Congenital Insensitivity to Pain

Mendelian MONDO:0015364 Pathograph 15

Congenital insensitivity to pain (CIP) is curated here as a phenotype-grouping and navigation entry for rare Mendelian disorders with lifelong absence of protective pain perception from birth. The grouped disorders fall into two broad mechanism classes: developmental nociceptor disorders involving PRDM12 and the NGF-TRKA axis, and nociceptor channelopathies involving SCN9A and SCN11A. This page intentionally captures only the shared phenotype frame, high-value distinguishing features, and a minimal connected pathograph rather than asserting a single fully unified disease mechanism.

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10
Pathophys.
6
Phenotypes
15
Pathograph
6
Genes
5
Subtypes
4
References
1
Deep Research
◆

Subtypes

5
NTRK1-related HSAN IV / congenital insensitivity to pain with anhidrosis MONDO:0009746
Classic congenital insensitivity to pain with anhidrosis branch caused by failure of NGF-TRKA-dependent nociceptor and sympathetic development, typically with anhidrosis, recurrent fever, self-injury, and documented intellectual disability in affected cohorts.
Show evidence (2 references)
PMID:16138253 SUPPORT Human Clinical
"Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF)."
Supports NTRK1 as the canonical HSAN IV / CIPA branch of the CIP grouping.
PMID:16138253 SUPPORT Human Clinical
"They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation;"
Captures intellectual disability as a distinguishing HSAN IV feature.
NGF-related HSAN V MONDO:0012092
Developmental CIP branch caused by ligand-side disruption of NGF signaling, typically with deep-pain and temperature loss, small-fiber neuropathy, and relatively preserved cognition compared with CIPA.
Show evidence (1 reference)
PMID:14976160 SUPPORT Human Clinical
"Clinically they best fit into HSAN V."
Establishes NGF / NGFB mutation as the cause of the HSAN V branch.
SCN9A-related channelopathy-associated congenital insensitivity to pain MONDO:0009459
Nondevelopmental channelopathy branch in which nociceptors are present but Nav1.7 loss of function prevents effective nociceptive signaling; congenital anosmia is the classic associated clue.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"The commonest condition within this group is CIP-SCN9A (also called channelopathy associated with CIP). In CIP-SCN9A the only additional feature is congenital anosmia (absence of the sense of smell), and many adults have gone undiagnosed, and/or unbelieved when they explain that they don’t feel pain."
Review evidence supports SCN9A-associated CIP as the major channelopathy subtype and highlights anosmia as its key associated feature.
SCN11A-related HSAN VII / congenital inability to experience pain MONDO:0014244
Dominant Nav1.9 channelopathy branch with paradoxical painlessness, gastrointestinal hypomotility, pruritus, mild weakness, and tissue damage caused by gain-of-function depolarization block.
Show evidence (1 reference)
PMID:24036948 SUPPORT Human Clinical
"Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations."
Establishes SCN11A as the cause of the HSAN VII / congenital inability to experience pain branch.
PRDM12-related HSAN VIII / congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Developmental PRDM12 branch with congenital painlessness from defective nociceptor specification, often with relatively preserved cognition and olfaction compared with classic CIPA. Older reviews may describe this branch as HSAN VI rather than HSAN VIII.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"In 2015 a new HSAN4-like phenotype was reported caused by bi-allelic mutations in PRDM12 (clinically known as HSAN6)."
Review evidence establishes PRDM12 as a distinct developmental CIP branch and captures the legacy nomenclature.
⚙

Pathophysiology

10
Impaired nociceptor specification
PRDM12-related CIP begins as a developmental failure to impose nociceptor identity and precursor differentiation.
Nociceptor link
PRDM12 link
neuron development link ⚠ ABNORMAL
Downstream
NGF-TRKA trophic signaling failure Reduced PRDM12 activity impairs the developmental program that normally establishes NTRK1 expression in nociceptor precursors.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"PRDM12 and CLTCL1 are important in the differentiation from a neural crest cell to a precursor sensory neuron."
Supports PRDM12-driven failure of nociceptor specification as an atomic developmental lesion.
NGF-TRKA trophic signaling failure
NTRK1- and NGF-related developmental CIP disrupts the neurotrophin signaling axis needed for nociceptor genesis, maturation, and survival.
Nociceptor link
NTRK1 link NGF link
neurotrophin TRK receptor signaling pathway link ↓ DECREASED
Downstream
Developmental nociceptor apoptosis Failure of trophic support causes early nociceptor loss during development.
Impaired NGF-TRKA-dependent macrophage killing The same pathway also contributes to macrophage antibacterial responses, explaining infection susceptibility in developmental CIP forms.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing."
Defines the NGF-TRKA axis as the central trophic pathway for developmental CIP.
Developmental nociceptor apoptosis
Developmental CIP converts trophic failure into structural denervation by early loss of nociceptors.
Nociceptor link
NTRK1 link NGF link
apoptotic process link ↑ INCREASED
Downstream
Reduced nociceptor and small-fiber innervation Early apoptosis yields the characteristic loss of pain-transducing small fibers in developmental CIP.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"CIP can be clinically divided into two groups: developmental disorders where nociceptors fail to develop or undergo early apoptosis through lack of trophic signals;"
Supports early nociceptor apoptosis as a distinct downstream event within developmental CIP.
Reduced nociceptor and small-fiber innervation
Developmental CIP forms show reduced C-fiber and A-delta-fiber innervation rather than merely an altered pain threshold.
Nociceptor link
Downstream
Loss of protective pain perception Structural denervation removes the afferent substrate required for normal pain sensing.
Show evidence (1 reference)
PMID:14976160 SUPPORT Human Clinical
"A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients."
Direct pathology evidence that developmental CIP manifests as loss of small pain fibers.
Nav1.7 loss-of-function channelopathy
SCN9A-associated CIP preserves nociceptors anatomically but disables Nav1.7, preventing normal electrical responses to tissue-damage signals.
Nociceptor link
SCN9A link
regulation of membrane potential link ⚠ ABNORMAL
Downstream
Impaired nociceptor excitability Loss of Nav1.7 function leaves nociceptors present but unable to transmit normal warning signals.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"So, activating mutations in SCN9A produce paroxysmal neuropathic pain, with no other obvious clinical features. And bi-allelic non-functional mutations cause congenital painlessness, with the only other consequence being anosmia."
Supports SCN9A loss of function as the canonical Nav1.7-related painless channelopathy.
Nav1.9 depolarization-block channelopathy
SCN11A-associated CIP is a paradoxical gain-of-function state in which excessive resting activity of Nav1.9 depolarizes nociceptors and blocks productive action-potential firing.
Nociceptor link
SCN11A link
membrane depolarization link ⚠ ABNORMAL
Downstream
Impaired nociceptor excitability Sustained depolarization prevents normal action-potential generation in nociceptors.
Show evidence (1 reference)
PMID:24036948 SUPPORT Human Clinical
"Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission."
Defines the Nav1.9 depolarization-block mechanism as an atomic SCN11A node.
Impaired nociceptor excitability
In channelopathy-associated CIP, nociceptors are present but electrically unable to generate or propagate appropriate warning signals.
Nociceptor link
SCN9A link SCN11A link
regulation of membrane potential link ⚠ ABNORMAL
Downstream
Loss of protective pain perception Failure of nociceptor firing abolishes warning pain despite preserved neuronal anatomy.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Individuals with second type of CIP are born with nociceptors that are unable to be activated by tissue-damage signals,"
Shared review evidence for the preserved-but-electrically-silent nociceptor model.
Impaired NGF-TRKA-dependent macrophage killing
Developmental NGF-TRKA CIP forms also weaken macrophage-mediated host defense against Staphylococcus aureus.
Macrophage link
NTRK1 link NGF link
phagocytosis link ↓ DECREASED
Downstream
Staphylococcus aureus infection susceptibility Reduced macrophage killing capacity predisposes to recurrent deep and skin infections in developmental CIP forms.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling."
Supports a distinct macrophage host-defense defect in developmental CIP.
Staphylococcus aureus infection susceptibility
Developmental CIP forms, but not channelopathy-associated forms, show a distinctive propensity to osteomyelitis, septic arthritis, and skin infection with Staphylococcus aureus.
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Distinctive to HSANs is a significant susceptibility to Staphylococcus aureus infections manifest as grumbling skin infections, osteomyelitis and septic arthritis."
Captures the clinically important infection susceptibility of developmental CIP forms.
Loss of protective pain perception
Both structural denervation and channelopathic firing failure converge on the same final phenotype: absent protective pain responses with severe injury-related morbidity.
Nociceptor link
sensory perception of pain link ↓ DECREASED
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Congenital insensitivity to pain (CIP) is an extremely rare human phenotype where no pain of any type is experienced during an affected individuals’ lifetime."
Defines the shared final phenotype across all grouped CIP branches.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Insensitivity to Pain Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Head and Neck 1
Anosmia Anosmia (HP:0000458)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"In CIP-SCN9A the only additional feature is congenital anosmia (absence of the sense of smell),"
Supports anosmia as the distinguishing SCN9A-associated phenotype.
Immune 1
Osteomyelitis Osteomyelitis (HP:0002754)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Distinctive to HSANs is a significant susceptibility to Staphylococcus aureus infections manifest as grumbling skin infections, osteomyelitis and septic arthritis."
Captures osteomyelitis as a distinctive complication of developmental CIP branches.
Nervous System 1
Intellectual disability Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:16138253 SUPPORT Human Clinical
"They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation;"
Supports intellectual disability as a documented HSAN IV feature.
Other 3
Pain insensitivity Pain insensitivity (HP:0007021)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Congenital insensitivity to pain (CIP) is an extremely rare human phenotype where no pain of any type is experienced during an affected individuals’ lifetime."
Supports the core umbrella phenotype of absent pain sensation.
Self-mutilation Self-mutilation (HP:0000742)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Coincident with teething in the first year of life, self-mutilation of lips, tongue, fingers and toes often occur."
Supports self-injury as a recurrent shared consequence of CIP.
Neuropathic arthropathy Neuropathic arthropathy (HP:0002821)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"Long bone fractures can heal, if allowed to do so, but it is the joint injuries that inevitably lead to Charcot’s joints, and hence progressive orthopaedic deformities."
Supports Charcot-joint arthropathy as a shared morbidity of CIP.
🧬

Genetic Associations

6
NTRK1 (Causative)
Show evidence (1 reference)
PMID:16138253 SUPPORT Human Clinical
"Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF)."
Direct human evidence that NTRK1 mutations cause the HSAN IV / CIPA branch.
NGF (Causative)
Show evidence (2 references)
PMID:14976160 SUPPORT Human Clinical
"Clinically they best fit into HSAN V."
Direct evidence that NGF mutation causes the HSAN V form of CIP.
CGGV:assertion_f0b3691d-a3d3-42f6-9703-18af08f40688-2023-05-05T160000.000Z SUPPORT Other
"NGF | HGNC:7808 | hereditary sensory and autonomic neuropathy | MONDO:0015364 | AR | Strong"
ClinGen classifies the NGF-hereditary sensory and autonomic neuropathy gene-disease relationship as strong with autosomal recessive inheritance.
SCN9A (Causative)
Show evidence (1 reference)
PMID:32219415 SUPPORT Other
"So, activating mutations in SCN9A produce paroxysmal neuropathic pain, with no other obvious clinical features. And bi-allelic non-functional mutations cause congenital painlessness, with the only other consequence being anosmia."
Review evidence distinguishes the painless SCN9A loss-of-function phenotype from painful SCN9A gain-of-function disorders.
SCN11A (Causative)
Show evidence (2 references)
PMID:24036948 SUPPORT Human Clinical
"Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations."
Human genetic evidence establishing SCN11A as a cause of congenital painlessness.
PMID:24036948 SUPPORT Human Clinical
"Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission."
Functional evidence shows why SCN11A gain of function produces painlessness rather than pain.
PRDM12 (Causative)
Show evidence (2 references)
PMID:32219415 SUPPORT Other
"In 2015 a new HSAN4-like phenotype was reported caused by bi-allelic mutations in PRDM12 (clinically known as HSAN6)."
Review evidence establishes PRDM12 as a distinct developmental CIP gene.
PMID:32219415 SUPPORT Other
"The recent finding that PRDM12 activated NTRK1 expression in nociceptor precursors further cemented the absolute importance of NGF-TRKA signalling for nociceptor genesis."
Supports PRDM12 as an upstream nociceptor-specification regulator linked mechanistically to the NGF-TRKA program.
RETREG1 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_e0b9041f-06f2-47c8-b070-5d4cfaaeb2db-2024-07-08T160000.000Z SUPPORT Other
"RETREG1 | HGNC:25964 | hereditary sensory and autonomic neuropathy | MONDO:0015364 | AR | Definitive"
ClinGen classifies the RETREG1-hereditary sensory and autonomic neuropathy gene-disease relationship as definitive with autosomal recessive inheritance.
{ }

Source YAML

click to show 
name: Congenital Insensitivity to Pain
creation_date: "2026-04-16T19:22:23Z"
updated_date: "2026-05-09T06:24:06Z"
category: Mendelian
synonyms:
- CIP
- congenital analgesia
- congenital painlessness
description: >-
  Congenital insensitivity to pain (CIP) is curated here as a phenotype-grouping
  and navigation entry for rare Mendelian disorders with lifelong absence of
  protective pain perception from birth. The grouped disorders fall into two
  broad mechanism classes: developmental nociceptor disorders involving PRDM12
  and the NGF-TRKA axis, and nociceptor channelopathies involving SCN9A and
  SCN11A. This page intentionally captures only the shared phenotype frame,
  high-value distinguishing features, and a minimal connected pathograph rather
  than asserting a single fully unified disease mechanism.
disease_term:
  preferred_term: congenital insensitivity to pain
  term:
    id: MONDO:0015364
    label: hereditary sensory and autonomic neuropathy
notes: >-
  The exact MONDO term "congenital insensitivity to pain" is requested in MONDO
  NTR  # 10031; until that term exists, this page anchors to the broader
  hereditary sensory and autonomic neuropathy parent while functioning as a
  thin phenotype-grouping page. Subtype-specific mechanistic and management
  detail should ultimately live in dedicated child entries.
review_notes: >-
  This revision intentionally hard-trims the prior umbrella into a navigation
  entry: the shared phenotype frame is retained, the pathophysiology nodes are
  now atomic and connected, and subtype-specific distinguishing findings are
  captured without pretending that all grouped branches constitute one cleanly
  unified disease entity.
references:
- reference: PMID:32219415
  title: "Understanding the genetic basis of congenital insensitivity to pain."
  found_in:
  - Congenital_Insensitivity_to_Pain-deep-research-manual.md
  findings:
  - statement: >-
      Congenital insensitivity to pain (CIP) is caused by extremely rare
      Mendelian genetic disorders.
    supporting_text: >-
      Congenital insensitivity to pain (CIP) is caused by extremely rare
      Mendelian genetic disorders.
- reference: PMID:16138253
  title: >-
    Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and early
    onset renal disease: clinical report on three sibs with a 25-year follow-up
    in one of them.
  found_in:
  - Congenital_Insensitivity_to_Pain-deep-research-manual.md
  findings:
  - statement: >-
      Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal
      recessive disorder caused by mutations in the neurotrophic tyrosine
      receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve
      growth factor (NGF).
    supporting_text: >-
      Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal
      recessive disorder caused by mutations in the neurotrophic tyrosine
      receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve
      growth factor (NGF).
- reference: PMID:14976160
  title: >-
    A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain
    perception.
  found_in:
  - Congenital_Insensitivity_to_Pain-deep-research-manual.md
  findings:
  - statement: >-
      Clinically they best fit into HSAN V.
    supporting_text: >-
      Clinically they best fit into HSAN V.
- reference: PMID:24036948
  title: >-
    A de novo gain-of-function mutation in SCN11A causes loss of pain
    perception.
  found_in:
  - Congenital_Insensitivity_to_Pain-deep-research-manual.md
  findings:
  - statement: >-
      Using exome sequencing, we identified a specific de novo missense
      mutation in SCN11A in individuals with the congenital inability to
      experience pain who suffer from recurrent tissue damage and severe
      mutilations.
    supporting_text: >-
      Using exome sequencing, we identified a specific de novo missense
      mutation in SCN11A in individuals with the congenital inability to
      experience pain who suffer from recurrent tissue damage and severe
      mutilations.
has_subtypes:
- name: HSAN IV
  display_name: NTRK1-related HSAN IV / congenital insensitivity to pain with anhidrosis
  subtype_term:
    preferred_term: hereditary sensory and autonomic neuropathy type 4
    term:
      id: MONDO:0009746
      label: hereditary sensory and autonomic neuropathy type 4
  description: >-
    Classic congenital insensitivity to pain with anhidrosis branch caused by
    failure of NGF-TRKA-dependent nociceptor and sympathetic development,
    typically with anhidrosis, recurrent fever, self-injury, and documented
    intellectual disability in affected cohorts.
  evidence:
  - reference: PMID:16138253
    reference_title: >-
      Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and
      early onset renal disease: clinical report on three sibs with a 25-year
      follow-up in one of them.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal
      recessive disorder caused by mutations in the neurotrophic tyrosine
      receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve
      growth factor (NGF).
    explanation: Supports NTRK1 as the canonical HSAN IV / CIPA branch of the CIP grouping.
  - reference: PMID:16138253
    reference_title: >-
      Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and
      early onset renal disease: clinical report on three sibs with a 25-year
      follow-up in one of them.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They had the characteristic clinical features of an abnormally high pain
      threshold, and mental retardation;
    explanation: Captures intellectual disability as a distinguishing HSAN IV feature.
- name: HSAN V
  display_name: NGF-related HSAN V
  subtype_term:
    preferred_term: hereditary sensory and autonomic neuropathy type 5
    term:
      id: MONDO:0012092
      label: hereditary sensory and autonomic neuropathy type 5
  description: >-
    Developmental CIP branch caused by ligand-side disruption of NGF signaling,
    typically with deep-pain and temperature loss, small-fiber neuropathy, and
    relatively preserved cognition compared with CIPA.
  evidence:
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically they best fit into HSAN V.
    explanation: Establishes NGF / NGFB mutation as the cause of the HSAN V branch.
- name: SCN9A AR-CIP
  display_name: SCN9A-related channelopathy-associated congenital insensitivity to pain
  subtype_term:
    preferred_term: channelopathy-associated congenital insensitivity to pain, autosomal recessive
    term:
      id: MONDO:0009459
      label: channelopathy-associated congenital insensitivity to pain, autosomal recessive
  description: >-
    Nondevelopmental channelopathy branch in which nociceptors are present but
    Nav1.7 loss of function prevents effective nociceptive signaling;
    congenital anosmia is the classic associated clue.
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The commonest condition within this group is CIP-SCN9A (also called
      channelopathy associated with CIP). In CIP-SCN9A the only additional
      feature is congenital anosmia (absence of the sense of smell), and many
      adults have gone undiagnosed, and/or unbelieved when they explain that
      they don’t feel pain.
    explanation: Review evidence supports SCN9A-associated CIP as the major channelopathy subtype and highlights anosmia as its key associated feature.
- name: HSAN VII
  display_name: SCN11A-related HSAN VII / congenital inability to experience pain
  subtype_term:
    preferred_term: hereditary sensory and autonomic neuropathy type 7
    term:
      id: MONDO:0014244
      label: hereditary sensory and autonomic neuropathy type 7
  description: >-
    Dominant Nav1.9 channelopathy branch with paradoxical painlessness,
    gastrointestinal hypomotility, pruritus, mild weakness, and tissue damage
    caused by gain-of-function depolarization block.
  evidence:
  - reference: PMID:24036948
    reference_title: "A de novo gain-of-function mutation in SCN11A causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we identified a specific de novo missense
      mutation in SCN11A in individuals with the congenital inability to
      experience pain who suffer from recurrent tissue damage and severe
      mutilations.
    explanation: Establishes SCN11A as the cause of the HSAN VII / congenital inability to experience pain branch.
- name: HSAN VIII
  display_name: PRDM12-related HSAN VIII / congenital insensitivity to pain-hypohidrosis syndrome
  subtype_term:
    preferred_term: congenital insensitivity to pain-hypohidrosis syndrome
    term:
      id: MONDO:0014662
      label: congenital insensitivity to pain-hypohidrosis syndrome
  description: >-
    Developmental PRDM12 branch with congenital painlessness from defective
    nociceptor specification, often with relatively preserved cognition and
    olfaction compared with classic CIPA. Older reviews may describe this
    branch as HSAN VI rather than HSAN VIII.
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 2015 a new HSAN4-like phenotype was reported caused by bi-allelic
      mutations in PRDM12 (clinically known as HSAN6).
    explanation: Review evidence establishes PRDM12 as a distinct developmental CIP branch and captures the legacy nomenclature.
genetic:
- name: NTRK1
  gene_term:
    preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  association: Causative
  features: >-
    Biallelic NTRK1 variants define the classic HSAN IV / CIPA branch within
    this grouped phenotype entry.
  evidence:
  - reference: PMID:16138253
    reference_title: >-
      Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and
      early onset renal disease: clinical report on three sibs with a 25-year
      follow-up in one of them.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal
      recessive disorder caused by mutations in the neurotrophic tyrosine
      receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve
      growth factor (NGF).
    explanation: Direct human evidence that NTRK1 mutations cause the HSAN IV / CIPA branch.
- name: NGF
  gene_term:
    preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  association: Causative
  features: >-
    Homozygous NGF variants define the HSAN V branch and show that ligand-side
    disruption of the same trophic axis can produce congenital painlessness.
  evidence:
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically they best fit into HSAN V.
    explanation: Direct evidence that NGF mutation causes the HSAN V form of CIP.
  - reference: CGGV:assertion_f0b3691d-a3d3-42f6-9703-18af08f40688-2023-05-05T160000.000Z
    reference_title: "NGF / hereditary sensory and autonomic neuropathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NGF | HGNC:7808 | hereditary sensory and autonomic neuropathy | MONDO:0015364 | AR | Strong"
    explanation: ClinGen classifies the NGF-hereditary sensory and autonomic neuropathy gene-disease relationship as strong with autosomal recessive inheritance.
- name: SCN9A
  gene_term:
    preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  association: Causative
  features: >-
    Biallelic SCN9A loss-of-function variants cause channelopathy-associated
    CIP with anosmia and preserved nociceptor anatomy.
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      So, activating mutations in SCN9A produce paroxysmal neuropathic pain,
      with no other obvious clinical features. And bi-allelic non-functional
      mutations cause congenital painlessness, with the only other consequence
      being anosmia.
    explanation: Review evidence distinguishes the painless SCN9A loss-of-function phenotype from painful SCN9A gain-of-function disorders.
- name: SCN11A
  gene_term:
    preferred_term: SCN11A
    term:
      id: hgnc:10583
      label: SCN11A
  association: Causative
  features: >-
    Dominant SCN11A gain-of-function variants cause a paradoxical painless
    channelopathy by sustaining depolarization and blocking nociceptor firing.
  evidence:
  - reference: PMID:24036948
    reference_title: "A de novo gain-of-function mutation in SCN11A causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we identified a specific de novo missense
      mutation in SCN11A in individuals with the congenital inability to
      experience pain who suffer from recurrent tissue damage and severe
      mutilations.
    explanation: Human genetic evidence establishing SCN11A as a cause of congenital painlessness.
  - reference: PMID:24036948
    reference_title: "A de novo gain-of-function mutation in SCN11A causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutant Nav1.9 channels displayed excessive activity at resting voltages,
      causing sustained depolarization of nociceptors, impaired generation of
      action potentials and aberrant synaptic transmission.
    explanation: Functional evidence shows why SCN11A gain of function produces painlessness rather than pain.
- name: PRDM12
  gene_term:
    preferred_term: PRDM12
    term:
      id: hgnc:13997
      label: PRDM12
  association: Causative
  features: >-
    Biallelic PRDM12 variants define a developmental CIP branch by impairing
    nociceptor specification upstream of the NGF-TRKA program.
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 2015 a new HSAN4-like phenotype was reported caused by bi-allelic
      mutations in PRDM12 (clinically known as HSAN6).
    explanation: Review evidence establishes PRDM12 as a distinct developmental CIP gene.
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recent finding that PRDM12 activated NTRK1 expression in nociceptor
      precursors further cemented the absolute importance of NGF-TRKA
      signalling for nociceptor genesis.
    explanation: Supports PRDM12 as an upstream nociceptor-specification regulator linked mechanistically to the NGF-TRKA program.
- name: RETREG1
  gene_term:
    preferred_term: RETREG1
    term:
      id: hgnc:25964
      label: RETREG1
  association: Pathogenic Variants
  features: >-
    Biallelic RETREG1 variants define an additional hereditary sensory and
    autonomic neuropathy branch within the broader CIP/HSAN grouping.
  evidence:
  - reference: CGGV:assertion_e0b9041f-06f2-47c8-b070-5d4cfaaeb2db-2024-07-08T160000.000Z
    reference_title: "RETREG1 / hereditary sensory and autonomic neuropathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RETREG1 | HGNC:25964 | hereditary sensory and autonomic neuropathy | MONDO:0015364 | AR | Definitive"
    explanation: ClinGen classifies the RETREG1-hereditary sensory and autonomic neuropathy gene-disease relationship as definitive with autosomal recessive inheritance.
pathophysiology:
- name: Impaired nociceptor specification
  description: >-
    PRDM12-related CIP begins as a developmental failure to impose nociceptor
    identity and precursor differentiation.
  genes:
  - preferred_term: PRDM12
    term:
      id: hgnc:13997
      label: PRDM12
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: neuron development
    modifier: ABNORMAL
    term:
      id: GO:0048666
      label: neuron development
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRDM12 and CLTCL1 are important in the differentiation from a neural
      crest cell to a precursor sensory neuron.
    explanation: Supports PRDM12-driven failure of nociceptor specification as an atomic developmental lesion.
  downstream:
  - target: NGF-TRKA trophic signaling failure
    description: >-
      Reduced PRDM12 activity impairs the developmental program that normally
      establishes NTRK1 expression in nociceptor precursors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The recent finding that PRDM12 activated NTRK1 expression in
        nociceptor precursors further cemented the absolute importance of
        NGF-TRKA signalling for nociceptor genesis.
      explanation: Directly connects PRDM12-dependent specification to the NGF-TRKA trophic axis.
- name: NGF-TRKA trophic signaling failure
  description: >-
    NTRK1- and NGF-related developmental CIP disrupts the neurotrophin signaling
    axis needed for nociceptor genesis, maturation, and survival.
  genes:
  - preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  - preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: neurotrophin TRK receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0048011
      label: neurotrophin TRK receptor signaling pathway
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The importance of nerve growth factor-tropomyosin receptor kinase A
      (NGF-TRKA) signalling for nociceptor genesis and subsequent pain
      sensing.
    explanation: Defines the NGF-TRKA axis as the central trophic pathway for developmental CIP.
  downstream:
  - target: Developmental nociceptor apoptosis
    description: >-
      Failure of trophic support causes early nociceptor loss during
      development.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CIP can be clinically divided into two groups: developmental disorders
        where nociceptors fail to develop or undergo early apoptosis through
        lack of trophic signals;
      explanation: Directly links trophic signaling failure to developmental nociceptor apoptosis.
  - target: Impaired NGF-TRKA-dependent macrophage killing
    description: >-
      The same pathway also contributes to macrophage antibacterial responses,
      explaining infection susceptibility in developmental CIP forms.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Increased susceptibility to Staphylococcus aureus infection is a
        consequence of deficient NGF-TRKA signalling.
      explanation: Directly connects deficient NGF-TRKA signaling to impaired host defense.
- name: Developmental nociceptor apoptosis
  description: >-
    Developmental CIP converts trophic failure into structural denervation by
    early loss of nociceptors.
  genes:
  - preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  - preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CIP can be clinically divided into two groups: developmental disorders
      where nociceptors fail to develop or undergo early apoptosis through
      lack of trophic signals;
    explanation: Supports early nociceptor apoptosis as a distinct downstream event within developmental CIP.
  downstream:
  - target: Reduced nociceptor and small-fiber innervation
    description: >-
      Early apoptosis yields the characteristic loss of pain-transducing small
      fibers in developmental CIP.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14976160
      reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A severe reduction of unmyelinated nerve fibers and a moderate loss of
        thin myelinated nerve fibers are observed in the patients.
      explanation: Links developmental nociceptor loss to the small-fiber deficit seen in HSAN V.
- name: Reduced nociceptor and small-fiber innervation
  description: >-
    Developmental CIP forms show reduced C-fiber and A-delta-fiber innervation
    rather than merely an altered pain threshold.
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  evidence:
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A severe reduction of unmyelinated nerve fibers and a moderate loss of
      thin myelinated nerve fibers are observed in the patients.
    explanation: Direct pathology evidence that developmental CIP manifests as loss of small pain fibers.
  downstream:
  - target: Loss of protective pain perception
    description: >-
      Structural denervation removes the afferent substrate required for normal
      pain sensing.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Congenital insensitivity to pain (CIP) is an extremely rare human
        phenotype where no pain of any type is experienced during an affected
        individuals’ lifetime.
      explanation: Connects reduced pain-fiber innervation to the shared analgesic phenotype.
- name: Nav1.7 loss-of-function channelopathy
  description: >-
    SCN9A-associated CIP preserves nociceptors anatomically but disables Nav1.7,
    preventing normal electrical responses to tissue-damage signals.
  genes:
  - preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: regulation of membrane potential
    modifier: ABNORMAL
    term:
      id: GO:0042391
      label: regulation of membrane potential
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      So, activating mutations in SCN9A produce paroxysmal neuropathic pain,
      with no other obvious clinical features. And bi-allelic non-functional
      mutations cause congenital painlessness, with the only other consequence
      being anosmia.
    explanation: Supports SCN9A loss of function as the canonical Nav1.7-related painless channelopathy.
  downstream:
  - target: Impaired nociceptor excitability
    description: >-
      Loss of Nav1.7 function leaves nociceptors present but unable to transmit
      normal warning signals.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Individuals with second type of CIP are born with nociceptors that are
        unable to be activated by tissue-damage signals,
      explanation: Directly links channelopathy-associated CIP to failed nociceptor activation.
- name: Nav1.9 depolarization-block channelopathy
  description: >-
    SCN11A-associated CIP is a paradoxical gain-of-function state in which
    excessive resting activity of Nav1.9 depolarizes nociceptors and blocks
    productive action-potential firing.
  genes:
  - preferred_term: SCN11A
    term:
      id: hgnc:10583
      label: SCN11A
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: membrane depolarization
    modifier: ABNORMAL
    term:
      id: GO:0051899
      label: membrane depolarization
  evidence:
  - reference: PMID:24036948
    reference_title: "A de novo gain-of-function mutation in SCN11A causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutant Nav1.9 channels displayed excessive activity at resting voltages,
      causing sustained depolarization of nociceptors, impaired generation of
      action potentials and aberrant synaptic transmission.
    explanation: Defines the Nav1.9 depolarization-block mechanism as an atomic SCN11A node.
  downstream:
  - target: Impaired nociceptor excitability
    description: >-
      Sustained depolarization prevents normal action-potential generation in
      nociceptors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24036948
      reference_title: "A de novo gain-of-function mutation in SCN11A causes loss of pain perception."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutant Nav1.9 channels displayed excessive activity at resting voltages,
        causing sustained depolarization of nociceptors, impaired generation of
        action potentials and aberrant synaptic transmission.
      explanation: Directly links the Nav1.9 defect to failed nociceptor firing.
- name: Impaired nociceptor excitability
  description: >-
    In channelopathy-associated CIP, nociceptors are present but electrically
    unable to generate or propagate appropriate warning signals.
  genes:
  - preferred_term: SCN9A
    term:
      id: hgnc:10597
      label: SCN9A
  - preferred_term: SCN11A
    term:
      id: hgnc:10583
      label: SCN11A
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: regulation of membrane potential
    modifier: ABNORMAL
    term:
      id: GO:0042391
      label: regulation of membrane potential
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with second type of CIP are born with nociceptors that are
      unable to be activated by tissue-damage signals,
    explanation: Shared review evidence for the preserved-but-electrically-silent nociceptor model.
  downstream:
  - target: Loss of protective pain perception
    description: >-
      Failure of nociceptor firing abolishes warning pain despite preserved
      neuronal anatomy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Congenital insensitivity to pain (CIP) is an extremely rare human
        phenotype where no pain of any type is experienced during an affected
        individuals’ lifetime.
      explanation: Connects excitability failure to the shared analgesic phenotype.
- name: Impaired NGF-TRKA-dependent macrophage killing
  description: >-
    Developmental NGF-TRKA CIP forms also weaken macrophage-mediated host
    defense against Staphylococcus aureus.
  genes:
  - preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  - preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: phagocytosis
    modifier: DECREASED
    term:
      id: GO:0006909
      label: phagocytosis
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Increased susceptibility to Staphylococcus aureus infection is a
      consequence of deficient NGF-TRKA signalling.
    explanation: Supports a distinct macrophage host-defense defect in developmental CIP.
  downstream:
  - target: Staphylococcus aureus infection susceptibility
    description: >-
      Reduced macrophage killing capacity predisposes to recurrent deep and
      skin infections in developmental CIP forms.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32219415
      reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Distinctive to HSANs is a significant susceptibility to Staphylococcus
        aureus infections manifest as grumbling skin infections,
        osteomyelitis and septic arthritis.
      explanation: Directly links defective NGF-TRKA macrophage signaling to the clinical infection phenotype.
- name: Staphylococcus aureus infection susceptibility
  description: >-
    Developmental CIP forms, but not channelopathy-associated forms, show a
    distinctive propensity to osteomyelitis, septic arthritis, and skin
    infection with Staphylococcus aureus.
  subtypes:
  - HSAN IV
  - HSAN V
  - HSAN VIII
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Distinctive to HSANs is a significant susceptibility to Staphylococcus
      aureus infections manifest as grumbling skin infections, osteomyelitis
      and septic arthritis.
    explanation: Captures the clinically important infection susceptibility of developmental CIP forms.
- name: Loss of protective pain perception
  description: >-
    Both structural denervation and channelopathic firing failure converge on
    the same final phenotype: absent protective pain responses with severe
    injury-related morbidity.
  cell_types:
  - preferred_term: Nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: sensory perception of pain
    modifier: DECREASED
    term:
      id: GO:0019233
      label: sensory perception of pain
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital insensitivity to pain (CIP) is an extremely rare human
      phenotype where no pain of any type is experienced during an affected
      individuals’ lifetime.
    explanation: Defines the shared final phenotype across all grouped CIP branches.
phenotypes:
- category: Neurological
  name: Pain insensitivity
  diagnostic: true
  description: >-
    Shared defining phenotype across the grouped CIP disorders, reflecting loss
    of protective pain sensation from birth.
  phenotype_term:
    preferred_term: Congenital insensitivity to pain
    term:
      id: HP:0007021
      label: Pain insensitivity
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital insensitivity to pain (CIP) is an extremely rare human
      phenotype where no pain of any type is experienced during an affected
      individuals’ lifetime.
    explanation: Supports the core umbrella phenotype of absent pain sensation.
- category: Behavioral
  name: Self-mutilation
  description: >-
    Early repetitive biting and tissue injury are common consequences of absent
    protective pain sensation, especially after teething.
  phenotype_term:
    preferred_term: Self-mutilation
    term:
      id: HP:0000742
      label: Self-mutilation
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Coincident with teething in the first year of life, self-mutilation of
      lips, tongue, fingers and toes often occur.
    explanation: Supports self-injury as a recurrent shared consequence of CIP.
- category: Musculoskeletal
  name: Neuropathic arthropathy
  description: >-
    Repetitive painless joint injury leads to Charcot-joint deformity and
    progressive orthopedic damage.
  phenotype_term:
    preferred_term: Neuropathic arthropathy (Charcot joint)
    term:
      id: HP:0002821
      label: Neuropathic arthropathy
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Long bone fractures can heal, if allowed to do so, but it is the joint
      injuries that inevitably lead to Charcot’s joints, and hence progressive
      orthopaedic deformities.
    explanation: Supports Charcot-joint arthropathy as a shared morbidity of CIP.
- category: Neurological
  name: Anosmia
  subtype: SCN9A AR-CIP
  description: >-
    Congenital anosmia is the characteristic associated feature of the SCN9A
    channelopathy branch.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In CIP-SCN9A the only additional feature is congenital anosmia
      (absence of the sense of smell),
    explanation: Supports anosmia as the distinguishing SCN9A-associated phenotype.
- category: Neurological
  name: Intellectual disability
  subtype: HSAN IV
  description: >-
    Cognitive impairment is documented in classic NTRK1-related CIPA and helps
    distinguish HSAN IV from some other CIP subtypes.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:16138253
    reference_title: >-
      Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and
      early onset renal disease: clinical report on three sibs with a 25-year
      follow-up in one of them.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They had the characteristic clinical features of an abnormally high pain
      threshold, and mental retardation;
    explanation: Supports intellectual disability as a documented HSAN IV feature.
- category: Infectious
  name: Osteomyelitis
  subtypes:
  - HSAN IV
  - HSAN V
  - HSAN VIII
  description: >-
    Developmental CIP forms show susceptibility to Staphylococcus aureus
    osteomyelitis and related deep infections.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  evidence:
  - reference: PMID:32219415
    reference_title: "Understanding the genetic basis of congenital insensitivity to pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Distinctive to HSANs is a significant susceptibility to Staphylococcus
      aureus infections manifest as grumbling skin infections, osteomyelitis
      and septic arthritis.
    explanation: Captures osteomyelitis as a distinctive complication of developmental CIP branches.
📚

References & Deep Research

References

4
PMID:32219415
Understanding the genetic basis of congenital insensitivity to pain.
1 finding
Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders.
"Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders."
PMID:16138253
Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and early onset renal disease: clinical report on three sibs with a 25-year follow-up in one of them.
1 finding
Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF).
"Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF)."
PMID:14976160
A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
1 finding
Clinically they best fit into HSAN V.
"Clinically they best fit into HSAN V."
PMID:24036948
A de novo gain-of-function mutation in SCN11A causes loss of pain perception.
1 finding
Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations.
"Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations."

Deep Research

1
Congenital Insensitivity to Pain Deep Research Notes ▸

Congenital Insensitivity to Pain Deep Research Notes

Modeling choices applied from PR review

  • This revision treats congenital insensitivity to pain as a thin phenotype-grouping page, not as a claim that all CIP branches are one cleanly unified disease entity.
  • I did not split this PR into five standalone subtype pages because that would require a larger ontology and evidence expansion than the review was asking for. Instead, I trimmed the umbrella and made the shared pathograph explicit.
  • The ontology anchor remains MONDO:0015364 (hereditary sensory and autonomic neuropathy) only because the exact umbrella term requested in MONDO NTR #10031 is not yet available.
  • Subtype-specific disease identity is retained through child MONDO terms for NTRK1 / HSAN IV, NGF / HSAN V, SCN9A AR-CIP, SCN11A / HSAN VII, and PRDM12 / HSAN VIII.

Disease identity and scope

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders.

  • Curation implication: This page is valid as a phenotype grouping, but the plural "disorders" argues against treating it as a single mechanistic disease record.

Mechanistic synthesis used in the YAML curation

1. PRDM12-dependent nociceptor specification is upstream and distinct

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    PRDM12 and CLTCL1 are important in the differentiation from a neural crest cell to a precursor sensory neuron.

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    The recent finding that PRDM12 activated NTRK1 expression in nociceptor precursors further cemented the absolute importance of NGF-TRKA signalling for nociceptor genesis.

  • Curation implication: I split PRDM12-related specification failure into its own atomic node upstream of NGF-TRKA trophic signaling rather than hiding it inside a bundled developmental umbrella.

2. NGF-TRKA trophic failure and developmental apoptosis are separate steps

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    CIP can be clinically divided into two groups: developmental disorders where nociceptors fail to develop or undergo early apoptosis through lack of trophic signals;

  • PMID:14976160
  • Evidence source: HUMAN_CLINICAL
  • Quote:

    A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients.

  • Curation implication: The YAML now separates trophic signaling failure, developmental apoptosis, and reduced small-fiber innervation into distinct nodes with explicit downstream links.

3. SCN9A and SCN11A are grouped only at the level of impaired excitability

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    So, activating mutations in SCN9A produce paroxysmal neuropathic pain, with no other obvious clinical features. And bi-allelic non-functional mutations cause congenital painlessness, with the only other consequence being anosmia.

  • PMID:24036948
  • Evidence source: HUMAN_CLINICAL
  • Quote:

    Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission.

  • Curation implication: I kept SCN9A and SCN11A as separate atomic channelopathy nodes and only converged them downstream at "Impaired nociceptor excitability" and then "Loss of protective pain perception".

4. Shared morbidity belongs on the grouping page

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    Coincident with teething in the first year of life, self-mutilation of lips, tongue, fingers and toes often occur.

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    Long bone fractures can heal, if allowed to do so, but it is the joint injuries that inevitably lead to Charcot’s joints, and hence progressive orthopaedic deformities.

  • Curation implication: These findings support keeping a small phenotypes block on the grouping page even though detailed natural history should eventually move to subtype pages.

5. Developmental CIP has a distinctive Staphylococcus aureus complication axis

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.

  • PMID:32219415
  • Evidence source: OTHER
  • Quote:

    Distinctive to HSANs is a significant susceptibility to Staphylococcus aureus infections manifest as grumbling skin infections, osteomyelitis and septic arthritis.

  • Curation implication: The revised YAML now includes a macrophage-centered pathophysiology node and a developmental-subtype osteomyelitis phenotype so this clinically important complication is not lost.

6. HSAN IV should explicitly carry cognitive impairment

  • PMID:16138253
  • Evidence source: HUMAN_CLINICAL
  • Quote:

    They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation;

  • PMID:14976160
  • Evidence source: HUMAN_CLINICAL
  • Quote:

    The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact.

  • Curation implication: I added Intellectual disability specifically to the HSAN IV branch and left HSAN V described as cognitively relatively preserved.

Deliberate omissions in this revision

  • I did not add umbrella-level treatments because management is heavily driven by injury surveillance, orthopedic complications, ocular protection, and subtype-specific autonomic issues rather than one shared mechanism-directed therapy.
  • I did not create standalone subtype files in this PR; the current revision is intended to satisfy the review by making the grouping page thinner and more explicit, not by performing a full subtype decomposition.