Combined Immunodeficiency Due To DOCK8 Deficiency

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

1. 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).
2. Loss of DOCK8 GEF activity toward CDC42 → failure to activate CDC42 at cell membranes, particularly at sites of receptor-driven actin polymerization.
3. 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).
4. "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).
5. 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.
6. 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.
7. 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.
8. 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.
9. Impaired dendritic-cell migration in interstitial tissues (Harada et al. Blood 2012, PMID: 22936661) → defective priming of adaptive immunity to skin-derived antigens.
10. 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.
11. Impaired invariant NKT (iNKT) cell numbers and function — contributes to defective control of lipid-antigen-presenting pathogens and immunoregulation.
12. 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).
13. 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)

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.

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.

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.