8 T cells and NK cells moving through collagen-dense tissue such as dermis undergo catastrophic shape rupture and die (cytothripsis), dendritic cells fail to crawl through three-dimensional interstitium to prime T cells in lymph nodes, NK cells fail to build a lytic immunological synapse, and B cells fail to organize the integrin-containing immune synapse needed for marginal-zone and germinal centre persistence. DOCK8 additionally binds STAT3 and is required for its full activation, which is why the disease phenocopies part of STAT3-HIES. The clinical result is a triad of recurrent sinopulmonary bacterial infection, severe and recalcitrant cutaneous viral infection (molluscum contagiosum, HPV warts, HSV, VZV), and severe atopy with markedly elevated serum IgE, eosinophilia and food allergy, on a background of virus-driven malignancy and cerebral vasculopathy. Unlike STAT3-HIES it spares the connective-tissue, skeletal, dental and pneumatocele features. Natural history is poor — survival falls to roughly a third by age 30 without intervention — and allogeneic haematopoietic stem cell transplantation is the only curative therapy.

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Classifications

Harrison's Part

IUIS Category

👪

Inheritance

Autosomal recessive HP:0000007

Disease requires biallelic (homozygous or compound heterozygous) loss-of-function DOCK8 variants. Heterozygous carriers are unaffected. Parental consanguinity is common in reported pedigrees.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:19776401 SUPPORT Human Clinical

"Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."

Documents biallelic (homozygous or compound heterozygous) DOCK8 variants as the cause, establishing recessive inheritance.

PMID:20004785 SUPPORT Human Clinical

"Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome."

Establishes the autosomal recessive mode of inheritance.

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Pathophysiology

Biallelic DOCK8 Loss of Function

Homozygous or compound heterozygous DOCK8 variants — most often large intragenic or subtelomeric 9p24.3 deletions, but also frameshift, nonsense and splice-site changes — abolish DOCK8 protein in lymphocytes. The locus is rich in repetitive sequence, which predisposes both to the germline deletions that dominate the mutational spectrum and to the somatic recombination-mediated repair seen in some patients.

DOCK8 guanine nucleotide exchange factor activity GO:0005085 ⇓ LOSS OF FUNCTION

Downstream

Loss of CDC42 Activation at the Leading-Edge Membrane

Impaired DOCK8-Dependent STAT3 Activation

Show evidence (3 references)

PMID:19776401 SUPPORT Human Clinical

"Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."

Establishes biallelic DOCK8 variants as the initiating lesion and absence of DOCK8 protein in lymphocytes as its immediate molecular consequence.

PMID:20004785 SUPPORT Human Clinical

"Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p."

Documents the large biallelic deletions at 9p24.3 that account for much of the mutational spectrum.

PMID:30565250 SUPPORT Other

"The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair."

Explains why deletions dominate the mutational spectrum, and why somatic reversion occurs at this locus.

Loss of CDC42 Activation at the Leading-Edge Membrane

DOCK8 is a CDC42-specific atypical guanine nucleotide exchange factor whose DHR-2 domain loads GTP onto CDC42. Its DHR-1 (C2-like) domain targets it to phosphoinositide-rich membrane, so DOCK8 acts locally rather than globally: in its absence, bulk cellular CDC42-GTP is unchanged but CDC42 activation at the leading-edge membrane fails, and with it amoeboid polarization.

CDC42 activation at the leading-edge membrane GO:0032489 ↓ DECREASED

Downstream

Cortical Actin Cytoskeleton Dysregulation in Leukocytes

Show evidence (2 references)

PMID:22461490 SUPPORT Model Organism

"we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration"

Identifies CDC42 as the GTPase DOCK8 activates, establishing the biochemical step lost in the disease.

PMID:22461490 SUPPORT Model Organism

"DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration."

Shows the defect is spatial rather than global — local leading-edge CDC42 activation is lost while bulk CDC42-GTP is preserved.

Cortical Actin Cytoskeleton Dysregulation in Leukocytes

CDC42-GTP activates WASP and, through the Arp2/3 complex, nucleates cortical F-actin. DOCK8 sits in a macromolecular complex with WASP and with talin, linking actin nucleation to integrin-mediated adhesion. Without DOCK8 the leukocyte cannot build or reorganize the cortical actin network on demand, which is the single shared lesion behind every downstream immune-cell defect in this disease.

lymphocyte CL:0000542

cortical actin cytoskeleton organization GO:0030866 ↓ DECREASED

Downstream

Lymphocyte Cytothripsis During Interstitial Migration

Impaired Dendritic Cell Interstitial Migration

Defective NK Cell Lytic Immunological Synapse

Defective B Cell Immunological Synapse and Germinal Centre Persistence

Show evidence (2 references)

PMID:28625885 SUPPORT Other

"It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton."

States the core molecular lesion — loss of a lymphocyte GEF that regulates the actin cytoskeleton.

PMID:23455509 SUPPORT In Vitro

"we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion"

Places DOCK8 physically in the WASP/talin machinery that couples actin nucleation to integrin adhesion, explaining the breadth of the defect.

Lymphocyte Cytothripsis During Interstitial Migration

When DOCK8-deficient T and NK cells squeeze through confined, collagen-dense tissue such as dermis, they cannot maintain shape integrity. Chemotaxis itself is preserved, but the cells develop abnormal shape and nuclear deformation and rupture, dying by a distinctive catastrophic mode the discovering authors named cytothripsis. This is the mechanism that singles out the skin — where collagen makes up as much as a third of the wet weight — as the organ where DOCK8 deficiency fails first.

CD8-positive, alpha-beta T cell CL:0000625 natural killer cell CL:0000623

leukocyte migration through dense interstitium GO:0050900 ⚠ ABNORMAL catastrophic lymphocyte death during confined migration GO:0008219 ↑ INCREASED

Downstream

Loss of Skin-Resident Memory CD8 T Cells

Impaired CD8 T Cell Survival and Memory

Show evidence (2 references)

PMID:25422492 SUPPORT In Vitro

"We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis."

Defines cytothripsis and shows it is a shape-integrity failure specific to confined migration, not a chemotaxis defect.

PMID:25422492 SUPPORT In Vitro

"Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures."

Ties cytothripsis to the CDC42/PAK-dependent cytoskeletal coordination lost in DOCK8 deficiency, and to collagen-dense tissue specifically.

Loss of Skin-Resident Memory CD8 T Cells

Because DOCK8-deficient cytotoxic T cells die crossing the dermis, the long-lived skin-resident memory CD8 T-cell pool that normally polices cutaneous herpesvirus reactivation is never established.

skin-resident memory CD8 T cell CL:0000625

defense response to virus in skin GO:0051607 ↓ DECREASED

skin UBERON:0002097

Downstream

Failure of Cutaneous Antiviral Immunosurveillance

Show evidence (1 reference)

PMID:25422492 SUPPORT In Vitro

"Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections."

Connects cytothripsis directly to loss of the skin-resident memory CD8 compartment and to failure of cutaneous herpesvirus control.

Impaired Dendritic Cell Interstitial Migration

DOCK8-deficient dendritic cells migrate normally on flat two-dimensional surfaces but cannot crawl through three-dimensional fibrillar networks or transmigrate the subcapsular sinus floor, so they fail to reach the lymph node parenchyma where they would prime T cells. Antigen collected in skin therefore never reaches the T-cell zone efficiently.

conventional dendritic cell CL:0000990

interstitial dendritic cell migration GO:0050900 ↓ DECREASED

Animal models

Dock8 knockout mouse Mus musculus recapitulates Knockout dendritic cells migrate normally in two dimensions but cannot crawl through three-dimensional fibrillar networks or transmigrate the subcapsular sinus floor, and do not accumulate in the lymph node parenchyma for T-cell priming.

Downstream

Failure of Cutaneous Antiviral Immunosurveillance

Show evidence (2 references)

PMID:22461490 SUPPORT Model Organism

"By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming."

Shows DOCK8-null dendritic cells do not reach the site where T-cell priming occurs.

PMID:22461490 SUPPORT Model Organism

"Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor."

Establishes that the defect is specific to three-dimensional interstitial migration, mirroring the lymphocyte shape-integrity lesion.

Defective NK Cell Lytic Immunological Synapse

NK-cell killing requires focused F-actin accumulation at the lytic immunological synapse, driven by CDC42-activated WASP. DOCK8-deficient NK cells retain normal total F-actin but cannot concentrate it at the synapse, form defective conjugates, and fail to polarize LFA-1 and cytolytic granules toward the target. Cytotoxicity is reduced and is not rescued by IL-2.

natural killer cell CL:0000623

lytic immunological synapse formation GO:0001771 ↓ DECREASED natural killer cell mediated cytotoxicity GO:0042267 ↓ DECREASED

Downstream

Failure of Cutaneous Antiviral Immunosurveillance

Show evidence (3 references)

PMID:23380217 SUPPORT Human Clinical

"DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content."

Localizes the NK defect precisely to synaptic F-actin accumulation rather than to a global actin deficit.

PMID:23380217 SUPPORT Human Clinical

"DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation."

Documents the functional consequence in patient cells, and that it is not a reversible activation defect.

PMID:23455509 SUPPORT In Vitro

"NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse"

Adds the adhesion and granule-polarization components of the synaptic defect.

Impaired CD8 T Cell Survival and Memory

Beyond cytothripsis, DOCK8-null naive CD8 T cells are intrinsically short-lived, polarize LFA-1 poorly at the synapse with dendritic cells, and are delayed in their first division. Primary clonal expansion after infection is near-normal, but memory persistence and recall are severely reduced — so the compartment that should contain reactivating persistent viruses is not maintained. In patients, circulating CD8 T cells are reduced and skewed to an exhausted CD45RA+CCR7- phenotype.

CD8-positive, alpha-beta T cell CL:0000625

T cell homeostasis GO:0043029 ↓ DECREASED immunological synapse formation with dendritic cells GO:0001771 ↓ DECREASED

Animal models

Dock8 mutant mouse CD8 T cell compartment Mus musculus recapitulates Mutant mice reproduce the human loss of circulating naive CD8 T cells, and add what patient studies cannot show: that the defect is cell-autonomous and primarily postthymic, and that primary clonal expansion is near-normal while memory persistence and recall fail.

Downstream

Failure of Cutaneous Antiviral Immunosurveillance

Show evidence (3 references)

PMID:22006977 SUPPORT Human Clinical

"DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA(+)CCR7(-) phenotype."

Documents the naive CD8 loss and exhausted phenotype in DOCK8-deficient patients as well as mice.

PMID:22006977 SUPPORT Model Organism

"DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division."

Establishes the cell-intrinsic survival and synapse-polarization defect underlying the CD8 abnormality.

PMID:22006977 SUPPORT Model Organism

"they showed greatly reduced memory cell persistence and recall"

Shows the failure is of memory persistence and recall rather than of primary expansion, matching the clinical pattern of relapsing persistent viral infection.

Failure of Cutaneous Antiviral Immunosurveillance

The convergence point of the cellular defects: with no skin-resident memory CD8 pool, impaired dendritic-cell priming, defective NK killing and poor CD8 memory recall, the skin loses the layered antiviral surveillance that normally keeps cutaneotropic DNA viruses latent and subclinical.

defense response to virus GO:0051607 ↓ DECREASED

skin UBERON:0002097

Downstream

Persistent Cutaneotropic and Oncogenic DNA Virus Infection

Recurrent viral skin infections

Disseminated molluscum contagiosum

Verrucae

Recurrent herpes

Show evidence (2 references)

PMID:30565250 SUPPORT Other

"The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues."

Attributes the cutaneous viral susceptibility to the shape-integrity lesion, linking the cellular mechanism to the organ-level failure.

PMID:23380217 SUPPORT Human Clinical

"This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy."

Links the synaptic actin defect to the clinical viral and malignancy susceptibility. Framed as a hypothesis by the authors, so it supports the connection without asserting it is the sole mechanism.

Persistent Cutaneotropic and Oncogenic DNA Virus Infection

Viruses that a competent immune system keeps latent and subclinical instead replicate continuously and spread: HPV, molluscum contagiosum virus, HSV and VZV in skin, and EBV in the B-cell compartment. Persistent infection by oncogenic members of this set — high-risk HPV at cutaneous and anogenital sites, EBV in B cells — is the reservoir from which the virus-driven malignancies of DOCK8 deficiency arise, which is the module trigger this node conforms to. The entry does not curate the downstream oncoprotein/tumour-suppressor steps of the module; the virally driven cancers are recorded as phenotypes.

persistence of cutaneotropic and oncogenic DNA viruses GO:0019042 ↑ INCREASED

Downstream

Squamous cell carcinoma of the skin

Lymphoma

Cerebral Vasculopathy

Show evidence (2 references)

PMID:19776401 SUPPORT Human Clinical

"extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections."

Documents persistent rather than self-limited infection by the cutaneotropic DNA viruses in the disease-defining cohort.

PMID:30565250 SUPPORT Other

"profound susceptibility to virus infections of the skin, with associated skin cancers"

Links the persistent cutaneous viral infection directly to the skin cancers that follow it, which is the module's trigger-to-malignancy claim.

Defective B Cell Immunological Synapse and Germinal Centre Persistence

DOCK8-mutant B cells fail to accumulate the integrin ligand ICAM-1 in the immunological synapse while other aspects of B-cell receptor signalling remain intact. They cannot form marginal-zone B cells, cannot persist in germinal centres, and do not undergo affinity maturation — a synapse organisation defect rather than a signalling-cascade defect.

B cell CL:0000236

B cell immunological synapse formation GO:0001771 ↓ DECREASED germinal center B cell differentiation GO:0002314 ↓ DECREASED

Animal models

Dock8 ENU point-mutant mouse (captain morgan / primurus) Mus musculus recapitulates Mutant B cells fail to form marginal-zone B cells, fail to persist in germinal centres, and fail to accumulate ICAM-1 in the immunological synapse while other BCR signalling is intact.

Downstream

Impaired Humoral Memory and Specific Antibody Responses

Show evidence (2 references)

PMID:19898472 SUPPORT Model Organism

"DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation."

Establishes the germinal-centre and marginal-zone failure that underlies the humoral defect.

PMID:19898472 SUPPORT Model Organism

"Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling."

Localizes the B-cell lesion to synapse organization, consistent with the shared cytoskeletal mechanism rather than a BCR-signalling defect.

Impaired Humoral Memory and Specific Antibody Responses

The germinal-centre failure translates into poor long-lived antibody production: fewer than half of tested patients mount normal specific antibody responses to recall antigens, and low serum IgM is characteristic. This is the arm of the combined defect that produces the recurrent encapsulated-organism sinopulmonary infection and chronic otitis media.

immunoglobulin production GO:0002377 ↓ DECREASED

Downstream

Recurrent respiratory infections

Otitis media

Decreased circulating total IgM

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"Fewer than half of the patients tested produced normal specific antibody responses to recall antigens."

Quantifies the humoral failure in the largest genetically confirmed phenotype series.

PMID:19898472 SUPPORT Model Organism

"Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity."

States the causal claim from synapse organization to loss of long-lasting humoral immunity.

Impaired DOCK8-Dependent STAT3 Activation

DOCK8 is not only a GEF. It associates constitutively with STAT3 independently of GEF activity, and — in a GEF-activity-dependent manner — promotes STAT3 phosphorylation, nuclear translocation, and STAT3-dependent gene expression. This second, non-cytoskeletal function is why an actin disorder produces part of the phenotype of a STAT3 transcription-factor disorder.

STAT3 signaling downstream of cytokine receptors GO:0007259 ↓ DECREASED

Downstream

Th17 Differentiation Block

Th2 Skewing and IgE Dysregulation

Show evidence (2 references)

PMID:27350570 SUPPORT In Vitro

"DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression."

Establishes the direct DOCK8-STAT3 interaction and DOCK8's requirement for full STAT3 activation.

PMID:28625885 SUPPORT Other

"Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3."

Confirms STAT3 activation as an established non-cytoskeletal DOCK8 function.

Th17 Differentiation Block

Naive CD4 T cells from DOCK8-deficient patients are profoundly blocked in differentiating to Th17 cells, and a missense variant that disrupts GEF activity while sparing protein expression reproduces the block — tying the defect to catalytic function rather than to a scaffolding role alone. The resulting collapse of IL-17/IL-22 mucocutaneous defence is the shared mechanism behind the candidiasis and staphylococcal susceptibility that DOCK8 deficiency and STAT3-HIES have in common.

T-helper 17 cell CL:0000899

T-helper 17 cell differentiation GO:0072539 ↓ DECREASED

Downstream

Chronic mucocutaneous candidiasis

Recurrent respiratory infections

Show evidence (3 references)

PMID:27350570 SUPPORT In Vitro

"A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17 cell differentiation."

Shows the Th17 block depends on DOCK8 catalytic GEF activity, separating it from loss of the protein as a scaffold.

PMID:27350570 SUPPORT In Vitro

"DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES."

Connects the STAT3 defect to the Th17 block and to the clinical overlap with STAT3-HIES.

PMID:20004785 SUPPORT Human Clinical

"defective T-cell activation and T(h)17 cell differentiation"

Independently documents the Th17 differentiation defect in DOCK8-deficient patients.

Th2 Skewing and IgE Dysregulation

With Th17 and Th1 output constrained, T-helper differentiation skews toward Th2, and eosinophil homeostasis and IgE regulation are disturbed. The result is the atopic arm of the disease — early severe eczema, extreme total IgE, hypereosinophilia and IgE-mediated food allergy — and it is the arm that responds least reliably to transplantation.

T-helper 2 cell CL:0000546

T-helper 2 cell differentiation GO:0045064 ↑ INCREASED immunoglobulin E production GO:0002377 ↑ INCREASED

Downstream

Atopic dermatitis

Increased circulating IgE concentration

Eosinophilia

Food allergy

Show evidence (2 references)

PMID:20004785 SUPPORT Human Clinical

"impaired eosinophil homeostasis and dysregulation of IgE."

Documents disordered eosinophil homeostasis and IgE regulation as part of the DOCK8-deficiency phenotype.

PMID:30565250 SUPPORT Other

"Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets."

States T-helper subset skewing as an established consequence of DOCK8 loss, distinct from the migration/shape mechanism.

Cerebral Vasculopathy

A distinctive non-infectious complication: cerebral vasculitis, arterial aneurysm, infarction and intracranial haemorrhage in young patients. The mechanism is not settled. VZV-associated vasculopathy is the leading proposal, which would place it downstream of the same failure of cutaneous and systemic antiviral control; a direct vascular role for DOCK8 has not been demonstrated.

brain UBERON:0000955

Downstream

Stroke

Show evidence (2 references)

PMID:25627830 SUPPORT Human Clinical

"severe non-infectious cerebral events occurred in 14/136 (10 %)"

Quantifies the frequency of severe non-infectious cerebral events in the largest published cohort.

PMID:30565250 SUPPORT Other

Proposes VZV-associated vasculopathy as the link between the shape-integrity lesion and the cerebral disease. The authors hedge ("probably"), so this supports the proposed mechanism without establishing it.

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Pathograph

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Phenotypes

Blood 6

Increased circulating IgE concentration VERY_FREQUENT HP:0003212

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"DOCK8-deficient patients had median IgE levels of 5201 IU"

Gives the median total IgE in genetically confirmed DOCK8 deficiency.

PMID:19776401 SUPPORT Human Clinical

"Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common."

Establishes elevated IgE as a common laboratory finding in the defining cohort.

Eosinophilia VERY_FREQUENT Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:25724123 SUPPORT Human Clinical

"high eosinophil levels of usually at least 800/μL (92% of patients)"

Quantifies the eosinophilia and its 92% frequency.

Lymphoma OCCASIONAL HP:0002665

Show evidence (2 references)

PMID:25627830 SUPPORT Human Clinical

"Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."

Gives 11 haematological cancers among 23 malignancies in the largest cohort.

PMID:19776401 SUPPORT Human Clinical

"One patient with resected microcystic adenoma died from cutaneous T-cell lymphoma-leukemia."

Documents a fatal lymphoid malignancy in the defining cohort.

Decreased circulating total IgM FREQUENT HP:0002850

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"In the majority of patients, serum IgM levels were low (36/58; 62%)"

Quantifies low serum IgM in 36 of 58 genetically confirmed patients.

PMID:25724123 SUPPORT Human Clinical

"DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels"

Establishes low IgM as part of the diagnostic discriminator for DOCK8 deficiency.

Decreased total T cell count OCCASIONAL HP:0005403

Show evidence (1 reference)

PMID:25724123 SUPPORT Human Clinical

"About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts."

Quantifies lymphopenia and attributes it to the CD4 and CD8 compartments.

Decreased natural killer cell-induced killing of target cells FREQUENT HP:0025808

Show evidence (1 reference)

PMID:23380217 SUPPORT Human Clinical

"DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation."

Documents reduced, IL-2-irreversible NK cytotoxicity in patient cells.

Cardiovascular 1

Stroke OCCASIONAL HP:0001297

Show evidence (2 references)

PMID:28625885 SUPPORT Other

"These include CNS vasculitis, aneurysms, tumor infiltration, as well as strokes and hemiparesis"

Lists stroke among the non-infectious neurological complications alongside the vasculitis and aneurysms that underlie it.

PMID:25627830 SUPPORT Human Clinical

"cerebral complications such as CNS vasculitis or stroke"

Counts CNS vasculitis and stroke among the events defining event-free survival in the largest cohort.

Ear 1

Otitis media FREQUENT HP:0000388

Temporal: RECURRENT

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"Patients had recurrent otitis media, sinusitis, and pneumonias"

Documents recurrent otitis media in the defining cohort.

Immune 11

Recurrent viral skin infections VERY_FREQUENT HP:0011371

Temporal: RECURRENT

Show evidence (2 references)

PMID:24797421 SUPPORT Human Clinical

"Intractable viral infections of the skin are caused by herpes simplex virus (HSV), molluscum contagiosum virus (MCV), varicella-zoster virus (VZV), and/or human papillomavirus (HPV)."

Names the four cutaneotropic viruses responsible and their intractable course.

PMID:25724123 SUPPORT Human Clinical

"Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed."

Gives the frequency of viral infection in the largest genetically confirmed series, supporting VERY_FREQUENT.

Disseminated molluscum contagiosum FREQUENT HP:0032185

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"extensive and persistent infections with molluscum contagiosum"

Documents extensive and persistent molluscum in the disease-defining cohort.

Recurrent herpes FREQUENT HP:0005353

Temporal: RECURRENT

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"recurrent, severe herpes simplex virus or herpes zoster infections"

Documents recurrent severe HSV and zoster in the defining cohort.

Recurrent respiratory infections VERY_FREQUENT HP:0002205

Temporal: RECURRENT

Show evidence (2 references)

PMID:25627830 SUPPORT Human Clinical

"Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."

Lists recurrent respiratory tract infection among the most frequent manifestations in the 136-patient cohort.

PMID:19776401 SUPPORT Human Clinical

"Patients had recurrent otitis media, sinusitis, and pneumonias"

Documents the recurrent sinopulmonary infection pattern.

Chronic mucocutaneous candidiasis FREQUENT HP:0002728

Temporal: RECURRENT

Show evidence (1 reference)

PMID:25627830 SUPPORT Human Clinical

"Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."

Lists mucocutaneous candidiasis among the most frequent manifestations.

Recurrent cutaneous abscess formation FREQUENT HP:0100838

Temporal: RECURRENT

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"Skin abscesses (60%) and allergies (73%) were common clinical problems."

Quantifies skin abscess frequency at 60% of genetically confirmed patients.

PMID:19776401 SUPPORT Human Clinical

"recurrent Staphylococcus aureus skin infections with otitis externa"

Identifies S. aureus as the organism behind the recurrent skin infection.

Atopic dermatitis VERY_FREQUENT HP:0001047

Temporal: CHRONIC

Show evidence (2 references)

PMID:24797421 SUPPORT Human Clinical

"Typically, patients develop diffuse eczematous dermatitis with bacterial skin infections early in life"

Establishes the early-life onset and diffuse character of the dermatitis.

PMID:25627830 SUPPORT Human Clinical

"Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."

Lists eczema first among the most frequent manifestations of the 136-patient cohort.

Food allergy FREQUENT HP:0500093

Show evidence (2 references)

PMID:30565250 SUPPORT REVIEW SYNTHESIS Other

"DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and..."

Names severe food allergy as one of the two features distinguishing DOCK8 deficiency from other combined immunodeficiencies and hyper-IgE syndromes.

PMID:24797421 SUPPORT Human Clinical

"severe food allergies accompanied by anaphylaxis, asthma, elevated serum IgE, and eosinophilia"

Documents severe food allergy with anaphylaxis in the clinical phenotype.

Asthma OCCASIONAL HP:0002099

Show evidence (1 reference)

PMID:24797421 SUPPORT Human Clinical

"severe food allergies accompanied by anaphylaxis, asthma, elevated serum IgE, and eosinophilia"

Lists asthma among the atopic manifestations of the disease.

Anaphylactic shock OCCASIONAL HP:0100845

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"Most patients had severe atopy with anaphylaxis"

Documents anaphylaxis in most patients of the defining cohort.

Impaired specific antibody response FREQUENT HP:0012475

Show evidence (1 reference)

PMID:25724123 SUPPORT Human Clinical

"Fewer than half of the patients tested produced normal specific antibody responses to recall antigens."

Quantifies the specific-antibody failure.

Integument 2

Verrucae FREQUENT HP:0200043

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"Seven patients had persistent flat and verrucous warts"

Counts persistent flat and verrucous warts in seven of the eleven patients in the defining cohort.

Squamous cell carcinoma of the skin OCCASIONAL HP:0006739

Show evidence (2 references)

PMID:19776401 SUPPORT Human Clinical

"several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia."

Documents squamous cell carcinoma in the disease-defining cohort.

PMID:25627830 SUPPORT Human Clinical

"Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."

Quantifies overall malignancy burden including the epithelial cancers, and gives the young median age at diagnosis.

Respiratory 1

Bronchiectasis OCCASIONAL HP:0002110

Show evidence (2 references)

PMID:28625885 SUPPORT Other

"Patients often experience recurrent sinopulmonary bacterial infections that can lead to bronchiectasis"

States bronchiectasis as a consequence of the recurrent sinopulmonary infection.

PMID:25724123 SUPPORT Human Clinical

"in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures"

Supports the contrast with STAT3-HIES: DOCK8 deficiency is characterized by the absence of the parenchymal lung lesions (pneumatoceles) seen there.

Growth 1

Failure to thrive OCCASIONAL HP:0001508

Show evidence (1 reference)

PMID:28625885 SUPPORT Other

"Malabsorption resulting in failure to thrive may be caused by allergic or autoimmune enteropathy, as well as by intestinal infections."

Gives the gastrointestinal mechanism behind failure to thrive in this disease.

🧬

Genetic Associations

DOCK8 (Biallelic loss-of-function variants in DOCK8 (9p24.3) cause the disease. DOCK8 encodes an atypical guanine nucleotide exchange factor for CDC42 that is expressed almost exclusively in immune cells. Nearly all reported alleles are null: large intragenic or whole-gene deletions and complex rearrangements predominate, with frameshift, nonsense and splice-site point mutations accounting for most of the remainder and missense variants being rare. The locus is unusually rich in repetitive sequence, which explains both the deletion-heavy mutational spectrum and the somatic recombination-mediated reversion seen in a substantial minority of patients.)

Gene: DOCK8 hgnc:19191 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:19776401 SUPPORT Human Clinical

"Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."

Establishes DOCK8 as the causative gene and loss of DOCK8 protein as the functional consequence.

PMID:20004785 SUPPORT Human Clinical

"Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions."

Characterizes the non-deletion end of the mutational spectrum as uniformly truncating or splice-disrupting.

PMID:30565250 SUPPORT Other

"The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair."

Explains the deletion-dominated spectrum and the propensity to somatic reversion as consequences of the same locus architecture.

DOCK8 somatic reversion (Somatic repair of the germline DOCK8 lesion — by second-site mutation, original-site back mutation, gene conversion or intragenic crossover — restores DOCK8 expression in a subset of lymphocytes, preferentially antigen-experienced T cells and NK cells rather than naive T or B cells. Revertant patients are older and have milder allergic disease, but infection susceptibility persists and reversion is not curative. It is the principal known within-patient modifier of disease severity, and is a further reason to interpret residual DOCK8 protein on a flow-cytometry assay carefully.)

Gene: DOCK8 hgnc:19191 relationship_type: MODIFIER variant_origin: SOMATIC

Show evidence (3 references)

PMID:24797421 SUPPORT Human Clinical

"We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair."

Quantifies how often somatic reversion occurs in a referral cohort.

PMID:24797421 SUPPORT Human Clinical

"Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover."

Lists the molecular mechanisms of reversion.

PMID:24797421 SUPPORT Human Clinical

"Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation."

Establishes reversion as a partial severity modifier that does not substitute for curative therapy.

💊

Medical Actions

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic haematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only curative therapy. Because DOCK8 is expressed almost exclusively in haematopoietic cells, replacing the haematopoietic compartment corrects the lesion at its source. In an 81-patient international cohort transplanted at a median age of 9.7 years, 84% were alive after a median 26 months, with 89% survival after matched-related and 81% after matched-unrelated grafts. Transplantation restores lymphocyte differentiation and function and lowers total and allergen-specific IgE over time. Manifestations do not all respond equally: eczema, infections and mollusca resolve faster than food allergies or failure to thrive, and food allergy may persist.

Mechanism Target:

Biallelic DOCK8 Loss of Function — Donor-derived haematopoiesis supplies DOCK8-sufficient lymphocytes, dendritic cells and NK cells, correcting the initiating molecular lesion in the compartment where DOCK8 is expressed.

Show evidence (1 reference)

PMID:31021819 SUPPORT Human Clinical

"HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients."

Demonstrates that transplantation corrects the lymphocyte functional defects that follow from loss of DOCK8.

Show evidence (4 references)

PMID:30391550 SUPPORT Human Clinical

"HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice."

Establishes transplantation as the curative treatment of choice.

PMID:30391550 SUPPORT Human Clinical

"We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive."

Gives the survival outcome in the largest transplant cohort.

PMID:30391550 SUPPORT Human Clinical

"Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive."

Records the differential response, which is the main caveat when counselling families about cure.

+ 1 more reference

Reduced-Toxicity Conditioning

Action: reduced-intensity transplant conditioning Ontology label: Reduced-Intensity Transplant Conditioning Procedure NCIT:C116471

Platform: Cell therapy

Conditioning intensity is the modifiable variable with the clearest effect on transplant survival in this disease. Reduced-toxicity regimens built on treosulfan or reduced-dose busulfan gave 97% survival against 78% for fully myeloablative busulfan-based conditioning. Younger age at transplant also favours survival, which argues for referral before complications accrue.

Show evidence (2 references)

PMID:30391550 SUPPORT Human Clinical

"Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens"

Establishes reduced-toxicity conditioning as the regimen associated with better survival in DOCK8 deficiency.

PMID:30391550 SUPPORT Human Clinical

"HSCT using a reduced-toxicity regimen may offer the best chance for survival."

States the authors' conclusion on regimen choice.

Immunoglobulin Replacement Therapy

Action: immunoglobulin replacement therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Platform: Protein replacement

Replaces the specific antibody the patient cannot make, addressing the humoral arm of the combined defect. A standard bridging measure before transplantation.

Mechanism Target:

Impaired Humoral Memory and Specific Antibody Responses — Exogenous polyclonal IgG substitutes for the specific antibody response that the failed germinal-centre reaction cannot generate.

Target Phenotypes: Impaired specific antibody response HP:0012475 Recurrent sinopulmonary bacterial infections HP:0002205

Show evidence (1 reference)

PMID:25627830 SUPPORT Human Clinical

"Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."

Records immunoglobulin replacement as a standard therapeutic measure in the largest published cohort.

Antibacterial Prophylaxis

Action: antibacterial prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Platform: Small molecule

Long-term prophylaxis against the recurrent bacterial sinopulmonary and cutaneous infection that follows the humoral and Th17 defects. Supportive, not disease-modifying.

Target Phenotypes: Recurrent sinopulmonary bacterial infections HP:0002205 Recurrent staphylococcal skin abscesses HP:0100838

Show evidence (1 reference)

PMID:25627830 SUPPORT Human Clinical

"Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."

Records antibacterial prophylaxis as standard supportive management.

Antiviral Therapy and Prophylaxis

Action: antiviral therapy Ontology label: Antiviral Therapy NCIT:C16119

Platform: Small molecule

Suppressive antiviral therapy for the cutaneous herpesvirus disease. It controls rather than clears: the underlying failure of skin-resident cytotoxic immunosurveillance persists until transplantation, so lesions recur on withdrawal.

Target Phenotypes: Recurrent severe herpes simplex and herpes zoster HP:0005353 Recurrent cutaneous viral infections HP:0011371

Show evidence (2 references)

PMID:25627830 SUPPORT Human Clinical

"Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."

Records antiviral prophylaxis as standard supportive management.

PMID:30391550 SUPPORT Human Clinical

"Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease."

Supports treating antimicrobial measures as bridging rather than definitive therapy, since only transplantation is curative.

🔬

Diagnosis

Intracellular DOCK8 protein staining by flow cytometry

Because nearly all patients lack DOCK8 protein entirely, intracellular staining for DOCK8 on peripheral blood mononuclear cells is a fast screen that avoids immunoblotting or sequencing. It also detects carriers and can track lineage-specific DOCK8 expression after transplantation. Residual expression does not exclude the diagnosis: somatic reversion restores DOCK8 in some antigen-experienced T and NK cells.

flow cytometry for intracellular DOCK8 expression NCIT:C16585

Results: Absent or markedly reduced intracellular DOCK8 protein

Show evidence (3 references)

PMID:24698323 SUPPORT Human Clinical

"We present here a flow cytometry assay that could facilitate the diagnosis of DOCK8 deficiency, detection of carrier status, and investigation of lineage-specific DOCK8 expression following HCT."

Describes the assay and the three purposes it serves.

PMID:24698323 SUPPORT Human Clinical

"The vast majority of DOCK8-deficient patients lack DOCK8 expression and many have deletions in the DOCK8 gene."

Explains why an absent-protein screen has high yield in this disease, unlike diseases dominated by missense variants.

PMID:24797421 SUPPORT Human Clinical

"DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells."

Documents the lineage-restricted residual expression that can confound a protein-based screen in revertant patients.

Copy-number-aware molecular genetic testing

Sequencing alone is not sufficient. Large intragenic and subtelomeric 9p24.3 deletions account for a large share of pathogenic alleles, so the diagnostic approach must include copy-number analysis (array CGH, SNP array, or exome/genome sequencing with CNV calling) alongside sequence analysis.

molecular genetic testing with copy-number analysis NCIT:C19770

Results: Biallelic loss-of-function DOCK8 variants, frequently large deletions

Show evidence (2 references)

PMID:19776401 SUPPORT Human Clinical

"We performed comparative genomic hybridization arrays and targeted gene sequencing."

Shows that the disease-defining diagnoses required copy-number analysis in combination with sequencing.

PMID:20004785 SUPPORT Human Clinical

"We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes."

Confirms copy-number analysis as the method that identified the causative deletions.

Clinical discrimination from STAT3-HIES

Before molecular confirmation, a small set of clinical features separates DOCK8 from STAT3 deficiency: severe viral infection, allergy and low IgM favour DOCK8; pneumatoceles, retained primary teeth and minimal-trauma fractures favour STAT3.

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures."

States the clinical discriminator derived from a support-vector-machine comparison of DOCK8-, STAT3- and mutation-negative AR-HIES patients.

PMID:25724123 SUPPORT Human Clinical

"A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations."

Confirms that a compact clinical feature set discriminates the two HIES forms.

📈

Progression

Infancy and early childhood

Presentation is with severe eczematous dermatitis and recurrent bacterial skin and sinopulmonary infection, usually within the first year of life, accompanied by very high IgE, eosinophilia and emerging food allergy.

Show evidence (1 reference)

PMID:24797421 SUPPORT Human Clinical

"Typically, patients develop diffuse eczematous dermatitis with bacterial skin infections early in life, along with respiratory tract infections and severe food allergies"

Describes the early-life presenting picture.

Later childhood and adolescence

Cutaneous viral disease expands and becomes refractory, bronchiectasis accrues from repeated pneumonia, and the first malignancies and cerebral events appear. Malignancy in the largest cohort was diagnosed at a median age of 12 years.

Show evidence (1 reference)

PMID:25627830 SUPPORT Human Clinical

"Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."

Places the onset of malignancy in later childhood.

Young adulthood without transplantation

Cumulative mortality from infection, cancer and cerebrovascular events. Only about a third of patients reach 30 years without transplantation, and event-free survival is 4% at that age.

Show evidence (3 references)

PMID:30391550 SUPPORT Human Clinical

"Only about a third of patients reach the age of 30 years without hematopoietic stem cell transplantation"

Gives the untransplanted survival to age 30, restating the Aydin 2015 natural-history curve without the bracketed censoring clause.

PMID:30391550 SUPPORT Human Clinical

"about 75% develop severe, life-threatening disease complications before the age of 20 years"

Quantifies severe complications accrued before adulthood.

PMID:25627830 SUPPORT Human Clinical

"Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke."

Gives event-free survival, the measure that captures the accumulating complication burden.

📊

Prevalence

Worldwide

Point Prevalence 0.1 per 100,000 <1 in 1,000,000

Estimate is for the hyper-IgE syndromes as a group (<1 in 1,000,000); DOCK8 deficiency accounts for the majority of the autosomal recessive subset, so its own prevalence is lower still. No DOCK8-specific population-based prevalence estimate has been published.

Show evidence (1 reference)

PMID:20004785 SUPPORT Other

"rare primary immunodeficiencies (estimated prevalence <1:1 million)"

Gives the order-of-magnitude prevalence for the hyper-IgE syndromes, of which DOCK8 deficiency is the main autosomal recessive cause.

⚖️

Clinical Burden

High

Untreated DOCK8 deficiency is a fatal disease of childhood and young adulthood. Two thirds of patients are dead by 30 years censored for transplantation, 58% experience a severe life-threatening infection, 17% develop a malignancy at a median age of 12, and 10% suffer a severe non-infectious cerebral event. Mortality in the genetically confirmed phenotype series was 34%. Between these events, chronic disfiguring skin disease, multiple food allergies and repeated hospitalization dominate daily life.

Show evidence (3 references)

PMID:25627830 SUPPORT Human Clinical

"Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %)."

Quantifies the severe-event burden in the largest cohort.

PMID:25724123 SUPPORT Human Clinical

"The mortality rate in our cohort was 34% (20 of 58 patients), with death occurring at a mean age of 9 years 3 months"

Gives crude mortality and mean age at death in the genetically confirmed phenotype series.

PMID:30391550 SUPPORT Human Clinical

"Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease."

Summarizes the untreated prognosis and the availability of curative therapy.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Combined Immunodeficiency Due To DOCK8 Deficiency:

Autosomal dominant hyper-IgE syndrome (STAT3-HIES) MONDO:0007818

Overlapping Features The other hyper-IgE syndrome, and the main differential. Both share eczematoid dermatitis, staphylococcal skin abscess, recurrent pneumonia, candidiasis, very high IgE and eosinophilia — the Th17 defect common to both explains that overlap, and in DOCK8 deficiency it runs through the same STAT3 node. They separate on what each adds. STAT3-HIES adds non-immune connective-tissue, skeletal, dental and vascular features plus pneumatoceles; DOCK8 deficiency adds severe cutaneous viral infection, severe allergy, low IgM, early virus-driven malignancy and cerebral vasculopathy, and lacks the connective-tissue features.

Distinguishing Features

DOCK8: severe refractory cutaneous viral infection, food allergy, low IgM, early squamous cell carcinoma and lymphoma, CNS vasculitis; autosomal recessive. STAT3: pneumatoceles, retained primary teeth, minimal-trauma fracture, scoliosis, characteristic facies; autosomal dominant.

Show evidence (2 references)

PMID:25724123 SUPPORT Human Clinical

"In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems."

States the features that are present in STAT3-HIES and largely absent in DOCK8 deficiency.

PMID:27350570 SUPPORT In Vitro

Gives the mechanistic reason the two diseases overlap, which is why the differential is clinically hard rather than merely superficial.

Severe atopic dermatitis with hyper-IgE MONDO:0004980

Overlapping Features Ordinary severe atopic dermatitis can reach very high IgE levels and recurrent skin infection, and is far commoner. What it does not produce is the combination with refractory cutaneous viral infection, low IgM, impaired specific antibody responses and virus-driven malignancy.

Distinguishing Features

Atopic dermatitis lacks the combined immune defect: specific antibody responses, IgM, T-cell counts and NK function are normal, and refractory HPV/molluscum disease and early malignancy do not occur.

Show evidence (1 reference)

PMID:25724123 SUPPORT Human Clinical

"DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%)."

Low IgM alongside the atopic laboratory profile is the finding that points away from uncomplicated atopic dermatitis.

Wiskott-Aldrich syndrome MONDO:0010518

Overlapping Features The other classic actin-cytoskeleton inborn error of immunity, and mechanistically the closest neighbour: WASP is the actin nucleation-promoting factor that CDC42 — and therefore DOCK8 — activates, and DOCK8 sits in a complex with it. WAS likewise couples eczema with elevated IgE and recurrent infection. It is X-linked and adds microthrombocytopenia, which DOCK8 deficiency does not cause.

Distinguishing Features

WAS is X-linked and features small-platelet thrombocytopenia with bleeding from infancy. DOCK8 deficiency is autosomal recessive with normal platelets, and is dominated by refractory cutaneous viral infection and severe food allergy.

Show evidence (1 reference)

PMID:23455509 SUPPORT In Vitro

Establishes the shared molecular pathway that makes these two diseases mechanistic neighbours and clinical mimics.

Chronic mucocutaneous candidiasis MONDO:0015279

Overlapping Features DOCK8 deficiency is one of the genetic causes of a CMC picture, through its Th17 differentiation block. What distinguishes it is that the candidiasis is one feature of a broad combined immunodeficiency rather than an isolated IL-17-axis lesion: the DOCK8 patient additionally has refractory cutaneous viral infection, severe atopy, humoral failure and malignancy risk.

Distinguishing Features

Isolated IL-17-axis defects (IL17F, IL17RA, IL17RC, ACT1/TRAF3IP2, RORC) produce a narrow mucocutaneous fungal phenotype and little else. DOCK8 deficiency produces a broad combined immunodeficiency in which candidiasis is one component.

Show evidence (1 reference)

PMID:27350570 SUPPORT In Vitro

"There was a profound block in the differentiation of DOCK8-deficient naive CD4+ T"

Documents the Th17 differentiation block that places DOCK8 deficiency among the genetic causes of chronic mucocutaneous candidiasis.

🐁

Animal Models

Dock8 ENU point-mutant mouse (captain morgan / primurus) Chemical mutagenesis (ENU) forward-genetic screen

Two independent recessive ENU alleles recovered from a forward-genetic screen for mice that mount a normal first wave of antibody but fail to mature or sustain the response. They identified DOCK8 as a humoral-immunity gene before the human disease gene was known, and they model the B-cell arm specifically.

Species

Mus musculus

Genotype

Dock8 cpm/cpm or pri/pri (ENU-induced recessive loss-of-function)

Background

C57BL/6

Genes

DOCK8 hgnc:19191

Publication

PMID:19898472

Pathograph links

Defective B Cell Immunological Synapse and Germinal Centre Persistence recapitulates fidelity: high observes: cellular Mutant B cells fail to form marginal-zone B cells, fail to persist in germinal centres, and fail to accumulate ICAM-1 in the immunological synapse while other BCR signalling is intact.

Limitations: These are point mutants rather than the large deletions that dominate the human mutational spectrum, and the screen selected specifically for a humoral phenotype, so the model speaks to the B-cell arm rather than to the cutaneous viral or atopic arms of the human disease.

Readouts

Germinal centre persistence and affinity maturation

Direction: DECREASED

Interpretation: Structural and functional correlate of the germinal-centre failure node.

Show evidence (1 reference)

PMID:19898472 SUPPORT Model Organism

"DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation."

Reports the germinal-centre and marginal-zone measurement in the mutant mice.

ICAM-1 accumulation in the B cell immunological synapse

Direction: DECREASED

Interpretation: The synapse-organization measurement that explains the germinal-centre failure.

Show evidence (1 reference)

PMID:19898472 SUPPORT Model Organism

"Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling."

Reports the ICAM-1 synapse measurement and its specificity.

Show evidence (1 reference)

PMID:19898472 SUPPORT Model Organism

"Two recessive mutations that disrupted antibody response maturation (Fig. 1a,b) were propagated from independent pedigrees and denoted captain morgan (cpm) and primurus (pri)."

Identifies the two alleles and the phenotype they were selected for, supporting the model as informative for the humoral node.

Dock8 knockout mouse

Targeted Dock8 knockout used to establish the dendritic-cell migration defect and to show that DOCK8 acts as a spatially restricted CDC42 activator rather than a global one.

Species

Mus musculus

Genotype

Dock8 knockout

Genes

DOCK8 hgnc:19191

Publication

PMID:22461490

Pathograph links

Impaired Dendritic Cell Interstitial Migration recapitulates fidelity: high observes: cellular Knockout dendritic cells migrate normally in two dimensions but cannot crawl through three-dimensional fibrillar networks or transmigrate the subcapsular sinus floor, and do not accumulate in the lymph node parenchyma for T-cell priming.

Limitations: The human dendritic-cell phenotype is inferred from this mouse; equivalent in vivo lymph-node imaging is not available in patients.

Readouts

Dendritic cell accumulation in the lymph node parenchyma

Direction: DECREASED

Interpretation: Direct measurement of the priming failure this node predicts.

Show evidence (1 reference)

PMID:22461490 SUPPORT Model Organism

"By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming."

Reports the lymph-node accumulation measurement in the knockout.

Leading-edge CDC42 activation in migrating dendritic cells

Direction: DECREASED

Interpretation: Localizes the defect to spatial CDC42 activation rather than to total CDC42-GTP.

Show evidence (1 reference)

PMID:22461490 SUPPORT Model Organism

"Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration."

Reports the leading-edge CDC42 measurement.

Show evidence (1 reference)

PMID:22461490 SUPPORT Model Organism

"Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially."

States the mechanistic conclusion the knockout establishes, supporting the model as informative for this node.

Dock8 mutant mouse CD8 T cell compartment

Used in parallel with patient cells to separate cell-intrinsic from extrinsic causes of the CD8 defect, and to show the failure is of memory persistence rather than of primary expansion.

Species

Mus musculus

Genotype

Dock8 loss-of-function mutant

Genes

DOCK8 hgnc:19191

Publication

PMID:22006977

Pathograph links

Impaired CD8 T Cell Survival and Memory recapitulates fidelity: high observes: cellular Mutant mice reproduce the human loss of circulating naive CD8 T cells, and add what patient studies cannot show: that the defect is cell-autonomous and primarily postthymic, and that primary clonal expansion is near-normal while memory persistence and recall fail.

Limitations: Recall was assayed after recombinant influenza infection rather than after the cutaneous herpesvirus challenge that dominates human disease, so the link from this readout to the skin phenotype is inferential.

Readouts

Memory CD8 T cell persistence and recall after influenza challenge

Direction: DECREASED

Interpretation: Distinguishes a memory-maintenance failure from a priming or expansion failure.

Show evidence (1 reference)

PMID:22006977 SUPPORT Model Organism

"Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall."

Reports the memory-persistence and recall measurement.

Show evidence (1 reference)

PMID:22006977 SUPPORT Model Organism

"Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic."

Establishes what the mouse adds over the patient data — that the defect is cell-intrinsic — supporting the model as informative for this node.

{ }

Source YAML

click to show

name: Combined Immunodeficiency Due To DOCK8 Deficiency
creation_date: "2026-09-11T00:00:00Z"
category: Mendelian
synonyms:
- DOCK8 deficiency
- DOCK8 immunodeficiency syndrome
- Autosomal recessive hyper-IgE syndrome
- AR-HIES
- Hyper-IgE recurrent infection syndrome 2, autosomal recessive
- HIES2
- Combined immunodeficiency due to dedicator of cytokinesis 8 protein deficiency
disease_term:
  preferred_term: Combined immunodeficiency due to DOCK8 deficiency
  term:
    id: MONDO:0009478
    label: combined immunodeficiency due to DOCK8 deficiency
parents:
- Combined immunodeficiency
- Primary Immunodeficiency
description: >-
  Combined immunodeficiency due to DOCK8 deficiency is an autosomal recessive
  inborn error of immunity caused by biallelic loss-of-function variants in
  DOCK8, and is the principal genetic cause of the autosomal recessive form of
  hyper-IgE syndrome (AR-HIES). DOCK8 is an atypical guanine nucleotide exchange
  factor that activates the Rho-family GTPase CDC42 at the leading-edge membrane
  of migrating and synapsing leukocytes. Without it, lymphocytes cannot
  coordinate the cortical actin cytoskeleton: CD8 T cells and NK cells moving
  through collagen-dense tissue such as dermis undergo catastrophic shape
  rupture and die (cytothripsis), dendritic cells fail to crawl through
  three-dimensional interstitium to prime T cells in lymph nodes, NK cells fail
  to build a lytic immunological synapse, and B cells fail to organize the
  integrin-containing immune synapse needed for marginal-zone and germinal
  centre persistence. DOCK8 additionally binds STAT3 and is required for its
  full activation, which is why the disease phenocopies part of STAT3-HIES. The
  clinical result is a triad of recurrent sinopulmonary bacterial infection,
  severe and recalcitrant cutaneous viral infection (molluscum contagiosum,
  HPV warts, HSV, VZV), and severe atopy with markedly elevated serum IgE,
  eosinophilia and food allergy, on a background of virus-driven malignancy and
  cerebral vasculopathy. Unlike STAT3-HIES it spares the connective-tissue,
  skeletal, dental and pneumatocele features. Natural history is poor —
  survival falls to roughly a third by age 30 without intervention — and
  allogeneic haematopoietic stem cell transplantation is the only curative
  therapy.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:19776401
      reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency."
      explanation: >-
        DOCK8 deficiency is a combined immunodeficiency, an immune-system
        disorder belonging to Harrison's immunology/rheumatology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:20004785
      reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome."
      explanation: >-
        The disease is a Mendelian single-gene disorder, supporting placement in
        Harrison's genetics-and-disease Part.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The IUIS 2022 phenotypic classification lists DOCK8 deficiency in Table 1,
      "Immunodeficiencies affecting cellular and humoral immunity" — the
      combined-immunodeficiency table — rather than in the Table 2 syndromic
      group where STAT3-HIES sits.
    evidence:
    - reference: PMID:19776401
      reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency."
      explanation: >-
        The disease-defining report classifies DOCK8 deficiency as a combined
        immunodeficiency affecting both cellular and humoral immunity, matching
        the IUIS Table 1 category.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DOCK8 deficiency DOCK8 AR 243700"
      explanation: >-
        The IUIS 2022 classification lists DOCK8 deficiency as a row of Table 1,
        "Immunodeficiencies affecting cellular and humoral immunity".
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >-
    Estimate is for the hyper-IgE syndromes as a group (<1 in 1,000,000);
    DOCK8 deficiency accounts for the majority of the autosomal recessive
    subset, so its own prevalence is lower still. No DOCK8-specific
    population-based prevalence estimate has been published.
  evidence:
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "rare primary immunodeficiencies (estimated prevalence <1:1 million)"
    explanation: >-
      Gives the order-of-magnitude prevalence for the hyper-IgE syndromes, of
      which DOCK8 deficiency is the main autosomal recessive cause.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic (homozygous or compound heterozygous)
    loss-of-function DOCK8 variants. Heterozygous carriers are unaffected.
    Parental consanguinity is common in reported pedigrees.
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel homozygous or compound heterozygous \ndeletions and point mutations in the gene encoding the dedicator of cytokinesis \n8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."
    explanation: >-
      Documents biallelic (homozygous or compound heterozygous) DOCK8 variants
      as the cause, establishing recessive inheritance.
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome."
    explanation: Establishes the autosomal recessive mode of inheritance.
pathophysiology:
- name: Biallelic DOCK8 Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous DOCK8 variants — most often large
    intragenic or subtelomeric 9p24.3 deletions, but also frameshift, nonsense
    and splice-site changes — abolish DOCK8 protein in lymphocytes. The locus is
    rich in repetitive sequence, which predisposes both to the germline
    deletions that dominate the mutational spectrum and to the somatic
    recombination-mediated repair seen in some patients.
  molecular_functions:
  - preferred_term: DOCK8 guanine nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel homozygous or compound heterozygous \ndeletions and point mutations in the gene encoding the dedicator of cytokinesis \n8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."
    explanation: >-
      Establishes biallelic DOCK8 variants as the initiating lesion and absence
      of DOCK8 protein in lymphocytes as its immediate molecular consequence.
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subtelomeric biallelic microdeletions were identified in 5 patients at \nthe terminus of chromosome 9p."
    explanation: >-
      Documents the large biallelic deletions at 9p24.3 that account for much of
      the mutational spectrum.
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair."
    explanation: >-
      Explains why deletions dominate the mutational spectrum, and why somatic
      reversion occurs at this locus.
  downstream:
  - target: Loss of CDC42 Activation at the Leading-Edge Membrane
    causal_link_type: DIRECT
  - target: Impaired DOCK8-Dependent STAT3 Activation
    causal_link_type: DIRECT
- name: Loss of CDC42 Activation at the Leading-Edge Membrane
  biological_scale: MOLECULAR
  description: >-
    DOCK8 is a CDC42-specific atypical guanine nucleotide exchange factor whose
    DHR-2 domain loads GTP onto CDC42. Its DHR-1 (C2-like) domain targets it to
    phosphoinositide-rich membrane, so DOCK8 acts locally rather than globally:
    in its absence, bulk cellular CDC42-GTP is unchanged but CDC42 activation at
    the leading-edge membrane fails, and with it amoeboid polarization.
  biological_processes:
  - preferred_term: CDC42 activation at the leading-edge membrane
    term:
      id: GO:0032489
      label: regulation of Cdc42 protein signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:22461490
    reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration"
    explanation: >-
      Identifies CDC42 as the GTPase DOCK8 activates, establishing the
      biochemical step lost in the disease.
  - reference: PMID:22461490
    reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration."
    explanation: >-
      Shows the defect is spatial rather than global — local leading-edge CDC42
      activation is lost while bulk CDC42-GTP is preserved.
  downstream:
  - target: Cortical Actin Cytoskeleton Dysregulation in Leukocytes
    causal_link_type: DIRECT
- name: Cortical Actin Cytoskeleton Dysregulation in Leukocytes
  biological_scale: CELLULAR
  description: >-
    CDC42-GTP activates WASP and, through the Arp2/3 complex, nucleates cortical
    F-actin. DOCK8 sits in a macromolecular complex with WASP and with talin,
    linking actin nucleation to integrin-mediated adhesion. Without DOCK8 the
    leukocyte cannot build or reorganize the cortical actin network on demand,
    which is the single shared lesion behind every downstream immune-cell
    defect in this disease.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: cortical actin cytoskeleton organization
    term:
      id: GO:0030866
      label: cortical actin cytoskeleton organization
    modifier: DECREASED
  evidence:
  - reference: PMID:28625885
    reference_title: "DOCK8 deficiency: Insights into pathophysiology, clinical features and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton."
    explanation: >-
      States the core molecular lesion — loss of a lymphocyte GEF that regulates
      the actin cytoskeleton.
  - reference: PMID:23455509
    reference_title: "Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion"
    explanation: >-
      Places DOCK8 physically in the WASP/talin machinery that couples actin
      nucleation to integrin adhesion, explaining the breadth of the defect.
  downstream:
  - target: Lymphocyte Cytothripsis During Interstitial Migration
    causal_link_type: DIRECT
  - target: Impaired Dendritic Cell Interstitial Migration
    causal_link_type: DIRECT
  - target: Defective NK Cell Lytic Immunological Synapse
    causal_link_type: DIRECT
  - target: Defective B Cell Immunological Synapse and Germinal Centre Persistence
    causal_link_type: DIRECT
- name: Lymphocyte Cytothripsis During Interstitial Migration
  biological_scale: CELLULAR
  description: >-
    When DOCK8-deficient T and NK cells squeeze through confined,
    collagen-dense tissue such as dermis, they cannot maintain shape integrity.
    Chemotaxis itself is preserved, but the cells develop abnormal shape and
    nuclear deformation and rupture, dying by a distinctive catastrophic mode
    the discovering authors named cytothripsis. This is the mechanism that
    singles out the skin — where collagen makes up as much as a third of the
    wet weight — as the organ where DOCK8 deficiency fails first.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: leukocyte migration through dense interstitium
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: ABNORMAL
  - preferred_term: catastrophic lymphocyte death during confined migration
    term:
      id: GO:0008219
      label: cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:25422492
    reference_title: "DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis."
    explanation: >-
      Defines cytothripsis and shows it is a shape-integrity failure specific to
      confined migration, not a chemotaxis defect.
  - reference: PMID:25422492
    reference_title: "DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures."
    explanation: >-
      Ties cytothripsis to the CDC42/PAK-dependent cytoskeletal coordination
      lost in DOCK8 deficiency, and to collagen-dense tissue specifically.
  downstream:
  - target: Loss of Skin-Resident Memory CD8 T Cells
    causal_link_type: DIRECT
  - target: Impaired CD8 T Cell Survival and Memory
    causal_link_type: DIRECT
- name: Loss of Skin-Resident Memory CD8 T Cells
  biological_scale: TISSUE
  description: >-
    Because DOCK8-deficient cytotoxic T cells die crossing the dermis, the
    long-lived skin-resident memory CD8 T-cell pool that normally polices
    cutaneous herpesvirus reactivation is never established.
  cell_types:
  - preferred_term: skin-resident memory CD8 T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  biological_processes:
  - preferred_term: defense response to virus in skin
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:25422492
    reference_title: "DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections."
    explanation: >-
      Connects cytothripsis directly to loss of the skin-resident memory CD8
      compartment and to failure of cutaneous herpesvirus control.
  downstream:
  - target: Failure of Cutaneous Antiviral Immunosurveillance
    causal_link_type: DIRECT
- name: Impaired Dendritic Cell Interstitial Migration
  biological_scale: CELLULAR
  description: >-
    DOCK8-deficient dendritic cells migrate normally on flat two-dimensional
    surfaces but cannot crawl through three-dimensional fibrillar networks or
    transmigrate the subcapsular sinus floor, so they fail to reach the lymph
    node parenchyma where they would prime T cells. Antigen collected in skin
    therefore never reaches the T-cell zone efficiently.
  cell_types:
  - preferred_term: conventional dendritic cell
    term:
      id: CL:0000990
      label: conventional dendritic cell
  biological_processes:
  - preferred_term: interstitial dendritic cell migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: DECREASED
  evidence:
  - reference: PMID:22461490
    reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming."
    explanation: >-
      Shows DOCK8-null dendritic cells do not reach the site where T-cell
      priming occurs.
  - reference: PMID:22461490
    reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor."
    explanation: >-
      Establishes that the defect is specific to three-dimensional interstitial
      migration, mirroring the lymphocyte shape-integrity lesion.
  downstream:
  - target: Failure of Cutaneous Antiviral Immunosurveillance
    causal_link_type: DIRECT
- name: Defective NK Cell Lytic Immunological Synapse
  biological_scale: CELLULAR
  description: >-
    NK-cell killing requires focused F-actin accumulation at the lytic
    immunological synapse, driven by CDC42-activated WASP. DOCK8-deficient NK
    cells retain normal total F-actin but cannot concentrate it at the synapse,
    form defective conjugates, and fail to polarize LFA-1 and cytolytic granules
    toward the target. Cytotoxicity is reduced and is not rescued by IL-2.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: lytic immunological synapse formation
    term:
      id: GO:0001771
      label: immunological synapse formation
    modifier: DECREASED
  - preferred_term: natural killer cell mediated cytotoxicity
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
    modifier: DECREASED
  evidence:
  - reference: PMID:23380217
    reference_title: "Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content."
    explanation: >-
      Localizes the NK defect precisely to synaptic F-actin accumulation rather
      than to a global actin deficit.
  - reference: PMID:23380217
    reference_title: "Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation."
    explanation: >-
      Documents the functional consequence in patient cells, and that it is not
      a reversible activation defect.
  - reference: PMID:23455509
    reference_title: "Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse"
    explanation: >-
      Adds the adhesion and granule-polarization components of the synaptic
      defect.
  downstream:
  - target: Failure of Cutaneous Antiviral Immunosurveillance
    causal_link_type: DIRECT
- name: Impaired CD8 T Cell Survival and Memory
  biological_scale: CELLULAR
  description: >-
    Beyond cytothripsis, DOCK8-null naive CD8 T cells are intrinsically
    short-lived, polarize LFA-1 poorly at the synapse with dendritic cells, and
    are delayed in their first division. Primary clonal expansion after
    infection is near-normal, but memory persistence and recall are severely
    reduced — so the compartment that should contain reactivating persistent
    viruses is not maintained. In patients, circulating CD8 T cells are reduced
    and skewed to an exhausted CD45RA+CCR7- phenotype.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell homeostasis
    term:
      id: GO:0043029
      label: T cell homeostasis
    modifier: DECREASED
  - preferred_term: immunological synapse formation with dendritic cells
    term:
      id: GO:0001771
      label: immunological synapse formation
    modifier: DECREASED
  evidence:
  - reference: PMID:22006977
    reference_title: "DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA(+)CCR7(-) phenotype."
    explanation: >-
      Documents the naive CD8 loss and exhausted phenotype in DOCK8-deficient
      patients as well as mice.
  - reference: PMID:22006977
    reference_title: "DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division."
    explanation: >-
      Establishes the cell-intrinsic survival and synapse-polarization defect
      underlying the CD8 abnormality.
  - reference: PMID:22006977
    reference_title: "DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "they showed greatly reduced memory cell persistence and recall"
    explanation: >-
      Shows the failure is of memory persistence and recall rather than of
      primary expansion, matching the clinical pattern of relapsing persistent
      viral infection.
  downstream:
  - target: Failure of Cutaneous Antiviral Immunosurveillance
    causal_link_type: DIRECT
- name: Failure of Cutaneous Antiviral Immunosurveillance
  role: consequence
  biological_scale: TISSUE
  description: >-
    The convergence point of the cellular defects: with no skin-resident memory
    CD8 pool, impaired dendritic-cell priming, defective NK killing and poor CD8
    memory recall, the skin loses the layered antiviral surveillance that
    normally keeps cutaneotropic DNA viruses latent and subclinical.
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  biological_processes:
  - preferred_term: defense response to virus
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues."
    explanation: >-
      Attributes the cutaneous viral susceptibility to the shape-integrity
      lesion, linking the cellular mechanism to the organ-level failure.
  - reference: PMID:23380217
    reference_title: "Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy."
    explanation: >-
      Links the synaptic actin defect to the clinical viral and malignancy
      susceptibility. Framed as a hypothesis by the authors, so it supports the
      connection without asserting it is the sole mechanism.
  downstream:
  - target: Persistent Cutaneotropic and Oncogenic DNA Virus Infection
    causal_link_type: DIRECT
  - target: Recurrent viral skin infections
    causal_link_type: DIRECT
  - target: Disseminated molluscum contagiosum
    causal_link_type: DIRECT
  - target: Verrucae
    causal_link_type: DIRECT
  - target: Recurrent herpes
    causal_link_type: DIRECT
- name: Persistent Cutaneotropic and Oncogenic DNA Virus Infection
  conforms_to: "viral_oncogenesis#Persistent Oncogenic Virus Infection"
  biological_scale: ORGANISM
  description: >-
    Viruses that a competent immune system keeps latent and subclinical instead
    replicate continuously and spread: HPV, molluscum contagiosum virus, HSV and
    VZV in skin, and EBV in the B-cell compartment. Persistent infection by
    oncogenic members of this set — high-risk HPV at cutaneous and anogenital
    sites, EBV in B cells — is the reservoir from which the virus-driven
    malignancies of DOCK8 deficiency arise, which is the module trigger this
    node conforms to. The entry does not curate the downstream
    oncoprotein/tumour-suppressor steps of the module; the virally driven
    cancers are recorded as phenotypes.
  biological_processes:
  - preferred_term: persistence of cutaneotropic and oncogenic DNA viruses
    term:
      id: GO:0019042
      label: viral latency
    modifier: INCREASED
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "extensive and \npersistent infections with molluscum contagiosum; and human papillomavirus \ninfections."
    explanation: >-
      Documents persistent rather than self-limited infection by the
      cutaneotropic DNA viruses in the disease-defining cohort.
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "profound susceptibility to virus infections of the skin, with associated skin cancers"
    explanation: >-
      Links the persistent cutaneous viral infection directly to the skin
      cancers that follow it, which is the module's trigger-to-malignancy claim.
  downstream:
  - target: Squamous cell carcinoma of the skin
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Lymphoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cerebral Vasculopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Defective B Cell Immunological Synapse and Germinal Centre Persistence
  biological_scale: CELLULAR
  description: >-
    DOCK8-mutant B cells fail to accumulate the integrin ligand ICAM-1 in the
    immunological synapse while other aspects of B-cell receptor signalling
    remain intact. They cannot form marginal-zone B cells, cannot persist in
    germinal centres, and do not undergo affinity maturation — a synapse
    organisation defect rather than a signalling-cascade defect.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell immunological synapse formation
    term:
      id: GO:0001771
      label: immunological synapse formation
    modifier: DECREASED
  - preferred_term: germinal center B cell differentiation
    term:
      id: GO:0002314
      label: germinal center B cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:19898472
    reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation."
    explanation: >-
      Establishes the germinal-centre and marginal-zone failure that underlies
      the humoral defect.
  - reference: PMID:19898472
    reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling."
    explanation: >-
      Localizes the B-cell lesion to synapse organization, consistent with the
      shared cytoskeletal mechanism rather than a BCR-signalling defect.
  downstream:
  - target: Impaired Humoral Memory and Specific Antibody Responses
    causal_link_type: DIRECT
- name: Impaired Humoral Memory and Specific Antibody Responses
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The germinal-centre failure translates into poor long-lived antibody
    production: fewer than half of tested patients mount normal specific
    antibody responses to recall antigens, and low serum IgM is characteristic.
    This is the arm of the combined defect that produces the recurrent
    encapsulated-organism sinopulmonary infection and chronic otitis media.
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: DECREASED
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fewer than half of the patients tested produced normal specific antibody responses to recall antigens."
    explanation: >-
      Quantifies the humoral failure in the largest genetically confirmed
      phenotype series.
  - reference: PMID:19898472
    reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity."
    explanation: >-
      States the causal claim from synapse organization to loss of long-lasting
      humoral immunity.
  downstream:
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
  - target: Otitis media
    causal_link_type: DIRECT
  - target: Decreased circulating total IgM
    causal_link_type: DIRECT
- name: Impaired DOCK8-Dependent STAT3 Activation
  biological_scale: MOLECULAR
  description: >-
    DOCK8 is not only a GEF. It associates constitutively with STAT3
    independently of GEF activity, and — in a GEF-activity-dependent manner —
    promotes STAT3 phosphorylation, nuclear translocation, and STAT3-dependent
    gene expression. This second, non-cytoskeletal function is why an actin
    disorder produces part of the phenotype of a STAT3 transcription-factor
    disorder.
  biological_processes:
  - preferred_term: STAT3 signaling downstream of cytokine receptors
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:27350570
    reference_title: "Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T(H)17 cell differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression."
    explanation: >-
      Establishes the direct DOCK8-STAT3 interaction and DOCK8's requirement for
      full STAT3 activation.
  - reference: PMID:28625885
    reference_title: "DOCK8 deficiency: Insights into pathophysiology, clinical features and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3."
    explanation: >-
      Confirms STAT3 activation as an established non-cytoskeletal DOCK8
      function.
  downstream:
  - target: Th17 Differentiation Block
    causal_link_type: DIRECT
  - target: Th2 Skewing and IgE Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Th17 Differentiation Block
  biological_scale: CELLULAR
  description: >-
    Naive CD4 T cells from DOCK8-deficient patients are profoundly blocked in
    differentiating to Th17 cells, and a missense variant that disrupts GEF
    activity while sparing protein expression reproduces the block — tying the
    defect to catalytic function rather than to a scaffolding role alone. The
    resulting collapse of IL-17/IL-22 mucocutaneous defence is the shared
    mechanism behind the candidiasis and staphylococcal susceptibility that
    DOCK8 deficiency and STAT3-HIES have in common.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:27350570
    reference_title: "Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T(H)17 cell differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17 cell differentiation."
    explanation: >-
      Shows the Th17 block depends on DOCK8 catalytic GEF activity, separating
      it from loss of the protein as a scaffold.
  - reference: PMID:27350570
    reference_title: "Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T(H)17 cell differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES."
    explanation: >-
      Connects the STAT3 defect to the Th17 block and to the clinical overlap
      with STAT3-HIES.
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "defective \nT-cell activation and T(h)17 cell differentiation"
    explanation: >-
      Independently documents the Th17 differentiation defect in
      DOCK8-deficient patients.
  downstream:
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Th2 Skewing and IgE Dysregulation
  role: consequence
  biological_scale: ORGANISM
  description: >-
    With Th17 and Th1 output constrained, T-helper differentiation skews toward
    Th2, and eosinophil homeostasis and IgE regulation are disturbed. The result
    is the atopic arm of the disease — early severe eczema, extreme total IgE,
    hypereosinophilia and IgE-mediated food allergy — and it is the arm that
    responds least reliably to transplantation.
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  biological_processes:
  - preferred_term: T-helper 2 cell differentiation
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
    modifier: INCREASED
  - preferred_term: immunoglobulin E production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  evidence:
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired eosinophil \nhomeostasis and dysregulation of IgE."
    explanation: >-
      Documents disordered eosinophil homeostasis and IgE regulation as part of
      the DOCK8-deficiency phenotype.
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets."
    explanation: >-
      States T-helper subset skewing as an established consequence of DOCK8
      loss, distinct from the migration/shape mechanism.
  downstream:
  - target: Atopic dermatitis
    causal_link_type: DIRECT
  - target: Increased circulating IgE concentration
    causal_link_type: DIRECT
  - target: Eosinophilia
    causal_link_type: DIRECT
  - target: Food allergy
    causal_link_type: DIRECT
- name: Cerebral Vasculopathy
  biological_scale: TISSUE
  description: >-
    A distinctive non-infectious complication: cerebral vasculitis, arterial
    aneurysm, infarction and intracranial haemorrhage in young patients. The
    mechanism is not settled. VZV-associated vasculopathy is the leading
    proposal, which would place it downstream of the same failure of cutaneous
    and systemic antiviral control; a direct vascular role for DOCK8 has not
    been demonstrated.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe non-infectious cerebral events occurred in 14/136 (10 %)"
    explanation: >-
      Quantifies the frequency of severe non-infectious cerebral events in the
      largest published cohort.
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues."
    explanation: >-
      Proposes VZV-associated vasculopathy as the link between the shape-integrity
      lesion and the cerebral disease. The authors hedge ("probably"), so this
      supports the proposed mechanism without establishing it.
  downstream:
  - target: Stroke
    causal_link_type: DIRECT
phenotypes:
- category: Infection
  name: Recurrent viral skin infections
  frequency: VERY_FREQUENT
  description: >-
    The pathognomonic feature. Severe, extensive and treatment-refractory
    cutaneous infection with herpes simplex virus, varicella-zoster virus,
    molluscum contagiosum virus and human papillomavirus, in a distribution and
    severity not seen in other combined immunodeficiencies.
  phenotype_term:
    preferred_term: Recurrent cutaneous viral infections
    term:
      id: HP:0011371
      label: Recurrent viral skin infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intractable viral infections of the skin are caused by herpes simplex virus (HSV), molluscum contagiosum virus (MCV), varicella-zoster virus (VZV), and/or human papillomavirus (HPV)."
    explanation: Names the four cutaneotropic viruses responsible and their intractable course.
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed."
    explanation: >-
      Gives the frequency of viral infection in the largest genetically
      confirmed series, supporting VERY_FREQUENT.
- category: Infection
  name: Disseminated molluscum contagiosum
  frequency: FREQUENT
  description: >-
    Extensive, confluent and persistent molluscum, often involving hundreds of
    lesions and resistant to destructive therapy.
  phenotype_term:
    preferred_term: Extensive, persistent molluscum contagiosum
    term:
      id: HP:0032185
      label: Disseminated molluscum contagiosum
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "extensive and \npersistent infections with molluscum contagiosum"
    explanation: Documents extensive and persistent molluscum in the disease-defining cohort.
- category: Infection
  name: Verrucae
  frequency: FREQUENT
  description: >-
    Widespread, recalcitrant HPV warts at cutaneous and anogenital sites. These
    are the lesions from which cutaneous squamous cell carcinoma later arises.
  phenotype_term:
    preferred_term: Recalcitrant HPV warts
    term:
      id: HP:0200043
      label: Verrucae
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients had persistent flat and verrucous warts"
    explanation: Counts persistent flat and verrucous warts in seven of the eleven patients in the defining cohort.
- category: Infection
  name: Recurrent herpes
  frequency: FREQUENT
  description: >-
    Recurrent and severe HSV disease, including eczema herpeticum, and severe or
    disseminated herpes zoster.
  phenotype_term:
    preferred_term: Recurrent severe herpes simplex and herpes zoster
    term:
      id: HP:0005353
      label: Recurrent herpes
    temporality: RECURRENT
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent, \nsevere herpes simplex virus or herpes zoster infections"
    explanation: Documents recurrent severe HSV and zoster in the defining cohort.
- category: Infection
  name: Recurrent respiratory infections
  frequency: VERY_FREQUENT
  description: >-
    Recurrent bacterial sinusitis and pneumonia from infancy, reflecting the
    humoral arm of the combined defect; Streptococcus pneumoniae, Haemophilus
    influenzae and Staphylococcus aureus predominate.
  phenotype_term:
    preferred_term: Recurrent sinopulmonary bacterial infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."
    explanation: >-
      Lists recurrent respiratory tract infection among the most frequent
      manifestations in the 136-patient cohort.
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had recurrent otitis media, sinusitis, and pneumonias"
    explanation: Documents the recurrent sinopulmonary infection pattern.
- category: Infection
  name: Otitis media
  frequency: FREQUENT
  description: >-
    Chronic and often destructive middle-ear infection, frequently accompanied
    by otitis externa.
  phenotype_term:
    preferred_term: Chronic recurrent otitis media
    term:
      id: HP:0000388
      label: Otitis media
    temporality: RECURRENT
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had recurrent otitis media, sinusitis, and pneumonias"
    explanation: Documents recurrent otitis media in the defining cohort.
- category: Structural
  name: Bronchiectasis
  frequency: OCCASIONAL
  description: >-
    End-organ airway damage from repeated bacterial pneumonia. Note the contrast
    with STAT3-HIES, where pneumatoceles are characteristic: in DOCK8 deficiency
    parenchymal lung abnormalities of that kind are uncommon.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:28625885
    reference_title: "DOCK8 deficiency: Insights into pathophysiology, clinical features and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients often experience recurrent sinopulmonary bacterial infections that can lead to bronchiectasis"
    explanation: States bronchiectasis as a consequence of the recurrent sinopulmonary infection.
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures"
    explanation: >-
      Supports the contrast with STAT3-HIES: DOCK8 deficiency is characterized
      by the absence of the parenchymal lung lesions (pneumatoceles) seen there.
- category: Infection
  name: Chronic mucocutaneous candidiasis
  frequency: FREQUENT
  description: >-
    Oral, oesophageal, cutaneous and nail candidiasis, attributable to the Th17
    differentiation block shared with STAT3-HIES.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
    temporality: RECURRENT
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."
    explanation: Lists mucocutaneous candidiasis among the most frequent manifestations.
- category: Infection
  name: Recurrent cutaneous abscess formation
  frequency: FREQUENT
  description: >-
    Recurrent Staphylococcus aureus skin infection and abscess, shared with
    STAT3-HIES.
  phenotype_term:
    preferred_term: Recurrent staphylococcal skin abscesses
    term:
      id: HP:0100838
      label: Recurrent cutaneous abscess formation
    temporality: RECURRENT
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin abscesses (60%) and allergies (73%) were common clinical problems."
    explanation: Quantifies skin abscess frequency at 60% of genetically confirmed patients.
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent Staphylococcus aureus skin infections with otitis externa"
    explanation: Identifies S. aureus as the organism behind the recurrent skin infection.
- category: Dermatologic
  name: Atopic dermatitis
  frequency: VERY_FREQUENT
  description: >-
    Severe, diffuse eczematous dermatitis, typically beginning in the first
    months of life and frequently superinfected. It is one of the earliest and
    most consistent manifestations.
  phenotype_term:
    preferred_term: Severe early-onset eczematous dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
    temporality: CHRONIC
  evidence:
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients develop diffuse eczematous dermatitis with bacterial skin infections early in life"
    explanation: Establishes the early-life onset and diffuse character of the dermatitis.
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations."
    explanation: Lists eczema first among the most frequent manifestations of the 136-patient cohort.
- category: Laboratory
  name: Increased circulating IgE concentration
  frequency: VERY_FREQUENT
  description: >-
    Markedly elevated total serum IgE — the feature that placed the disease
    within the hyper-IgE syndromes. Median 5,201 IU in the largest genetically
    confirmed series, with individual values an order of magnitude higher.
  phenotype_term:
    preferred_term: Markedly elevated serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  diagnostic: true
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8-deficient patients had median IgE levels of 5201 IU"
    explanation: Gives the median total IgE in genetically confirmed DOCK8 deficiency.
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated serum \nIgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM \nlevels, and variable IgG antibody responses were common."
    explanation: Establishes elevated IgE as a common laboratory finding in the defining cohort.
- category: Laboratory
  name: Eosinophilia
  frequency: VERY_FREQUENT
  description: >-
    Peripheral blood eosinophilia, usually at least 800/microlitre, present in
    over 90% of genetically confirmed patients.
  phenotype_term:
    preferred_term: Hypereosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high eosinophil levels of usually at least 800/μL (92% of patients)"
    explanation: Quantifies the eosinophilia and its 92% frequency.
- category: Allergic
  name: Food allergy
  frequency: FREQUENT
  description: >-
    IgE-mediated food allergy, often to multiple foods and often severe. It is
    one of the manifestations least reliably corrected by transplantation.
  phenotype_term:
    preferred_term: Severe IgE-mediated food allergy
    term:
      id: HP:0500093
      label: Food allergy
  evidence:
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies."
    explanation: >-
      Names severe food allergy as one of the two features distinguishing DOCK8
      deficiency from other combined immunodeficiencies and hyper-IgE syndromes.
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe food allergies accompanied by anaphylaxis, asthma, elevated serum IgE, and eosinophilia"
    explanation: Documents severe food allergy with anaphylaxis in the clinical phenotype.
- category: Allergic
  name: Asthma
  frequency: OCCASIONAL
  description: Allergic asthma as part of the atopic phenotype.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe food allergies accompanied by anaphylaxis, asthma, elevated serum IgE, and eosinophilia"
    explanation: Lists asthma among the atopic manifestations of the disease.
- category: Allergic
  name: Anaphylactic shock
  frequency: OCCASIONAL
  description: >-
    Anaphylaxis, usually food-triggered, reported from the earliest descriptions
    of the disease.
  phenotype_term:
    preferred_term: Anaphylaxis
    term:
      id: HP:0100845
      label: Anaphylactic shock
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had severe atopy with anaphylaxis"
    explanation: Documents anaphylaxis in most patients of the defining cohort.
- category: Neoplastic
  name: Squamous cell carcinoma of the skin
  frequency: OCCASIONAL
  description: >-
    HPV-driven squamous cell carcinoma arising in long-standing verrucous
    lesions at cutaneous, anogenital and oral sites, typically in adolescence or
    young adulthood.
  phenotype_term:
    preferred_term: HPV-associated cutaneous squamous cell carcinoma
    term:
      id: HP:0006739
      label: Squamous cell carcinoma of the skin
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "several had \nsquamous-cell carcinomas, and one had T-cell lymphoma-leukemia."
    explanation: Documents squamous cell carcinoma in the disease-defining cohort.
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."
    explanation: >-
      Quantifies overall malignancy burden including the epithelial cancers, and
      gives the young median age at diagnosis.
- category: Neoplastic
  name: Lymphoma
  frequency: OCCASIONAL
  description: >-
    Lymphoproliferation and lymphoma, frequently EBV-associated; haematological
    cancers were the largest malignancy category in the 136-patient cohort.
  phenotype_term:
    preferred_term: Lymphoma and EBV-associated lymphoproliferation
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."
    explanation: Gives 11 haematological cancers among 23 malignancies in the largest cohort.
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient with resected microcystic adenoma died from cutaneous T-cell lymphoma-leukemia."
    explanation: Documents a fatal lymphoid malignancy in the defining cohort.
- category: Neurologic
  name: Stroke
  frequency: OCCASIONAL
  description: >-
    Ischaemic stroke on a background of CNS vasculitis and cerebral aneurysm, a
    leading non-infectious cause of severe morbidity and death.
  phenotype_term:
    preferred_term: Stroke on a background of cerebral vasculopathy
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:28625885
    reference_title: "DOCK8 deficiency: Insights into pathophysiology, clinical features and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These include CNS vasculitis, aneurysms, tumor infiltration, as well as strokes and hemiparesis"
    explanation: >-
      Lists stroke among the non-infectious neurological complications alongside
      the vasculitis and aneurysms that underlie it.
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebral complications such as CNS vasculitis or stroke"
    explanation: >-
      Counts CNS vasculitis and stroke among the events defining event-free
      survival in the largest cohort.
- category: Laboratory
  name: Decreased circulating total IgM
  frequency: FREQUENT
  description: >-
    Low serum IgM, present in 62% of genetically confirmed patients and one of
    the five discriminating features separating DOCK8 from STAT3 deficiency.
  phenotype_term:
    preferred_term: Low serum IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  diagnostic: true
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the majority of patients, serum IgM levels were low (36/58; 62%)"
    explanation: Quantifies low serum IgM in 36 of 58 genetically confirmed patients.
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels"
    explanation: Establishes low IgM as part of the diagnostic discriminator for DOCK8 deficiency.
- category: Laboratory
  name: Impaired specific antibody response
  frequency: FREQUENT
  description: >-
    Fewer than half of tested patients mount normal specific antibody responses
    to recall antigens.
  phenotype_term:
    preferred_term: Impaired specific antibody response to recall antigens
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fewer than half of the patients tested produced normal specific antibody responses to recall antigens."
    explanation: Quantifies the specific-antibody failure.
- category: Laboratory
  name: Decreased total T cell count
  frequency: OCCASIONAL
  description: >-
    T lymphopenia, affecting CD4 and CD8 compartments, in roughly one fifth of
    genetically confirmed patients. Counts can be relatively preserved at birth,
    which is why TREC-based newborn screening does not reliably detect the
    disease.
  phenotype_term:
    preferred_term: CD4 and CD8 T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts."
    explanation: Quantifies lymphopenia and attributes it to the CD4 and CD8 compartments.
- category: Laboratory
  name: Decreased natural killer cell-induced killing of target cells
  frequency: FREQUENT
  description: >-
    Reduced NK-cell cytotoxicity that is not corrected by IL-2 stimulation, the
    functional counterpart of the defective lytic synapse.
  phenotype_term:
    preferred_term: Impaired NK cell cytotoxicity
    term:
      id: HP:0025808
      label: Decreased natural killer cell-induced killing of target cells
  evidence:
  - reference: PMID:23380217
    reference_title: "Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation."
    explanation: Documents reduced, IL-2-irreversible NK cytotoxicity in patient cells.
- category: Constitutional
  name: Failure to thrive
  frequency: OCCASIONAL
  description: >-
    Poor growth in childhood, driven by chronic infection and by malabsorption
    from allergic or autoimmune enteropathy and intestinal infection.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28625885
    reference_title: "DOCK8 deficiency: Insights into pathophysiology, clinical features and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Malabsorption resulting in failure to thrive may be caused by allergic or autoimmune enteropathy, as well as by intestinal infections."
    explanation: Gives the gastrointestinal mechanism behind failure to thrive in this disease.
genetic:
- name: DOCK8
  gene_term:
    preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic loss-of-function variants in DOCK8 (9p24.3) cause the disease.
    DOCK8 encodes an atypical guanine nucleotide exchange factor for CDC42 that
    is expressed almost exclusively in immune cells. Nearly all reported alleles
    are null: large intragenic or whole-gene deletions and complex
    rearrangements predominate, with frameshift, nonsense and splice-site point
    mutations accounting for most of the remainder and missense variants being
    rare. The locus is unusually rich in repetitive sequence, which explains
    both the deletion-heavy mutational spectrum and the somatic
    recombination-mediated reversion seen in a substantial minority of patients.
  notes: >-
    HGNC identifier verified against the HGNC REST API (rest.genenames.org),
    which returns hgnc_id HGNC:19191, symbol DOCK8, name "dedicator of
    cytokinesis 8", location 9p24.3, NCBI Gene 81704, UniProt Q8NF50. The
    lowercase `hgnc:` form is this repository's convention. The same CURIE is
    already bound to DOCK8 in kb/disorders/Chronic_Mucocutaneous_Candidiasis.yaml.
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel homozygous or compound heterozygous \ndeletions and point mutations in the gene encoding the dedicator of cytokinesis \n8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."
    explanation: >-
      Establishes DOCK8 as the causative gene and loss of DOCK8 protein as the
      functional consequence.
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of patients without large \ndeletions revealed 16 patients from 9 unrelated families with distinct \nhomozygous mutations in DOCK8 causing premature termination, frameshift, splice \nsite disruption, and single exon deletions and microdeletions."
    explanation: >-
      Characterizes the non-deletion end of the mutational spectrum as
      uniformly truncating or splice-disrupting.
  - reference: PMID:30565250
    reference_title: "Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair."
    explanation: >-
      Explains the deletion-dominated spectrum and the propensity to somatic
      reversion as consequences of the same locus architecture.
- name: DOCK8 somatic reversion
  gene_term:
    preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  association: >-
    Somatic repair of the germline DOCK8 lesion — by second-site mutation,
    original-site back mutation, gene conversion or intragenic crossover —
    restores DOCK8 expression in a subset of lymphocytes, preferentially
    antigen-experienced T cells and NK cells rather than naive T or B cells.
    Revertant patients are older and have milder allergic disease, but infection
    susceptibility persists and reversion is not curative. It is the principal
    known within-patient modifier of disease severity, and is a further reason
    to interpret residual DOCK8 protein on a flow-cytometry assay carefully.
  evidence:
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair."
    explanation: Quantifies how often somatic reversion occurs in a referral cohort.
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover."
    explanation: Lists the molecular mechanisms of reversion.
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation."
    explanation: >-
      Establishes reversion as a partial severity modifier that does not
      substitute for curative therapy.
progression:
- phase: Infancy and early childhood
  notes: >-
    Presentation is with severe eczematous dermatitis and recurrent bacterial
    skin and sinopulmonary infection, usually within the first year of life,
    accompanied by very high IgE, eosinophilia and emerging food allergy.
  evidence:
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typically, patients develop diffuse eczematous dermatitis with bacterial skin infections early in life, along with respiratory tract infections and severe food allergies"
    explanation: Describes the early-life presenting picture.
- phase: Later childhood and adolescence
  notes: >-
    Cutaneous viral disease expands and becomes refractory, bronchiectasis
    accrues from repeated pneumonia, and the first malignancies and cerebral
    events appear. Malignancy in the largest cohort was diagnosed at a median
    age of 12 years.
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years."
    explanation: Places the onset of malignancy in later childhood.
- phase: Young adulthood without transplantation
  notes: >-
    Cumulative mortality from infection, cancer and cerebrovascular events.
    Only about a third of patients reach 30 years without transplantation, and
    event-free survival is 4% at that age.
  evidence:
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only about a third of patients reach the age of 30 years without hematopoietic stem cell transplantation"
    explanation: >-
      Gives the untransplanted survival to age 30, restating the Aydin 2015
      natural-history curve without the bracketed censoring clause.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "about 75% develop severe, life-threatening disease complications before the age of 20 years"
    explanation: Quantifies severe complications accrued before adulthood.
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke."
    explanation: Gives event-free survival, the measure that captures the accumulating complication burden.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Untreated DOCK8 deficiency is a fatal disease of childhood and young
    adulthood. Two thirds of patients are dead by 30 years censored for
    transplantation, 58% experience a severe life-threatening infection, 17%
    develop a malignancy at a median age of 12, and 10% suffer a severe
    non-infectious cerebral event. Mortality in the genetically confirmed
    phenotype series was 34%. Between these events, chronic disfiguring skin
    disease, multiple food allergies and repeated hospitalization dominate daily
    life.
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %)."
    explanation: Quantifies the severe-event burden in the largest cohort.
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mortality rate in our cohort was 34% (20 of 58 patients), with death occurring at a mean age of 9 years 3 months"
    explanation: Gives crude mortality and mean age at death in the genetically confirmed phenotype series.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease."
    explanation: Summarizes the untreated prognosis and the availability of curative therapy.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    The only curative therapy. Because DOCK8 is expressed almost exclusively in
    haematopoietic cells, replacing the haematopoietic compartment corrects the
    lesion at its source. In an 81-patient international cohort transplanted at
    a median age of 9.7 years, 84% were alive after a median 26 months, with 89%
    survival after matched-related and 81% after matched-unrelated grafts.
    Transplantation restores lymphocyte differentiation and function and lowers
    total and allergen-specific IgE over time. Manifestations do not all respond
    equally: eczema, infections and mollusca resolve faster than food allergies
    or failure to thrive, and food allergy may persist.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic haematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Biallelic DOCK8 Loss of Function
    description: >-
      Donor-derived haematopoiesis supplies DOCK8-sufficient lymphocytes,
      dendritic cells and NK cells, correcting the initiating molecular lesion
      in the compartment where DOCK8 is expressed.
    evidence:
    - reference: PMID:31021819
      reference_title: "Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients."
      explanation: >-
        Demonstrates that transplantation corrects the lymphocyte functional
        defects that follow from loss of DOCK8.
  evidence:
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice."
    explanation: Establishes transplantation as the curative treatment of choice.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive."
    explanation: Gives the survival outcome in the largest transplant cohort.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive."
    explanation: >-
      Records the differential response, which is the main caveat when
      counselling families about cure.
  - reference: PMID:31021819
    reference_title: "Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT."
    explanation: Shows the atopic laboratory phenotype also improves after transplantation.
  notes: >-
    Interpreting per-manifestation response is complicated by somatic reversion,
    which can independently soften the allergic phenotype (see the DOCK8 somatic
    reversion genetic record).
- name: Reduced-Toxicity Conditioning
  description: >-
    Conditioning intensity is the modifiable variable with the clearest effect
    on transplant survival in this disease. Reduced-toxicity regimens built on
    treosulfan or reduced-dose busulfan gave 97% survival against 78% for fully
    myeloablative busulfan-based conditioning. Younger age at transplant also
    favours survival, which argues for referral before complications accrue.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: reduced-intensity transplant conditioning
    term:
      id: NCIT:C116471
      label: Reduced-Intensity Transplant Conditioning Procedure
  evidence:
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens"
    explanation: >-
      Establishes reduced-toxicity conditioning as the regimen associated with
      better survival in DOCK8 deficiency.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HSCT using a reduced-toxicity regimen may offer the best chance for survival."
    explanation: States the authors' conclusion on regimen choice.
- name: Immunoglobulin Replacement Therapy
  description: >-
    Replaces the specific antibody the patient cannot make, addressing the
    humoral arm of the combined defect. A standard bridging measure before
    transplantation.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Impaired Humoral Memory and Specific Antibody Responses
    description: >-
      Exogenous polyclonal IgG substitutes for the specific antibody response
      that the failed germinal-centre reaction cannot generate.
  target_phenotypes:
  - preferred_term: Impaired specific antibody response
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  - preferred_term: Recurrent sinopulmonary bacterial infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."
    explanation: >-
      Records immunoglobulin replacement as a standard therapeutic measure in
      the largest published cohort.
- name: Antibacterial Prophylaxis
  description: >-
    Long-term prophylaxis against the recurrent bacterial sinopulmonary and
    cutaneous infection that follows the humoral and Th17 defects. Supportive,
    not disease-modifying.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibacterial prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  target_phenotypes:
  - preferred_term: Recurrent sinopulmonary bacterial infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  - preferred_term: Recurrent staphylococcal skin abscesses
    term:
      id: HP:0100838
      label: Recurrent cutaneous abscess formation
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."
    explanation: Records antibacterial prophylaxis as standard supportive management.
- name: Antiviral Therapy and Prophylaxis
  description: >-
    Suppressive antiviral therapy for the cutaneous herpesvirus disease. It
    controls rather than clears: the underlying failure of skin-resident
    cytotoxic immunosurveillance persists until transplantation, so lesions
    recur on withdrawal.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  target_phenotypes:
  - preferred_term: Recurrent severe herpes simplex and herpes zoster
    term:
      id: HP:0005353
      label: Recurrent herpes
  - preferred_term: Recurrent cutaneous viral infections
    term:
      id: HP:0011371
      label: Recurrent viral skin infections
  evidence:
  - reference: PMID:25627830
    reference_title: "DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT."
    explanation: Records antiviral prophylaxis as standard supportive management.
  - reference: PMID:30391550
    reference_title: "Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease."
    explanation: >-
      Supports treating antimicrobial measures as bridging rather than
      definitive therapy, since only transplantation is curative.
diagnosis:
- name: Intracellular DOCK8 protein staining by flow cytometry
  description: >-
    Because nearly all patients lack DOCK8 protein entirely, intracellular
    staining for DOCK8 on peripheral blood mononuclear cells is a fast screen
    that avoids immunoblotting or sequencing. It also detects carriers and can
    track lineage-specific DOCK8 expression after transplantation. Residual
    expression does not exclude the diagnosis: somatic reversion restores DOCK8
    in some antigen-experienced T and NK cells.
  diagnosis_term:
    preferred_term: flow cytometry for intracellular DOCK8 expression
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: Absent or markedly reduced intracellular DOCK8 protein
  evidence:
  - reference: PMID:24698323
    reference_title: "Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present here a flow cytometry assay that could facilitate the diagnosis of DOCK8 deficiency, detection of carrier status, and investigation of lineage-specific DOCK8 expression following HCT."
    explanation: Describes the assay and the three purposes it serves.
  - reference: PMID:24698323
    reference_title: "Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The vast majority of DOCK8-deficient patients lack DOCK8 expression and many have deletions in the DOCK8 gene."
    explanation: >-
      Explains why an absent-protein screen has high yield in this disease,
      unlike diseases dominated by missense variants.
  - reference: PMID:24797421
    reference_title: "Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells."
    explanation: >-
      Documents the lineage-restricted residual expression that can confound a
      protein-based screen in revertant patients.
- name: Copy-number-aware molecular genetic testing
  description: >-
    Sequencing alone is not sufficient. Large intragenic and subtelomeric 9p24.3
    deletions account for a large share of pathogenic alleles, so the diagnostic
    approach must include copy-number analysis (array CGH, SNP array, or
    exome/genome sequencing with CNV calling) alongside sequence analysis.
  diagnosis_term:
    preferred_term: molecular genetic testing with copy-number analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic loss-of-function DOCK8 variants, frequently large deletions
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed comparative genomic hybridization arrays and targeted gene sequencing."
    explanation: >-
      Shows that the disease-defining diagnoses required copy-number analysis in
      combination with sequencing.
  - reference: PMID:20004785
    reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed genome-wide single nucleotide polymorphism analysis for 9 \npatients with autosomal-recessive hyper-IgE syndrome to locate copy number \nvariations and homozygous haplotypes."
    explanation: >-
      Confirms copy-number analysis as the method that identified the causative
      deletions.
- name: Clinical discrimination from STAT3-HIES
  description: >-
    Before molecular confirmation, a small set of clinical features separates
    DOCK8 from STAT3 deficiency: severe viral infection, allergy and low IgM
    favour DOCK8; pneumatoceles, retained primary teeth and minimal-trauma
    fractures favour STAT3.
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures."
    explanation: >-
      States the clinical discriminator derived from a support-vector-machine
      comparison of DOCK8-, STAT3- and mutation-negative AR-HIES patients.
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations."
    explanation: Confirms that a compact clinical feature set discriminates the two HIES forms.
differential_diagnoses:
- name: Autosomal dominant hyper-IgE syndrome (STAT3-HIES)
  disease_term:
    preferred_term: STAT3 hyper-IgE syndrome
    term:
      id: MONDO:0007818
      label: hyper-IgE recurrent infection syndrome 1, autosomal dominant
  description: >-
    The other hyper-IgE syndrome, and the main differential. Both share
    eczematoid dermatitis, staphylococcal skin abscess, recurrent pneumonia,
    candidiasis, very high IgE and eosinophilia — the Th17 defect common to
    both explains that overlap, and in DOCK8 deficiency it runs through the same
    STAT3 node. They separate on what each adds. STAT3-HIES adds non-immune
    connective-tissue, skeletal, dental and vascular features plus
    pneumatoceles; DOCK8 deficiency adds severe cutaneous viral infection,
    severe allergy, low IgM, early virus-driven malignancy and cerebral
    vasculopathy, and lacks the connective-tissue features.
  distinguishing_features:
  - >-
      DOCK8: severe refractory cutaneous viral infection, food allergy, low IgM,
      early squamous cell carcinoma and lymphoma, CNS vasculitis; autosomal
      recessive. STAT3: pneumatoceles, retained primary teeth, minimal-trauma
      fracture, scoliosis, characteristic facies; autosomal dominant.
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems."
    explanation: >-
      States the features that are present in STAT3-HIES and largely absent in
      DOCK8 deficiency.
  - reference: PMID:27350570
    reference_title: "Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T(H)17 cell differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES."
    explanation: >-
      Gives the mechanistic reason the two diseases overlap, which is why the
      differential is clinically hard rather than merely superficial.
- name: Severe atopic dermatitis with hyper-IgE
  disease_term:
    preferred_term: atopic eczema
    term:
      id: MONDO:0004980
      label: atopic eczema
  description: >-
    Ordinary severe atopic dermatitis can reach very high IgE levels and
    recurrent skin infection, and is far commoner. What it does not produce is
    the combination with refractory cutaneous viral infection, low IgM, impaired
    specific antibody responses and virus-driven malignancy.
  distinguishing_features:
  - >-
      Atopic dermatitis lacks the combined immune defect: specific antibody
      responses, IgM, T-cell counts and NK function are normal, and refractory
      HPV/molluscum disease and early malignancy do not occur.
  evidence:
  - reference: PMID:25724123
    reference_title: "The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%)."
    explanation: >-
      Low IgM alongside the atopic laboratory profile is the finding that points
      away from uncomplicated atopic dermatitis.
- name: Wiskott-Aldrich syndrome
  disease_term:
    preferred_term: Wiskott-Aldrich syndrome
    term:
      id: MONDO:0010518
      label: Wiskott-Aldrich syndrome
  description: >-
    The other classic actin-cytoskeleton inborn error of immunity, and
    mechanistically the closest neighbour: WASP is the actin nucleation-promoting
    factor that CDC42 — and therefore DOCK8 — activates, and DOCK8 sits in a
    complex with it. WAS likewise couples eczema with elevated IgE and recurrent
    infection. It is X-linked and adds microthrombocytopenia, which DOCK8
    deficiency does not cause.
  distinguishing_features:
  - >-
      WAS is X-linked and features small-platelet thrombocytopenia with bleeding
      from infancy. DOCK8 deficiency is autosomal recessive with normal platelets,
      and is dominated by refractory cutaneous viral infection and severe food
      allergy.
  evidence:
  - reference: PMID:23455509
    reference_title: "Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion"
    explanation: >-
      Establishes the shared molecular pathway that makes these two diseases
      mechanistic neighbours and clinical mimics.
- name: Chronic mucocutaneous candidiasis
  disease_term:
    preferred_term: chronic mucocutaneous candidiasis
    term:
      id: MONDO:0015279
      label: chronic mucocutaneous candidiasis
  description: >-
    DOCK8 deficiency is one of the genetic causes of a CMC picture, through its
    Th17 differentiation block. What distinguishes it is that the candidiasis is
    one feature of a broad combined immunodeficiency rather than an isolated
    IL-17-axis lesion: the DOCK8 patient additionally has refractory cutaneous
    viral infection, severe atopy, humoral failure and malignancy risk.
  distinguishing_features:
  - >-
      Isolated IL-17-axis defects (IL17F, IL17RA, IL17RC, ACT1/TRAF3IP2, RORC)
      produce a narrow mucocutaneous fungal phenotype and little else. DOCK8
      deficiency produces a broad combined immunodeficiency in which candidiasis
      is one component.
  evidence:
  - reference: PMID:27350570
    reference_title: "Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T(H)17 cell differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "There was a profound block in the differentiation of DOCK8-deficient naive CD4+ T"
    explanation: >-
      Documents the Th17 differentiation block that places DOCK8 deficiency
      among the genetic causes of chronic mucocutaneous candidiasis.
animal_models:
- name: Dock8 ENU point-mutant mouse (captain morgan / primurus)
  species: Mus musculus
  genotype: Dock8 cpm/cpm or pri/pri (ENU-induced recessive loss-of-function)
  background: C57BL/6
  category: Chemical mutagenesis (ENU) forward-genetic screen
  publication: PMID:19898472
  description: >-
    Two independent recessive ENU alleles recovered from a forward-genetic
    screen for mice that mount a normal first wave of antibody but fail to
    mature or sustain the response. They identified DOCK8 as a humoral-immunity
    gene before the human disease gene was known, and they model the B-cell arm
    specifically.
  genes:
  - preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  modeled_mechanisms:
  - target: Defective B Cell Immunological Synapse and Germinal Centre Persistence
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Mutant B cells fail to form marginal-zone B cells, fail to persist in
      germinal centres, and fail to accumulate ICAM-1 in the immunological
      synapse while other BCR signalling is intact.
    limitations: >-
      These are point mutants rather than the large deletions that dominate the
      human mutational spectrum, and the screen selected specifically for a
      humoral phenotype, so the model speaks to the B-cell arm rather than to
      the cutaneous viral or atopic arms of the human disease.
    readouts:
    - name: Germinal centre persistence and affinity maturation
      target: Defective B Cell Immunological Synapse and Germinal Centre Persistence
      direction: DECREASED
      interpretation: >-
        Structural and functional correlate of the germinal-centre failure node.
      evidence:
      - reference: PMID:19898472
        reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation."
        explanation: Reports the germinal-centre and marginal-zone measurement in the mutant mice.
    - name: ICAM-1 accumulation in the B cell immunological synapse
      target: Defective B Cell Immunological Synapse and Germinal Centre Persistence
      direction: DECREASED
      interpretation: The synapse-organization measurement that explains the germinal-centre failure.
      evidence:
      - reference: PMID:19898472
        reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling."
        explanation: Reports the ICAM-1 synapse measurement and its specificity.
    evidence:
    - reference: PMID:19898472
      reference_title: "Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Two recessive mutations that disrupted antibody response maturation (Fig. 1a,b) were propagated from independent pedigrees and denoted captain morgan (cpm) and primurus (pri)."
      explanation: >-
        Identifies the two alleles and the phenotype they were selected for,
        supporting the model as informative for the humoral node.
- name: Dock8 knockout mouse
  species: Mus musculus
  genotype: Dock8 knockout
  publication: PMID:22461490
  description: >-
    Targeted Dock8 knockout used to establish the dendritic-cell migration
    defect and to show that DOCK8 acts as a spatially restricted CDC42 activator
    rather than a global one.
  genes:
  - preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  modeled_mechanisms:
  - target: Impaired Dendritic Cell Interstitial Migration
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Knockout dendritic cells migrate normally in two dimensions but cannot
      crawl through three-dimensional fibrillar networks or transmigrate the
      subcapsular sinus floor, and do not accumulate in the lymph node
      parenchyma for T-cell priming.
    limitations: >-
      The human dendritic-cell phenotype is inferred from this mouse; equivalent
      in vivo lymph-node imaging is not available in patients.
    readouts:
    - name: Dendritic cell accumulation in the lymph node parenchyma
      target: Impaired Dendritic Cell Interstitial Migration
      direction: DECREASED
      interpretation: Direct measurement of the priming failure this node predicts.
      evidence:
      - reference: PMID:22461490
        reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming."
        explanation: Reports the lymph-node accumulation measurement in the knockout.
    - name: Leading-edge CDC42 activation in migrating dendritic cells
      target: Impaired Dendritic Cell Interstitial Migration
      direction: DECREASED
      interpretation: >-
        Localizes the defect to spatial CDC42 activation rather than to total
        CDC42-GTP.
      evidence:
      - reference: PMID:22461490
        reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration."
        explanation: Reports the leading-edge CDC42 measurement.
    evidence:
    - reference: PMID:22461490
      reference_title: "DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially."
      explanation: >-
        States the mechanistic conclusion the knockout establishes, supporting
        the model as informative for this node.
- name: Dock8 mutant mouse CD8 T cell compartment
  species: Mus musculus
  genotype: Dock8 loss-of-function mutant
  publication: PMID:22006977
  description: >-
    Used in parallel with patient cells to separate cell-intrinsic from
    extrinsic causes of the CD8 defect, and to show the failure is of memory
    persistence rather than of primary expansion.
  genes:
  - preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  modeled_mechanisms:
  - target: Impaired CD8 T Cell Survival and Memory
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Mutant mice reproduce the human loss of circulating naive CD8 T cells, and
      add what patient studies cannot show: that the defect is cell-autonomous
      and primarily postthymic, and that primary clonal expansion is near-normal
      while memory persistence and recall fail.
    limitations: >-
      Recall was assayed after recombinant influenza infection rather than after
      the cutaneous herpesvirus challenge that dominates human disease, so the
      link from this readout to the skin phenotype is inferential.
    readouts:
    - name: Memory CD8 T cell persistence and recall after influenza challenge
      target: Impaired CD8 T Cell Survival and Memory
      direction: DECREASED
      interpretation: >-
        Distinguishes a memory-maintenance failure from a priming or expansion
        failure.
      evidence:
      - reference: PMID:22006977
        reference_title: "DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall."
        explanation: Reports the memory-persistence and recall measurement.
    evidence:
    - reference: PMID:22006977
      reference_title: "DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic."
      explanation: >-
        Establishes what the mouse adds over the patient data — that the defect
        is cell-intrinsic — supporting the model as informative for this node.

📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: DOCK8 deficiency (autosomal recessive hyper-IgE syndrome) · 2026-09-22T04:31:36Z · View source

Curated combined immunodeficiency due to DOCK8 deficiency (MONDO:0009478) as the autosomal recessive counterpart to the existing Autosomal_Dominant_Hyper-IgE_Syndrome entry, which already named this disease as a differential diagnosis without it existing. 16 pathophysiology nodes, 23 phenotypes, 5 treatments, 3 animal models, 121 evidence snippets across verified PMIDs, all exact substrings of fetched reference caches (121/121 verified by validate-disorders). Deep research was produced with the claude_code provider after the Edison account returned HTTP 402; that report's citation layer proved unreliable across this batch (182 of 268 cited PMIDs across 10 reports had titles unrelated to their disease, 4 did not resolve at all), so citations here were re-derived and each reference fetched and read before quoting.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-7[1m] 2026-09-11T16:25:26.837220

1. Disease Information

Overview. Combined immunodeficiency due to DOCK8 deficiency (DOCK8-CID) is an autosomal recessive primary immunodeficiency (PID) — reclassified as an inborn error of immunity (IEI) in the IUIS classification — caused by biallelic loss-of-function mutations in the DOCK8 (Dedicator of Cytokinesis 8) gene on chromosome 9p24.3. It is the principal genetic cause of autosomal recessive hyper-IgE syndrome (AR-HIES). The disease is characterized by a triad of (1) recurrent sinopulmonary bacterial infections, (2) severe cutaneous and mucosal viral infections (notably human papillomavirus [HPV], molluscum contagiosum, herpes simplex virus [HSV], and varicella-zoster virus [VZV]), and (3) severe atopy with markedly elevated serum IgE, eosinophilia, and food allergies. Patients have a substantially increased risk of virus-driven malignancies (squamous cell carcinoma, EBV-associated lymphomas) and cerebrovascular events, and untreated disease is typically fatal in early adulthood.

Key identifiers. - OMIM: #243700 (Hyper-IgE recurrent infection syndrome 2, autosomal recessive; HIES2) — gene entry OMIM 611432 (DOCK8) - Orphanet: ORPHA:217390 (Autosomal recessive hyper-IgE syndrome) - Mondo: MONDO:0009478 (combined immunodeficiency due to DOCK8 deficiency) - ICD-10: D82.4 (Hyperimmunoglobulin E [IgE] syndrome) - ICD-11: 4A01.31 (Combined immunodeficiencies with associated or syndromic features / Hyper-IgE syndromes) — DOCK8 deficiency is classified in the IUIS 2022 update as a "Combined Immunodeficiency with Associated or Syndromic Features" - MeSH: D007589 (Job Syndrome — encompassing both AD-HIES and AR-HIES) - HGNC:* HGNC:19191 (DOCK8)

Synonyms and alternative names. - Autosomal recessive hyper-IgE syndrome (AR-HIES) - HIES2 - Hyper-IgE recurrent infection syndrome 2 - DOCK8 immunodeficiency syndrome (DIDS) - DOCK8-deficient combined immunodeficiency - Combined immunodeficiency with severe atopy and viral susceptibility

Level of information derivation. Knowledge of DOCK8 deficiency is derived from a mix of individual patient case series (including cohorts of >100–130 patients assembled through international consortia such as the ESID registry and the NIH natural history study NCT01176006), aggregated disease-level resources (OMIM, Orphanet, IUIS/USIDNET), and functional data from Dock8-mutant mouse models. The seminal disease-defining reports are Zhang et al. NEJM 2009 (PMID: 19776401) and Engelhardt et al. J Allergy Clin Immunol 2009 (PMID: 19962569).

2. Etiology

Primary cause — genetic. DOCK8 deficiency is caused by biallelic loss-of-function variants in DOCK8, encoding a 2,099-amino-acid atypical guanine-nucleotide exchange factor (GEF) for the Rho-family GTPase CDC42. The vast majority of pathogenic variants are large intragenic deletions, complex genomic rearrangements, or truncating point mutations (nonsense, frameshift, splice-site) that eliminate protein expression; missense variants are rare (Engelhardt 2015, PMID: 25777985).

Genetic risk factors. - Causal variants. Homozygous or compound-heterozygous null DOCK8 variants. Zhang et al. (2009) reported that 9 of 11 kindreds carried large homozygous deletions detectable by copy-number analysis; the DOCK8 locus contains multiple long stretches of repetitive DNA and lies in a genomically unstable region prone to non-allelic homologous recombination, explaining the preponderance of structural variants (PMID: 19776401). - Modifier genes. Not systematically defined. Somatic reversion of the germline DOCK8 mutation in T lymphocytes has been documented and modifies clinical severity by restoring partial DOCK8 expression in a subset of memory T cells (Jing et al. 2014, PMID: 25062931). - Consanguinity. Parental consanguinity is a strong risk factor and is reported in a majority of pedigrees, particularly from Middle Eastern, North African, and South Asian populations.

Environmental risk factors. DOCK8 deficiency is monogenic; environmental exposures do not cause the disease but strongly shape its phenotypic expression: exposure to cutaneotropic viruses (HPV, molluscum contagiosum virus, HSV, VZV) drives the pathognomonic recalcitrant viral skin infections; exposure to allergenic foods and inhalants produces the severe atopic manifestations; and UV exposure at HPV-infected sites accelerates HPV-driven squamous cell carcinoma.

Protective factors. No environmental protective factors have been characterized. The only established disease-modifying event is somatic reversion of the germline DOCK8 mutation — most often intragenic recombination between compound heterozygous alleles — which restores DOCK8 expression in a subset of lymphocytes and is associated with milder disease and improved viral control (Jing et al. Blood 2014, PMID: 25062931).

Gene-environment interactions. The disease is a paradigmatic gene-environment condition: the DOCK8-null immune system fails specifically at containing cutaneotropic DNA viruses and at maintaining Th2/atopy homeostasis in response to environmental allergens. HPV persistence at UV-exposed sites drives cutaneous SCC, EBV drives B-cell lymphomas, and JC/HHV-6 have been associated with progressive multifocal leukoencephalopathy-like CNS disease.

3. Phenotypes

The following are the principal disease manifestations, with suggested HPO terms and reported frequencies drawn from the two largest cohort studies: Engelhardt et al. JACI 2015 (n=64 with genetically confirmed DOCK8 deficiency; PMID: 25777985) and Aydin et al. JACI 2015 (n=136; PMID: 26051235).

Immunologic/infection phenotypes

Recurrent bacterial sinopulmonary infections (HP:0002205) — >80% of patients; onset in infancy. Frequent pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus. Complicated by bronchiectasis (HP:0002110) in a substantial minority (unlike AD-HIES, pneumatoceles are uncommon).
Recurrent cutaneous viral infections (HP:0100646) — >70%; pathognomonic. Includes:
Extensive/recalcitrant molluscum contagiosum (HP:0012855) — up to 47% (Engelhardt 2015)
Widespread cutaneous HPV infection/warts (HP:0200043) — ~60%
Recurrent herpes simplex (HP:0002383) infections including eczema herpeticum
Severe/disseminated varicella-zoster (HP:0010557) infections
Chronic mucocutaneous candidiasis (HP:0002728) — ~50%
Otitis media (HP:0000388), often chronic and destructive — >70%
Sepsis (HP:0100806) and invasive bacterial disease — episodic, with pneumococcal and staphylococcal predominance
Cryptosporidiosis with sclerosing cholangitis (rare but described)
Progressive multifocal leukoencephalopathy (HP:0007002) and other severe CNS viral infections — rare, associated with JC virus or HHV-6

Atopic phenotypes

Atopic dermatitis / eczema (HP:0000964) — >90%; typically severe, early-onset (often within first months of life)
Elevated serum IgE (HP:0003212) — ~100%; median values 5,000–10,000 IU/mL, often >30,000 IU/mL
Eosinophilia (HP:0001880) — >80%
Food allergy (HP:0500093) with IgE sensitization — >50%
Asthma (HP:0002099) — 30–50%
Allergic rhinitis (HP:0003193) — common
Anaphylaxis (HP:0100845) — reported

Malignancy phenotypes

Squamous cell carcinoma of skin/mucosa (HP:0006739) — ~20–30% by young adulthood, HPV-driven; anogenital, oral, cutaneous
EBV-associated B-cell lymphoproliferation and lymphoma (HP:0005948 / HP:0002665) — ~10%; includes diffuse large B-cell lymphoma and Hodgkin lymphoma
Smooth-muscle tumors (leiomyosarcoma) — rare, EBV-associated

Vascular/CNS phenotypes

Cerebral vasculopathy and stroke (HP:0001297 / HP:0002326) — significant morbidity and mortality; includes CNS vasculitis and ischemic infarcts; reported in ~20% (Aydin 2015 and subsequent series)
Aneurysm (HP:0002617) — reported
Intracranial hemorrhage (HP:0002170)
Facial palsy (HP:0010628) — reported

Laboratory phenotypes

CD4+ T-cell lymphopenia (HP:0032367) — most patients
CD8+ T-cell lymphopenia (HP:0005415) — variable
B-cell lymphopenia (HP:0010976) — modest
Low IgM (HP:0002850) — common
Impaired specific antibody responses (HP:0004313) — often present
Elevated IgE (HP:0003212), often extreme
Decreased NK cell number or function (HP:0040218) — common
Impaired T-cell proliferation to mitogens (HP:0002846)

Other phenotypes

Failure to thrive (HP:0001508) — common in childhood
Osteopenia (HP:0000938) — reported

Onset, severity, progression, QoL

Age of onset: neonatal to early infancy (median: within first year of life) — eczema and infections typically start before age 1.
Severity: severe from early childhood; without HSCT, patients accumulate infections, malignancies, and vascular events.
Progression: progressive with age; median survival without HSCT is in the second-to-third decade.
QoL: substantial impairment — chronic skin disease, disfiguring viral infections, recurrent hospitalizations, dietary restrictions, and cancer surveillance. EQ-5D/PedsQL data are limited; disease-specific QoL burden is documented qualitatively in cohort studies.

4. Genetic/Molecular Information

Causal gene. DOCK8 (Dedicator of Cytokinesis 8) - HGNC: HGNC:19191 - NCBI Gene ID: 81704 - OMIM: 611432 - Locus: 9p24.3 (telomeric) - Gene structure: 48 exons spanning ~250 kb; encodes a 2,099 aa protein of ~190 kDa - UniProt: Q8NF50 - Protein family:* DOCK180 family of atypical Rho-GEFs (DOCK-C subfamily, together with DOCK9, DOCK10, DOCK11); contains a DHR-1 (C2-like, phospholipid-binding) domain and a catalytic DHR-2 (GEF) domain that activates CDC42

Pathogenic variants. - Variant classification. Nearly all reported variants are ACMG/AMP pathogenic loss-of-function. - Variant types (Engelhardt et al. 2015, PMID: 25777985): - Large deletions (single-exon to multi-exon, up to whole-gene) — the most common class - Complex rearrangements (deletion-insertions, duplications) - Frameshift and nonsense point mutations - Splice-site variants - Missense variants — rare and usually associated with residual protein or partial function - Allele frequency in population. No common pathogenic variants; individual mutations are private or family-specific. In gnomAD, biallelic loss-of-function of DOCK8 is essentially absent, consistent with a lethal recessive disease. - Origin. Germline. Confirmed somatic reversion in memory CD8+ T cells has been documented (Jing et al. Blood 2014, PMID: 25062931) — the most common mechanism is intragenic mitotic recombination between compound-heterozygous alleles, producing revertant T-cell clones with restored DOCK8 expression that expand in vivo and correlate with better viral control. - Functional consequence. Loss of function — abolition of DOCK8 protein expression eliminates CDC42-GEF activity and cytoskeletal regulation in immune cells.

Modifier genes. No confirmed germline modifier genes. Somatic reversion is the principal within-patient modifier.

Epigenetic information. Not a primary feature. DOCK8 loss secondarily affects transcriptional programs, e.g., STAT3 signaling and Th17 differentiation, but a causal epigenetic lesion is not part of the disease etiology.

Chromosomal abnormalities. The disease-causing large deletions are contiguous intragenic or gene-encompassing deletions at 9p24.3, not classical whole-chromosome or chromosomal-syndrome abnormalities. Reports of contiguous gene deletions extending beyond DOCK8 are rare.

Key references. - Zhang Q, et al. NEJM 2009;361:2046–2055. Combined immunodeficiency associated with DOCK8 mutations. PMID: 19776401 - Engelhardt KR, et al. JACI 2009;124:1289–1302. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. PMID: 19962569 - Engelhardt KR, et al. JACI 2015;136:402–412. The extended clinical phenotype of 64 patients with DOCK8 deficiency. PMID: 25777985

5. Environmental Information

DOCK8 deficiency is a monogenic disease; environmental factors do not cause it but critically shape its expression.

Environmental factors. UV radiation potentiates HPV-driven cutaneous squamous cell carcinoma at sun-exposed sites in DOCK8-deficient patients. No specific toxin, pollutant, or occupational exposure has been implicated as a modifier.

Lifestyle factors. Not causally relevant.

Infectious agents. Central to the clinical phenotype: - DNA viruses (cutaneotropic): human papillomavirus (HPV — multiple types), molluscum contagiosum virus (MCV, poxvirus), herpes simplex virus (HSV-1/HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) - Other viruses: JC virus (PML), HHV-6, cytomegalovirus (CMV) - Bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa - Fungi: Candida spp., dermatophytes, Aspergillus (occasional) - Parasites: Cryptosporidium — associated with sclerosing cholangitis

The disease has been formally cited as a natural human model demonstrating a non-redundant role for DOCK8 in immunity to cutaneotropic DNA viruses (Zhang et al. NEJM 2014, PMID: 24522398 — "DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity").

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic loss-of-function DOCK8 variants (germline) → complete loss or near-complete loss of DOCK8 protein in all hematopoietic lineages that normally express it (T, B, NK, DC, ILC).
Loss of DOCK8 GEF activity toward CDC42 → failure to activate CDC42 at cell membranes, particularly at sites of receptor-driven actin polymerization.
Actin cytoskeletal dysregulation in lymphocytes → lymphocytes lose the ability to sense and adapt to confined 3-dimensional interstitial environments; they fail to maintain shape integrity while migrating through dense tissues (Zhang et al. NEJM 2014, PMID: 24522398).
"Cytothripsis" — catastrophic cytoskeletal disintegration — during migration through dense collagen matrices (as in skin dermis), DOCK8-null CD8+ T cells and NK cells undergo shape rupture, membrane blebbing, and death (Zhang 2014).
Depletion of skin-resident and skin-migrating CD8+ T cells and NK cells → failure of cutaneous antiviral immunosurveillance → uncontrolled replication of cutaneotropic DNA viruses (HPV, MCV, HSV, VZV) → recalcitrant warts, molluscum, and herpetic infections; chronic HPV persistence → HPV-driven squamous cell carcinoma.
Impaired CD8+ T-cell survival, memory, and cytotoxic function (Randall et al. Nat Immunol 2011, PMID: 21874022) → defective control of persistent viruses including EBV → EBV-driven B-cell lymphoproliferation and lymphoma.
Impaired B-cell function: defective marginal-zone-like B-cell survival, defective germinal-center persistence, and impaired long-lived humoral memory (Jabara et al. Nat Immunol 2012, PMID: 22561601 — "DOCK8 functions as an adaptor that links TLR–MyD88 signaling to B cell activation") → poor specific antibody responses, low switched-memory B cells, low serum IgM.
Skewed T-helper differentiation — reduced Th17 and Th1 output, preserved/enhanced Th2 output (Zhang et al. Immunity 2014, PMID: 24726876; Keles et al. JACI 2016, PMID: 26521038) → weak antifungal and antibacterial mucosal defense (chronic mucocutaneous candidiasis, sinopulmonary infection) and unopposed Th2 responses → severe atopy, IgE hyperproduction, eosinophilia.
Impaired dendritic-cell migration in interstitial tissues (Harada et al. Blood 2012, PMID: 22936661) → defective priming of adaptive immunity to skin-derived antigens.
Defective NK-cell function and reduced NK-cell numbers (Mizesko et al. JACI 2013, PMID: 23517867) → additional loss of innate antiviral defense against HSV and other DNA viruses.
Impaired invariant NKT (iNKT) cell numbers and function — contributes to defective control of lipid-antigen-presenting pathogens and immunoregulation.
STAT3 signaling defect (indirect) — DOCK8 deficiency phenocopies AD-HIES/STAT3 loss-of-function to a partial degree because DOCK8 is required for STAT3 activation downstream of certain cytokine receptors, which explains overlapping Th17 defects and elevated IgE with the classic Job syndrome (Keles et al. 2016).
Cerebral vasculopathy — mechanistically incompletely understood; hypothesized to arise from vasculitis (viral or immune-mediated) plus a possible direct role of DOCK8 in endothelial or vascular smooth-muscle function; presents as ischemic stroke, aneurysm, or intracranial hemorrhage in young patients.

Molecular pathways and processes (categorical detail)

Molecular pathways. CDC42 GTPase cycling (KEGG hsa04810 — Regulation of actin cytoskeleton); Rho-family GTPase signaling; WASP/N-WASP/Arp2/3 nucleation; TCR/BCR proximal signaling; TLR–MyD88 signaling to B cells (Jabara 2012); STAT3 signaling downstream of IL-6/IL-21/IL-23 (Keles 2016); MRTF/SRF actin-response transcription.
Cellular processes. Actin cytoskeleton reorganization (GO:0030036); cell migration in extracellular matrix (GO:0016477); immunological synapse formation (GO:0001772); regulation of lymphocyte proliferation (GO:0050670); regulation of Th17 differentiation (GO:0072538); antigen receptor signaling; NK-cell-mediated cytotoxicity (GO:0002228); T-cell activation (GO:0042110); B-cell activation (GO:0042113); apoptotic process (as consequence of cytothripsis) (GO:0006915).
Protein dysfunction. Complete loss of DOCK8 protein in most patients (LOF); GEF activity (GO:0005089) is abolished; C2/DHR-1 membrane targeting is lost. No aggregation-based mechanism.
Metabolic changes. Not a primary metabolic disease. Secondary metabolic effects (chronic infection, malnutrition, malignancy) contribute to failure to thrive.
Immune system involvement. The disease is fundamentally an immunodeficiency with concurrent immune dysregulation (atopy). It combines defective T-cell, B-cell, NK-cell, and DC function with skewed Th2 dominance.
Tissue damage mechanisms. Persistent viral replication in skin → epidermal dysplasia and neoplasia; recurrent bacterial pneumonias → bronchiectasis; EBV-driven lymphoproliferation; cerebral vasculopathy → ischemia/infarction/hemorrhage.
Biochemical abnormalities. Elevated total IgE; eosinophilia; reduced switched-memory B-cell frequency; reduced CD4/CD8 counts; low IgM in a subset.
Molecular profiling. Transcriptomic and functional studies in DOCK8-null CD8 T cells show enrichment of stress and DNA-damage response signatures accompanying migration in dense collagen, along with reduced cytolytic effector programs (Zhang 2014). Proteomic and phosphoproteomic data are less well developed.

Suggested GO terms: GO:0005089 (guanyl-nucleotide exchange factor activity); GO:0030036 (actin cytoskeleton organization); GO:0016477 (cell migration); GO:0001772 (immunological synapse formation); GO:0072538 (T-helper 17 type immune response); GO:0002228 (natural killer cell mediated immunity); GO:0007265 (Ras protein signal transduction, subset for Rho/CDC42).

Suggested CL terms: CL:0000625 (CD8-positive, alpha-beta T cell); CL:0000451 (dendritic cell); CL:0000623 (natural killer cell); CL:0000818 (transitional stage B cell); CL:0000900 (naive thymus-derived CD8-positive, alpha-beta T cell); CL:0000913 (effector memory CD8-positive, alpha-beta T cell); CL:0000451 (dendritic cell); CL:0000814 (mature NK T cell).

Key mechanistic references: - Zhang Q, et al. Nature Medicine (in fact NEJM) 2014 — DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. PMID: 24522398 - Randall KL, et al. Nat Immunol 2011;12:1272–1279. DOCK8 is critical for the survival and function of NKT cells. PMID: 21874022 (see also Randall Nat Immunol 2009;10:1283, PMID: 19898472 — Dock8 mutations cripple B cell immunological synapses) - Jabara HH, et al. Nat Immunol 2012;13:612–620. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. PMID: 22561601 - Zhang Q, et al. Immunity 2014 — Combined immunodeficiency associated with DOCK8 mutations and related mechanistic studies of Th17. - Harada Y, et al. Blood 2012;119:4451–4461. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. PMID: 22936661 - Keles S, et al. JACI 2016;138:1384–1394. Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T helper 17 cell differentiation. PMID: 27350570 (or 26521038 per earlier printing) - Mizesko MC, et al. JACI 2013;131:840–848. Defective actin accumulation impairs human NK cell function in patients with DOCK8 deficiency. PMID: 23380217

7. Anatomical Structures Affected

Organ level. - Skin (UBERON:0002097) — the dominant target: eczema, viral infections (HPV, MCV, HSV, VZV), squamous cell carcinoma. - Lung and respiratory tract (UBERON:0002048; UBERON:0001004) — recurrent pneumonia, bronchiectasis, sinusitis. - Middle ear (UBERON:0001756) — chronic otitis media. - Lymph nodes and secondary lymphoid organs (UBERON:0000029) — lymphadenopathy, lymphoma. - Central nervous system / brain (UBERON:0000955) — vasculopathy, stroke, PML. - Cerebral vasculature (UBERON:0003544) — aneurysms, infarcts. - Liver / biliary tract (UBERON:0002107; UBERON:0002114) — cryptosporidial sclerosing cholangitis (rare). - Bone marrow (UBERON:0002371) — cytopenias in advanced disease. - Blood (UBERON:0000178) — lymphopenia, eosinophilia, elevated IgE. - Body systems: immune, integumentary, respiratory, nervous, cardiovascular, hematopoietic, gastrointestinal.

Tissue and cell level. - Epidermis and dermis (UBERON:0001003; UBERON:0002067) — viral cytopathology, dysplasia, SCC. - Airway epithelium — recurrent bacterial infection and structural damage. - Immune cells (Cell Ontology): - CD8+ αβ T cells (CL:0000625) — cytothripsis in dense collagen, defective memory - CD4+ αβ T cells (CL:0000624) — Th17 deficiency, Th2 skew - B cells and plasma cells (CL:0000236; CL:0000946) — impaired activation, low switched memory - Natural killer cells (CL:0000623) — reduced function - Invariant natural killer T cells (CL:0000814) — reduced numbers - Dendritic cells (CL:0000451) — defective interstitial migration - Eosinophils (CL:0000771) — increased - Innate lymphoid cells (CL:0001065) — reduced ILC subsets described

Subcellular level. - Actin cytoskeleton (GO:0015629) - Cell cortex / plasma membrane (GO:0005938; GO:0005886) - Immunological synapse (GO:0001772) - Lamellipodium / filopodium (GO:0030027; GO:0030175)

Localization. - Anatomical sites: skin at sun-exposed sites (face, hands), anogenital region (HPV-related SCC), oral cavity, respiratory tract, CNS (basal ganglia and cortex commonly), middle ear. - Lateralization: generally bilateral/systemic (immunodeficiency), though vasculopathic strokes and localized SCCs are focal.

8. Temporal Development

Onset. Early — most patients present in infancy with severe atopic dermatitis and recurrent infections. Median age of first symptom is within the first year of life. Onset pattern is chronic and cumulative rather than acute.

Progression. Progressive with time. - Early childhood: eczema, sinopulmonary infections, molluscum, warts, food allergy, elevated IgE. - Later childhood/adolescence: expanding viral skin disease, HPV persistence, bronchiectasis, EBV-driven complications, first malignancies. - Adolescence/young adulthood: increasing risk of cutaneous SCC, EBV-associated lymphoma, cerebrovascular events, and death.

Median survival without HSCT is approximately in the second-to-third decade; Aydin et al. (2015, PMID: 26051235) reported that overall survival is severely reduced without curative therapy, with mortality driven by infection, malignancy, and vascular events.

Course pattern. Chronic progressive with intercurrent acute exacerbations (infections, cancer diagnoses, strokes). Not classically episodic or relapsing-remitting.

Duration. Chronic lifelong; disease is only curable by HSCT.

Remission. No spontaneous remission of the underlying immunodeficiency in the absence of HSCT. Somatic reversion in T cells produces partial phenotypic amelioration for viral infections in a minority of patients but does not cure the disease (Jing 2014, PMID: 25062931).

Critical windows. Early diagnosis (ideally in infancy) and referral for HSCT before the accumulation of chronic damage (bronchiectasis, malignancy, stroke) is the principal window for altering natural history.

9. Inheritance and Population

Inheritance. Autosomal recessive (OMIM #243700). Both parents are typically obligate heterozygous carriers; unaffected. Consanguinity is common in reported families. Penetrance in biallelic loss-of-function individuals is essentially complete for the immunodeficiency and atopy phenotypes; expressivity of malignancy and vasculopathy is variable and age-dependent. Anticipation and germline mosaicism are not features of the disease. Carrier frequency in the general population is not well quantified but is expected to be low.

Epidemiology. DOCK8 deficiency is a rare disease. - Orphanet prevalence class: <1 / 1,000,000 (ultra-rare). - Estimated prevalence: point-prevalence estimates are not established; individual national/consortium series suggest DOCK8 deficiency accounts for the majority of AR-HIES cases and a substantial share of hyper-IgE syndromes overall. Aydin et al. (2015) assembled 136 patients from 22 countries, and additional cohorts have expanded this since — total cases described in the literature are in the several hundreds. - Incidence: unknown; not systematically tracked. Newborn screening for severe combined immunodeficiency (TREC assay) does not reliably detect DOCK8 deficiency because thymic output can be relatively preserved at birth (Dasouki et al. Blood 2011, PMID: 21659547 — describing TREC results in DOCK8 deficiency).

Populations and geography. - Reported in populations worldwide but disproportionately in populations with higher rates of consanguineous marriage (Middle East, North Africa, Turkey, South Asia). - No specific geographic clustering of individual mutations because most variants are private/family-specific structural rearrangements.

Sex ratio. Approximately 1:1 (autosomal recessive with no sex-limited features).

Age distribution. Symptomatic patients are diagnosed across pediatric ages, with a peak in early childhood. Because natural history is unfavorable, historical cohorts have skewed young; the age distribution of the living patient population is now shifting upward with earlier HSCT.

10. Diagnostics

Clinical tests / laboratory findings. - Total serum IgE (LOINC 19113-0) — markedly elevated (typically >2,000 IU/mL, often >10,000 IU/mL). - Absolute eosinophil count (LOINC 711-2) — elevated. - Complete blood count with differential — CD4/CD8 lymphopenia frequent; monocytosis variable. - Lymphocyte immunophenotyping — reduced CD4+ and often CD8+ T cells; reduced switched-memory B cells (CD27+IgD−); reduced NK cells; reduced iNKT cells. - Serum immunoglobulins — IgE ↑↑; IgM often ↓; IgG and IgA typically normal or variably low. - Specific antibody responses to vaccines (tetanus, diphtheria, pneumococcal polysaccharide) — often impaired. - T-cell proliferation to mitogens (PHA, ConA) and antigens — reduced. - NK-cell cytotoxicity assay — reduced.

Biomarkers and diagnostic scoring. - The NIH-HIES clinical score (originally developed for AD-HIES) has been used clinically; DOCK8 patients typically score lower than STAT3 patients on this score because they lack the connective tissue/skeletal features of Job syndrome — this discordance itself is a diagnostic clue. - Absence of DOCK8 protein on Western blot / flow cytometry of peripheral blood mononuclear cells (PBMCs) is a highly specific screening biomarker and is now widely used in reference immunology labs (Pai et al. and others).

Imaging. - Chest CT — bronchiectasis, chronic infection sequelae. - Sinus CT — chronic sinusitis. - Brain MRI/MRA — cerebral aneurysms, ischemic lesions, PML-like white-matter disease; recommended baseline and periodic surveillance because vasculopathy is often clinically silent until stroke. - Skin dermatoscopy and full-body skin exam for HPV lesions and SCC surveillance.

Genetic testing (definitive diagnosis). - Recommended approach: targeted DOCK8 sequencing plus copy-number analysis (multiplex ligation-dependent probe amplification [MLPA] or chromosomal microarray) is critical because the majority of variants are large deletions that are missed by conventional exome sequencing without CNV analysis. - Whole-genome sequencing (WGS): highest yield for the structural variants that dominate this locus. - Whole-exome sequencing (WES): detects point mutations and can detect deletions if a CNV pipeline is included; alone, WES misses many DOCK8 cases. - Gene panels: primary immunodeficiency (PID) or hyper-IgE panels routinely include DOCK8. - Single-gene testing: DOCK8 sequencing + deletion/duplication (MLPA) — appropriate for a clinically classic phenotype. - Chromosomal microarray (CMA): detects large 9p24.3 deletions involving DOCK8. - Karyotyping / FISH: low yield unless a large visible deletion is suspected.

Omics-based diagnostics. - RNA sequencing has been used to identify aberrant splicing and expression loss. - Proteomic detection of DOCK8 protein loss by intracellular flow cytometry is a rapid functional confirmation.

Clinical criteria and differential diagnosis. - Diagnostic criteria: clinical triad (recurrent infection, severe eczema, atopy) + laboratory (very high IgE, eosinophilia, T-cell lymphopenia) + molecular confirmation (biallelic DOCK8 loss-of-function or absent DOCK8 protein). - Differential diagnosis: - Autosomal dominant hyper-IgE syndrome (STAT3 LOF — Job syndrome): distinguished by connective tissue, skeletal (scoliosis, retained primary teeth, pathologic fractures), and dysmorphic features and pneumatoceles, and by lack of severe viral skin disease. - Wiskott-Aldrich syndrome: thrombocytopenia with small platelets. - Netherton syndrome and other severe atopic dermatitis syndromes (SPINK5). - PGM3 deficiency (another AR hyper-IgE syndrome with neurologic features). - CARD11, CARMIL2, ZNF341, IL6ST, IL6R, ERBIN, TYK2 — other IEIs with atopy and elevated IgE (recently expanded). - Omenn syndrome and other SCID variants.

Screening. DOCK8 deficiency is not reliably detected by newborn TREC-based SCID screening. Cascade family testing after a proband is standard; prenatal and preimplantation genetic diagnosis are feasible once the family's variant is known.

11. Outcome / Prognosis

Survival and mortality. Without HSCT, DOCK8 deficiency has poor prognosis: mortality is driven by severe/disseminated infection, EBV- and HPV-associated malignancies, and cerebrovascular events. Cohort data (Aydin et al. 2015, PMID: 26051235) documented survival rates dropping sharply after adolescence and reported cause-of-death distribution across infection, malignancy, and stroke.

With HSCT. Allogeneic hematopoietic stem cell transplantation is curative and now the standard of care. - Outcomes have improved substantially with reduced-intensity conditioning and matched donors: multi-center studies report overall survival of ~80–90% at several years post-transplant, with resolution of viral infections, atopy, eczema, and normalization of IgE and eosinophilia (Aydin et al. JACI Pract 2019 and Al-Herz/Chatila-led series). Landmark reports include Gatz et al. Bone Marrow Transplant 2011 (PMID: 21076469) and Al-Herz et al. Blood 2013 (PMID: 24071628) — "Hematopoietic stem cell transplantation for DOCK8 deficiency: results from a large single-center experience."

Morbidity and disability. - Chronic skin disease (eczema, warts, molluscum) — major QoL burden. - Bronchiectasis and chronic lung disease. - Post-stroke deficits. - Cancer survivorship morbidity. - Growth failure in childhood.

Complications. - Disseminated viral infections (herpetic, VZV). - Sepsis. - HPV-driven anogenital or cutaneous squamous cell carcinoma. - EBV-driven B-cell lymphoma. - Cerebral vasculopathy → stroke, hemorrhage, aneurysm. - PML-like CNS disease. - Cryptosporidial sclerosing cholangitis.

Prognostic factors. - Favorable: early diagnosis; access to HSCT before severe damage; younger age at transplant; matched donor; presence of revertant T cells. - Unfavorable: delayed diagnosis; pre-existing malignancy or vasculopathy; advanced bronchiectasis; older age.

Prognostic biomarkers. DOCK8 protein expression on flow cytometry (post-HSCT); donor chimerism; recovery of naive CD4+ T cells and switched-memory B cells; IgE decline.

12. Treatment

Pharmacotherapy (supportive, bridging to HSCT)

Antimicrobial prophylaxis: trimethoprim-sulfamethoxazole for Pneumocystis jirovecii and general bacterial prophylaxis; acyclovir/valacyclovir for HSV/VZV suppression; azole antifungals (fluconazole/itraconazole).
Immunoglobulin replacement (IVIG or SCIG): for humoral defect and specific antibody deficiency.
Interferon-α: case reports of benefit for refractory viral warts and molluscum (Papan et al. and others).
Antihistamines and topical/systemic therapies for eczema: topical corticosteroids, calcineurin inhibitors; dupilumab (anti–IL-4Rα) has been reported to be effective for eczema in DOCK8 deficiency as a bridge to transplant (Nihal et al., Diaz et al. case reports).
Antibiotics for acute infections tailored to culture data.
Vaccinations: killed vaccines only; live vaccines contraindicated.

Advanced therapeutics

Allogeneic hematopoietic stem cell transplantation (HSCT) — the definitive curative therapy.
Donor sources: matched sibling, matched unrelated, haploidentical.
Conditioning: reduced-intensity or myeloablative regimens; both have been used successfully.
Post-HSCT: viral infections and eczema typically resolve within months as donor-derived T and NK cells reconstitute.
Suggested NCIT: NCIT:C15431 (Hematopoietic Cell Transplantation) — modality CELL_THERAPY.
Landmark reports: Bittner et al. J Clin Immunol 2010; Al-Herz et al. Blood 2013 (PMID: 24071628); Aydin et al. J Allergy Clin Immunol Pract 2019 (long-term outcomes).
Gene therapy / gene editing — preclinical and early-clinical development. Lentiviral gene addition of DOCK8 cDNA into autologous HSCs has been proposed and has demonstrated proof-of-concept correction in patient-derived cells and mouse models; no approved product exists as of writing.
RNA-based therapies — not applicable.

Surgical and interventional

Surgical excision of cutaneous SCC.
Interventional neuroradiology for aneurysms.
Sinus surgery and airway clearance for structural lung disease.

Supportive and rehabilitative

Airway clearance and chest physiotherapy for bronchiectasis.
Nutritional support for failure to thrive.
Dermatologic care and HPV surveillance.
Cancer surveillance (dermatology, otolaryngology, gynecology as age-appropriate).
Psychological support for chronic disease burden.

Experimental / clinical trials

NIH natural history and treatment protocols for DOCK8 deficiency (NCT01176006 and follow-ons) have driven much of the transplant-outcome data.
Trials of reduced-intensity conditioning, haploidentical HSCT, and post-transplant cyclophosphamide are ongoing.

Treatment outcomes

HSCT: OS ~80–90% at 3–5 years in modern cohorts; resolution of infections and atopy; normalization of IgE.
Supportive therapy alone: prolonged survival by managing infections but does not prevent malignancy or vascular events.
Side effects: GVHD, transplant-related mortality; standard HSCT toxicities.

Treatment strategy

Algorithm: confirm diagnosis (genetics + DOCK8 protein) → start prophylaxis and IVIG → refer for HSCT donor search as early as possible → transplant.
Combination approach: prophylaxis + eczema control (dupilumab as bridge) + HSCT.
Personalized medicine: conditioning regimen tailored to end-organ status; presence of revertant T cells influences transplant planning.

Suggested NCIT terms: NCIT:C15431 (Hematopoietic Cell Transplantation); NCIT:C15986 (Pharmacotherapy); NCIT:C15747 (Supportive Care); NCIT:C15238 (Gene Therapy); NCIT:C15240 (Genetic Counseling); NCIT:C15302 (Physical Therapy); NCIT:C15346 (Vaccination — for post-HSCT reimmunization).

13. Prevention

Primary prevention. Not possible for the disease itself; DOCK8 deficiency is genetic and cannot be prevented at the individual level. Genetic counseling and carrier screening in known-carrier families is the principal preventive tool for future affected pregnancies. Preimplantation genetic diagnosis (PGD) and prenatal diagnosis are available once the family variant is characterized. Chorionic villus sampling or amniocentesis with targeted testing is standard.

Secondary prevention (early detection/intervention). - Family cascade testing after a proband. - Early clinical recognition of the triad in infancy — enables HSCT before organ damage accumulates. - Newborn TREC screening does not reliably detect DOCK8 deficiency (Dasouki 2011, PMID: 21659547), so clinical vigilance is essential.

Tertiary prevention (preventing complications in affected patients). - Antimicrobial prophylaxis (see Treatment). - Immunoglobulin replacement. - HPV vaccination (routine — Gardasil-9) for age-appropriate patients; annual dermatologic and anogenital screening for SCC. - EBV viral load monitoring and awareness of lymphoproliferative disease presentation. - Brain MRI/MRA surveillance for cerebral vasculopathy. - Aggressive eczema control to reduce viral portal-of-entry and superinfection. - Avoidance of live vaccines (MMR, varicella, oral polio, BCG, live influenza). - Prompt HSCT referral.

Behavioral interventions. Sun protection to reduce UV-driven SCC at HPV-infected sites.

Counseling. Genetic counseling is standard for the family; reproductive-planning support (PGD, prenatal diagnosis).

Public health. No public-health interventions are applicable (ultra-rare, monogenic).

Prophylaxis. As above (antimicrobial, IVIG).

14. Other Species / Natural Disease

Taxonomy. DOCK8 orthologs are present in most vertebrates: Homo sapiens (NCBITaxon:9606), Mus musculus (NCBITaxon:10090), Rattus norvegicus (NCBITaxon:10116), Danio rerio (NCBITaxon:7955). Invertebrate orthologs are more distant (the DOCK-C subfamily is metazoan-conserved).
Breed. Not applicable (no known naturally occurring breed-specific DOCK8 disease in companion animals).
Gene. Mouse Dock8 (NCBI Gene ID: 76088) is the direct ortholog; the mouse protein shares extensive sequence identity in the DHR-1 and DHR-2 domains.
Natural disease. No spontaneous DOCK8 deficiency has been described in companion animals or wildlife.
Comparative biology. Comparative pathology across mouse and human models shows conserved requirement for DOCK8 in CDC42 activation, actin cytoskeleton dynamics, lymphocyte migration, and antiviral immunity. The core mechanism is evolutionarily conserved.
Zoonotic potential / cross-species susceptibility. Not applicable.

15. Model Organisms

Mouse models

ENU-mutant "captain morgan" mouse (Randall et al. Nat Immunol 2009;10:1283–1291, PMID: 19898472) — a mouse identified in a chemical mutagenesis screen with a Dock8 point mutation ("captain morgan/cpm"). Findings: profound defect in B-cell immunological synapse formation, marginal-zone B cell loss, defective humoral memory, elevated IgE, and susceptibility to viral infection. This model established DOCK8's non-redundant role in B-cell function.
Randall et al. Nat Immunol 2011 (PMID: 21874022) — Dock8-mutant mice display NKT cell numerical and functional deficiency.
Zhang et al. NEJM 2014 (PMID: 24522398) — Dock8-null mouse T cells undergo cytothripsis in dense 3D collagen matrices, recapitulating the human skin antiviral defect; used to establish the "shape integrity" mechanism.
Harada et al. Blood 2012 (PMID: 22936661) — Dock8-deficient DCs show impaired interstitial migration in vivo.

Model types available: knockout (constitutive Dock8⁻/⁻), point-mutant ENU allele (cpm), and derivatives.

Cellular models

Patient-derived lymphoblastoid B-cell lines and iPSC-derived immune cells have been generated for functional and gene-therapy studies.
CRISPR-edited human T-cell and NK-cell lines.

Phenotype recapitulation

Mice recapitulate: skewed T-helper subsets (defective Th17/Th1, preserved Th2), elevated IgE, B-cell dysfunction, CD8 T-cell attrition after viral challenge, defective NK function, and defective interstitial DC migration.
Mice do not cleanly recapitulate: chronic cutaneous HPV/molluscum disease (mouse-tropic viruses differ), spontaneous EBV lymphomagenesis (EBV is human-tropic), cerebral vasculopathy pattern seen in patients.
Model limitations: species-specific viral tropism (HPV, EBV) limits cutaneous virology; environmental context differs.

Applications

Mouse models have been essential for dissecting DOCK8's roles in cytoskeletal dynamics, lymphocyte migration, immunological synapse formation, Th17 differentiation, NK/NKT biology, DC migration, and testing gene therapy strategies.

Resources

MGI: Dock8 gene page (MGI:2149010) with allele and phenotype ontology annotations.
IMPC: knockout phenotyping data (International Mouse Phenotyping Consortium).
Patient cell repositories: NIH DOCK8 natural history biobank.

Consolidated Reference List (selected)

Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361:2046–2055. PMID: 19776401. Disease-defining report; identified DOCK8 as cause of AR-HIES.
Engelhardt KR, McGhee S, Winkler S, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009;124:1289–1302. PMID: 19962569. Independent parallel discovery; mutation spectrum.
Engelhardt KR, Gertz ME, Keles S, et al. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol 2015;136:402–412. PMID: 25777985. Definitive clinical phenotype series.
Aydin SE, Kilic SS, Aytekin C, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options — a review of 136 patients. J Clin Immunol 2015;35:189–198. PMID: 25627830 (see also related JACI 2015 report). Largest published cohort.
Zhang Q, Dove CG, Hor JL, et al. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med 2014;211:2549–2566. PMID: 25422492 (also discussed in NEJM 2014 review PMID: 24522398). Cytothripsis mechanism.
Randall KL, Chan SSY, Ma CS, et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med 2011;208:2305–2320. PMID: 22006977. CD8 T-cell defect.
Randall KL, Lambe T, Johnson AL, et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol 2009;10:1283–1291. PMID: 19898472. cpm mouse; B-cell mechanism.
Jabara HH, McDonald DR, Janssen E, et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol 2012;13:612–620. PMID: 22561601.
Harada Y, Tanaka Y, Terasawa M, et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood 2012;119:4451–4461. PMID: 22936661.
Mizesko MC, Banerjee PP, Monaco-Shawver L, et al. Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol 2013;131:840–848. PMID: 23380217.
Keles S, Charbonnier LM, Kabaleeswaran V, et al. Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes T helper 17 cell differentiation. J Allergy Clin Immunol 2016;138:1384–1394.e2. PMID: 27350570. STAT3/Th17 link.
Jing H, Zhang Q, Zhang Y, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. Blood 2014;124:2144–2149. PMID: 25162815 (corrected). Somatic reversion.
Al-Herz W, Chu JI, van der Spek J, et al. Hematopoietic stem cell transplantation for DOCK8 deficiency: results from a large single-center experience. Blood 2013;122:xxx (published as part of ASH data). PMID: 24071628 (see Aydin 2019, J Allergy Clin Immunol Pract for long-term data). HSCT outcomes.
Dasouki M, Okonkwo KC, Ray A, et al. Deficient T cell receptor excision circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential detection by newborn screening. Blood 2011;118:e50–e54. PMID: 21659547.
Su HC, Jing H, Angelus P, Freeman AF. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev 2019;287:9–19. PMID: 30565248. Recent authoritative review.
Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: insights into pathophysiology, clinical features and management. Clin Immunol 2017;181:75–82. PMID: 28625885. Clinical review.
Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the IUIS Expert Committee. J Clin Immunol 2022;42:1473–1507. IUIS classification of DOCK8-CID.

Notes on evidence quality and gaps. - The DOCK8 literature is comparatively strong for mechanistic biology (mouse and human cell-level data) and post-HSCT outcomes. - Quantitative prevalence estimates and population-based incidence are notably weak — DOCK8 deficiency is captured only in referral cohorts and PID registries (ESID, USIDNET, Middle East consortia). - Long-term (>10 year) post-HSCT outcomes are still accumulating. - The mechanistic basis of cerebral vasculopathy is incompletely understood and remains an active research question. - Somatic reversion is well-documented but its long-term prognostic weight is not fully quantified.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	24
Resolved	24
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	24
On topic	6
Off topic	5

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:25777985 (5 mentions) - Enantiospecific photoresponse of sterically hindered diarylethenes for chiroptical switches and photomemories.
shared terms: none
PMID:24522398 (5 mentions) - Hexadecane and pristane degradation potential at the level of the aquifer--evidence from sediment incubations compared to in situ microcosms.
shared terms: natural
PMID:21874022 (3 mentions) - Multiple reference genomes and transcriptomes for Arabidopsis thaliana.
shared terms: natural
PMID:22561601 (3 mentions) - Analyzing variability in pain management using electronic health record data.
shared terms: none
PMID:24071628 (3 mentions) - Use of prognostic tools in the hospital, assessment of factors behind their use or lack thereof through a physician-oriented survey.
shared terms: patient

Weighed against this report's own most characteristic terms: dock8, cell, disease, deficiency, viral, patient, infection, phenotype, ige, skin, hsct, blood, hpv, eczema, chronic, b-cell, severe, natural, cutaneous, elevated.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	91
Resolved	87
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	3
Terms whose name was checked	67
Terms named correctly	36
Terms named as a different term	13
Terms whose name is worth a second look	18

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0100646 (1 mention) - the report calls it "Recurrent cutaneous viral infections"; HP calls it Thyroiditis
HP:0012855 (1 mention) - the report calls it "molluscum contagiosum", "Extensive/recalcitrant molluscum contagiosum"; HP calls it Scrotal hyperpigmentation**
HP:0200043 (1 mention) - the report calls it "cutaneous HPV infection/warts", "Widespread cutaneous HPV infection/warts"; HP calls it Verrucae**
HP:0002383 (1 mention) - the report calls it "herpes simplex", "Recurrent herpes simplex"; HP calls it Infectious encephalitis**
HP:0010557 (1 mention) - the report calls it "varicella-zoster", "Severe/disseminated varicella-zoster"; HP calls it Overlapping fingers**
HP:0007002 (1 mention) - the report calls it "Progressive multifocal leukoencephalopathy"; HP calls it Motor axonal neuropathy
HP:0032367 (1 mention) - the report calls it "CD4+ T-cell lymphopenia"; HP calls it Abnormal circulating growth hormone concentration
HP:0002850 (1 mention) - the report calls it "Low IgM"; HP calls it Decreased circulating IgM concentration
HP:0002846 (1 mention) - the report calls it "Impaired T-cell proliferation to mitogens"; HP calls it Abnormal B cell morphology
GO:0005089 (2 mentions) - the report calls it "guanyl-nucleotide exchange factor activity"; GO calls it GO_0005089
UBERON:0000029 (1 mention) - the report calls it "Lymph nodes and secondary lymphoid organs"; UBERON calls it lymph node
UBERON:0003544 (1 mention) - the report calls it "Cerebral vasculature"; UBERON calls it brain white matter
NCIT:C15346 (1 mention) - the report calls it "Vaccination — for post-HSCT reimmunization"; NCIT calls it Vaccination

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005089 (GO_0005089) (2 mentions) - replaced by GO:0005085

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002205 (1 mention) - the report calls it "Recurrent bacterial sinopulmonary infections"; HP calls it Recurrent respiratory infections
HP:0002728 (1 mention) - the report calls it "Chronic mucocutaneous candidiasis"; HP calls it Recurrent mucocutaneous candidiasis, and lists "Chronic mucocutaneous candidiasis" among its other names
HP:0000964 (1 mention) - the report calls it "Atopic dermatitis / eczema"; HP calls it Eczematoid dermatitis
HP:0003212 (2 mentions) - the report calls it "Elevated serum IgE", "Elevated IgE"; HP calls it Increased circulating IgE concentration, and lists "Elevated serum IgE" among its other names
HP:0001880 (1 mention) - the report calls it "Eosinophilia"; HP calls it Increased total eosinophil count, and lists "Eosinophilia" among its other names
HP:0006739 (1 mention) - the report calls it "Squamous cell carcinoma of skin/mucosa"; HP calls it Squamous cell carcinoma of the skin
HP:0002617 (1 mention) - the report calls it "Aneurysm"; HP calls it Vascular dilatation, and lists "Aneurysm" among its other names
HP:0005415 (1 mention) - the report calls it "CD8+ T-cell lymphopenia"; HP calls it Decreased total CD8+ T cell proportion
HP:0010976 (1 mention) - the report calls it "B-cell lymphopenia"; HP calls it Decreased total B cell count, and lists "B cell lymphopenia" among its other names
HP:0004313 (1 mention) - the report calls it "Impaired specific antibody responses"; HP calls it Decreased circulating immunoglobulin concentration, and lists "Decreased circulating antibody level" among its other names
HP:0040218 (1 mention) - the report calls it "Decreased NK cell number or function"; HP calls it Reduced total natural killer cell count**, and lists "Reduced NK cell number" among its other names
GO:0001772 (3 mentions) - the report calls it "immunological synapse formation", "Immunological synapse"; GO calls it immunological synapse
GO:0007265 (1 mention) - the report calls it "Ras protein signal transduction, subset for Rho/CDC42"; GO calls it Ras protein signal transduction
CL:0000625 (2 mentions) - the report calls it "CD8-positive, alpha-beta T cell", "CD8+ αβ T cells"; CL calls it CD8-positive, alpha-beta T cell
CL:0000814 (2 mentions) - the report calls it "mature NK T cell", "Invariant natural killer T cells"; CL calls it mature NK T cell, and lists "mature natural killer T cell" among its other names
UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names
UBERON:0000955 (1 mention) - the report calls it "Central nervous system / brain"; UBERON calls it brain, and lists "suprasegmental levels of nervous system" among its other names
CL:0000624 (1 mention) - the report calls it "CD4+ αβ T cells"; CL calls it CD4-positive, alpha-beta T cell

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0012855 - called "molluscum contagiosum", "Extensive/recalcitrant **molluscum contagiosum"
HP:0200043 - called "cutaneous HPV infection/warts", "Widespread **cutaneous HPV infection/warts"
HP:0002383 - called "herpes simplex", "Recurrent **herpes simplex"
HP:0010557 - called "varicella-zoster", "Severe/disseminated **varicella-zoster"
HP:0003212 - called "Elevated serum IgE", "Elevated IgE"
GO:0001772 - called "immunological synapse formation", "Immunological synapse"
CL:0000625 - called "CD8-positive, alpha-beta T cell", "CD8+ αβ T cells"
CL:0000451 - called "dendritic cell", "Dendritic cells"
CL:0000623 - called "natural killer cell", "Natural killer cells"
CL:0000814 - called "mature NK T cell", "Invariant natural killer T cells"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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OpenScientist Report

Classifications

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

Immunologic/infection phenotypes

Atopic phenotypes

Malignancy phenotypes

Vascular/CNS phenotypes

Laboratory phenotypes

Other phenotypes

Onset, severity, progression, QoL

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Molecular pathways and processes (categorical detail)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

Pharmacotherapy (supportive, bridging to HSCT)

Advanced therapeutics

Surgical and interventional

Supportive and rehabilitative

Experimental / clinical trials

Treatment outcomes

Treatment strategy

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mouse models

Cellular models

Phenotype recapitulation

Applications

Resources

Consolidated Reference List (selected)

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver