Familial Visceral Neuropathy 2

Mendelian MONDO:0030399 Pathograph 15 Show in embeddings browser Enteric Neuropathy Neurocristopathy

Familial visceral neuropathy 2 is an autosomal recessive neurocristopathy caused by biallelic ERBB2 variants. ERBB2 and ERBB3 are the two receptors of the neuregulin-1 (NRG1) signalling system, and they work only as a pair: ERBB3 binds NRG1 but is catalytically weak, while ERBB2 has no ligand of its own but supplies the kinase activity. Loss of ERBB2 kinase function therefore disables NRG1 signalling through the heterodimer, and the reported homozygous kinase-domain variant drastically reduces phosphorylation of both receptors. Single-cell expression data and a conditional mouse knockout place this signalling requirement in enteric progenitor cells, so the developing gut is incompletely colonized by enteric neural crest derivatives. The histological result in the two ERBB2 siblings is aganglionosis with hyperplasia of nerve fibres, and hypoganglionosis; the clinical result is congenital gastrointestinal dysmotility, reported as severe constipation and as short-segment Hirschsprung disease in the two affected siblings. The phenotype extends beyond the gut to axonal peripheral neuropathy, ptosis, sensorineural hearing loss and clubfeet, consistent with NRG1/ERBB signalling being required in other neural crest and peripheral nervous system derivatives.

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1
Inheritance
5
Pathophys.
7
Phenotypes
1
Hypotheses
3
Gaps
15
Pathograph
1
Genes
2
Medical Actions
1
Models
3
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Homozygous ERBB2 p.(Ala710Val) in two affected siblings of a consanguineous family, with both healthy parents heterozygous. This is a different genetic architecture from isolated Hirschsprung disease, which is oligogenic with RET as the major locus — a contrast the source paper draws explicitly.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:33497358 SUPPORT Human Clinical
"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis."
Establishes biallelic inheritance. Note the phenotype list here spans both genes in the paper; the ERBB2-specific features are recorded separately below.
PMID:33497358 SUPPORT Human Clinical
"Sanger sequencing confirmed that the 2 affected children are homozygous while the healthy parents are heterozygous for the ERBB2 variant"
Segregation in the single reported family: both affected siblings homozygous, both parents heterozygous and healthy.
PMID:33497358 SUPPORT Human Clinical
"Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes."
States the contrasting genetic architecture of the two disorders this entity sits between, which is why it is curated separately from both.
◈

Mechanistic Hypotheses

1
Canonical NRG1/ERBB Enteric Progenitor Model
canonical_nrg1_erbb_enteric_progenitor_model CANONICAL
A homozygous ERBB2 kinase-domain variant removes neuregulin-1 signalling through the ERBB2/ERBB3 heterodimer in enteric progenitor cells, leaving the gut incompletely colonized by enteric neural crest derivatives; the resulting aganglionosis or hypoganglionosis produces congenital gastrointestinal dysmotility. Whether a smooth muscle lesion accompanies it is not established for ERBB2 disease — see the knowledge gap below — so the model does not include one. The model rests on the localization of ERBB3 function to enteric progenitors in mouse single-cell data and a conditional knockout, together with the functional demonstration that the ERBB2 variant drastically reduces phosphorylation of both receptors.
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Discussions and Knowledge Gaps

3
Do intestinal smooth muscle abnormalities occur in ERBB2-related enteric neuropathy at all, and if so are they a primary consequence of lost ERBB signalling in muscle or secondary to the absent enteric innervation?
KNOWLEDGE GAP fvn2_smooth_muscle_primary_or_secondary
Attached to
pathophysiology#Incomplete Enteric Nervous System Colonization
The cohort-wide histology reports smooth muscle abnormalities alongside the ganglion cell deficit, but Table 1 scores that row NA for both ERBB2 patients and positive only in an ERBB3 patient, so it is not established for this disease. The ERBB pathway's role was in any case localized to enteric progenitors — not to muscle. If the muscle lesion is primary, this disorder is not purely neuropathic and its classification within chronic intestinal pseudo-obstruction changes; if secondary, restoring innervation would in principle be sufficient. Nothing in the reported data separates the two.
Should VSCN2 (ERBB2) and VSCN1 (ERBB3) be one disease entry or two?
KNOWLEDGE GAP fvn2_erbb2_erbb3_same_entity
Attached to
pathophysiology#Disrupted NRG1-ERBB Signaling in Enteric Progenitors
ERBB2 and ERBB3 signal only as a heterodimer, and the two genotypes were reported together in one paper with one phenotypic spectrum, which is a strong argument for a single mechanistic entity. MONDO and OMIM give them separate concepts, and this entry follows that. The question is worth recording because a grouping over the NRG1/ERBB enteric axis may be the better structure once more patients are published — and because the two concepts are easy to transpose, the numbering running opposite to the gene numbering.
Should enteric neural crest colonization failure be factored out of Hirschsprung disease, this entry, and the neuropathic CIPO entries as a mechanism module?
KNOWLEDGE GAP fvn2_no_enteric_neural_crest_module
Attached to
pathophysiology#Incomplete Enteric Nervous System Colonization
The knowledge base already carries Hirschsprung disease and chronic intestinal pseudo-obstruction, both of which restate a migration-proliferation-differentiation chain that this entry restates a third time with a different upstream ligand-receptor pair. That repetition across independently curated entries is what `kb/modules/` exists to absorb. No such module exists, so this entry declares no `conforms_to`.
⚙

Pathophysiology

5
Biallelic ERBB2 Kinase-Domain Variant
Homozygous ERBB2 c.2129C>T, p.(Ala710Val), a kinase-domain missense change, in both affected siblings of the single reported family. Immunoblot analysis of Neuro-2a cells overexpressing wild-type or mutant protein showed that this variant drastically decreases phosphorylation of both ERBB2 itself and its partner ERBB3 — that is, the lesion is a kinase defect that propagates across the heterodimer rather than a defect in receptor abundance.
ERBB2 hgnc:3430 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ERBB2 (hgnc:3430), qualified as loss of function. hgnc:3430 is a gene from the HUGO Gene Nomenclature Committee. ⇓ LOSS OF FUNCTION
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Germline homozygous ERBB2 kinase-domain missense allele p.(Ala710Val). Loss of function is established functionally by the loss of receptor phosphorylation rather than inferred from the variant class.
Downstream
Disrupted NRG1-ERBB Signaling in Enteric Progenitors A kinase-dead ERBB2 cannot phosphorylate the heterodimer, so neuregulin-1 binding by ERBB3 no longer produces a signal.
Show evidence (2 references)
PMID:33497358 SUPPORT In Vitro
"revealed a drastic decrease of both ERBB2 and ERBB3"
The immunoblot result showing that the ERBB2 variant reduces phosphorylation of both receptors, which is the molecular lesion this node describes.
PMID:33497358 SUPPORT In Vitro
"The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors."
Describes the functional assays used across the whole series. The ERBB2 allele falls in the altered-phosphorylation group rather than the decreased-expression group.
Disrupted NRG1-ERBB Signaling in Enteric Progenitors
ERBB3 and ERBB2 are the receptors for neuregulin-1 and signal as a heterodimer — ERBB3 has minimal intrinsic kinase activity and ERBB2 has no ligand of its own, so neither works without the other. That obligate pairing is why variants in either gene converge on one phenotype, and why an ERBB2 kinase defect removes NRG1 signalling as effectively as losing the ligand-binding receptor would. Cell-type-specific analysis in mouse single-cell RNA sequencing data together with a conditional ErbB3-deficient mouse localized the requirement to enteric progenitor cells. That localization is what makes this a developmental disorder of gut colonization rather than a defect in mature enteric neurons.
enteric neural crest-derived progenitor CL:0000333 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enteric neural crest-derived progenitor, annotated with migratory neural crest cell (CL:0000333). CL:0000333 is a cell type from the Cell Ontology.
ERBB2-ERBB3 heterodimer signaling GO:0038133 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ERBB2-ERBB3 heterodimer signaling, annotated with ERBB2-ERBB3 signaling pathway (GO:0038133). GO:0038133 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Conditional ErbB3-deficient mouse Mouse partially recapitulates The model established that the NRG1/ERBB requirement in this system sits in enteric progenitors rather than in mature enteric neurons or in smooth muscle.
Downstream
Incomplete Enteric Nervous System Colonization Enteric progenitors deprived of NRG1/ERBB signalling fail to populate the gut wall normally.
Extra-Intestinal Neural Crest and Peripheral Nerve Involvement The same signalling requirement in other neural crest and peripheral nervous system derivatives, including Schwann cell precursors.
Show evidence (2 references)
PMID:33497358 SUPPORT Model Organism
"The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors."
Localizes the requirement to enteric progenitor cells, which is the claim this node makes. Note the conditional knockout targets ErbB3.
PMID:33720042 SUPPORT Model Organism
"Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells."
Names *both* receptors as expressed in enteric neuronal progenitors, which is what extends the localization above from ERBB3 to the ERBB2 gene this entry is about.
Incomplete Enteric Nervous System Colonization
The histological lesion. In the ERBB2 sibling who came to resection (F5:II-2), colon histology showed absent ganglion cells with hyperplasia of nerve fibres. Table 1 additionally scores him positive for hypoganglionosis. Intestinal smooth muscle abnormality is **not** an established ERBB2 finding and this entry does not claim it: Table 1 scores that row `NA` for both ERBB2 patients, and its single positive is F1:II-3, an ERBB3 patient. The abstract sentence naming all three findings together spans both genes and does not license a gene-scoped claim. The smooth muscle thread is kept below as an open question about the pathway rather than as a feature of this disease.
enteric neuron CL:0007011 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves decreased enteric neuron (CL:0007011). CL:0007011 is a cell type from the Cell Ontology. ↓ DECREASED
enteric nervous system development GO:0048484 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased enteric nervous system development (GO:0048484). GO:0048484 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Congenital Gastrointestinal Dysmotility A gut wall lacking its normal complement of enteric neurons cannot generate coordinated propulsive motility.
Show evidence (2 references)
PMID:33497358 SUPPORT Human Clinical
"In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
Colon resection histology in the ERBB2 sibling F5:II-2 — the only gene-scoped histology in the paper, and the basis for this node. It names both halves of the claim: the absent ganglion cells and the hyperplasia of nerve fibres.
PMID:33497358 SUPPORT Human Clinical
"Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities."
The cohort-wide histological summary. Recorded for completeness, but note it spans both genes: the smooth muscle component is scored NA in both ERBB2 patients, so this sentence does not establish it for this disease.
Congenital Gastrointestinal Dysmotility
The clinical output. In the two reported ERBB2 patients this took the form of severe constipation and, in the brother, short-segment Hirschsprung disease with hypoganglionosis; both were scored negative for chronic intestinal pseudo-obstruction. Across the wider NRG1/ERBB series the same lesion produces Hirschsprung disease in some patients and CIPO in others, which is informative in itself — the two clinical labels describe where along the gut the colonization deficit falls rather than two different diseases — but CIPO is not a feature of this concept as reported.
Downstream
Severe Constipation Failure of propulsive motility in the aganglionic and hypoganglionic gut.
Short-Segment Hirschsprung Disease Where the colonization deficit stops short of the proximal gut, the result is a short aganglionic distal segment.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility."
States the clinical output and its breadth as the authors' conclusion.
Extra-Intestinal Neural Crest and Peripheral Nerve Involvement
The affected siblings had axonal peripheral neuropathy, ptosis, sensorineural ("perceptive") hearing loss and clubfeet alongside the gastrointestinal disease. These are what mark the disorder as a broader neurocristopathy rather than an isolated gut disease, and they are the features that should prompt ERBB2 sequencing in a patient who would otherwise be worked up as isolated Hirschsprung disease.
Downstream
Peripheral Axonal Neuropathy Loss of NRG1/ERBB signalling in Schwann cell precursors and peripheral nerve.
Ptosis Neural-crest-derived contribution to periocular structures.
Sensorineural Hearing Loss Neural-crest and Schwann cell precursor contribution to the auditory pathway.
Arthrogryposis Multiplex Congenita Congenital joint contractures, plausibly secondary to reduced fetal movement from the peripheral nerve involvement, though this was not demonstrated and the source is inconsistent about whether the ERBB2 siblings had contractures beyond the feet.
Clubfeet Foot deformity accompanying the congenital contractures.
Show evidence (2 references)
PMID:33497358 SUPPORT Human Clinical
"axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
Enumerates the extra-intestinal features in the proband of the single ERBB2 family.
PMID:9338783 SUPPORT Model Organism
"Homozygous erbB3 mutant embryos lack Schwann-cell precursors and Schwann cells that accompany peripheral axons of sensory and motor neurons."
Grounds the Schwann cell precursor step behind the peripheral neuropathy, which the entry previously asserted without support. Mouse ErbB3, so the inference to a human ERBB2 kinase defect runs through the obligate heterodimer.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Visceral Neuropathy 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Digestive 2
Severe Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019), qualified as temporality chronic. HP:0002019 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"presented severe constipation that eased after 5 years of age,"
Documents the presenting gastrointestinal feature and its course in the proband of the single ERBB2 family.
Short-Segment Hirschsprung Disease Aganglionic megacolon HP:0002251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aganglionic megacolon (HP:0002251). HP:0002251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
Colon resection histology in the affected brother, naming him explicitly and establishing absent ganglion cells.
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
Names perceptive hearing loss among the proband's features.
Eye 1
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
Names ptosis among the proband's features.
Limbs 1
Clubfeet Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
Names clubfeet among the proband's features.
Musculoskeletal 1
Arthrogryposis Multiplex Congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33497358 SUPPORT Human Clinical
"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis."
Establishes arthrogryposis as one of the four features varying across the series. Cohort-wide rather than ERBB2-scoped; the per-patient scoring is Table 1's, which cannot be quoted as a snippet.
PMID:33497358 REFUTE Human Clinical
"5 patients with neurocristopathies (4 of them with HSCR, 3 with peripheral neuropathy) and 3 fetuses with arthrogryposis multiplex congenita"
Cuts against arthrogryposis in the ERBB2 siblings. The paper's cohort description splits its subjects into five patients with neurocristopathies and three fetuses with arthrogryposis multiplex congenita — and both ERBB2 siblings are among the five, not the three. Graded REFUTE because it contradicts the Table 1 scoring for these patients specifically.
Nervous System 1
Peripheral Axonal Neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
Names axonal peripheral neuropathy among the proband's features.
🧬

Genetic Associations

1
ERBB2
Gene: ERBB2 hgnc:3430 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ERBB2 (hgnc:3430). hgnc:3430 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33497358 SUPPORT Human Clinical
"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals"
Establishes ERBB2 as one of the two disease genes in this series.
PMID:33497358 SUPPORT Human Clinical
"missense variant (c.2129C>T, p.(Ala710Val)) within ERBB2"
Names the specific ERBB2 allele in the single family that defines this concept.
💊

Medical Actions

2
Surgical Resection of the Aganglionic Segment
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Resection of the aganglionic bowel, the standard management of Hirschsprung disease and the one intervention documented in a reported ERBB2 patient — the histology that establishes the diagnosis in F5:II-2 came from a colon resection specimen. It removes the non-functioning segment; it does not restore enteric innervation to the remaining gut, which is why dysmotility can persist after surgery.
Mechanism Target:
MODULATES Congenital Gastrointestinal Dysmotility — Removes the aganglionic segment obstructing transit. It does not address the colonization deficit itself.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
The diagnostic histology in this patient came from a colon resection specimen — the quoted sentence says so, which is what documents that resection was performed.
Genetic Counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling for an autosomal recessive disorder in a consanguineous family, with a 1-in-4 recurrence risk per pregnancy once the biallelic genotype is known. Both parents in the reported family are heterozygous carriers and healthy.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"healthy parents are heterozygous for the ERBB2 variant"
Establishes the carrier state of both parents, which is what makes recurrence risk counselling applicable.
🔬

Diagnosis

2
Gut histopathology
Full-thickness or suction rectal biopsy assessing ganglion cell density. Both aganglionosis and hypoganglionosis occur — in the same ERBB2 patient — so a report of ganglion cells present does not exclude the diagnosis. Assessing the muscle layer is reasonable given the wider NRG1/ERBB series, but note that no ERBB2 patient has had it assessed, so that is an extrapolation rather than a finding.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
The gene-scoped histology result, in the ERBB2 sibling who came to colon resection.
Trio-exome sequencing
Molecular diagnosis. Every reported patient was ascertained this way; the combination of gastrointestinal dysmotility with peripheral neuropathy or arthrogryposis is the clinical pattern that should trigger it, since isolated Hirschsprung disease and CIPO have different genetic workups.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals"
Describes the diagnostic method used in the defining series.
📊

Prevalence

2
Worldwide, published cases
Cases In Literature Ultra Rare
Eight individuals in the defining series, but that count spans both the ERBB3 and the ERBB2 genotypes. Only two of them — a sister and brother in one consanguineous family — carry the ERBB2 genotype that defines this concept. No incidence or prevalence estimate exists, and gene-disease validity rests on that single family.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"biallelic variants in ERBB3 and ERBB2 in 8 individuals"
Gives the size of the reported cohort.
Worldwide live births (Hirschsprung disease, for context)
Birth Prevalence 20.0 per 100,000 1–9 per 10,000 (births)
This is the incidence of Hirschsprung disease as a whole, recorded only as context for how much rarer this Mendelian entity is. It is not a rate for familial visceral neuropathy 2 and must not be read as one.
Show evidence (1 reference)
PMID:33497358 SUPPORT Human Clinical
"Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births."
Provides the Hirschsprung disease incidence used here purely as a comparator.
🐁

Animal Models

1
Conditional ErbB3-deficient mouse
Conditional ErbB3 knockout used, together with mouse single-cell RNA sequencing, to localize the NRG1/ERBB requirement to enteric progenitor cells.
Species
Mouse
Genotype
Conditional ErbB3 knockout
Publication
PMID:33497358
Pathograph links
Disrupted NRG1-ERBB Signaling in Enteric Progenitors partially recapitulates fidelity: moderate The model established that the NRG1/ERBB requirement in this system sits in enteric progenitors rather than in mature enteric neurons or in smooth muscle.
Limitations: The model targets ErbB3, the partner receptor, not ErbB2 — the gene of this disease. Because the two signal only as a heterodimer that is a defensible proxy, but it is a proxy, and it is why this link is PARTIALLY_RECAPITULATES rather than RECAPITULATES. A conditional knockout is also a complete loss in the targeted lineage, whereas the patient allele is a kinase-domain missense change, so the model speaks to where the pathway is required and not to how much residual signalling the human disease retains. The extra-intestinal features were not addressed by this model.
Show evidence (1 reference)
PMID:33497358 SUPPORT Model Organism
"in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors"
The model result that grounds this link.
{ }

Source YAML

click to show 
name: Familial Visceral Neuropathy 2
creation_date: "2026-08-31T22:00:00Z"
category: Mendelian
synonyms:
- visceral neuropathy, familial, 2, autosomal recessive
- VSCN2
- ERBB2-related enteric neuropathy
- ERBB2-related neurocristopathy with gastrointestinal dysmotility
disease_term:
  preferred_term: visceral neuropathy, familial, 2, autosomal recessive
  term:
    id: MONDO:0030399
    label: visceral neuropathy, familial, 2, autosomal recessive
parents:
- Enteric Neuropathy
- Neurocristopathy
description: >
  Familial visceral neuropathy 2 is an autosomal recessive neurocristopathy
  caused by biallelic ERBB2 variants. ERBB2 and ERBB3 are the two receptors of
  the neuregulin-1 (NRG1) signalling system, and they work only as a pair:
  ERBB3 binds NRG1 but is catalytically weak, while ERBB2 has no ligand of its
  own but supplies the kinase activity. Loss of ERBB2 kinase function
  therefore disables NRG1 signalling through the heterodimer, and the reported
  homozygous kinase-domain variant drastically reduces phosphorylation of both
  receptors. Single-cell expression data and a conditional mouse knockout
  place this signalling requirement in enteric progenitor cells, so the
  developing gut is incompletely colonized by enteric neural crest
  derivatives. The histological result in the two ERBB2 siblings is
  aganglionosis with hyperplasia of nerve fibres, and hypoganglionosis; the
  clinical result is
  congenital gastrointestinal dysmotility, reported as severe constipation and
  as short-segment Hirschsprung disease in the two affected siblings. The
  phenotype extends beyond the gut to axonal peripheral neuropathy, ptosis,
  sensorineural hearing loss and clubfeet, consistent with NRG1/ERBB
  signalling being required in other neural crest and peripheral nervous
  system derivatives.
notes: >
  Ultra-rare, and the cohort is a single family. The disease-defining report
  is Le et al. (J Clin Invest 2021), which identified biallelic ERBB3 and
  ERBB2 variants in eight individuals across five families by trio-exome
  sequencing. Only family F5 — two siblings born to consanguineous parents,
  homozygous for ERBB2 p.(Ala710Val) — carries the ERBB2 genotype, and it is
  that family alone that defines this concept. The ERBB3 families in the same
  paper define familial visceral neuropathy 1 (VSCN1, OMIM:243180), a separate
  MONDO concept, and are out of scope here.

  **Do not read the paper's eight-patient phenotype list as this disease's
  phenotype list.** That list spans both genes, and the two do not carry the
  same features. Per Table 1 of the source, the ERBB2 siblings are positive
  for arthrogryposis, peripheral neuropathy, hearing loss and ptosis, and are
  explicitly **negative** for chronic intestinal pseudo-obstruction, external
  auditory canal agenesis, dysautonomia, pigmentation defect and cardiac
  defect — several of which are positive in the ERBB3 families. The
  intrauterine growth retardation and multiple pterygiums described for the
  ERBB3 fetuses of families F3 and F4 are likewise not attributed to the
  ERBB2 siblings. Only what Table 1 and the case description record for
  family F5 is curated here.

  The CIPO point deserves emphasis because it is counterintuitive: this
  concept sits in the differential for chronic intestinal pseudo-obstruction,
  and yet neither reported ERBB2 patient had CIPO. Their gastrointestinal
  disease was severe constipation and, in the brother, short-segment
  Hirschsprung disease with hypoganglionosis. An entry that listed CIPO as a
  feature here would be contradicted by the source's own table.

  Three things this entry is careful about:

  First, **the relationship to Hirschsprung disease is overlap, not
  identity.** `kb/disorders/Hirschsprung_Disease.yaml` covers the common,
  oligogenic, RET-driven disease. The eight reported ERBB3/ERBB2 patients
  "variably associat[ed]" Hirschsprung disease, chronic intestinal
  pseudo-obstruction, peripheral neuropathy and arthrogryposis — meaning some
  presented as Hirschsprung disease and some did not. The entry records the
  shared enteric-neural-crest mechanism and keeps the entities separate,
  because a Mendelian recessive gene with extra-intestinal features is not the
  same disease as oligogenic RET-associated Hirschsprung disease even where
  the gut histology converges.

  Second, **the relationship to chronic intestinal pseudo-obstruction is the
  same shape.** `kb/disorders/Chronic_Intestinal_Pseudoobstruction.yaml`
  carries a "Neuropathic" subtype as a physiological category, not as a
  genetic entity, and lists no ERBB2. This entry is the Mendelian entity that
  can present as neuropathic dysmotility; it is not a duplicate of that
  clinical syndrome entry.

  Third, **the gene assignment was checked, not assumed.** The two familial
  visceral neuropathy concepts are easy to transpose: VSCN1 (OMIM:243180) is
  the ERBB3 disease and VSCN2 (OMIM:619465, this entry) is the ERBB2 disease,
  which is the opposite of what the gene numbering suggests. The assignment
  here follows the MedGen gene-disease link for the OMIM concept that
  MONDO:0030399 cross-references.

  No `conforms_to` was declared: `kb/modules/` has no enteric or neural-crest
  developmental module. That gap is recorded in `discussions` below rather
  than left silent.

  **Deep-research provenance.** An OpenScientist run
  (`research/Familial_Visceral_Neuropathy_2-deep-research-openscientist.md`,
  5/5 references resolved and on topic) is committed alongside this entry. Its
  substantive contribution was catching a gene error: the first draft of this
  entry attributed MONDO:0030399 to ERBB3, and the report identified ERBB2.
  The correction was then verified independently against the MedGen
  gene-disease links rather than accepted from the report.

  Two of that report's suggested NCIT bindings are badly wrong and must not be
  reused — `NCIT:C157763` is offered as "surgical procedure" but is
  *Metastatic Bladder Small Cell Neuroendocrine Carcinoma*, and `NCIT:C1516`
  is offered as "supportive care" but is *Lisofylline*. The report's own term
  validation flags both, which is the check working. The two NCIT terms this
  entry does bind (`NCIT:C15329` Surgical Procedure and `NCIT:C15240` Genetic
  Counseling) were selected independently of the report.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Homozygous ERBB2 p.(Ala710Val) in two affected siblings of a
    consanguineous family, with both healthy parents heterozygous. This is a
    different genetic architecture from isolated Hirschsprung disease, which
    is oligogenic with RET as the major locus — a contrast the source paper
    draws explicitly.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis."
    explanation: >
      Establishes biallelic inheritance. Note the phenotype list here spans
      both genes in the paper; the ERBB2-specific features are recorded
      separately below.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing \nconfirmed that the 2 affected children are homozygous while the \nhealthy parents are heterozygous for the ERBB2 variant"
    explanation: >
      Segregation in the single reported family: both affected siblings
      homozygous, both parents heterozygous and healthy.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes."
    explanation: >
      States the contrasting genetic architecture of the two disorders this
      entity sits between, which is why it is curated separately from both.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Eight individuals in the defining series, but that count spans both the
    ERBB3 and the ERBB2 genotypes. Only two of them — a sister and brother in
    one consanguineous family — carry the ERBB2 genotype that defines this
    concept. No incidence or prevalence estimate exists, and gene-disease
    validity rests on that single family.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic variants in ERBB3 and ERBB2 in 8 individuals"
    explanation: >-
      Gives the size of the reported cohort.
- population: Worldwide live births (Hirschsprung disease, for context)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 20.0
  notes: >-
    This is the incidence of Hirschsprung disease as a whole, recorded only
    as context for how much rarer this Mendelian entity is. It is not a rate
    for familial visceral neuropathy 2 and must not be read as one.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births."
    explanation: >-
      Provides the Hirschsprung disease incidence used here purely as a
      comparator.
pathophysiology:
- name: Biallelic ERBB2 Kinase-Domain Variant
  biological_scale: MOLECULAR
  description: >
    Homozygous ERBB2 c.2129C>T, p.(Ala710Val), a kinase-domain missense
    change, in both affected siblings of the single reported family. Immunoblot
    analysis of Neuro-2a cells overexpressing wild-type or mutant protein
    showed that this variant drastically decreases phosphorylation of both
    ERBB2 itself and its partner ERBB3 — that is, the lesion is a kinase
    defect that propagates across the heterodimer rather than a defect in
    receptor abundance.
  genes:
  - preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    description: >-
      Germline homozygous ERBB2 kinase-domain missense allele p.(Ala710Val).
      Loss of function is established functionally by the loss of receptor
      phosphorylation rather than inferred from the variant class.
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed a drastic decrease of both ERBB2 and ERBB3"
    explanation: >
      The immunoblot result showing that the ERBB2 variant reduces
      phosphorylation of both receptors, which is the molecular lesion this
      node describes.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors."
    explanation: >
      Describes the functional assays used across the whole series. The
      ERBB2 allele falls in the altered-phosphorylation group rather than the
      decreased-expression group.
  downstream:
  - target: Disrupted NRG1-ERBB Signaling in Enteric Progenitors
    description: >-
      A kinase-dead ERBB2 cannot phosphorylate the heterodimer, so
      neuregulin-1 binding by ERBB3 no longer produces a signal.
    causal_link_type: DIRECT

- name: Disrupted NRG1-ERBB Signaling in Enteric Progenitors
  biological_scale: CELLULAR
  description: >
    ERBB3 and ERBB2 are the receptors for neuregulin-1 and signal as a
    heterodimer — ERBB3 has minimal intrinsic kinase activity and ERBB2 has no
    ligand of its own, so neither works without the other. That obligate
    pairing is why variants in either gene converge on one phenotype, and why
    an ERBB2 kinase defect removes NRG1 signalling as effectively as losing
    the ligand-binding receptor would. Cell-type-specific analysis in mouse
    single-cell RNA sequencing data together with a conditional
    ErbB3-deficient mouse localized the requirement to enteric progenitor
    cells. That localization is what makes this a developmental disorder of
    gut colonization rather than a defect in mature enteric neurons.
  biological_processes:
  - preferred_term: ERBB2-ERBB3 heterodimer signaling
    modifier: DECREASED
    term:
      id: GO:0038133
      label: ERBB2-ERBB3 signaling pathway
  cell_types:
  - preferred_term: enteric neural crest-derived progenitor
    term:
      id: CL:0000333
      label: migratory neural crest cell
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors."
    explanation: >
      Localizes the requirement to enteric progenitor cells, which is the
      claim this node makes. Note the conditional knockout targets ErbB3.
  - reference: PMID:33720042
    reference_title: "Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells."
    explanation: >
      Names *both* receptors as expressed in enteric neuronal progenitors,
      which is what extends the localization above from ERBB3 to the ERBB2
      gene this entry is about.
  downstream:
  - target: Incomplete Enteric Nervous System Colonization
    description: >-
      Enteric progenitors deprived of NRG1/ERBB signalling fail to populate
      the gut wall normally.
    causal_link_type: DIRECT
  - target: Extra-Intestinal Neural Crest and Peripheral Nerve Involvement
    description: >-
      The same signalling requirement in other neural crest and peripheral
      nervous system derivatives, including Schwann cell precursors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of Schwann cell precursors, which in mouse depend on ErbB3 to accompany peripheral axons
    - The populations mediating the ptosis and hearing loss were not localized in the way the enteric requirement was

- name: Incomplete Enteric Nervous System Colonization
  biological_scale: TISSUE
  description: >
    The histological lesion. In the ERBB2 sibling who came to resection
    (F5:II-2), colon histology showed absent ganglion cells with hyperplasia
    of nerve fibres. Table 1 additionally scores him positive for
    hypoganglionosis.

    Intestinal smooth muscle abnormality is **not** an established ERBB2
    finding and this entry does not claim it: Table 1 scores that row `NA`
    for both ERBB2 patients, and its single positive is F1:II-3, an ERBB3
    patient. The abstract sentence naming all three findings together spans
    both genes and does not license a gene-scoped claim. The smooth muscle
    thread is kept below as an open question about the pathway rather than as
    a feature of this disease.
  biological_processes:
  - preferred_term: enteric nervous system development
    modifier: DECREASED
    term:
      id: GO:0048484
      label: enteric nervous system development
  cell_types:
  - preferred_term: enteric neuron
    term:
      id: CL:0007011
      label: enteric neuron
    modifier: DECREASED
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
    explanation: >
      Colon resection histology in the ERBB2 sibling F5:II-2 — the only
      gene-scoped histology in the paper, and the basis for this node. It
      names both halves of the claim: the absent ganglion cells and the
      hyperplasia of nerve fibres.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities."
    explanation: >
      The cohort-wide histological summary. Recorded for completeness, but
      note it spans both genes: the smooth muscle component is scored NA in
      both ERBB2 patients, so this sentence does not establish it for this
      disease.
  downstream:
  - target: Congenital Gastrointestinal Dysmotility
    description: >-
      A gut wall lacking its normal complement of enteric neurons cannot
      generate coordinated propulsive motility.
    causal_link_type: DIRECT

- name: Congenital Gastrointestinal Dysmotility
  biological_scale: ORGANISM
  description: >
    The clinical output. In the two reported ERBB2 patients this took the
    form of severe constipation and, in the brother, short-segment
    Hirschsprung disease with hypoganglionosis; both were scored negative for
    chronic intestinal pseudo-obstruction. Across the wider NRG1/ERBB series
    the same lesion produces Hirschsprung disease in some patients and CIPO in
    others, which is informative in itself — the two clinical labels describe
    where along the gut the colonization deficit falls rather than two
    different diseases — but CIPO is not a feature of this concept as
    reported.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility."
    explanation: >
      States the clinical output and its breadth as the authors' conclusion.
  downstream:
  - target: Severe Constipation
    description: Failure of propulsive motility in the aganglionic and hypoganglionic gut.
    causal_link_type: DIRECT
  - target: Short-Segment Hirschsprung Disease
    description: >-
      Where the colonization deficit stops short of the proximal gut, the
      result is a short aganglionic distal segment.
    causal_link_type: DIRECT

- name: Extra-Intestinal Neural Crest and Peripheral Nerve Involvement
  biological_scale: ORGANISM
  description: >
    The affected siblings had axonal peripheral neuropathy, ptosis,
    sensorineural ("perceptive") hearing loss and clubfeet alongside the
    gastrointestinal disease. These are what mark the disorder as a broader
    neurocristopathy rather than an isolated gut disease, and they are the
    features that should prompt ERBB2 sequencing in a patient who would
    otherwise be worked up as isolated Hirschsprung disease.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
    explanation: >
      Enumerates the extra-intestinal features in the proband of the single
      ERBB2 family.
  - reference: PMID:9338783
    reference_title: "Severe neuropathies in mice with targeted mutations in the ErbB3 receptor."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous erbB3 mutant embryos lack Schwann-cell precursors and Schwann cells that accompany peripheral axons of sensory and motor neurons."
    explanation: >
      Grounds the Schwann cell precursor step behind the peripheral
      neuropathy, which the entry previously asserted without support.
      Mouse ErbB3, so the inference to a human ERBB2 kinase defect runs
      through the obligate heterodimer.
  downstream:
  - target: Peripheral Axonal Neuropathy
    description: Loss of NRG1/ERBB signalling in Schwann cell precursors and peripheral nerve.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The cell population mediating the neuropathy was not localized in these patients
  - target: Ptosis
    description: Neural-crest-derived contribution to periocular structures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Not investigated in these patients
  - target: Sensorineural Hearing Loss
    description: Neural-crest and Schwann cell precursor contribution to the auditory pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Not investigated in these patients
  - target: Arthrogryposis Multiplex Congenita
    description: >-
      Congenital joint contractures, plausibly secondary to reduced fetal
      movement from the peripheral nerve involvement, though this was not
      demonstrated and the source is inconsistent about whether the ERBB2
      siblings had contractures beyond the feet.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Whether the contractures are secondary to fetal akinesia was not established
  - target: Clubfeet
    description: Foot deformity accompanying the congenital contractures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Not investigated in these patients
mechanistic_hypotheses:
- hypothesis_group_id: canonical_nrg1_erbb_enteric_progenitor_model
  hypothesis_label: Canonical NRG1/ERBB Enteric Progenitor Model
  status: CANONICAL
  description: >-
    A homozygous ERBB2 kinase-domain variant removes neuregulin-1 signalling
    through the ERBB2/ERBB3 heterodimer in enteric progenitor cells,
    leaving the gut incompletely colonized by enteric neural crest
    derivatives; the resulting aganglionosis or hypoganglionosis produces
    congenital gastrointestinal dysmotility. Whether a smooth muscle lesion
    accompanies it is not established for ERBB2 disease — see the knowledge
    gap below — so the model does not include one. The model rests on the localization of
    ERBB3 function to enteric progenitors in mouse single-cell data and a
    conditional knockout, together with the functional demonstration that the
    ERBB2 variant drastically reduces phosphorylation of both receptors.
discussions:
- discussion_id: fvn2_smooth_muscle_primary_or_secondary
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do intestinal smooth muscle abnormalities occur in ERBB2-related enteric
    neuropathy at all, and if so are they a primary consequence of lost ERBB
    signalling in muscle or secondary to the absent enteric innervation?
  attaches_to:
  - pathophysiology#Incomplete Enteric Nervous System Colonization
  rationale: >-
    The cohort-wide histology reports smooth muscle abnormalities alongside
    the ganglion cell deficit, but Table 1 scores that row NA for both ERBB2
    patients and positive only in an ERBB3 patient, so it is not established
    for this disease. The ERBB pathway's role was in any case localized to
    enteric progenitors — not to muscle. If the muscle lesion is primary, this disorder is not purely
    neuropathic and its classification within chronic intestinal
    pseudo-obstruction changes; if secondary, restoring innervation would in
    principle be sufficient. Nothing in the reported data separates the two.
- discussion_id: fvn2_erbb2_erbb3_same_entity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Should VSCN2 (ERBB2) and VSCN1 (ERBB3) be one disease entry or two?
  attaches_to:
  - pathophysiology#Disrupted NRG1-ERBB Signaling in Enteric Progenitors
  rationale: >-
    ERBB2 and ERBB3 signal only as a heterodimer, and the two genotypes were
    reported together in one paper with one phenotypic spectrum, which is a
    strong argument for a single mechanistic entity. MONDO and OMIM give them
    separate concepts, and this entry follows that. The question is worth
    recording because a grouping over the NRG1/ERBB enteric axis may be the
    better structure once more patients are published — and because the two
    concepts are easy to transpose, the numbering running opposite to the
    gene numbering.
- discussion_id: fvn2_no_enteric_neural_crest_module
  kind: KNOWLEDGE_GAP
  prompt: >-
    Should enteric neural crest colonization failure be factored out of
    Hirschsprung disease, this entry, and the neuropathic CIPO entries as a
    mechanism module?
  attaches_to:
  - pathophysiology#Incomplete Enteric Nervous System Colonization
  rationale: >-
    The knowledge base already carries Hirschsprung disease and chronic
    intestinal pseudo-obstruction, both of which restate a
    migration-proliferation-differentiation chain that this entry restates a
    third time with a different upstream ligand-receptor pair. That
    repetition across independently curated entries is what `kb/modules/`
    exists to absorb. No such module exists, so this entry declares no
    `conforms_to`.
phenotypes:
- name: Severe Constipation
  category: Gastrointestinal
  description: >
    Severe constipation from birth, the presenting gastrointestinal feature in
    the proband. It eased after age five, which is worth recording: the
    dysmotility in this disease is not uniformly progressive.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
    temporality: CHRONIC
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented severe constipation that eased after 5 years of age,"
    explanation: >
      Documents the presenting gastrointestinal feature and its course in the
      proband of the single ERBB2 family.
- name: Short-Segment Hirschsprung Disease
  category: Gastrointestinal
  description: >
    Short-segment aganglionosis in the proband's brother, with colon resection
    histology showing absent ganglion cells and nerve fibre hyperplasia.
    Hypoganglionosis is scored alongside it in the source's Table 1, and the
    two coexist in this disease — a biopsy reporting ganglion cells present
    does not exclude the diagnosis. That one sibling had Hirschsprung disease
    and the other did not, on the same homozygous genotype, is the clearest
    evidence in this family that the gut phenotype is variable rather than
    determined by genotype alone.
  phenotype_term:
    preferred_term: Aganglionic megacolon
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
    explanation: >
      Colon resection histology in the affected brother, naming him
      explicitly and establishing absent ganglion cells.
- name: Peripheral Axonal Neuropathy
  category: Neurological
  description: >
    Axonal peripheral neuropathy, one of the extra-intestinal features that
    marks this as a neurocristopathy rather than an isolated enteric disease.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
    explanation: >
      Names axonal peripheral neuropathy among the proband's features.
- name: Ptosis
  category: Ophthalmological
  description: >
    Ptosis, reported in the proband.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
    explanation: >
      Names ptosis among the proband's features.
- name: Sensorineural Hearing Loss
  category: Otological
  description: >
    Perceptive (sensorineural) hearing loss. Consistent with a neural crest
    and Schwann cell precursor requirement for NRG1/ERBB signalling, though
    the cellular basis was not investigated in these patients.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
    explanation: >
      Names perceptive hearing loss among the proband's features.
- name: Clubfeet
  category: Musculoskeletal
  description: >
    Talipes equinovarus, named in the case description of the proband. Note
    that the source's Table 1 additionally scores both siblings positive for
    arthrogryposis, while the narrative description of family F5 lists
    clubfeet and not arthrogryposis. No sentence in the source distinguishes
    the two for these patients, and a table cell of "+" is not a quotable
    claim, so arthrogryposis is not curated as a separate phenotype here. If
    a later report describes contractures beyond the feet in an ERBB2
    patient, it should be added then.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axonal peripheral neuropathy, ptosis, perceptive hearing loss, and clubfeet"
    explanation: >
      Names clubfeet among the proband's features.
- name: Arthrogryposis Multiplex Congenita
  category: Musculoskeletal
  description: >
    Congenital joint contractures. The source is internally inconsistent about
    this in the ERBB2 siblings and the entry records that rather than picking
    a side. Table 1 scores arthrogryposis `+` for both F5:II-1 and F5:II-2.
    But the paper's own cohort description attributes arthrogryposis multiplex
    congenita to the three *fetuses* — all ERBB3 — while describing the five
    non-fetal patients, F5's two included, as neurocristopathies with
    Hirschsprung disease and peripheral neuropathy. The narrative account of
    family F5 names clubfeet and no other contracture.

    The most parsimonious reconciliation is that Table 1's `+` for F5 is
    scoring the clubfeet, in which case this phenotype and `Clubfeet` are one
    finding recorded twice. It is curated because a table positive in 2/2
    patients should not be silently dropped, and flagged because it may be
    double-counting.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis."
    explanation: >
      Establishes arthrogryposis as one of the four features varying across
      the series. Cohort-wide rather than ERBB2-scoped; the per-patient
      scoring is Table 1's, which cannot be quoted as a snippet.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "5 patients with neurocristopathies \n(4 of them with HSCR, 3 with peripheral neuropathy) and 3 fetuses \nwith arthrogryposis multiplex congenita"
    explanation: >
      Cuts against arthrogryposis in the ERBB2 siblings. The paper's cohort
      description splits its subjects into five patients with
      neurocristopathies and three fetuses with arthrogryposis multiplex
      congenita — and both ERBB2 siblings are among the five, not the three.
      Graded REFUTE because it contradicts the Table 1 scoring for these
      patients specifically.
genetic:
- name: ERBB2
  gene_term:
    preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  relationship_type: CAUSATIVE
  notes: >
    ERBB2 (HER2) encodes the kinase-active, ligand-orphan partner of the
    neuregulin-1 receptor system. It is the gene of MONDO:0030399 /
    OMIM:619465, per the MedGen gene-disease link for that OMIM concept.
    ERBB3 is the gene of the sibling concept VSCN1 (OMIM:243180) — note the
    disease numbering runs opposite to the gene numbering, which makes the
    two easy to transpose. Gene-disease validity here rests on a single
    family.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals"
    explanation: >
      Establishes ERBB2 as one of the two disease genes in this series.
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "missense variant (c.2129C>T, p.(Ala710Val)) within ERBB2"
    explanation: >
      Names the specific ERBB2 allele in the single family that defines this
      concept.
animal_models:
- name: Conditional ErbB3-deficient mouse
  species: Mouse
  genotype: Conditional ErbB3 knockout
  publication: PMID:33497358
  description: >
    Conditional ErbB3 knockout used, together with mouse single-cell RNA
    sequencing, to localize the NRG1/ERBB requirement to enteric progenitor
    cells.
  modeled_mechanisms:
  - target: Disrupted NRG1-ERBB Signaling in Enteric Progenitors
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model established that the NRG1/ERBB requirement in this system
      sits in enteric progenitors rather than in mature enteric neurons or in
      smooth muscle.
    limitations: >-
      The model targets ErbB3, the partner receptor, not ErbB2 — the gene of
      this disease. Because the two signal only as a heterodimer that is a
      defensible proxy, but it is a proxy, and it is why this link is
      PARTIALLY_RECAPITULATES rather than RECAPITULATES. A conditional
      knockout is also a complete loss in the targeted lineage, whereas the
      patient allele is a kinase-domain missense change, so the model speaks
      to where the pathway is required and not to how much residual
      signalling the human disease retains. The extra-intestinal features were
      not addressed by this model.
    evidence:
    - reference: PMID:33497358
      reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors"
      explanation: >-
        The model result that grounds this link.
diagnosis:
- name: Gut histopathology
  description: >
    Full-thickness or suction rectal biopsy assessing ganglion cell density.
    Both aganglionosis and hypoganglionosis occur — in the same ERBB2
    patient — so a report of ganglion cells present does not exclude the
    diagnosis. Assessing the muscle layer is reasonable given the wider
    NRG1/ERBB series, but note that no ERBB2 patient has had it assessed, so
    that is an extrapolation rather than a finding.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
    explanation: >
      The gene-scoped histology result, in the ERBB2 sibling who came to
      colon resection.
- name: Trio-exome sequencing
  description: >
    Molecular diagnosis. Every reported patient was ascertained this way; the
    combination of gastrointestinal dysmotility with peripheral neuropathy or
    arthrogryposis is the clinical pattern that should trigger it, since
    isolated Hirschsprung disease and CIPO have different genetic workups.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals"
    explanation: >
      Describes the diagnostic method used in the defining series.

treatments:
- name: Surgical Resection of the Aganglionic Segment
  description: >
    Resection of the aganglionic bowel, the standard management of
    Hirschsprung disease and the one intervention documented in a reported
    ERBB2 patient — the histology that establishes the diagnosis in F5:II-2
    came from a colon resection specimen. It removes the non-functioning
    segment; it does not restore enteric innervation to the remaining gut,
    which is why dysmotility can persist after surgery.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Congenital Gastrointestinal Dysmotility
    treatment_effect: MODULATES
    description: >-
      Removes the aganglionic segment obstructing transit. It does not
      address the colonization deficit itself.
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient F5:II-2, histology revealed a lack of ganglion cells and a hyperplasia of nerve fibers in the colon resection specimen"
    explanation: >
      The diagnostic histology in this patient came from a colon resection
      specimen — the quoted sentence says so, which is what documents that
      resection was performed.
- name: Genetic Counselling
  description: >
    Counselling for an autosomal recessive disorder in a consanguineous
    family, with a 1-in-4 recurrence risk per pregnancy once the biallelic
    genotype is known. Both parents in the reported family are heterozygous
    carriers and healthy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33497358
    reference_title: "Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "healthy parents are heterozygous for the ERBB2 variant"
    explanation: >
      Establishes the carrier state of both parents, which is what makes
      recurrence risk counselling applicable.

references:
- reference: PMID:33497358
  title: Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.
- reference: PMID:33720042
  title: "Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3."
- reference: PMID:9338783
  title: Severe neuropathies in mice with targeted mutations in the ErbB3 receptor.
📚

References & Deep Research

References

3
PMID:33497358
Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.
No top-level findings curated for this source.
PMID:33720042
Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3.
No top-level findings curated for this source.
PMID:9338783
Severe neuropathies in mice with targeted mutations in the ErbB3 receptor.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Ultra-rare, and the cohort is a single family. The disease-defining report is Le et al. (J Clin Invest 2021), which identified biallelic ERBB3 and ERBB2 variants in eight individuals across five families by trio-exome sequencing. Only family F5 — two siblings born to consanguineous parents, homozygous for ERBB2 p.(Ala710Val) — carries the ERBB2 genotype, and it is that family alone that defines this concept. The ERBB3 families in the same paper define familial visceral neuropathy 1 (VSCN1, OMIM:243180), a separate MONDO concept, and are out of scope here. **Do not read the paper's eight-patient phenotype list as this disease's phenotype list.** That list spans both genes, and the two do not carry the same features. Per Table 1 of the source, the ERBB2 siblings are positive for arthrogryposis, peripheral neuropathy, hearing loss and ptosis, and are explicitly **negative** for chronic intestinal pseudo-obstruction, external auditory canal agenesis, dysautonomia, pigmentation defect and cardiac defect — several of which are positive in the ERBB3 families. The intrauterine growth retardation and multiple pterygiums described for the ERBB3 fetuses of families F3 and F4 are likewise not attributed to the ERBB2 siblings. Only what Table 1 and the case description record for family F5 is curated here. The CIPO point deserves emphasis because it is counterintuitive: this concept sits in the differential for chronic intestinal pseudo-obstruction, and yet neither reported ERBB2 patient had CIPO. Their gastrointestinal disease was severe constipation and, in the brother, short-segment Hirschsprung disease with hypoganglionosis. An entry that listed CIPO as a feature here would be contradicted by the source's own table. Three things this entry is careful about: First, **the relationship to Hirschsprung disease is overlap, not identity.** `kb/disorders/Hirschsprung_Disease.yaml` covers the common, oligogenic, RET-driven disease. The eight reported ERBB3/ERBB2 patients "variably associat[ed]" Hirschsprung disease, chronic intestinal pseudo-obstruction, peripheral neuropathy and arthrogryposis — meaning some presented as Hirschsprung disease and some did not. The entry records the shared enteric-neural-crest mechanism and keeps the entities separate, because a Mendelian recessive gene with extra-intestinal features is not the same disease as oligogenic RET-associated Hirschsprung disease even where the gut histology converges. Second, **the relationship to chronic intestinal pseudo-obstruction is the same shape.** `kb/disorders/Chronic_Intestinal_Pseudoobstruction.yaml` carries a "Neuropathic" subtype as a physiological category, not as a genetic entity, and lists no ERBB2. This entry is the Mendelian entity that can present as neuropathic dysmotility; it is not a duplicate of that clinical syndrome entry. Third, **the gene assignment was checked, not assumed.** The two familial visceral neuropathy concepts are easy to transpose: VSCN1 (OMIM:243180) is the ERBB3 disease and VSCN2 (OMIM:619465, this entry) is the ERBB2 disease, which is the opposite of what the gene numbering suggests. The assignment here follows the MedGen gene-disease link for the OMIM concept that MONDO:0030399 cross-references. No `conforms_to` was declared: `kb/modules/` has no enteric or neural-crest developmental module. That gap is recorded in `discussions` below rather than left silent. **Deep-research provenance.** An OpenScientist run (`research/Familial_Visceral_Neuropathy_2-deep-research-openscientist.md`, 5/5 references resolved and on topic) is committed alongside this entry. Its substantive contribution was catching a gene error: the first draft of this entry attributed MONDO:0030399 to ERBB3, and the report identified ERBB2. The correction was then verified independently against the MedGen gene-disease links rather than accepted from the report. Two of that report's suggested NCIT bindings are badly wrong and must not be reused — `NCIT:C157763` is offered as "surgical procedure" but is *Metastatic Bladder Small Cell Neuroendocrine Carcinoma*, and `NCIT:C1516` is offered as "supportive care" but is *Lisofylline*. The report's own term validation flags both, which is the check working. The two NCIT terms this entry does bind (`NCIT:C15329` Surgical Procedure and `NCIT:C15240` Genetic Counseling) were selected independently of the report.

Create: Familial Visceral Neuropathy 2 (ERBB2) · 2026-08-31T21:51:49Z · View source

De-novo curation of familial visceral neuropathy 2 (MONDO:0030399) resolving curation claim #10294. The first draft attributed this concept to ERBB3; it is ERBB2. The two familial visceral neuropathy concepts run opposite to the gene numbering - VSCN1/OMIM:243180 is ERBB3 and VSCN2/OMIM:619465 is ERBB2 - and the stub carried no genes block to contradict the assumption. The OpenScientist deep-research run flagged it and the correction was then verified independently against MedGen gene-disease links (VSCN2 -> Gene 2064 ERBB2; VSCN1 -> Gene 2065 ERBB3) rather than accepted from the report. A correction comment was posted on the claim issue. Second precision point: the defining paper (PMID:33497358) reports eight individuals across both genes, so its phenotype list must not be copied wholesale - arthrogryposis with multiple pterygiums and intrauterine growth retardation belong to the ERBB3 fetuses of families F3 and F4. Only what family F5 was reported to have is curated: severe constipation easing after age five, short-segment Hirschsprung disease in the brother, axonal peripheral neuropathy, ptosis, sensorineural hearing loss and clubfeet. The mechanism is a kinase defect - ERBB3 binds NRG1 but is catalytically weak, ERBB2 has no ligand but supplies the kinase - and the homozygous p.Ala710Val kinase-domain variant drastically reduces phosphorylation of both receptors. The conditional ErbB3 mouse is linked as PARTIALLY_RECAPITULATES rather than RECAPITULATES because it targets the partner receptor, not the disease gene. Deep research: one OpenScientist run, committed, 5/5 references resolved and on topic; note two of its suggested NCIT bindings are badly wrong (NCIT:C157763 offered as surgical procedure is a bladder carcinoma term; NCIT:C1516 offered as supportive care is Lisofylline), which its own term validation flags - this entry binds no NCIT terms. Validated with just validate (22/22 snippets verified), just validate-terms, check-entity-refs and the snippet/folded-hyphen gates.

OpenScientist ▸
Familial Visceral Neuropathy 2 (VSCN2): Comprehensive Disease Characterization Report
openscientist-autonomous 5 citations 2026-08-31T21:27:45.234199

Familial Visceral Neuropathy 2 (VSCN2): Comprehensive Disease Characterization Report

Disease: Familial Visceral Neuropathy 2 (VSCN2) OMIM: #619465 · MONDO: MONDO:0030399 · Gene: ERBB2 (HER2, 17q12; MIM 164870; HGNC:3430) Category: Mendelian (autosomal recessive neurocristopathy) Report date: 2026-08-31

Summary

Familial Visceral Neuropathy 2 (VSCN2; OMIM #619465) is an ultra-rare autosomal recessive developmental neurocristopathy caused by biallelic loss-of-function variants in ERBB2 (HER2), the ligand-orphan but kinase-active partner of the neuregulin-1 (NRG1) receptor system. The disorder was defined in a single consanguineous Turkish family (a sister and brother) reported by Le et al. in 2021, who carried a homozygous kinase-domain missense variant, c.2129C>T; p.Ala710Val (A710V) in ERBB2 (NM_004448.3). Functional assays showed this variant drastically reduces phosphorylation of both ERBB2 and its heterodimeric partner ERBB3, establishing loss of NRG1/ERBB signaling as the mechanistic root of disease [PMID: 33497358].

Because ERBB3 binds NRG1 with high affinity but is catalytically weak, and ERBB2 is a ligand orphan but a strong kinase, functional NRG1 signaling requires an ERBB3/ERBB2 heterodimer. Loss of ERBB2 kinase activity therefore cripples signaling that is essential for the survival, proliferation, and migration of neural-crest-derived enteric neuronal progenitors and Schwann cell precursors that colonize the gut. The clinical consequence is a gastrointestinal dysmotility syndrome spanning colonic aganglionosis/hypoganglionosis (Hirschsprung disease, HSCR) and chronic intestinal pseudo-obstruction (CIPO), accompanied by peripheral axonal neuropathy, bilateral facial paresis, sensorineural hearing loss, ptosis, and additional musculoskeletal and endocrine features. Gut histology in affected individuals revealed aganglionosis, hypoganglionosis, and intestinal smooth-muscle abnormalities [PMID: 33497358].

VSCN2 sits within an allelic/pathway series built around the NRG1/ERBB axis: VSCN1 (OMIM #243180, ERBB3), VSCN2 (OMIM #619465, ERBB2), and the dominant VSCN3 (#609629); ERBB3 also underlies Lethal Congenital Contractural Syndrome type 2 (LCCS2, #607598). As of 2026, VSCN2 remains a single-family entity with a gene–disease validity classification of LIMITED, and there is no disease-specific therapy — management is supportive and surgical (pull-through for aganglionosis, nutritional support for dysmotility) with genetic counseling for prevention.

1. Disease Information

Overview. VSCN2 is a congenital disorder of gastrointestinal motility caused by defective development of the enteric nervous system (ENS) and peripheral nervous system, arising from biallelic ERBB2 dysfunction. It is a neurocristopathy — a disease of neural-crest-derived tissues — combining features of Hirschsprung disease, chronic intestinal pseudo-obstruction, and peripheral neuropathy [PMID: 33497358; PMID: 33720042].

Key identifiers.

Resource Identifier
OMIM #619465 — Visceral neuropathy, familial, 2, autosomal recessive
MONDO MONDO:0030399
Gene (OMIM) ERBB2 — MIM 164870
HGNC HGNC:3430 (ERBB2)
MedGen Concept present for the disorder
Orphanet No dedicated ORPHA code specific to type 2 (VSCN1 = ORPHA99811)
ICD-11 No type-2-specific code (VSCN1 maps to DA90.2)

Synonyms / alternative names. Visceral neuropathy, familial, 2, autosomal recessive; VSCN2. Gene aliases for ERBB2: HER2, NEU, CD340, HER-2, VSCN2.

Data source type. Information is derived from aggregated disease-level resources (OMIM, MONDO, GenCC, PanelApp) and a primary case series of individual patients (Le et al. 2021), not EHR-scale populations. The entire VSCN2 clinical picture derives from two siblings in one consanguineous Turkish family.

2. Etiology

Disease causal factors. VSCN2 is a monogenic, autosomal recessive genetic disorder. The primary cause is biallelic loss-of-function of ERBB2, disrupting NRG1/ERBB signaling required for ENS and Schwann cell development. There is no infectious or environmental cause; it is a developmental (neurocristopathy) mechanism.

"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis." [PMID: 33497358]

Genetic risk factors. The sole established genetic risk factor is inheritance of two loss-of-function ERBB2 alleles. In the index family, the causal variant is homozygous p.Ala710Val, a kinase-domain missense change absent from gnomAD. Consanguinity is a major contributing factor (parents were heterozygous carriers).

Environmental risk factors. None established. As a fully penetrant Mendelian developmental disorder in the reported family, environmental exposures are not implicated.

Protective factors. None reported. No protective alleles or environmental modifiers are known. (Given a single family, statistical assessment of modifiers is not possible.)

Gene–environment interactions. None documented for VSCN2. Mechanistically, the disorder is driven by developmental loss of a receptor tyrosine kinase pathway rather than gene–environment interplay.

3. Phenotypes

The full phenotype spectrum derives from the two Turkish siblings (Le et al. 2021, family 5) plus the broader ERBB3/ERBB2 case series. Onset is congenital/pediatric, and expressivity is variable (HP:0003812).

Phenotype Type HPO term Notes / frequency
Intestinal dysmotility / severe constipation Clinical sign HP:0002019 (constipation) Core feature; irregular bowel evacuation
Colonic aganglionosis (Hirschsprung disease) Pathology HP:0002251 (aganglionic megacolon) Rectal aganglionosis with submucosal nerve-fiber hyperplasia
Hypoganglionosis (above aganglionic segment) Pathology — Present in gut histology
Chronic intestinal pseudo-obstruction (CIPO) Clinical sign HP:0002580 Neurogenic dysmotility
Peripheral axonal neuropathy Clinical sign HP:0003477 (peripheral neuropathy) Axonal type
Bilateral facial paresis Clinical sign HP:0007209 Cranial nerve involvement
Sensorineural hearing loss Lab/clinical HP:0000407 —
Ptosis (unilateral) Physical HP:0007687 / HP:0000508 —
Hypotonia Clinical sign HP:0001252 —
Mild developmental delay Behavioral/neuro HP:0001263 —
Clubfeet / talipes Physical HP:0001762 —
Scoliosis Physical HP:0002650 —
Micropenis Physical HP:0000054 Endocrine involvement
Low testosterone Lab abnormality HP:0040171 —
Small nose / hypoplastic alae nasi Physical HP:0000160 / HP:0000389 Facial dysmorphism
Arthrogryposis (broader series) Physical HP:0002804 Seen in ERBB3 cases; part of NRG1/ERBB spectrum

"biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities." [PMID: 33497358]

Severity/progression. Severe, congenital-onset, chronic. GI dysmotility is life-limiting and requires lifelong management. Quality-of-life impact: major — chronic constipation/pseudo-obstruction, dependence on nutritional support/surgery, hearing and neuromuscular impairment. No formal EQ-5D/SF-36 data exist for this ultra-rare entity.

4. Genetic / Molecular Information

Causal gene. ERBB2 (HER2/NEU; 17q12; MIM 164870; HGNC:3430) — encodes a transmembrane EGF-family receptor tyrosine kinase.

Pathogenic variant (index family).

Feature Detail
Variant c.2129C>T (NM_004448.3), p.Ala710Val (A710V)
Zygosity Homozygous (consanguineous; parents heterozygous)
Location Highly conserved residue within the tyrosine kinase domain
Type Missense
Population frequency Absent from gnomAD
Functional consequence Loss of function — drastic decrease in phosphorylation of both ERBB2 and ERBB3 (Neuro-2a overexpression)
Origin Germline
ACMG interpretation Pathogenic / likely pathogenic in context (segregation + functional + absence from population)

"The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors." [PMID: 33497358]

Functional class. Loss of function (reduced receptor phosphorylation/kinase output). No gain-of-function or dominant-negative mechanism in VSCN2 (in contrast to oncogenic ERBB2 amplification/activating mutations in cancer).

Related disorders / allelic series. - VSCN1 — OMIM #243180, ERBB3 (MIM 190151), autosomal recessive. - VSCN2 — OMIM #619465, ERBB2, autosomal recessive. - VSCN3 — OMIM #609629, autosomal dominant. - LCCS2 (Lethal Congenital Contractural Syndrome 2) — OMIM #607598, ERBB3.

Modifier genes / epigenetics / chromosomal abnormalities. None specifically established for VSCN2. SOX10 directly activates ERBB3 transcription via an intronic neural-crest enhancer (ERBB3_MCS6) — relevant to the shared regulatory network but not a documented VSCN2 modifier. No large-scale chromosomal abnormalities are implicated.

5. Environmental Information

Environmental factors: None known. Lifestyle factors: None applicable. Infectious agents: None — VSCN2 is a genetic developmental disorder with no infectious trigger. This section is not applicable to VSCN2 beyond noting that consanguinity (a demographic, not environmental, factor) increases recessive risk.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic ERBB2 loss-of-function variant (p.A710V, kinase domain) → leads to a catalytically impaired ERBB2 receptor with drastically reduced autophosphorylation/trans-phosphorylation capacity [PMID: 33497358].
  2. Because ERBB3 is ligand-binding but kinase-dead and ERBB2 is the kinase-active partner, impaired ERBB2 → results in failure of the NRG1 → ERBB3/ERBB2 heterodimer to trans-phosphorylate ERBB3 C-terminal tyrosines (Y1054–Y1328) [Reactome R-HSA-1227986].
  3. Loss of ERBB3 phosphotyrosine docking sites → results in attenuated recruitment/activation of two downstream cascades (branch point):
  4. 3a. PI3K → AKT survival arm → normally phosphorylates/inhibits pro-apoptotic BAD, GSK3, FKHR-L1; its attenuation → leads to reduced survival of Schwann cell precursors and enteric progenitors [PMID: 11312610].
  5. 3b. RAS → RAF → MEK → ERK (MAPK) proliferation/migration arm → its attenuation → leads to impaired proliferation and migration of progenitors.
  6. Reduced survival/proliferation/migration of neural-crest-derived enteric neuronal progenitors and Schwann cell precursors (SCPs) → results in failure of these cells to fully colonize the gut and populate peripheral nerves [PMID: 33720042].
  7. Incomplete ENS colonization → results in colonic aganglionosis (rectum) and hypoganglionosis above the aganglionic segment, with compensatory submucosal nerve-fiber hyperplasia [PMID: 33497358].
  8. Absent/atrophic enteric ganglia and smooth-muscle abnormalities → lead to loss of coordinated peristalsis → clinical Hirschsprung disease / chronic intestinal pseudo-obstruction (functional obstruction, severe constipation).
  9. In parallel (branch), SCP/Schwann-cell deficiency along peripheral and cranial nerves → leads to peripheral axonal neuropathy, bilateral facial paresis, sensorineural hearing loss, and ptosis; neural-crest contributions to other structures → musculoskeletal/craniofacial and endocrine features (inferred from neural-crest biology and the broader ERBB3/ERBB2 series).

Detail by category

  • Molecular pathways: NRG1/ERBB receptor tyrosine kinase signaling → PI3K–AKT and RAS–MAPK (KEGG "ErbB signaling pathway"; Reactome "Signaling by ERBB2", R-HSA-1227986). cAMP/PKA potentiates NRG1-induced ERBB2/ERBB3 phosphorylation and both downstream arms.
  • Cellular processes: Progenitor survival (anti-apoptosis via AKT→BAD), proliferation, and directed migration (via GRB2/SHC, PLCγ/Ca²⁺-calcineurin, FAK, Rac/Cdc42).
  • Protein dysfunction: Loss of ERBB2 kinase output; the receptor pair is asymmetric and complementary — ERBB3 (high-affinity NRG1 binding, weak kinase) + ERBB2 (ligand-orphan, active kinase). A710V abolishes the kinase contribution.
  • Immune involvement: Not implicated.
  • Tissue damage mechanism: Developmental failure/hypoplasia of neural-crest derivatives (not oxidative/ischemic injury).
  • Molecular profiling: Mouse single-cell RNA-seq confirmed Erbb3/Erbb2 expression in enteric neuronal progenitor cells; a conditional ErbB3-deficient model revealed a primary role for ERBB3 in enteric progenitors [PMID: 33497358; PMID: 33720042].

"Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells." [PMID: 33720042]

"The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors." [PMID: 33497358]

ASCII schematic

   NRG1
     │ (binds)
     ▼
  ERBB3 ──heterodimer── ERBB2  ◄── p.A710V (kinase-dead) = VSCN2 lesion
  (kinase-weak)         (kinase-active)
     │  trans-phosphorylation of ERBB3 Y1054..Y1328
     ├───────────────┬──────────────────┐
     ▼               ▼
  PI3K→AKT        RAS→MAPK
  (survival)      (proliferation/migration)
     │               │
     └──────┬────────┘
    ▼
  Enteric progenitors + Schwann cell precursors
  (survive, proliferate, migrate, colonize gut/nerves)
    │  FAILS when ERBB2 kinase is lost
    ▼
  Aganglionosis / hypoganglionosis  +  peripheral neuropathy
  → HSCR / CIPO                      → facial paresis, hearing loss, ptosis

GO term suggestions: GO:0038128 (ERBB2 signaling pathway), GO:0007399 (nervous system development), GO:0048484 (enteric nervous system development), GO:0014010 (Schwann cell proliferation), GO:0043524 (negative regulation of neuron apoptotic process), GO:0016477 (cell migration). CL term suggestions: CL:0011103 (enteric neuron), CL:0002375 (Schwann cell precursor), CL:0000333 (migratory neural crest cell).

7. Anatomical Structures Affected

Organ level (primary): Large intestine / colon and rectum (UBERON:0001155 colon; UBERON:0001052 rectum) — site of aganglionosis. Small and large bowel broadly in CIPO. Secondary / body systems: Digestive system (UBERON:0001007), peripheral nervous system (UBERON:0000010), cranial nerves (facial nerve UBERON:0001647), inner ear/cochlea (sensorineural hearing loss; UBERON:0001846), musculoskeletal (spine, feet), and reproductive/endocrine (micropenis, low testosterone).

Tissue/cell level: Enteric ganglia within the myenteric (Auerbach; UBERON:0002439) and submucosal (Meissner; UBERON:0013529) plexuses; intestinal smooth muscle (UBERON:0001529); peripheral nerve Schwann cells. Cell populations: enteric neurons and their progenitors (CL:0011103), Schwann cells / SCPs (CL:0002573 / CL:0002375), neural-crest-derived cells.

Subcellular level: Plasma membrane receptor tyrosine kinase complex (GO:0005886 plasma membrane; GO:0004714 transmembrane receptor protein tyrosine kinase activity). No mitochondrial/lysosomal defect implicated.

Localization / lateralization: GI involvement follows the aganglionic segment (distal colon/rectum). Facial paresis is bilateral; ptosis reported unilateral; overall a mixed lateralization pattern.

8. Temporal Development

  • Onset: Congenital / neonatal–pediatric. GI dysmotility and HSCR features manifest early in life; developmental/craniofacial and neuromuscular features are present from birth.
  • Onset pattern: Chronic, developmental (insidious progression of dysmotility complications).
  • Progression: Chronic and lifelong. Enteric aganglionosis is a fixed developmental deficit; secondary complications (pseudo-obstruction, nutritional failure) can be progressive without intervention.
  • Course pattern: Chronic-progressive with episodic pseudo-obstruction crises; not relapsing-remitting.
  • Remission: No spontaneous remission; surgical management (pull-through) can relieve the aganglionic obstruction but does not cure the underlying neuropathy.
  • Critical periods: The developmental window of neural-crest colonization of the gut (embryonic) is the mechanistically critical period — clinically not therapeutically accessible postnatally.

9. Inheritance and Population

  • Inheritance: Autosomal recessive. Homozygous causal variant in the consanguineous index family; heterozygous parents unaffected.
  • Penetrance: Presumed complete in biallelic carriers (based on single family; formal penetrance estimate not possible).
  • Expressivity: Variable across the broader NRG1/ERBB series (HP:0003812).
  • Consanguinity: Central — the disorder was identified in a consanguineous Turkish family; consanguinity is the main route to homozygosity.
  • Founder effect / carrier frequency: Not established; variant absent from gnomAD, so no population carrier frequency is defined.
  • Epidemiology: Ultra-rare — VSCN2 remains a single-family entity as of 2026, with no additional ERBB2-specific families reported (2022–2026 literature review). No prevalence/incidence figures exist. Context: Hirschsprung disease overall has an incidence of ~1 in 5,000 live births, but VSCN2 is a vanishingly small molecular subset.
  • Demographics: Reported in a Turkish family (one affected sister and one affected brother); sex ratio not meaningfully estimable (both sexes affected). Gene–disease validity: LIMITED (GenCC/PanelApp).

"The patients carried homozygous or heterozygous variants in ERBB3 or ERBB2, which encode transmembrane epidermal growth factor receptors that bind neuroregulin 1 (NRG1)." [PMID: 33720042]

10. Diagnostics

Molecular diagnosis (definitive): - Whole-exome sequencing (WES) — the method that established the diagnosis (trio/WES in Le et al. 2021). Trio design aids interpretation. - Whole-genome sequencing (WGS) — useful for non-coding/structural variants when WES is negative. - Targeted NGS gene panels for HSCR/CIPO/pediatric intestinal pseudo-obstruction (e.g., Genomics England PanelApp panel 1217 includes ERBB2). - Single-gene ERBB2 sequencing with segregation (confirm parental heterozygosity).

"Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2." [PMID: 33497358]

Histopathology (cornerstone for the aganglionosis component): - Rectal suction biopsy — absence of ganglion cells with hypertrophied acetylcholinesterase (AChE)-positive cholinergic nerve trunks. - Calretinin immunohistochemistry — loss of staining is characteristic of Hirschsprung disease (sensitivity ~80–100%, specificity ~99–100%). - Full-thickness bowel biopsy in selected cases; findings include aganglionosis, hypoganglionosis, submucosal nerve-fiber hyperplasia, and smooth-muscle abnormalities.

CIPO workup: Exclude mechanical obstruction (CT/MRI); metabolic panel; endoscopy; GI scintigraphy; antroduodenal/small-bowel manometry (neuropathic pattern — abnormal migrating motor complex, non-propagated bursts); anorectal manometry (absent recto-anal inhibitory reflex in HSCR).

Adjunct testing: Nerve conduction studies/EMG (confirm axonal peripheral neuropathy); audiometry (sensorineural hearing loss); ophthalmologic assessment (ptosis).

Differential diagnosis: VSCN1 (ERBB3) and VSCN3; syndromic HSCR (e.g., RET, EDNRB, SOX10 — Waardenburg–Shah); other causes of CIPO (myogenic vs neurogenic); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); LCCS2. Molecular testing distinguishes these.

Screening: Cascade carrier testing in the family; prenatal/preimplantation testing feasible once the familial variant is known.

11. Outcome / Prognosis

  • Survival / mortality: No formal survival statistics for this ultra-rare entity. Prognosis is driven by the severity of intestinal dysmotility; CIPO with intestinal failure carries substantial morbidity/mortality and may require long-term parenteral nutrition.
  • Morbidity / function: High chronic morbidity — dependence on nutritional support and/or surgery, peripheral neuropathy, hearing impairment, and developmental delay affecting daily functioning.
  • Complications: Pseudo-obstruction crises, malnutrition/intestinal failure, enterocolitis (HSCR-associated), complications of surgery and long-term nutrition support.
  • Recovery potential: The developmental enteric deficit is not reversible; surgery relieves the aganglionic segment but underlying dysmotility and extraintestinal features persist.
  • Prognostic factors: Extent of aganglionosis/dysmotility, presence of intestinal failure, and severity of extraintestinal (neuromuscular, hearing) involvement. No validated molecular prognostic biomarkers.

12. Treatment

There is no disease-specific pharmacotherapy, gene therapy, or cell therapy for VSCN2. Management is supportive and surgical, targeting the manifestations.

Modality Intervention NCIT suggestion
Surgical (HSCR) Pull-through resection of aganglionic segment (Soave, Duhamel, Swenson) NCIT:C157763 (surgical procedure)
Nutritional Enteral/parenteral nutrition for dysmotility/intestinal failure NCIT:C15184 (nutritional support)
GI supportive Prokinetics, laxatives, bowel decompression for CIPO NCIT:C1516 (supportive care)
Neuromuscular Physical/occupational therapy for neuropathy, hypotonia NCIT:C15315 (rehabilitation therapy)
Sensory Hearing aids / audiologic support for sensorineural hearing loss —
Endocrine Testosterone/androgen evaluation for micropenis/low testosterone —
Ophthalmology Ptosis management —
  • Pharmacogenomics: Not applicable (no targeted drug).
  • Advanced / experimental therapeutics: No gene, RNA, or cell therapies in trials for VSCN2. (The many ERBB2/HER2-targeted oncology agents — e.g., trastuzumab, trastuzumab deruxtecan — are irrelevant here, as VSCN2 is caused by loss, not gain, of ERBB2 function; HER2 antagonism would be counterproductive.)
  • Treatment strategy: Multidisciplinary care (pediatric surgery, gastroenterology/motility, neurology, audiology, nutrition, genetics). Personalized approach centered on the individual's dysmotility burden.

13. Prevention

  • Primary prevention: Genetic counseling for consanguineous families and known carriers; awareness of autosomal recessive recurrence risk (25% for carrier couples).
  • Secondary prevention: Cascade carrier screening within the affected family; prenatal diagnosis or preimplantation genetic testing (PGT) once the familial ERBB2 variant is identified. Early recognition of HSCR/CIPO in at-risk newborns enables timely surgical/nutritional intervention.
  • Tertiary prevention: Prevention of complications — enterocolitis prophylaxis in HSCR, nutritional monitoring to prevent intestinal failure, and rehabilitation to limit neuromuscular disability.
  • Immunization / public-health / environmental interventions: Not applicable (non-infectious genetic disorder).
  • Counseling: NSGC/ACMG-guided genetic counseling is the principal preventive tool.

14. Other Species / Natural Disease

  • Taxonomy / model species: Mus musculus (NCBI:txid10090) and Danio rerio (zebrafish, NCBI:txid7955) are the principal experimental species; no naturally occurring companion-animal or wildlife VSCN2 analog is catalogued in OMIA.
  • Orthologous genes: Mouse Erbb2 (NCBI Gene 13866), Erbb3 (NCBI Gene 13867), Nrg1 (NCBI Gene 211323); strongly conserved.
  • Comparative biology / conservation: The NRG1/ERBB3/ERBB2 axis is deeply conserved across vertebrates in Schwann cell and neural-crest development. Mouse and zebrafish loss-of-function phenocopy key components (Schwann cell precursor loss; reduced enteric/sympathetic ganglia).
  • Zoonotic potential: None (genetic disorder).

15. Model Organisms

Mouse and zebrafish models robustly validate the ERBB2/ERBB3/NRG1 mechanism.

Model Phenotype Recapitulation of VSCN2 Reference
Erbb2-null mouse Embryonic lethal ~E10.5 (cardiac ventricular trabeculation defect) Limited by early lethality; ENS not fully assessable Erickson 1997 [PMID: 9362461]
Nrg1 (heregulin)-null mouse Embryonic lethal ~E10.5 (cardiac) Confirms NRG1 as the ligand of the axis [PMID: 9362461]
Erbb3-null mouse Lethal ~E13.5; absent Schwann cell precursors; generalized neural-crest defect (reduced cranial ganglia, enteric ganglia, adrenal chromaffin cells) Strong — recapitulates peripheral neuropathy + reduced enteric ganglia Riethmacher 1997 [PMID: 9338783]
Cardiac-rescued Erbb2-null mouse Survive to birth; lack Schwann cells, lose motor/sensory neurons Strong for peripheral component Woldeyesus/Morris, Neuron 1999
Wnt1-Cre;Erbb3 conditional Depletes cervical sympatho-enteric population (E10); esophageal ganglia reduced ~68% at E13.5; reduced foregut Sox10+ cells at E10.5 Directly models enteric progenitor failure [PMID: 33497358]
erbb2/erbb3 mutant zebrafish Early ENS grossly normal (redundancy/timing; dual vagal SCP + trunk crest origin) Highlights model limitation/redundancy (Le et al. discussion)

"Schwann-cell precursors" — Riethmacher et al. showed Erbb3-null mice lack Schwann-cell precursors, recapitulating the peripheral neuropathy component. [PMID: 9338783]

Model limitations: Conventional Erbb2/Nrg1 knockouts die too early (cardiac lethality) to assess ENS directly; conditional/rescue models are required. Zebrafish show ENS redundancy, so early enteric formation can appear normal. These caveats reflect pathway redundancy and the dual embryonic origin of enteric neurons rather than absence of a role.

Applications: Single-cell RNA-seq and conditional deletion models establish cell-type-specific ERBB function in enteric progenitors and Schwann cell precursors — the core disease mechanism.

Mechanistic Model / Interpretation

VSCN2 is best understood as a kinase-deficiency neurocristopathy. The NRG1 receptor system is intrinsically split into a ligand-binding subunit (ERBB3) and a catalytic subunit (ERBB2). Neither works alone: signaling demands the ERBB3/ERBB2 heterodimer, in which ERBB2 phosphorylates ERBB3's cytoplasmic tail to create docking sites for PI3K–AKT (survival) and RAS–MAPK (proliferation/migration). The VSCN2 lesion (homozygous p.A710V in the ERBB2 kinase domain) removes the catalytic half of this obligate partnership, functionally silencing NRG1 signaling despite intact ligand and intact ERBB3.

Developmentally, the cells most dependent on this signal are neural-crest-derived enteric progenitors and Schwann cell precursors, which must survive, proliferate, and migrate to colonize the gut and peripheral nerves. Their signaling failure produces the disease's dual signature: enteric aganglionosis/hypoganglionosis (→ HSCR/CIPO) in the gut and Schwann-cell/peripheral-nerve deficiency (→ axonal neuropathy, facial paresis, sensorineural hearing loss, ptosis). Mouse genetics corroborates each branch — Erbb3/Erbb2/Nrg1 nulls lose Schwann cell precursors and show reduced enteric ganglia, and conditional Wnt1-Cre;Erbb3 deletion specifically depletes sympatho-enteric progenitors. The convergence of human genetics, patient-cell functional assays (reduced ERBB2/ERBB3 phosphorylation), single-cell expression data, and conditional mouse models makes this one of the more mechanistically complete rare-disease causal chains.

The disorder anchors a coherent allelic/pathway series: recessive ERBB3 (VSCN1, LCCS2) and recessive ERBB2 (VSCN2) lesions produce overlapping neurocristopathy phenotypes, consistent with their shared obligate-heterodimer biology.

Evidence Base

PMID Title / focus Role in this report
33497358 Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans (Le et al., J Clin Invest 2021) Primary defining paper. Identifies biallelic ERBB2/ERBB3 variants in 8 individuals; defines VSCN2 (ERBB2 A710V); functional loss-of-function assays; single-cell + conditional mouse validation.
33720042 Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3 (Gershon commentary) Confirms ERBB2/ERBB3 as NRG1-binding EGF receptors expressed in enteric neuronal progenitors; frames HSCR/CIPO as congenital motility defects.
9338783 Riethmacher et al. 1997 — Erbb3-null mouse Model evidence: absence of Schwann-cell precursors; neural-crest/enteric ganglia defect.
9362461 Erickson et al. 1997 — Erbb2/Nrg1 nulls Model evidence: early cardiac-lethal phenotypes; establishes ligand/receptor pairing.
11312610 Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival Mechanistic: defines the PI3K/AKT/BAD survival arm downstream of NRG1-ERBB.

Evidence-source types: Human clinical/genetic (PMID 33497358; commentary 33720042); model organism (PMID 9338783, 9362461, conditional models); in vitro functional (patient fibroblast RT-qPCR, Neuro-2a immunoblot; PMID 33497358); biochemical/pathway (PMID 11312610; Reactome R-HSA-1227986).

(Note: The breast-cancer HER2 therapy papers retrieved during investigation — PMIDs 40759100, 32715420, 28366406, 18650157 — pertain to oncologic HER2 gain-of-function targeting and are not applicable to VSCN2, a loss-of-function disorder. They are excluded from the mechanistic evidence base.)

Limitations and Knowledge Gaps

  1. Single-family disease. All VSCN2-specific clinical data derive from two siblings in one consanguineous Turkish family. Penetrance, expressivity, natural history, prognosis, and prevalence cannot be estimated; gene–disease validity is LIMITED.
  2. One variant. Only p.A710V is documented for ERBB2 in VSCN2; the full mutational spectrum, genotype–phenotype correlations, and allele frequencies are unknown.
  3. No epidemiologic data. No prevalence/incidence, sex ratio, or geographic distribution beyond the index Turkish family.
  4. No dedicated Orphanet/ICD-11 code for type 2, complicating standardized cataloguing.
  5. Model caveats. Conventional Erbb2 knockouts are cardiac-lethal before ENS assessment; zebrafish show ENS redundancy — so the enteric role relies on conditional/rescue models and human genetics rather than a direct Erbb2 enteric knockout phenotype.
  6. No therapeutics. No disease-specific treatment exists; management is empiric/supportive.
  7. Extraintestinal features under-characterized. The mechanistic link between ERBB2 loss and craniofacial/endocrine features (micropenis, low testosterone, hypoplastic alae nasi) is inferred from neural-crest biology, not directly demonstrated.

Proposed Follow-up Experiments / Actions

  1. Patient ascertainment / matchmaking. Deposit the ERBB2 variant in ClinVar and use GeneMatcher/Matchmaker Exchange to find additional VSCN2 families, enabling genotype–phenotype and penetrance analysis.
  2. Allelic-series functional platform. Establish a standardized ERBB2/ERBB3 phosphorylation and PI3K-AKT/MAPK reporter assay to classify future ERBB2 variants (VUS resolution per ACMG PS3/BS3).
  3. Conditional Erbb2 enteric knockout. Generate a Wnt1-Cre;Erbb2 (or inducible Sox10-CreER;Erbb2) mouse to directly test the enteric requirement for ERBB2 (paralleling the existing Erbb3 conditional), bypassing cardiac lethality.
  4. Patient iPSC → enteric neural crest / organoid model. Differentiate patient-derived iPSCs into enteric neural crest and gut organoids to model colonization failure and screen small molecules acting downstream of the receptor block.
  5. Extraintestinal mechanism mapping. Lineage-tracing in conditional models to test whether craniofacial/endocrine features arise from specific neural-crest sublineages, formalizing the currently inferred steps.
  6. Registry / natural history. Create an NRG1/ERBB-spectrum (VSCN1/2/3, LCCS2) registry to aggregate ultra-rare cases and define prognosis and management outcomes.
  7. Ontology curation. Propose a dedicated Orphanet/ICD-11 entry and HPO annotation set for VSCN2 to improve knowledge-base interoperability.

Prepared from a 5-iteration autonomous investigation. Core citations: PMID 33497358, PMID 33720042, PMID 9338783, PMID 9362461, PMID 11312610.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

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

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 45
Resolved 44
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 28
Terms named correctly 11
Terms named as a different term 14
Terms whose name is worth a second look 3

Terms the report names something else

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

  • MONDO:0030399 (2 mentions) - the report calls it "MONDO"; MONDO calls it visceral neuropathy, familial, 2, autosomal recessive
  • HP:0003812 (2 mentions) - the report calls it "variable", "Expressivity: Variable across the broader NRG1/ERBB series"; HP calls it Phenotypic variability**
  • HP:0002580 (1 mention) - the report calls it "Clinical sign"; HP calls it Volvulus
  • HP:0000407 (1 mention) - the report calls it "Lab/clinical"; HP calls it Sensorineural hearing impairment
  • HP:0001252 (1 mention) - the report calls it "Clinical sign"; HP calls it Hypotonia
  • HP:0001263 (1 mention) - the report calls it "Behavioral/neuro"; HP calls it Global developmental delay
  • HP:0001762 (1 mention) - the report calls it "Physical"; HP calls it Talipes equinovarus
  • HP:0002650 (1 mention) - the report calls it "Physical"; HP calls it Scoliosis
  • HP:0000054 (1 mention) - the report calls it "Physical"; HP calls it Micropenis
  • HP:0040171 (1 mention) - the report calls it "Lab abnormality"; HP calls it Decreased serum testosterone concentration
  • HP:0002804 (1 mention) - the report calls it "Physical"; HP calls it Arthrogryposis multiplex congenita
  • NCIT:C157763 (1 mention) - the report calls it "surgical procedure"; NCIT calls it Metastatic Bladder Small Cell Neuroendocrine Carcinoma
  • NCIT:C15184 (1 mention) - the report calls it "nutritional support"; NCIT calls it Behavioral Intervention
  • NCIT:C1516 (1 mention) - the report calls it "supportive care"; NCIT calls it Lisofylline

Terms whose name is worth a second look

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

  • HP:0003477 (1 mention) - the report calls it "peripheral neuropathy"; HP calls it Peripheral axonal neuropathy
  • HP:0007209 (1 mention) - the report calls it "Clinical sign"; HP calls it Facial paralysis, and lists "Facial paresis" among its other names
  • CL:0011103 (2 mentions) - the report calls it "enteric neuron"; CL calls it sympathetic neuron

Terms named inconsistently

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

  • HP:0003812 - called "variable", "Expressivity:** Variable across the broader NRG1/ERBB series"