OTULIN-Related Autoinflammatory Syndrome

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

ORAS is caused by biallelic (homozygous or compound heterozygous) hypomorphic loss-of-function OTULIN variants, reported in consanguineous and unrelated families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients."

Documents biallelic OTULIN mutations across three families with four affected patients.

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Pathophysiology

6

OTULIN Loss-of-Function Variant

Biallelic hypomorphic variants in OTULIN (FAM105B) reduce the activity of this M1-linked-specific deubiquitinase.

OTULIN hgnc:25118

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

cysteine-type deubiquitinase activity GO:0004843 ↓ DECREASED

Downstream

Impaired Linear Deubiquitination

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity"

Establishes loss-of-function OTULIN variants, in a linear-linkage deubiquitinase, as the cause.

Impaired Linear Deubiquitination

OTULIN normally removes M1 (linear)-linked polyubiquitin assembled by LUBAC. Reduced activity leaves a defect in linear deubiquitination and accumulation of linear ubiquitin aggregates.

protein deubiquitination GO:0016579 ↓ DECREASED

Downstream

Increased Canonical NF-kB Signaling

Fibroblast LUBAC Degradation and Reduced TNF Signaling

Sensitisation to TNF-Induced Cell Death

Show evidence (1 reference)

PMID:27559085 SUPPORT In vitro / ex vivo

"showed a substantial defect in the linear deubiquitination of target molecules"

Documents the core molecular defect: impaired linear deubiquitination.

Increased Canonical NF-kB Signaling

Accumulated linear ubiquitin drives increased signaling in the canonical NF-kappaB pathway, raising proinflammatory cytokine production.

monocyte CL:0000576

positive regulation of canonical NF-kappaB signal transduction GO:0043123 ↑ INCREASED

Animal models

Myeloid-specific Otulin knockout mouse (LysM-Cre) Mouse recapitulates Myeloid Otulin deletion reproduces the M1-Ub accumulation and spontaneous NF-kappaB activation of the human myeloid arm.

Downstream

Systemic Autoinflammation

Show evidence (1 reference)

PMID:27559085 SUPPORT In vitro / ex vivo

"showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates"

Links the deubiquitination defect to increased canonical NF-kappaB signaling and linear ubiquitin accumulation.

Fibroblast LUBAC Degradation and Reduced TNF Signaling

In OTULIN-deficient fibroblasts LUBAC is degraded and its recruitment to the TNF receptor signaling complex falls, so the fibroblast TNF-mediated signaling response is reduced rather than increased. This cell-type-specific LUBAC degradation is the defining result of Damgaard et al. 2019 and is the mirror image of the increased NF-kappaB seen in monocytes.

fibroblast CL:0000057

tumor necrosis factor-mediated signaling pathway GO:0033209 ↓ DECREASED

Downstream

Sensitisation to TNF-Induced Cell Death

Show evidence (1 reference)

PMID:30804083 SUPPORT In vitro / ex vivo

"LUBAC recruitment and M1-linked Ub conjugation at the TNF-RSC are reduced, accompanied by impaired TNF signalling, decreased IL-8 secretion and sensitisation to TNF-induced cell death in the presence of CHX"

Documents reduced LUBAC recruitment and impaired (not increased) TNF signalling in patient fibroblasts, correcting the direction of the fibroblast TNF response.

Sensitisation to TNF-Induced Cell Death

Both patient fibroblasts and OTULIN-deficient monocytes are sensitised to TNF-induced death, and apoptotic cells are present in patient skin lesions, contributing to the panniculitis and tissue inflammation.

fibroblast CL:0000057 monocyte CL:0000576

apoptotic process GO:0006915 ↑ INCREASED

Downstream

Systemic Autoinflammation

Show evidence (1 reference)

PMID:30804083 SUPPORT In vitro / ex vivo

"both patient-derived fibroblasts and OTULIN-deficient monocytes are sensitised to certain types of TNF-induced death, and apoptotic cells are evident in ORAS patient skin lesions"

Documents TNF-induced death sensitisation in both cell types and apoptosis in patient skin, the cell-death arm of the disease.

Systemic Autoinflammation

Excess NF-kappaB-driven cytokines and TNF-induced cell death produce a neonatal-onset systemic autoinflammatory illness with skin, gastrointestinal, and constitutional features.

Downstream

Recurrent fever

Panniculitis

Failure to thrive

Diarrhea

Arthritis

Sterile skin abscess

Lipodystrophy

Leukocytosis

Elevated C-reactive protein

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency."

Summarises the neonatal-onset systemic autoinflammatory presentation.

⬡

Pathograph

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Phenotypes

9

Blood 1

Leukocytosis VERY_FREQUENT Increased total leukocyte count HP:0001974

Show evidence (1 reference)

PMID:40734169 SUPPORT Human clinical

"leukocytosis, thrombocytosis, and increased inflammatory markers"

Leukocytosis is among the near-universal laboratory findings of ORAS (11/11 in the pooled series).

Digestive 1

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:30804083 SUPPORT Human clinical

"haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea"

Documents diarrhoea among the inflammatory symptoms of ORAS.

Immune 2

Panniculitis VERY_FREQUENT HP:0012490

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency."

Documents neutrophilic dermatitis/panniculitis as the characteristic skin lesion.

Sterile skin abscess FREQUENT Cutaneous abscess HP:0031292

Show evidence (1 reference)

PMID:40734169 SUPPORT Human clinical

"diffuse sterile abscesses (skin, spleen, and lung)"

Diffuse sterile abscesses, including cutaneous, are a consistent ORAS feature (skin abscess 6/13 in the pooled table).

Metabolism 2

Recurrent fever VERY_FREQUENT HP:0001954

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency."

Documents neonatal-onset fever as a presenting feature.

Elevated C-reactive protein VERY_FREQUENT Elevated circulating C-reactive protein concentration HP:0011227

Show evidence (1 reference)

PMID:40734169 SUPPORT Human clinical

"Elevated inflammatory markers | 11 (100)"

Pooled case series and literature review: elevated inflammatory markers in 11/11 (100%).

Musculoskeletal 2

Arthritis FREQUENT HP:0001369

Show evidence (1 reference)

PMID:30804083 SUPPORT Human clinical

"panniculitis, arthritis and diarrhoea, showing that haematopoietic cells are crucial for manifestation of the disease"

Lists arthritis among the inflammatory manifestations of ORAS.

Lipodystrophy FREQUENT HP:0009125

Show evidence (1 reference)

PMID:40734169 SUPPORT Human clinical

"lipodystrophy, which are considered as the most observed features in reported literature"

Lipodystrophy is among the most frequently observed features of ORAS (≈45% in the pooled series).

Growth 1

Failure to thrive VERY_FREQUENT HP:0001508

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency."

Documents failure to thrive as a presenting feature.

🧬

Genetic Associations

1

OTULIN variants

Gene: OTULIN hgnc:25118 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27559085 SUPPORT Human clinical

"We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients."

Documents the missense and frameshift OTULIN variant classes across three families.

💊

Medical Actions

3

TNF Inhibitor Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: infliximab NCIT:C1789 adalimumab NCIT:C65216 etanercept NCIT:C2381

Because ORAS is driven by dysregulated TNF signaling and TNF-induced cell death, TNF inhibition is mechanistically rational and ameliorates inflammation in patients. Agents used include the monoclonal antibodies infliximab and adalimumab and the receptor-fusion protein etanercept; because the class spans both antibody and fusion-protein platforms, no single therapeutic_modality value is asserted.

Mechanism Target:

Sensitisation to TNF-Induced Cell Death — Neutralizing TNF interrupts the TNF signaling and TNF-induced death that drive ORAS inflammation.

Show evidence (1 reference)

PMID:30804083 SUPPORT Human clinical

"Treatment with TNF inhibitors such as antibodies (e.g. infliximab) or TNF blockers (e.g. etanercept) effectively ameliorates inflammation, but there is currently no cure for ORAS."

Documents that TNF inhibitors ameliorate ORAS inflammation, the target of this therapy.

Show evidence (1 reference)

PMID:30804083 SUPPORT Human clinical

"Treatment with TNF inhibitors such as antibodies (e.g. infliximab) or TNF blockers (e.g. etanercept) effectively ameliorates inflammation, but there is currently no cure for ORAS."

Direct evidence that TNF inhibition ameliorates inflammation in ORAS.

IL-1 Blockade (anakinra)

Action: Pharmacotherapy NCIT:C15986

Agent: anakinra NCIT:C38717

IL-1 blockade was tried but, unlike TNF inhibition, did not improve symptoms in a reported patient, consistent with TNF rather than IL-1 as the dominant driver.

Show evidence (1 reference)

PMID:30804083 REFUTE Human clinical

"anakinra was added to the treatment regimen without any improvement of her symptoms"

Refutes efficacy of IL-1 blockade: the patient did not improve on anakinra.

Hematopoietic Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Allogeneic haematopoietic stem cell transplantation produced complete resolution of inflammation in a transplanted patient, demonstrating that haematopoietic cells drive the clinical disease. The disease relapsed nine months later as donor chimerism fell, so HSCT is potentially curative rather than an established cure.

Mechanism Target:

Systemic Autoinflammation — Replacing the patient's haematopoietic compartment removes the OTULIN-deficient inflammatory cells that drive disease.

Show evidence (1 reference)

PMID:30804083 SUPPORT Human clinical

"haematopoietic cells are necessary for clinical manifestation of ORAS"

Establishes the haematopoietic compartment as the driver that transplant replaces.

Show evidence (2 references)

PMID:30804083 SUPPORT Human clinical

"haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea"

Documents complete resolution of ORAS inflammation immediately after transplant.

PMID:30804083 SUPPORT Human clinical

"relapsed with fevers, panniculitis and arthritis, albeit with less severe symptoms than before the transplantation"

Documents post-transplant relapse at nine months as donor chimerism fell, so the result is not an established cure.

🔬

Diagnosis

1

Molecular and inflammatory-marker diagnosis

Diagnosis rests on identifying biallelic OTULIN variants by gene or exome sequencing together with laboratory evidence of systemic inflammation (leukocytosis and elevated CRP/ESR).

Show evidence (2 references)

PMID:40734169 SUPPORT Human clinical

"leukocytosis, and high inflammatory markers"

Laboratory inflammation (leukocytosis, high inflammatory markers) accompanies the molecular diagnosis.

PMID:40734169 SUPPORT Human clinical

"Whole-exome sequencing (WES) revealed a novel homozygous pathogenic mutation in the OTULIN gene"

Molecular diagnosis is by sequencing (whole-exome) identifying the biallelic OTULIN variant.

📊

Prevalence

1

Reported ORAS case series and literature

Cases/families reported in the literature Ultra-rare

ORAS is ultra-rare; a 2025 pooled case series and literature review totalled 13 reported patients. That total includes heterozygous dominant-negative (p.C129S) cases, a distinct form from the autosomal-recessive disease this entry scopes; see the entry-level note.

Show evidence (1 reference)

PMID:40734169 SUPPORT Human clinical

"patients with ORAS observed in our series and reported literature (n = 13)"

Pooled series and literature review totals 13 reported ORAS patients.

🐁

Animal Models

1

Myeloid-specific Otulin knockout mouse (LysM-Cre)

Species

Mouse

Genotype

Otulin conditional knockout; LysM-Cre (myeloid-restricted deletion)

Publication

PMID:27523608

Pathograph links

Increased Canonical NF-kB Signaling recapitulates fidelity: moderate observes: cellular Myeloid Otulin deletion reproduces the M1-Ub accumulation and spontaneous NF-kappaB activation of the human myeloid arm.

Limitations: The deletion is myeloid-restricted, so it models the myeloid NF-kappaB arm but does not spontaneously reproduce the panniculitis and diarrhoea of human ORAS.

Show evidence (1 reference)

PMID:27523608 SUPPORT Model organism

"accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells"

The LysM-Cre myeloid Otulin knockout shows M1-Ub accumulation and spontaneous NF-kappaB activation.

{ }

Source YAML

click to show

name: OTULIN-Related Autoinflammatory Syndrome
creation_date: "2026-11-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: OTULIN-related autoinflammatory syndrome
  term:
    id: MONDO:0014912
    label: autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive
description: >-
  OTULIN-related autoinflammatory syndrome (ORAS; otulipenia; AIPDS, autosomal
  recessive) is a severe, neonatal-onset systemic autoinflammatory disease caused
  by biallelic loss-of-function variants in OTULIN, a deubiquitinase that removes
  methionine-1 (M1, linear)-linked polyubiquitin conjugated by the linear
  ubiquitin chain assembly complex (LUBAC). Loss of OTULIN activity lets linear
  ubiquitin accumulate, which increases canonical NF-kappaB signaling and
  proinflammatory cytokine output and, in a cell-type-specific way, dysregulates
  TNF signaling and sensitises cells to TNF-induced death. Patients present in the
  neonatal period with recurrent fever, neutrophilic dermatitis and panniculitis,
  diarrhea, and failure to thrive. TNF-directed therapy is rational and
  haematopoietic stem cell transplantation is potentially curative (the one
  transplanted patient later relapsed as donor chimerism fell), showing that
  haematopoietic cells drive the clinical disease.
synonyms:
- otulipenia
- ORAS
- OTULIN-related autoinflammatory syndrome
- autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive
- AIPDS
parents:
- hereditary disease
- autoinflammatory syndrome
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ORAS is caused by biallelic (homozygous or compound heterozygous) hypomorphic
    loss-of-function OTULIN variants, reported in consanguineous and unrelated
    families.
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two missense and one frameshift mutations in one Pakistani
      and two Turkish families with four affected patients.
    explanation: >-
      Documents biallelic OTULIN mutations across three families with four
      affected patients.
genetic:
- name: OTULIN variants
  gene_term:
    preferred_term: OTULIN
    term:
      id: hgnc:25118
      label: OTULIN
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic hypomorphic OTULIN variants cause ORAS. Reported classes are
    homozygous missense and frameshift variants (Zhou 2016, PMID:27559085), a
    canonical splice-site variant (Nabavi 2019, PMID:30796585), and an atypical
    late-onset compound-heterozygous case (Zinngrebe 2022, PMID:35170849); the
    first report (Damgaard 2016, PMID:27523608) described a homozygous missense
    in a consanguineous family. Specific variant notations (for example p.L272P,
    p.Y244C, p.G174Dfs*2, p.G281R, c.864+2T>C, the compound-het p.M86I/p.W167S,
    and p.V185F) are catalogued in Table 1 of PMID:40734169; the structured
    evidence here quotes the variant-class sentence rather than the table.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_ebcd5c52-5f40-45d1-bcab-3a6162c188d7-2026-05-19T160000.000Z
    evidence:
    - reference: CGGV:assertion_ebcd5c52-5f40-45d1-bcab-3a6162c188d7-2026-05-19T160000.000Z
      reference_title: "OTULIN / autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "OTULIN | HGNC:25118 | autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive | MONDO:0014912 | AR | Definitive | SOP12 | Monogenic Autoinflammatory Diseases Gene Curation Expert Panel | 2026-05-19T16:00:00.000Z"
      explanation: >-
        ClinGen's Monogenic Autoinflammatory Diseases GCEP classifies the
        OTULIN-AIPDS/ORAS (autosomal recessive) relationship as Definitive.
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified two missense and one frameshift mutations in one Pakistani
      and two Turkish families with four affected patients.
    explanation: >-
      Documents the missense and frameshift OTULIN variant classes across three
      families.
pathophysiology:
- name: OTULIN Loss-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Biallelic hypomorphic variants in OTULIN (FAM105B) reduce the activity of
    this M1-linked-specific deubiquitinase.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: OTULIN
    term:
      id: hgnc:25118
      label: OTULIN
  molecular_functions:
  - preferred_term: cysteine-type deubiquitinase activity
    term:
      id: GO:0004843
      label: cysteine-type deubiquitinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an autoinflammatory disease caused by loss-of-function mutations in OTULIN
      (FAM105B), encoding a deubiquitinase with linear linkage specificity
    explanation: >-
      Establishes loss-of-function OTULIN variants, in a linear-linkage
      deubiquitinase, as the cause.
  downstream:
  - target: Impaired Linear Deubiquitination
    causal_link_type: DIRECT
- name: Impaired Linear Deubiquitination
  biological_scale: MOLECULAR
  description: >-
    OTULIN normally removes M1 (linear)-linked polyubiquitin assembled by LUBAC.
    Reduced activity leaves a defect in linear deubiquitination and accumulation
    of linear ubiquitin aggregates.
  biological_processes:
  - preferred_term: protein deubiquitination
    term:
      id: GO:0016579
      label: protein deubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showed a substantial defect in the linear deubiquitination of target
      molecules
    explanation: >-
      Documents the core molecular defect: impaired linear deubiquitination.
  downstream:
  - target: Increased Canonical NF-kB Signaling
    causal_link_type: DIRECT
  - target: Fibroblast LUBAC Degradation and Reduced TNF Signaling
    causal_link_type: DIRECT
  - target: Sensitisation to TNF-Induced Cell Death
    causal_link_type: DIRECT
- name: Increased Canonical NF-kB Signaling
  biological_scale: CELLULAR
  description: >-
    Accumulated linear ubiquitin drives increased signaling in the canonical
    NF-kappaB pathway, raising proinflammatory cytokine production.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showed evidence for increased signaling in the canonical NF-κB pathway and
      accumulated linear ubiquitin aggregates
    explanation: >-
      Links the deubiquitination defect to increased canonical NF-kappaB
      signaling and linear ubiquitin accumulation.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: DIRECT
- name: Fibroblast LUBAC Degradation and Reduced TNF Signaling
  biological_scale: CELLULAR
  description: >-
    In OTULIN-deficient fibroblasts LUBAC is degraded and its recruitment to the
    TNF receptor signaling complex falls, so the fibroblast TNF-mediated signaling
    response is reduced rather than increased. This cell-type-specific LUBAC
    degradation is the defining result of Damgaard et al. 2019 and is the mirror
    image of the increased NF-kappaB seen in monocytes.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: tumor necrosis factor-mediated signaling pathway
    term:
      id: GO:0033209
      label: tumor necrosis factor-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      LUBAC recruitment and M1-linked Ub conjugation at the TNF-RSC are reduced,
      accompanied by impaired TNF signalling, decreased IL-8 secretion and
      sensitisation to TNF-induced cell death in the presence of CHX
    explanation: >-
      Documents reduced LUBAC recruitment and impaired (not increased) TNF
      signalling in patient fibroblasts, correcting the direction of the
      fibroblast TNF response.
  downstream:
  - target: Sensitisation to TNF-Induced Cell Death
    causal_link_type: DIRECT
- name: Sensitisation to TNF-Induced Cell Death
  biological_scale: CELLULAR
  description: >-
    Both patient fibroblasts and OTULIN-deficient monocytes are sensitised to
    TNF-induced death, and apoptotic cells are present in patient skin lesions,
    contributing to the panniculitis and tissue inflammation.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      both patient-derived fibroblasts and OTULIN-deficient monocytes are
      sensitised to certain types of TNF-induced death, and apoptotic cells are
      evident in ORAS patient skin lesions
    explanation: >-
      Documents TNF-induced death sensitisation in both cell types and apoptosis
      in patient skin, the cell-death arm of the disease.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: DIRECT
- name: Systemic Autoinflammation
  biological_scale: ORGANISM
  description: >-
    Excess NF-kappaB-driven cytokines and TNF-induced cell death produce a
    neonatal-onset systemic autoinflammatory illness with skin, gastrointestinal,
    and constitutional features.
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presented with neonatal-onset fever, neutrophilic
      dermatitis/panniculitis, and failure to thrive, but without obvious primary
      immunodeficiency.
    explanation: >-
      Summarises the neonatal-onset systemic autoinflammatory presentation.
  downstream:
  - target: Recurrent fever
    causal_link_type: DIRECT
  - target: Panniculitis
    causal_link_type: DIRECT
  - target: Failure to thrive
    causal_link_type: DIRECT
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Arthritis
    causal_link_type: DIRECT
  - target: Sterile skin abscess
    causal_link_type: DIRECT
  - target: Lipodystrophy
    causal_link_type: DIRECT
  - target: Leukocytosis
    causal_link_type: DIRECT
  - target: Elevated C-reactive protein
    causal_link_type: DIRECT
phenotypes:
- name: Recurrent fever
  category: Constitutional
  description: >-
    Neonatal-onset recurrent fever is a presenting feature.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presented with neonatal-onset fever, neutrophilic
      dermatitis/panniculitis, and failure to thrive, but without obvious primary
      immunodeficiency.
    explanation: >-
      Documents neonatal-onset fever as a presenting feature.
- name: Panniculitis
  category: Dermatological
  description: >-
    Neutrophilic dermatitis and panniculitis are the characteristic skin lesions;
    the recurrent nodular (neutrophilic dermatosis) rash reported in the cohort is
    counted here.
  phenotype_term:
    preferred_term: Panniculitis
    term:
      id: HP:0012490
      label: Panniculitis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presented with neonatal-onset fever, neutrophilic
      dermatitis/panniculitis, and failure to thrive, but without obvious primary
      immunodeficiency.
    explanation: >-
      Documents neutrophilic dermatitis/panniculitis as the characteristic skin
      lesion.
- name: Failure to thrive
  category: Constitutional
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27559085
    reference_title: "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presented with neonatal-onset fever, neutrophilic
      dermatitis/panniculitis, and failure to thrive, but without obvious primary
      immunodeficiency.
    explanation: >-
      Documents failure to thrive as a presenting feature.
- name: Diarrhea
  category: Gastrointestinal
  description: >-
    Diarrhea is part of the systemic inflammatory illness and resolves with
    curative transplantation.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      haematopoietic stem cell transplantation leads to complete resolution of
      inflammatory symptoms, including fevers, panniculitis and diarrhoea
    explanation: >-
      Documents diarrhoea among the inflammatory symptoms of ORAS.
- name: Arthritis
  category: Musculoskeletal
  description: >-
    Inflammatory arthritis is part of the systemic illness in a substantial
    minority of patients.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  frequency: FREQUENT
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      panniculitis, arthritis and diarrhoea, showing that haematopoietic cells
      are crucial for manifestation of the disease
    explanation: >-
      Lists arthritis among the inflammatory manifestations of ORAS.
- name: Sterile skin abscess
  category: Dermatological
  description: >-
    Sterile (neutrophilic) abscesses occur in skin and also in spleen and lung;
    reported in roughly half of patients.
  phenotype_term:
    preferred_term: Sterile cutaneous abscess
    term:
      id: HP:0031292
      label: Cutaneous abscess
  frequency: FREQUENT
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diffuse sterile abscesses (skin, spleen, and lung)
    explanation: >-
      Diffuse sterile abscesses, including cutaneous, are a consistent ORAS
      feature (skin abscess 6/13 in the pooled table).
- name: Lipodystrophy
  category: Dermatological
  description: >-
    Lipodystrophy (loss of subcutaneous fat, in part a sequela of panniculitis)
    is reported in roughly 45% of patients.
  phenotype_term:
    preferred_term: Lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lipodystrophy, which are considered as the most observed features in
      reported literature
    explanation: >-
      Lipodystrophy is among the most frequently observed features of ORAS
      (≈45% in the pooled series).
- name: Leukocytosis
  category: Laboratory
  description: >-
    Leukocytosis is a near-universal laboratory marker of the systemic
    inflammation.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukocytosis, thrombocytosis, and increased inflammatory markers
    explanation: >-
      Leukocytosis is among the near-universal laboratory findings of ORAS
      (11/11 in the pooled series).
- name: Elevated C-reactive protein
  category: Laboratory
  description: >-
    Elevated inflammatory markers (CRP and ESR) are present in essentially all
    patients.
  phenotype_term:
    preferred_term: Elevated inflammatory markers (CRP/ESR)
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated inflammatory markers | 11 (100)
    explanation: >-
      Pooled case series and literature review: elevated inflammatory markers in
      11/11 (100%).
treatments:
- name: TNF Inhibitor Therapy
  description: >-
    Because ORAS is driven by dysregulated TNF signaling and TNF-induced cell
    death, TNF inhibition is mechanistically rational and ameliorates
    inflammation in patients. Agents used include the monoclonal antibodies
    infliximab and adalimumab and the receptor-fusion protein etanercept;
    because the class spans both antibody and fusion-protein platforms, no single
    therapeutic_modality value is asserted.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
  target_mechanisms:
  - target: Sensitisation to TNF-Induced Cell Death
    description: >-
      Neutralizing TNF interrupts the TNF signaling and TNF-induced death that
      drive ORAS inflammation.
    evidence:
    - reference: PMID:30804083
      reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with TNF inhibitors such as antibodies (e.g. infliximab) or TNF
        blockers (e.g. etanercept) effectively ameliorates inflammation, but there
        is currently no cure for ORAS.
      explanation: >-
        Documents that TNF inhibitors ameliorate ORAS inflammation, the target of
        this therapy.
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with TNF inhibitors such as antibodies (e.g. infliximab) or TNF
      blockers (e.g. etanercept) effectively ameliorates inflammation, but there
      is currently no cure for ORAS.
    explanation: >-
      Direct evidence that TNF inhibition ameliorates inflammation in ORAS.
- name: IL-1 Blockade (anakinra)
  description: >-
    IL-1 blockade was tried but, unlike TNF inhibition, did not improve symptoms
    in a reported patient, consistent with TNF rather than IL-1 as the dominant
    driver.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anakinra was added to the treatment regimen without any improvement of her
      symptoms
    explanation: >-
      Refutes efficacy of IL-1 blockade: the patient did not improve on anakinra.
- name: Hematopoietic Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    Allogeneic haematopoietic stem cell transplantation produced complete
    resolution of inflammation in a transplanted patient, demonstrating that
    haematopoietic cells drive the clinical disease. The disease relapsed nine
    months later as donor chimerism fell, so HSCT is potentially curative rather
    than an established cure.
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Systemic Autoinflammation
    description: >-
      Replacing the patient's haematopoietic compartment removes the
      OTULIN-deficient inflammatory cells that drive disease.
    evidence:
    - reference: PMID:30804083
      reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        haematopoietic cells are necessary for clinical manifestation of ORAS
      explanation: >-
        Establishes the haematopoietic compartment as the driver that transplant
        replaces.
  evidence:
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      haematopoietic stem cell transplantation leads to complete resolution of
      inflammatory symptoms, including fevers, panniculitis and diarrhoea
    explanation: >-
      Documents complete resolution of ORAS inflammation immediately after
      transplant.
  - reference: PMID:30804083
    reference_title: "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      relapsed with fevers, panniculitis and arthritis, albeit with less severe
      symptoms than before the transplantation
    explanation: >-
      Documents post-transplant relapse at nine months as donor chimerism fell,
      so the result is not an established cure.
diagnosis:
- name: Molecular and inflammatory-marker diagnosis
  description: >-
    Diagnosis rests on identifying biallelic OTULIN variants by gene or exome
    sequencing together with laboratory evidence of systemic inflammation
    (leukocytosis and elevated CRP/ESR).
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukocytosis, and high inflammatory markers
    explanation: >-
      Laboratory inflammation (leukocytosis, high inflammatory markers)
      accompanies the molecular diagnosis.
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) revealed a novel homozygous pathogenic
      mutation in the OTULIN gene
    explanation: >-
      Molecular diagnosis is by sequencing (whole-exome) identifying the biallelic
      OTULIN variant.
animal_models:
- name: Myeloid-specific Otulin knockout mouse (LysM-Cre)
  species: Mouse
  genotype: Otulin conditional knockout; LysM-Cre (myeloid-restricted deletion)
  publication: PMID:27523608
  modeled_mechanisms:
  - target: Increased Canonical NF-kB Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Myeloid Otulin deletion reproduces the M1-Ub accumulation and spontaneous
      NF-kappaB activation of the human myeloid arm.
    limitations: >-
      The deletion is myeloid-restricted, so it models the myeloid NF-kappaB arm
      but does not spontaneously reproduce the panniculitis and diarrhoea of
      human ORAS.
    evidence:
    - reference: PMID:27523608
      reference_title: "The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation
        in myeloid cells
      explanation: >-
        The LysM-Cre myeloid Otulin knockout shows M1-Ub accumulation and
        spontaneous NF-kappaB activation.
prevalence:
- population: Reported ORAS case series and literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    ORAS is ultra-rare; a 2025 pooled case series and literature review totalled
    13 reported patients. That total includes heterozygous dominant-negative
    (p.C129S) cases, a distinct form from the autosomal-recessive disease this
    entry scopes; see the entry-level note.
  evidence:
  - reference: PMID:40734169
    reference_title: "Expanding the phenotypic and genetic spectrum of ORAS with novel homozygous variant in OTULIN gene: a case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients with ORAS observed in our series and reported literature (n = 13)
    explanation: >-
      Pooled series and literature review totals 13 reported ORAS patients.
notes: >-
  Named for the causal gene and the established names (otulipenia, ORAS); the
  MONDO label "autoinflammation, panniculitis, and dermatosis syndrome,
  autosomal recessive" (AIPDS) is retained as a synonym. OTULIN is M1
  (linear)-linkage-specific; the generic protein-deubiquitination GO term is used
  because no M1/linear-specific deubiquitination term is available. No mechanism
  module is conformed to: there is no dismech LUBAC / linear-ubiquitin / TNF-NF-kB
  autoinflammation module, consistent with the sibling LUBAC-axis entries (A20
  haploinsufficiency, HOIP deficiency), which are likewise unconformed. OTULIN
  haploinsufficiency (autosomal dominant; susceptibility to Staphylococcus aureus
  alpha-toxin-mediated necrosis; PMID:35587511) is a mechanistically distinct
  allelic disorder and is deliberately out of scope for this autosomal-recessive
  entry; it should be curated separately rather than folded in here. A
  heterozygous dominant-negative OTULIN variant (p.C129S) has also been reported
  (PMID:40734169) and is likewise outside this recessive entry's scope.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: OTULIN-related autoinflammatory syndrome (ORAS) · 2026-11-01T05:11:54Z · View source

Created the OTULIN-related autoinflammatory syndrome (otulipenia / ORAS; AIPDS-AR) entry. Deep research via claude_code; preflight-dr confirmed OTULIN dominant with matching OMIM 617099 (TNF is the disease's own effector). Evidence anchored on fetched primary abstracts/full text (Zhou 2016 PNAS otulipenia discovery PMID:27559085, Damgaard 2019 EMBO Mol Med ORAS mechanism+HSCT cure PMID:30804083). Atomic pathograph: biallelic OTULIN LOF -> impaired linear (M1) deubiquitination -> increased canonical NF-kB signaling (monocyte) and dysregulated TNF signaling/TNF-induced cell death (fibroblast) -> neonatal-onset systemic autoinflammation; 4/4 phenotypes connected (recurrent fever, panniculitis, failure to thrive, diarrhea). Treatments: TNF inhibitor therapy and curative haematopoietic cell transplantation. Generic protein-deubiquitination GO term used (no M1/linear-specific term available); no LUBAC/NF-kB module as conformance target, consistent with A20 and HOIP sibling entries. All gates pass.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-opus-4-8, claude-opus-5-5 4 citations 2026-11-01T04:47:52.461436

1. Disease Information

Overview. OTULIN-Related Autoinflammatory Syndrome (ORAS), also called otulipenia or autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive (AIPDS), is a monogenic systemic autoinflammatory disease. The classical recessive form presents in the neonatal period or early infancy with recurrent fever, neutrophilic dermatitis/panniculitis, lipodystrophy, diarrhea, arthritis/arthralgia, and failure to thrive, driven by dysregulated NF-κB signalling and excess M1(linear)-linked polyubiquitin. It was described essentially simultaneously in 2016 by two groups.

Zhou et al. (PNAS 2016, PMID:27559085): "Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease." Abstract: "Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive" (abstract-derived).
Damgaard et al. (Cell 2016, PMID:27523608): "A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition" termed OTULIN-related autoinflammatory syndrome (ORAS) (full-text-derived).

Synonyms / alternative names: otulipenia; ORAS; OTULIN deficiency; AIPDS / AIPDSB; "autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive"; "Infantile-onset periodic fever–panniculitis–dermatosis syndrome" (Orphanet preferred label). The condition belongs to the "relopathies" / "ubiquitin-related autoinflammatory diseases" group (Steiner, Curr Rheumatol Rep 2018, PMID:29846841; Aksentijevich & Zhou, Front Immunol 2017, PMID:28469620).

Information source. Aggregated from disease-level resources (OMIM, Orphanet, ClinGen) and from individual patient case reports/series (PMID:27559085, 27523608, 30804083, 30796585, 35170849, 38914362, 40734169, 41293556). This is a rare disease documented through small case series, not EHR-scale cohorts.

2. Etiology

Primary cause — genetic. ORAS is a monogenic disease caused by variants in OTULIN. Two genetic/inheritance architectures are now recognised:

Recessive loss-of-function (classical otulipenia/ORAS): biallelic hypomorphic or amorphic variants → reduced OTULIN catalytic activity/stability → accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation. "an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B)" (PMID:27559085, abstract).
Dominant OTULIN haploinsufficiency: heterozygous deleterious variants (or 5p chromosomal loss) causing a different, infection/trauma-triggered necrosis syndrome (Spaan et al., Science 2022, PMID:35587511).
Dominant-negative heterozygous ORAS: rare heterozygous variants (e.g. p.Cys129Ser, p.Arg306Gln) that poison the pathway and produce a spontaneous-inflammation ORAS phenotype despite one normal allele (Davidson, PMID:38630025; Takeda, PMID:38652464).

Genetic risk factors. The disease-causing variant is the cause; consanguinity is a major risk factor for the recessive form (multiple consanguineous Arab, Turkish, Pakistani, Iranian, Moroccan families — PMID:27559085, 40734169, 38914362). No separate susceptibility loci or modifier genes are established, though background LUBAC-pathway genes (RNF31/HOIP [hgnc:16031], RBCK1/HOIL-1, SHARPIN [hgnc:25321]) are mechanistically related.

Environmental risk / trigger factors. Central to the haploinsufficiency form: "episodes of life-threatening necrosis, typically triggered by S. aureus infection" (PMID:35587511, abstract). Broader triggers were later reported: "previously underappreciated triggers, including mechanical or iatrogenic traumas" and "pseudomonal or clostridial infections" (van der Linden, J Hum Immun 2025, PMID:41293556, abstract). Surgery/wound healing is a documented trigger (Nguyen, ACR Open Rheumatol 2025, PMID:40084498, post-operative necrosis). Staels (Front Immunol 2024, PMID:38827742): "OTULIN haploinsufficiency predisposes to environmentally directed inflammation."

Protective factors. For the α-toxin/staphylococcal haploinsufficiency phenotype, naturally acquired anti-α-toxin antibodies are protective and explain incomplete penetrance: "Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance" (PMID:35587511, abstract). No dietary/lifestyle protective factors are established.

Gene–environment interaction. The haploinsufficiency phenotype is the clearest G×E example in the group: a germline heterozygous OTULIN defect is clinically silent until an environmental insult (S. aureus α-toxin, trauma, surgery) precipitates tissue necrosis, and anti-toxin humoral immunity modifies penetrance.

3. Phenotypes

Frequencies below are pooled from a 13-patient table (3 new + 10 literature) in AlSaleem et al. (Pediatr Rheumatol 2025, PMID:40734169, full-text, Table 2) for the recessive form, supplemented by the founding series. Interpret pooled percentages cautiously — total documented classical cases number only in the low dozens.

Classical recessive ORAS (neonatal/infantile autoinflammation)

Phenotype	Type	Frequency (pooled)	HPO suggestion
Recurrent fever / fever	Symptom	13/13 (100%)	HP:0001954 Recurrent fever; HP:0001945 Fever
Neutrophilic dermatitis / skin rash	Clinical sign	~100% cutaneous	HP:0000988 Skin rash; HP:0031234 Neutrophilic infiltration of the skin; HP:0010783 Erythema
Panniculitis (often septal, neutrophilic)	Clinical sign	high (nodular rash 72%)	HP:0012490 Panniculitis
Lipodystrophy	Physical manifestation	5/11 (~45%)	HP:0009125 Lipodystrophy
Failure to thrive	Physical manifestation	9/11 (82%)	HP:0001508 Failure to thrive
Diarrhea / GI involvement	Symptom	8/11 (72%)	HP:0002014 Diarrhea
Arthritis / arthralgia	Clinical sign	~45% musculoskeletal	HP:0001369 Arthritis; HP:0002829 Arthralgia
Leukocytosis / neutrophilia	Lab abnormality	11/11 (100%)	HP:0001974 Leukocytosis; HP:0011897 Neutrophilia
Elevated CRP / ESR	Lab abnormality	11/11 (100%)	HP:0011227 Elevated CRP; HP:0003565 Elevated ESR
Thrombocytosis	Lab abnormality	common (plt >1000×10⁹/L in acute cases)	HP:0001894 Thrombocytosis
Lymphadenopathy	Clinical sign	reported	HP:0002716 Lymphadenopathy
Hepatosplenomegaly / splenomegaly	Clinical sign	reported	HP:0001433 Hepatosplenomegaly; HP:0001744 Splenomegaly
Sterile abscesses (skin, splenic, pulmonary)	Clinical sign	abscesses 54% (AlSaleem series)	HP:0031292 Cutaneous abscess; HP:0025059 Splenic abscess; HP:0025044 Lung abscess
Recurrent infections	Clinical sign	6/11 (54%)	HP:0002719 Recurrent infections
Autoantibodies (ANA, dsDNA)	Lab abnormality	reported (Damgaard)	HP:0003493 Antinuclear antibody positivity
Progressive steatotic liver disease	Physical manifestation	≥1 patient (10–13 mo)	HP:0001397 Hepatic steatosis

Quotes: "Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive" (PMID:27559085); "fever, panniculitis, diarrhea, and arthritis" (Zinngrebe, PMID:35170849). Liver: "OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10-13 months of age" (Damgaard, Cell Death Differ 2020, PMID:32231246).

Atypical / late-onset recessive: Zinngrebe (PMID:35170849) reported a 7-year-old with "a life-threatening autoinflammatory episode with sterile abscess formation" (compound-het p.M86I/p.W167S) and proposed splitting ORAS into classical and atypical (fulminant late-onset) forms. AlSaleem's 3 Arab patients (p.Val185Phe) also had non-neonatal onset (12 mo, 24 mo, 4 y): "none of our patients had an early or neonatal onset."

OTULIN haploinsufficiency (distinct phenotype)

Phenotype	Type	HPO suggestion
Life-threatening skin necrosis	Clinical sign	HP:0200042 Skin ulcer; HP:0100659 (necrosis)
Pulmonary necrosis / necrotizing pneumonia	Clinical sign	HP:0002090 Pneumonia; HP:0025044 Lung abscess
Severe staphylococcal (±Pseudomonas/clostridial) disease	Clinical sign	HP:0002719 Recurrent infections
Fasciitis / necrotizing soft-tissue infection	Clinical sign	— (HP:0100536 inflammation)
Onset usually adolescence, trauma/surgery-triggered	Temporal	—

"Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection" (PMID:35587511). "six unrelated patients who carry rare, predicted deleterious variants" with skin/lung necrosis (PMID:41293556).

Isolated pyoderma gangrenosum (newest allelic presentation)

Swaminathan et al. (Nat Immunol 2026, PMID:42297973): three patients from two kindreds with homozygous p.R57C, an isolated PG phenotype. "OTULIN-R57C is catalytically active but is unable to bind the linear ubiquitin assembly complex"; "Patient monocytes show heightened expression of IL1B" (abstract). HPO: HP:0025452 Pyoderma gangrenosum.

Quality-of-life impact. Not formally quantified with EQ-5D/SF-36 in the literature. Qualitatively severe: classical cases require chronic biologic therapy, cause growth failure and lipodystrophy; untreated disease is potentially fatal; haploinsufficiency carries risk of life-threatening necrotic episodes.

4. Genetic / Molecular Information

Causal gene. OTULIN (HGNC:25118, 5p15.2). Encodes a 352-aa OTU-family deubiquitinase that is exquisitely specific for Met1 (linear/M1) polyubiquitin (Keusekotten, Cell 2013, PMID:23746843: "specifically hydrolyzing Met1-linked polyubiquitin"). GO suggestions: GO:0101005 deubiquitinase activity; GO:0004843 cysteine-type deubiquitinase activity; GO:0016579 protein deubiquitination (with M1/linear specificity noted in preferred_term); GO:0097039 protein linear polyubiquitination (the substrate it reverses).

Pathogenic variants — recessive ORAS (biallelic)

Variant (protein)	cDNA	Family/ancestry	Zygosity	Ref
p.Leu272Pro	c.815T>C	Pakistani (3 sibs)	Homozygous	PMID:27523608, 27559085
p.Tyr244Cys	c.731A>G	Turkish	Homozygous	PMID:27559085
*p.Gly174Aspfs2**	c.517delC (frameshift)	Turkish	Homozygous	PMID:27559085
p.Gly281Arg	—	Arab	Homozygous	PMID:30804083
p.Trp199Arg	c.595T>A	Moroccan	Homozygous	PMID:38914362
p.Val185Phe	c.553G>T	Arab (3 families)	Homozygous	PMID:40734169
p.Met86Ile / p.Trp167Ser	c.258G>A / c.500G>C	Greek	Compound het (atypical)	PMID:35170849
splice c.864+2T>C	—	Iranian	Homozygous	(literature table, PMID:40734169)

Variant classes: predominantly missense hypomorphs, one frameshift, one splice-site. Functional consequence = loss of function / hypomorph: p.L272P is "less stable and 1,000–10,000 times less active against M1-linked di- and tetraubiquitin" (PMID:27523608, full text); mutant OTULIN "had decreased enzyme activity relative to cells transfected with WT OTULIN" (PMID:27559085). All founding variants were absent from ExAC and ethnically matched controls.

Variants — dominant OTULIN haploinsufficiency

Spaan (PMID:35587511): six heterozygous variants in 7 patients / 6 kindreds — p.Asp246Val, p.Glu95X (nonsense), p.Asp268TfsX5 (frameshift), p.Asn341Asp, p.Pro254Ser, p.Arg263Gln. Alleles were hypomorphic/amorphic (<25% WT NF-κB inhibition); cumulative population frequency of such alleles ≈ 6×10⁻⁵; constraint metrics LoFtool 0.115, CoNeS −0.78 (intolerant to haploinsufficiency). The disorder is phenocopied by the 5p−/Cri-du-Chat deletion when it removes one OTULIN copy. Additional haploinsufficiency variant: p.Arg263Trp (post-surgical necrosis; PMID:40084498).

Dominant-negative heterozygous ORAS

p.Cys129Ser — abolishes DUB activity without destabilising protein; "the first dominant-negative mutation linked to ORAS"; "Altered ubiquitination of LUBAC inhibits its recruitment to the TNF receptor signaling complex" (Davidson, J Exp Med 2024, PMID:38630025).
p.Arg306Gln (de novo) + p.Pro152Leu — "the de novo p.R306Q variant exhibits attenuated deubiquitination activity" and acts dominant-negatively (Takeda, J Exp Med 2024, PMID:38652464).
p.R57C — catalytically intact but LUBAC-binding-deficient (PUB-interacting motif); isolated PG (PMID:42297973).

Modifier genes / epigenetics / chromosomal. No modifier genes established. The main chromosomal abnormality relevant is the 5p terminal deletion (Cri-du-Chat) acting as a haploinsufficiency phenocopy (PMID:35587511). No disease-specific epigenetic mechanism reported.

5. Environmental Information

Infectious triggers: Staphylococcus aureus (α-toxin) is the paradigmatic trigger of haploinsufficiency necrosis (NCBITaxon:1280); also Pseudomonas and Clostridium species (PMID:41293556). A tubercular cutaneous abscess has been reported in a haploinsufficient infant (Ks, Indian J Pediatr 2025, PMID:40711650).
Physical/iatrogenic: mechanical trauma and surgery/wound healing precipitate necrotic episodes (PMID:41293556; PMID:40084498 "Failure to Close").
Lifestyle factors: none established.
For classical recessive ORAS, inflammation is largely spontaneous/constitutive rather than environmentally triggered, though LPS amplifies cytokine output ex vivo.

6. Mechanism / Pathophysiology

Causal chain (recessive loss-of-function ORAS)

Biallelic hypomorphic OTULIN variant → reduced OTULIN catalytic activity/stability (leads to) failure to hydrolyse Met1-linked polyubiquitin. (Demonstrated: PMID:27523608, 27559085.)
Loss of M1-chain editing → accumulation of M1-linked polyubiquitin, especially on/around LUBAC (HOIP/HOIL-1/SHARPIN) signalling complexes. "accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells" (PMID:27523608). (Demonstrated.)
Spontaneous, ligand-independent activation of canonical NF-κB in myeloid cells (monocytes/macrophages) → constitutive transcription of proinflammatory cytokines. (results in) (Demonstrated in patient monocytes and mouse BMDMs.)
Overproduction of TNF, IL-1β, IL-6, IL-12/IL-18, IFN-γ → systemic autoinflammation (fever, panniculitis, FTT). "higher IL-1β, IL-6, IL-12, IL-18, and IFN-γ" (PMID:27559085, full text). (Demonstrated.)
Branch A — cell-type-specific LUBAC degradation: in B and T cells, OTULIN loss paradoxically causes "downregulation of M1-polyubiquitin signaling by degradation of LUBAC" (HOIP and SHARPIN reduced, proteasome-dependent) (PMID:27523608; Damgaard EMBO Mol Med 2019, PMID:30804083: "loss of OTULIN in patient-derived fibroblasts leads to a reduction in LUBAC levels"). (Demonstrated.)
Branch B — sensitisation to TNF-induced cell death: "both patient-derived fibroblasts and OTULIN-deficient monocytes are sensitised to certain types of TNF-induced death"; "apoptotic cells are evident in ORAS patient skin lesions" (PMID:30804083). Cell death (apoptosis/necroptosis) further amplifies inflammation. (Demonstrated.)
Branch C — hepatic: hepatocyte OTULIN loss → aberrant mTOR activation and FADD/RIPK1-kinase-dependent hepatocyte apoptosis → steatosis→steatohepatitis→fibrosis→HCC (mouse + 1 patient). "steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation" and "inhibition of mTOR by rapamycin...significantly reduces the liver pathology" (PMID:32231246); "OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis" (Verboom, Cell Rep 2020, PMID:32075762). (Model-organism + case.)
Clinical manifestation: recurrent fever, neutrophilic dermatosis/panniculitis, lipodystrophy, arthritis, diarrhea, FTT.

Note the cell-type paradox (key mechanistic insight): OTULIN loss is not uniformly pro- or anti-inflammatory — it increases M1-Ub/NF-κB in myeloid cells but degrades LUBAC in lymphocytes. "OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death" (PMID:30804083).

Causal chain (dominant haploinsufficiency necrosis)

Heterozygous OTULIN LOF (50% dosage) → "accumulation of linear ubiquitin in dermal fibroblasts" (CL:0002551 fibroblast of dermis) (PMID:35587511).
→ OTULIN-dependent accumulation of caveolin-1 (CAV1, hgnc:1527) high-MW K63-ubiquitinated complexes at the fibroblast surface.
→ caveolin-1 facilitates α-toxin binding and ADAM10 (hgnc:188) retention at the surface → heightened susceptibility to S. aureus α-toxin cytotoxicity. "facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin" (PMID:35587511).
→ trauma/infection trigger → tissue necrosis of skin and lungs; modified by anti-α-toxin antibody titres (penetrance ≈30%).

This is a non-hematopoietic (stromal) mechanism in humans — PBMCs and NF-κB signalling in blood cells were largely normal — contrasting with the hematopoietic-driven inflammation of mouse models (PMID:38827742).

Mechanistic modules / pathways (for KB linking)

Molecular pathways: canonical NF-κB (GO:0007249; dysregulated positive GO:0043123), TNF-mediated signalling (GO:0033209), mTOR/TORC1 (GO:0038202, GO:0032006), NLRP3 inflammasome assembly (GO:0044546), Wnt/angiogenesis (developmental gumby role, GO:0001525, GO:0016055; PMID:23708998).
Cellular processes: inflammatory response (GO:0006954), extrinsic apoptosis (GO:0097191), necroptosis (GO:0070266 / GO:0097300), TNF/IL-1β/IL-6 production (GO:0032640/0032611/0032635), neutrophil chemotaxis (GO:0030593). Doglio (Sci Immunol 2023, PMID:38000038): myeloid OTULIN loss "couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion."
Protein dysfunction: loss of OTU-domain M1-Ub hydrolase function; LUBAC (GO:0071797 LUBAC complex) dysregulation (OTULIN normally restrains LUBAC autoubiquitination — Heger, Nature 2018, PMID:29950720; Lyu, Mol Cell 2026, PMID:42880249).
Cell types (CL): monocyte CL:0000576 / classical monocyte CL:0000860; macrophage CL:0000235; neutrophil CL:0000775; dermal fibroblast CL:0002551; keratinocyte CL:0000312 (Schünke, Nat Commun 2021, PMID:34625557 — RIPK1-mediated keratinocyte necroptosis); hepatocyte CL:0000182; B cell CL:0000236; T cell CL:0000084.

7. Anatomical Structures Affected

Primary: skin (UBERON:0002097 skin of body; UBERON:0002067 dermis), subcutaneous adipose tissue / panniculus (UBERON:0002190, UBERON:0002072 hypodermis), joints, gastrointestinal tract (UBERON:0000160 intestine).
Secondary / systemic: liver (UBERON:0002107) — steatosis→HCC; lung (UBERON:0002048) — necrosis/abscess (haploinsufficiency); spleen (UBERON:0002106) — abscesses/splenomegaly; blood/bone marrow (UBERON:0000178 / UBERON:0002371) — leukocytosis, thrombocytosis.
Body systems: integumentary, musculoskeletal, digestive, hematologic/immune, hepatic, respiratory.
Subcellular: cytoplasmic ubiquitin–proteasome/signalling machinery; plasma-membrane caveolae (caveolin-1) in the haploinsufficiency mechanism. GO cellular components: plasma membrane caveola, cytosol.
Lateralization: systemic/bilateral; abscesses and necrotic lesions are focal/multifocal.

8. Temporal Development

Onset: Classical recessive — neonatal to early infancy (first weeks of life; often premature birth, HP:0001622). Atypical/late-onset recessive — childhood (e.g. 7 y; or 1–4 y in the p.V185F families). Haploinsufficiency necrosis — typically adolescence, trigger-dependent.
Onset pattern: recurrent/episodic flares of systemic inflammation (recessive); acute trigger-provoked necrotic crises (haploinsufficiency).
Progression: without effective therapy, potentially fatal (septicaemia, multiorgan inflammation, renal failure, pulmonary edema — deaths at 16 mo and 5 y in the founding Pakistani family, PMID:27523608; a fatal Iranian splice-variant case). Chronic relapsing course with growth failure and lipodystrophy if untreated; liver disease can progress steatosis→fibrosis→HCC.
Remission: treatment-induced remission achievable with anti-TNF/anti-IL-1 (recessive) and with HSCT (see §12). Haploinsufficiency episodes are acute and recurrent.
Critical window: early diagnosis and TNF blockade (or definitive HSCT) before irreversible organ damage.

9. Inheritance and Population

Inheritance: Autosomal recessive for classical ORAS/otulipenia (ClinGen Gene–Disease Validity: OTULIN – AIPDS, AR, Definitive, Monogenic Autoinflammatory Disease GCEP, 2026-05-19). Autosomal dominant for OTULIN haploinsufficiency and for the dominant-negative variants (p.C129S, p.R306Q).
Penetrance: complete-to-high for biallelic LOF; incomplete (~30%) for haploinsufficiency, modified by anti-α-toxin antibodies (PMID:35587511: "3 of 10" ORAS-parent carriers had a milder phenotype).
Expressivity: variable (classical vs atypical/fulminant; isolated PG).
Consanguinity: major driver of recessive cases (Arab, Turkish, Pakistani, Iranian, Moroccan consanguineous families).
Carrier/allele frequency: cumulative deleterious-allele frequency ≈ 6×10⁻⁵ (haploinsufficiency alleles; PMID:35587511).
Epidemiology: Orphanet prevalence "Not yet documented"; ultra-rare, <50 classical patients reported worldwide. Orphanet notes "At least four cases" originally; literature now totals a few dozen across both forms. No reliable incidence/prevalence per 100,000 exists. PrevalenceClass suggestion: NOT_YET_DOCUMENTED; qualitative ULTRA_RARE.
Founder effects: recurrent ancestry-specific homozygous variants reflect consanguinity rather than classic founder haplotypes. Sex ratio: no sex bias established (X-autosome: gene is autosomal). Geographic: cases concentrated in consanguineous populations of the Middle East, North Africa, South Asia, Turkey; haploinsufficiency cases more geographically dispersed.

10. Diagnostics

Laboratory (LOINC-codable): persistently elevated CRP and ESR, leukocytosis/neutrophilia, thrombocytosis, elevated serum proinflammatory cytokines (TNF, IL-6, IL-18, IL-1β), hypergammaglobulinemia and autoantibodies (ANA/dsDNA) in some; negative microbial cultures during sterile flares. Research assay: elevated free M1(linear)-linked polyubiquitin chains in patient leukocytes (diagnostic hallmark; PMID:27523608).
Functional immunology: increased basal/LPS-stimulated cytokine production by patient monocytes; reduced LUBAC (HOIP/SHARPIN) in lymphocytes; NF-κB reporter assays showing reduced inhibition by mutant OTULIN.
Histopathology: neutrophilic dermatosis / septal or lobular panniculitis, sometimes with small/medium-vessel vasculitis; sterile abscesses.
Imaging: CT for pulmonary/splenic/hepatic abscesses; characterises necrotic lesions in haploinsufficiency.
Genetic testing (diagnostic gold standard): single-gene OTULIN sequencing, autoinflammatory gene panels, or WES/WGS (most founding cases found by exome). Chromosomal microarray/karyotype where a 5p deletion (Cri-du-Chat phenocopy) is suspected. GTR lists clinical OTULIN testing.
Clinical criteria: no formal consensus diagnostic criteria; diagnosis = compatible autoinflammatory phenotype + biallelic (or relevant heterozygous) pathogenic OTULIN variant + supportive functional data. Screened at autoinflammatory-disease registries (Infevers OTULIN variant database).
Differential diagnosis: other relopathies/LUBAC defects (HOIL-1/RBCK1, HOIP/RNF31 deficiency), RIPK1 deficiency (PMID:31213653), DIRA (IL1RN), DITRA (IL36RN), CANDLE/PRAAS, Mevalonate kinase deficiency/HIDS, TRAPS, FMF, CINCA/NOMID, deficiency of ADA2, and (for necrosis form) primary necrotizing soft-tissue infection. Distinguishing feature: M1-polyubiquitin accumulation and OTULIN genotype.
Screening: carrier/cascade testing in consanguineous families; prenatal/preimplantation testing feasible for known familial variants.

11. Outcome / Prognosis

Mortality: historically high in untreated classical disease — e.g. two of three affected siblings in the founding family died (pneumococcal sepsis at 16 mo; systemic inflammation with ARF/pulmonary edema at age 5) before anti-TNF was available (PMID:27523608, full text); a homozygous splice-variant Iranian patient died. Haploinsufficiency necrosis is life-threatening during crises.
With treatment: prognosis is substantially improved by TNF inhibition and transformed by HSCT (potentially curative for the hematopoietic-driven recessive disease). Patient V:2 (p.L272P) "alive at age 11 with well-controlled disease" on infliximab; HSCT gave "complete resolution of inflammatory symptoms" (PMID:30804083).
Morbidity: growth failure/FTT, lipodystrophy, joint disease, recurrent abscesses, and (long-term) risk of hepatic fibrosis/HCC; necrotic tissue loss and post-surgical complications in haploinsufficiency.
Prognostic factors: genotype (amorph vs hypomorph), time to diagnosis/treatment, organ involvement (liver, lung), anti-α-toxin antibody status (haploinsufficiency penetrance). No validated prognostic biomarker beyond inflammatory markers and M1-Ub load.

12. Treatment

Suggested NCIT terms in brackets; most pharmacotherapy uses generic action NCIT:C15986 (Pharmacotherapy) + a therapeutic_agent.

TNF inhibitors — mainstay of recessive ORAS. "treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes" (PMID:27523608).
Infliximab [NCIT:C1789] — complete response in p.L272P patient (resolution within ~1 month; PMID:27559085).
Adalimumab [NCIT:C65216] — remission in the AlSaleem p.V185F patients (monotherapy maintenance; PMID:40734169).
Etanercept [NCIT:C2381] — partial response (p.G174fs; PMID:27559085). Therapeutic modality: MONOCLONAL_ANTIBODY (infliximab/adalimumab) vs soluble receptor (etanercept).
Fasciitis/skin necrosis in haploinsufficiency: "excessive inflammation in OTULIN haploinsufficiency can be effectively treated by TNF inhibition" (Arts, PMID:38129331); post-operative necrosis improved on glucocorticoids + infliximab (PMID:40084498).
IL-1 inhibition — variable. Anakinra [NCIT:C38717] gave complete response in one Turkish patient (p.Y244C) but was ineffective in others; canakinumab [NCIT:C80971] precipitated macrophage activation syndrome in one patient (PMID:27559085). IL-1β blockade proposed for the PG phenotype (PMID:42297973).
Glucocorticoids [NCIT:C2323 / prednisolone NCIT:C769, prednisone NCIT:C770] — control acute flares; used as bridge/adjunct.
Other immunomodulators: methotrexate [NCIT:C642] (adjunct to infliximab), azathioprine (ineffective alone), ruxolitinib [NCIT:C77888] (JAK inhibitor, tried in a dominant case).
mTOR inhibition (mechanistic rationale, hepatic): rapamycin/sirolimus [NCIT:C1212; CHEBI:9168] reduced liver pathology in OTULIN-deficient mice — a candidate for hepatic involvement, not yet standard clinical practice (PMID:32231246).
Definitive / curative: Allogeneic HSCT [NCIT:C46089 / Hematopoietic Cell Transplantation NCIT:C15431] — complete resolution in a transplanted ORAS patient; rationale that "haematopoietic cells are necessary for clinical manifestation of ORAS" (PMID:30804083). (Note: one literature case failed HSCT and responded instead to etanercept — PMID:40734169 Table.)
Haploinsufficiency-specific supportive care: aggressive antibiotic therapy [NCIT:C15620] for staphylococcal infection, surgical debridement [NCIT:C51682] of necrotic tissue, and proposed (investigational) α-toxin-neutralizing monoclonal antibodies ± steroids (PMID:35587511). ADAM10 inhibition / cyclodextrin protected cells in vitro only.
Genetic counseling [NCIT:C15240] for families (AR recurrence risk, consanguinity).

Treatment strategy: distinguish the two diseases — recessive ORAS → cytokine blockade (TNF first-line) ± HSCT; haploinsufficiency → trigger avoidance, prompt anti-staphylococcal therapy, TNF blockade for the hyperinflammatory component. Pharmacogenomics: none established.

13. Prevention

Primary: no population prevention; genetic counseling and carrier/cascade screening in consanguineous families; prenatal/preimplantation genetic diagnosis for known familial variants.
Secondary: early genetic diagnosis in a neonate/infant with recurrent fever + neutrophilic panniculitis + FTT, enabling early anti-TNF before organ damage.
Tertiary: chronic cytokine blockade to prevent flares; hepatic surveillance (steatosis→HCC risk); for haploinsufficiency — trigger avoidance (wound/surgical prophylaxis, prompt treatment of S. aureus), and antibody-mediated protection concepts.
Immunization: no disease-specific vaccine; standard immunisation with attention to live-vaccine caution under biologics; anti-α-toxin vaccination is a theoretical research direction for haploinsufficiency.

14. Other Species / Natural Disease

Taxonomy: mechanistic/genetic models in mouse (Mus musculus, NCBITaxon:10090). The gene was first characterised in mouse as gumby/*Fam105b (Rivkin et al., Nature 2013, PMID:23708998 — angiogenesis/Otulin developmental role). Human pathogen relevant to the haploinsufficiency form: Staphylococcus aureus* (NCBITaxon:1280).
Orthologous gene: mouse Otulin (Entrez 71753). Strong evolutionary conservation of the OTU domain and M1-Ub machinery (LUBAC/OTULIN axis conserved across vertebrates).
Natural animal disease: no naturally occurring OTULIN autoinflammatory disease is catalogued in OMIA for companion animals/livestock (based on this literature review); disease knowledge in animals is from engineered models, not spontaneous disease.
Comparative pathology caveat: mouse haploinsufficiency inflammation is hematopoietic-driven, whereas human haploinsufficiency necrosis is non-hematopoietic/stromal — an explicit human–model mismatch (PMID:38827742 vs 35587511), important for KB HUMAN_MODEL_MISMATCH annotation.
Zoonosis: not applicable (the disease is genetic; the trigger S. aureus is a common commensal/pathogen, not a zoonotic transmission of the disease).

15. Model Organisms

Germline knockout mouse (Otulin LacZ / gumby): homozygous loss is embryonic lethal (~E12.5–E14), with angiogenesis/Wnt defects (PMID:23708998; PMID:27523608 full text). Models early developmental OTULIN function; not viable for inflammation study.
Catalytically inactive knock-in (Otulin C129A/gumby-type): Heger et al. (Nature 2018, PMID:29950720) — "Catalytically inactive OTULIN knock-in mice died midgestation from TNFR1- and RIPK1-kinase-dependent cell death"; rescued by co-deletion of Casp8/Ripk3; elevated type I IFN. Establishes OTULIN restrains LUBAC and limits cell death/inflammation.
Conditional (Cre-lox) tissue-specific deletions (key for dissecting cell-type contributions; PMID:27523608 full text):
LysM-Cre (myeloid): viable; splenomegaly/hepatomegaly, leukocytosis, elevated serum cytokines (TNF, IL-6, IL-1β, G-CSF), fibrosis, autoantibodies — recapitulates systemic autoinflammation.
CD4-Cre (T cell) and MB1-Cre (B cell): no overt inflammatory phenotype → inflammation is myeloid-driven.
CreERT2 (tamoxifen-inducible, bone-marrow chimera): rapid wasting, neutrophilia, high TNF/IL-6/G-CSF; anti-TNF prevents wasting — supports anti-TNF efficacy.
Epidermis-specific (keratinocyte): skin inflammation via TNFR1/RIPK1-kinase-dependent necroptosis (Schünke, Nat Commun 2021, PMID:34625557).
Hepatocyte-specific: steatohepatitis→fibrosis→HCC, FADD/RIPK1-dependent, mTOR-associated (PMID:32231246, 32075762).
Myeloid (RIPK3/Nlrp3 axis): PMID:38000038.
Haploinsufficient mouse (Otulin+/−): LPS-provoked hyperinflammation driven by CD64+ monocytes/macrophages — but hematopoietic-driven, unlike human (PMID:38827742) — a documented translational limitation.
Patient iPSC model: iPSC line from a patient homozygous for L272P (Chen, Stem Cell Res 2020, PMID:32721894; line NIHTVBi014-A) — a human cellular NAM for mechanism/drug studies.
Resources: MGI (mouse Otulin), IMPC/KOMP (knockout alleles), Cellosaurus (iPSC line).
Model recapitulation summary: tissue-specific conditional KOs faithfully reproduce organ-specific disease (skin, liver, myeloid inflammation) and validate TNF/RIPK1 as drivers; whole-body null is lethal (developmental confounder); haploinsufficiency mouse diverges from the human stromal/α-toxin mechanism.

Key Evidence Citations (PMIDs)

PMID	Role	Evidence type
27559085	Founding description, otulipenia, variants L272P/Y244C/G174fs	HUMAN_CLINICAL
27523608	Founding ORAS, L272P, anti-TNF, LysM-Cre mouse	HUMAN_CLINICAL + MODEL_ORGANISM (split)
23746843	OTULIN = Met1-specific DUB, structure, LUBAC	IN_VITRO
23708998	gumby/Fam105b, angiogenesis, mouse	MODEL_ORGANISM
30804083	Cell-type-specific LUBAC degradation, G281R, HSCT cure	HUMAN_CLINICAL + IN_VITRO
30796585	Novel homozygous mutation case (abstract not public)	HUMAN_CLINICAL
35170849	Atypical late-onset ORAS, M86I/W167S	HUMAN_CLINICAL
38914362	New case W199R + GenIA review	HUMAN_CLINICAL
40734169	3 Arab patients V185F + 13-patient pooled table	HUMAN_CLINICAL
32231246	Liver disease, mTOR/rapamycin	HUMAN_CLINICAL + MODEL_ORGANISM
32075762	Hepatocyte apoptosis→HCC, FADD/RIPK1	MODEL_ORGANISM
29950720	Catalytic-dead KI mouse, LUBAC regulation	MODEL_ORGANISM
34625557	Keratinocyte necroptosis mouse	MODEL_ORGANISM
38000038	Myeloid RIPK3→NLRP3→IL-1β	MODEL_ORGANISM
35587511	Haploinsufficiency, caveolin-1/α-toxin, 5p−, penetrance	HUMAN_CLINICAL + IN_VITRO
41293556	Haploinsufficiency, broadened triggers, 6 patients	HUMAN_CLINICAL
38578307	Haploinsufficiency hyperinflammation	HUMAN_CLINICAL
38129331	Haploinsufficiency fasciitis treated by TNF inhibition	HUMAN_CLINICAL
40084498	Post-surgical necrosis, R263W	HUMAN_CLINICAL
38630025	Dominant-negative C129S	HUMAN_CLINICAL + IN_VITRO
38652464	Dominant-negative R306Q (de novo)	HUMAN_CLINICAL + IN_VITRO
42297973	Isolated pyoderma gangrenosum, R57C	HUMAN_CLINICAL + IN_VITRO
32721894	Patient iPSC (L272P)	IN_VITRO
38827742	Otulin+/− mouse (human-model mismatch)	MODEL_ORGANISM

Curation notes / flags for KB entry

The existing kb/disorders/OTULIN-Related_Autoinflammatory_Syndrome.yaml is a bare skeleton (name, synonyms, MONDO:0014912, one empty pathophysiology node, one phenotype stub) with no evidence. This report provides the content to populate it.
Two (arguably three) distinct diseases share this gene. Recommend modelling classical recessive ORAS as the primary entry, with OTULIN haploinsufficiency either as a has_subtypes stratum or (given two divergent axes — inheritance AD vs AR, and a distinct stromal/α-toxin mechanism and necrosis phenotype) a candidate separate entry per the Mendelian lump/split rules. Capture the dominant-negative heterozygous ORAS (C129S, R306Q) via an Inheritance block + variant_origin/functional_impact_category: DOMINANT_NEGATIVE.
Inheritance: bind AR as primary (ClinGen Definitive, AR, 2026-05-19 — record as gene_disease_validity with classified_by: CLINGEN, quoting the CGGV row after fetching it). Add a separate AD mode for haploinsufficiency.
Human–model mismatch (PMID:38827742 vs 35587511) is a clean HUMAN_MODEL_MISMATCH discussion candidate.
Cancer link: hepatocellular carcinoma via chronic hepatocyte death (mouse + case) — note but do not over-claim in humans (single patient with steatotic liver disease, HCC shown in mouse).
Before curating: run just fetch-reference for each PMID above, ORPHA:500062, and the ClinGen CGGV assertion; verify every snippet as an exact substring per the dismech-references workflow (the short quotes in this report are abstract/full-text excerpts gathered via EuropePMC and must be re-verified against the fetched cache before use as evidence snippet: values).

Sources: Orphanet ORPHA:500062 / Infevers · MONDO:0014912 (OLS4) · ClinGen OTULIN (HGNC:25118) · MalaCards AIPDSB · PubMed/EuropePMC records for the PMIDs cited above.

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	34
Resolved	34
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	34
On topic	22
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	99
Resolved	96
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	16
Terms named correctly	11
Terms named as a different term	1
Terms whose name is worth a second look	4

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:

NCIT:C15620 (1 mention) - the report calls it "antibiotic therapy", "Haploinsufficiency-specific supportive care: aggressive antibiotic therapy"; NCIT calls it Antibiotic Therapy

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:

MONDO:0014912 (9 mentions) - the report calls it "OLS4"; MONDO calls it autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, and lists "ORAS" among its other names
HP:0031281 (1 mention) - the report calls it "Sialadenitis / parotitis"; HP calls it Sialadenitis
HP:0025452 (2 mentions) - the report calls it "Pyoderma gangrenosum (R57C only)"; HP calls it Pyoderma gangrenosum
NCIT:C642 (1 mention) - the report calls it "Other immunomodulators: methotrexate"; NCIT calls it Methotrexate**

Terms named inconsistently

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

NCIT:C15620 - called "antibiotic therapy", "Haploinsufficiency-specific supportive care: aggressive antibiotic therapy"

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: OMIM, ORPHA.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

Classical recessive ORAS (neonatal/infantile autoinflammation)

OTULIN haploinsufficiency (distinct phenotype)

Isolated pyoderma gangrenosum (newest allelic presentation)

4. Genetic / Molecular Information

Pathogenic variants — recessive ORAS (biallelic)

Variants — dominant OTULIN haploinsufficiency

Dominant-negative heterozygous ORAS

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (recessive loss-of-function ORAS)

Causal chain (dominant haploinsufficiency necrosis)

Mechanistic modules / pathways (for KB linking)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Evidence Citations (PMIDs)

Curation notes / flags for KB entry

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver