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 three broad mechanism classes: developmental nociceptor disorders involving PRDM12 and the NGF-TRKA axis, nociceptor channelopathies involving SCN9A and SCN11A, and transcriptional deregulation within surviving nociceptors in the autosomal dominant ZFHX2 (Marsili) type, where there is no peripheral neuropathy at all. 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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name: Congenital Insensitivity to Pain
creation_date: "2026-04-16T19:22:23Z"
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 three
broad mechanism classes: developmental nociceptor disorders involving PRDM12
and the NGF-TRKA axis, nociceptor channelopathies involving SCN9A and SCN11A,
and transcriptional deregulation within surviving nociceptors in the autosomal
dominant ZFHX2 (Marsili) type, where there is no peripheral neuropathy at all.
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:1060232
label: congenital insensitivity to pain
mappings:
mondo_mappings:
- term:
id: MONDO:1060232
label: congenital insensitivity to pain
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
Primary MONDO identifier for this entry. MONDO defines the term as "A rare
hereditary sensory and autonomic neuropathy characterized by the inability
to perceive physical pain from birth", which is exactly this entry's scope.
Its gene-bearing children are the five subtypes this entry already curated
(NTRK1, NGF, SCN9A, SCN11A, PRDM12) together with the ZFHX2 Marsili type
added in the same pass.
- term:
id: MONDO:0015364
label: hereditary sensory and autonomic neuropathy
mapping_predicate: skos:broadMatch
mapping_source: MONDO
mapping_justification: >-
The previous `disease_term` binding of this entry, retained as a broader
cross-reference. It is the MONDO parent of the exact term above and
subsumes the sensory and autonomic neuropathies that are not congenital
insensitivity to pain, which this entry does not cover.
notes: >-
GeneReviews baseline: two chapters cover this entry's scope and are now listed
in `references:` - the `Congenital Insensitivity to Pain Overview`
(PMID:29419974), which matches this entry's name exactly, and
`NTRK1 Congenital Insensitivity to Pain with Anhidrosis` (PMID:20301726) for
the HSAN IV branch. Neither is quoted as evidence: only their abstracts are
cached, and the overview's abstract is a statement of the chapter's purpose
rather than a finding, so there is no propositional sentence in the cached
text to quote. They are recorded as the baseline this entry should be mined
against when full text becomes available.
MONDO anchor. An earlier revision of this entry recorded that no MONDO term
for "congenital insensitivity to pain" existed and anchored to the broader
hereditary sensory and autonomic neuropathy parent instead. That is no longer
the case: `runoak -i ols:mondo search 'congenital insensitivity to pain'`
returns `MONDO:1060232 congenital insensitivity to pain` as its first hit, and
`MONDO:1060232` is now this entry's `disease_term`. The previous anchor
`MONDO:0015364` is kept as a `skos:broadMatch` cross-reference. Subtype-specific
mechanistic and management detail should still ultimately live in dedicated
child entries.
Series completeness under the exact term. `MONDO:1060232` has eight
hierarchical descendants. Six are curated here as `has_subtypes` rows:
`MONDO:0009746` (HSAN IV, NTRK1), `MONDO:0012092` (HSAN V, NGF),
`MONDO:0009459` (SCN9A channelopathy-associated CIP), `MONDO:0014244`
(HSAN VII, SCN11A), `MONDO:0014662` (CIP-hypohidrosis, PRDM12) and
`MONDO:0958106` (Marsili type, ZFHX2). The remaining two carry no causal gene
in MONDO and are not curated: `MONDO:0016319` congenital insensitivity to pain
with hyperhidrosis and `MONDO:0018682` congenital insensitivity to pain with
severe intellectual disability. Each is named after an additional clinical
feature rather than a gene, and each is xrefed only to Orphanet and MedGen with
no OMIM entry, so there is no gene for this pass to wire; they are recorded
here so the gap is visible rather than silent.
Genes moved out by the re-anchoring. The previous broad anchor pulled in a
RETREG1 `genetic:` record whose own notes said it should move rather than be
duplicated if this entry were ever re-anchored on a true
congenital-insensitivity-to-pain class. RETREG1 is the HSAN2B gene and is
already curated at the right granularity as an HSAN2B `has_subtypes` row with
its own `genetic:` record on Hereditary Sensory and Autonomic Neuropathy Type 2,
so the record here has been removed rather than rewritten. The ClinGen
assertion it carried is made against `MONDO:0015364`, which is now only a
`skos:broadMatch` cross-reference on this entry.
Diseases the previous broad anchor also reached, and why they are not curated
here. Cold-induced sweating syndrome 1 (`MONDO:0010091`, CRLF1) and 2
(`MONDO:0012467`, CLCF1), PERCHING syndrome (`MONDO:0014890`, KLHL7),
hereditary sensory and autonomic neuropathy type 1A (`MONDO:0008086`, SPTLC1)
and hereditary sensory neuropathy type 1F (`MONDO:0014286`, ATL3) are all
hierarchical descendants of `MONDO:0015364`; none is a descendant of
`MONDO:1060232`, and none is congenital insensitivity to pain. MONDO files the
first three under `MONDO:0015526 cold-induced sweating syndrome`, and defines
CISS1 as "a severe disorder characterized by muscular contractions at birth,
intermittent hyperthermia, facial abnormalities and camptodactyly" — a
phenotype that does not include absence of pain. PERCHING is a multisystem
KLHL7 syndrome whose MONDO definition enumerates postural, palatal, ocular,
respiratory, contractural, growth and feeding features, and it has an open
stub (`stubs/PERCHING_Syndrome.yaml`) rather than a home here; MONDO's placement
of it under cold-induced sweating syndrome is itself worth checking upstream.
HSAN1A and HSN1F both sit under `MONDO:0018213 hereditary sensory and autonomic
neuropathy type 1`, a separate series this KB curates in its own entries:
HSAN1A is already curated as Hereditary Sensory and Autonomic Neuropathy
Type 1A on `MONDO:0008086`, and HSN1F belongs beside the other HSN1 atlastin
form, Hereditary Sensory Neuropathy Type 1D (ATL1).
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:29419974
title: "Congenital Insensitivity to Pain Overview."
tags:
- GeneReviews
- reference: PMID:20301726
title: "NTRK1 Congenital Insensitivity to Pain with Anhidrosis."
tags:
- GeneReviews
- 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.
genes:
- preferred_term: NTRK1
term:
id: hgnc:8031
label: NTRK1
- 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.
genes:
- preferred_term: NGF
term:
id: hgnc:7808
label: NGF
- 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.
genes:
- preferred_term: SCN9A
term:
id: hgnc:10597
label: SCN9A
- 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.
genes:
- preferred_term: SCN11A
term:
id: hgnc:10583
label: SCN11A
- 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.
genes:
- preferred_term: PRDM12
term:
id: hgnc:13997
label: PRDM12
- name: Marsili type
display_name: ZFHX2-related congenital insensitivity to pain (Marsili syndrome)
subtype_term:
preferred_term: congenital insensitivity to pain syndrome, Marsili type
term:
id: MONDO:0958106
label: congenital insensitivity to pain syndrome, Marsili type
description: >-
Autosomal dominant branch, and the only one in this entry that is neither a
developmental nociceptor disorder nor a sodium-channel channelopathy. A
heterozygous ZFHX2 missense variant segregates with pain insensitivity across
three generations of one Italian family, in whom the phenotype is
hyposensitivity to noxious heat with painless bone fractures and explicitly
no peripheral neuropathy — so the nociceptors are present and the defect is
in the transcriptional programme they run.
genes:
- preferred_term: ZFHX2
term:
id: hgnc:20152
label: ZFHX2
evidence:
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures."
explanation: >-
The clinical description of this subtype: heat hyposensitivity and painless
fractures in six affected members of one family.
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy."
explanation: >-
Establishes autosomal dominant inheritance and the absence of a peripheral
neuropathy, which is what separates this subtype from the HSAN branches
curated alongside it.
genetic:
- name: NTRK1
gene_term:
preferred_term: NTRK1
term:
id: hgnc:8031
label: NTRK1
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: HSAN IV
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
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: HSAN V
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
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: SCN9A AR-CIP
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
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: HSAN VII
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
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: HSAN VIII
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: ZFHX2
gene_term:
preferred_term: ZFHX2
term:
id: hgnc:20152
label: ZFHX2
association: Causal
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: Marsili type
notes: >-
Zinc finger homeobox 2, a transcriptional regulator expressed in small
diameter sensory neurons. A single heterozygous missense variant changing a
conserved arginine within a homeodomain segregates with pain insensitivity in
the reported family; mice carrying the orthologous change and Zfhx2 null mice
both show pain-sensitivity deficits. The human evidence is one family, so this
record rests on segregation plus two mouse models rather than on independent
human replication.
evidence:
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity."
explanation: >-
The human genetic evidence: a ZFHX2 point mutation segregating with the
pain-insensitive phenotype, in a gene expressed in small diameter sensory
neurons.
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain."
explanation: >-
Identifies the variant as a homeodomain arginine substitution, the basis for
treating it as a change in ZFHX2's transcriptional function.
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity."
explanation: >-
Two independent mouse genotypes reproduce the pain-sensitivity deficit,
which is the non-human support this single-family association rests on.
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.
- target: Intellectual disability
description: >-
NTRK1-related CIPA includes intellectual disability as part of the
developmental HSAN IV phenotype; the intervening CNS mechanism is not
resolved in this umbrella entry.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: >-
The NTRK1-related CIPA sibling report documents mental retardation
alongside the pain-insensitivity phenotype, supporting the branch-level
link to intellectual disability.
- 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
conforms_to: "nociceptor_sodium_channel_excitability#Loss of Nociceptor Sodium Current"
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
molecular_functions:
- preferred_term: voltage-gated sodium channel activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0005248
label: voltage-gated sodium channel activity
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.
- target: Anosmia
description: >-
SCN9A loss-of-function channelopathy causes congenital painlessness with
anosmia as the characteristic additional feature.
causal_link_type: DIRECT
- name: Nav1.9 depolarization-block channelopathy
conforms_to: "nociceptor_sodium_channel_excitability#Sustained Nociceptor Depolarization and Conduction Block"
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
conforms_to: "nociceptor_sodium_channel_excitability#Nociceptor Action Potential Threshold and Firing"
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.
downstream:
- target: Osteomyelitis
description: >-
Staphylococcus aureus susceptibility in developmental CIP can manifest as
osteomyelitis.
causal_link_type: DIRECT
- 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.
downstream:
- target: Pain insensitivity
description: >-
Loss of protective pain perception is the defining pain-insensitivity
phenotype.
causal_link_type: DIRECT
- target: Self-mutilation
description: >-
Absent protective pain sensation permits repetitive biting and tissue
injury without normal warning pain.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Neuropathic arthropathy
description: >-
Repetitive painless joint injury leads to Charcot-joint arthropathy and
progressive orthopedic damage.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: ZFHX2-dependent transcriptional programme deregulation in nociceptors
biological_scale: MOLECULAR
description: >-
The Marsili-type lesion. ZFHX2 encodes a transcriptional regulator expressed
in small diameter sensory neurons; the homeodomain arginine substitution
found in the affected family deregulates expression of genes implicated in
peripheral pain mechanisms in dorsal root ganglia. Unlike the PRDM12 and
NGF-TRKA branches, the nociceptors themselves are not lost — the reported
disorder is explicitly not associated with a peripheral neuropathy — so the
claim here is a change in the programme those surviving neurons express.
cell_types:
- preferred_term: nociceptor
term:
id: CL:0000198
label: pain receptor cell
biological_processes:
- preferred_term: regulation of gene expression
term:
id: GO:0010468
label: regulation of gene expression
modifier: DYSREGULATED
genes:
- preferred_term: ZFHX2
term:
id: hgnc:20152
label: ZFHX2
downstream:
- target: Loss of protective pain perception
description: >-
Deregulated expression of pain-related genes in dorsal root ganglion
neurons reduces pain sensitivity without removing the neurons, which is the
route from the ZFHX2 lesion to the shared loss of protective pain
perception in this entry.
evidence:
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms."
explanation: >-
The measurement behind this node: mutant dorsal root ganglia show altered
expression of pain-related genes, which is the dysregulated
gene-expression claim bound here.
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity."
explanation: >-
Supports the cell type bound on this node — small diameter sensory neurons —
and the identity of ZFHX2 as a transcription factor.
- reference: PMID:29253101
reference_title: A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy."
explanation: >-
Source for the distinction this node draws from the developmental branches:
there is no peripheral neuropathy, so the nociceptors are not lost.
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.
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.
MONDO:0015364 (hereditary sensory and
autonomic neuropathy) only because the exact umbrella term requested in MONDO
NTR #10031 is not yet available.NTRK1 / HSAN IV, NGF / HSAN V, SCN9A AR-CIP, SCN11A / HSAN VII, and
PRDM12 / HSAN VIII.OTHERCongenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders.
OTHERPRDM12 and CLTCL1 are important in the differentiation from a neural crest cell to a precursor sensory neuron.
OTHERThe recent finding that PRDM12 activated NTRK1 expression in nociceptor precursors further cemented the absolute importance of NGF-TRKA signalling for nociceptor genesis.
OTHERThe importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.
OTHERCIP can be clinically divided into two groups: developmental disorders where nociceptors fail to develop or undergo early apoptosis through lack of trophic signals;
HUMAN_CLINICALA severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients.
OTHERSo, 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.
HUMAN_CLINICALMutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission.
SCN9A and SCN11A as separate atomic channelopathy nodes and only
converged them downstream at "Impaired nociceptor excitability" and then
"Loss of protective pain perception".OTHERCoincident with teething in the first year of life, self-mutilation of lips, tongue, fingers and toes often occur.
OTHERLong 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.
phenotypes block on the grouping page
even though detailed natural history should eventually move to subtype pages.OTHERIncreased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.
OTHERDistinctive to HSANs is a significant susceptibility to Staphylococcus aureus infections manifest as grumbling skin infections, osteomyelitis and septic arthritis.
HUMAN_CLINICALThey had the characteristic clinical features of an abnormally high pain threshold, and mental retardation;
HUMAN_CLINICALThe 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.
Intellectual disability specifically to the HSAN IV branch and left
HSAN V described as cognitively relatively preserved.