Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome

Mendelian MONDO:0017123 Pathograph 26 Show in embeddings browser Renal tubular transport disease inborn disorder of bilirubin metabolism hereditary disease Intracellular trafficking disorder

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a lethal autosomal recessive multisystem disorder caused by biallelic loss-of-function variants in VPS33B (ARCS1) or its obligate partner VIPAS39/VIPAR (ARCS2). These two proteins form the CHEVI (class C Homologues in Endosome-Vesicle Interaction) tethering complex, which acts with RAB11A on the apical recycling endosome pathway. Loss of CHEVI function destroys apical-basolateral polarity in hepatocytes and renal proximal tubular cells and cripples the biogenesis of two specialised lysosome-related organelles - the epidermal lamellar body and the platelet alpha-granule. The cardinal triad is neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction (usually renal Fanconi syndrome), and neonatal cholestasis with a characteristically normal or low serum gamma-glutamyltransferase; ichthyosis, intractable diarrhoea, severe failure to thrive, dysmorphism, central nervous system malformation, sensorineural deafness and an alpha-granule-deficient bleeding diathesis are common. Most affected infants die within the first year of life. Nomenclature. This entry deliberately carries the ARC name and MONDO:0017123 because that is the entity whose mechanism is curated here. Two historical clinical labels resolve into it and are retained as synonyms. The first is Fanconi-ichthyosis-dysmorphism (FID) syndrome, also called Deal-Barratt-Dillon syndrome, described in 1990 in six infants of consanguineous parentage who shared renal Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea, two of them with grey-platelet-like platelet morphology, all dead before 6 months of age. A 2001 multicentre ARC series concluded explicitly that this association "is part of the ARC spectrum", and the molecular basis was then established as VPS33B (2004) and VIPAS39 (2010). The FID presentation is the arthrogryposis-poor end of the spectrum: arthrogryposis is not obligate, and patients with complete loss-of-function VPS33B alleles have been reported with ichthyosis, cholestasis and renal dysfunction but no contractures. Note that the "Fanconi" in the FID label refers to the renal proximal tubulopathy, NOT to Fanconi anaemia - a conflation that persists in some classifications (see `discussions` and `notes`). Management is supportive; no disease-modifying therapy exists. Liver and kidney biopsy carry a very high risk of fatal bleeding from the platelet alpha-granule defect, so molecular diagnosis is preferred over tissue sampling.

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Mappings

MONDO

MONDO:0022948 Deal Barratt Dillon syndrome Not Yet Curated

MONDO:0022948 is the historical Deal-Barratt-Dillon / FID clinical label, carrying "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea" as a synonym (from MESH:C538206). Deliberately recorded as a close rather than narrow match, unlike the ICD-11 FID class: MONDO:0022948 is an unreconciled stub - no textual definition, no gene association, no OMIM xref - and it sits under MONDO:0001083 Fanconi renotubular syndrome rather than under MONDO:0017123, so its intended extension is not formally recoverable from MONDO. Asserting a hierarchical narrowMatch would over-claim knowledge of a class that has not been given an extension; closeMatch states the association without the subset claim. MONDO's placement does at least get the "Fanconi" homonym right. See the `mondo_deal_barratt_dillon_unreconciled_stub` discussion.

MONDO:0008822 arthrogryposis, renal dysfunction, and cholestasis 1 Not Yet Curated

The VPS33B-defined child class, curated here as the ARCS1 subtype.

MONDO:0013255 arthrogryposis, renal dysfunction, and cholestasis 2 Not Yet Curated

The VIPAS39-defined child class, curated here as the ARCS2 subtype.

ICD-11 Foundation

icd11f:235762608 Fanconi-ichthyosis-dysmorphism syndrome

The ICD-11 Foundation entity for the historical FID label. Recorded as a narrow match now that this entry targets the ARC spectrum (MONDO:0017123) on the strength of PMID:11668108, which concluded the FID association "is part of the ARC spectrum": FID denotes the arthrogryposis-poor end of this entry's extension rather than the whole of it. The narrow match rests on that ARC-spectrum literature and not on the ICD-11 definition, because the ICD-11 text does not faithfully reproduce the original Deal-Barratt-Dillon description — it substitutes the homonym error, reading "the association of Fanconi anaemia, ichthyosis, musculo-skeletal anomalies, jaundice, and diarrhoea" where PMID:2206896 says "the Fanconi syndrome". The ICD-11 parentage propagates the same misreading (see the `fid_icd11_fanconi_anaemia_misparent` discussion).

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Inheritance

Autosomal recessive HP:0000007

All six infants in the original FID series were born to consanguineous couples, consistent with autosomal recessive inheritance of a rare founder or private allele. ARC-spectrum disease, to which FID belongs, is an established autosomal recessive disorder caused by biallelic VPS33B or VIPAS39 variants.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:2206896 SUPPORT Human Clinical

"six infants, from consanguineous marriages, with a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

Consanguinity in all six index families supports recessive inheritance of the FID phenotype.

PMID:25239142 SUPPORT Human Clinical

"Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene."

Establishes autosomal recessive inheritance for the ARC spectrum that subsumes FID.

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Subtypes

ARCS1 (VPS33B-related) MONDO:0008822

VPS33B hgnc:12712 {'name': 'Autosomal recessive'}

ARC syndrome caused by biallelic VPS33B variants at 15q26.1, accounting for roughly three-quarters of cases. VPS33B is the Sec1/Munc18-family subunit of the CHEVI complex. The allelic spectrum is dominated by null variants, and no VPS33B protein is detectable in tissues from classical cases; rare hypomorphic alleles retaining partial VPS33B-VIPAR interaction produce attenuated phenotypes with survival into childhood.

Show evidence (2 references)

PMID:15052268 SUPPORT Human Clinical

"we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"

Establishes VPS33B as the ARCS1 disease gene.

PMID:20190753 SUPPORT Human Clinical

"Germline mutations in VPS33B are found in approximately 75% of individuals with ARC"

Quantifies the ARCS1 share of the spectrum.

ARCS2 (VIPAS39/VIPAR-related) MONDO:0013255

VIPAS39 hgnc:20347 {'name': 'Autosomal recessive'}

ARC syndrome caused by biallelic VIPAS39 (formerly C14orf133, protein VIPAR) variants, accounting for the cases without VPS33B lesions. VIPAR is the obligate binding partner of VPS33B within the CHEVI complex. Reported alleles are predicted null, and no clinical differences distinguish ARCS2 from ARCS1, consistent with the two proteins acting as a single functional complex.

Show evidence (2 references)

PMID:20190753 SUPPORT Human Clinical

"Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."

Establishes VIPAS39 as the ARCS2 locus.

PMID:20190753 SUPPORT Human Clinical

"We detected no differences in clinical symptoms, signs or disease course between subjects in VPS33B- and VIPAR-mutated ARC subsets."

Documents locus-independence of the clinical phenotype.

Discussions and Knowledge Gaps

Should the ICD-11 Foundation classification of Fanconi-ichthyosis-dysmorphism syndrome as a child of Fanconi anaemia be corrected to renal Fanconi syndrome?

INTERPRETATION OPEN fid_icd11_fanconi_anaemia_misparent

Attached to

pathophysiology#Proximal Tubular Apical Transport Failure

The ICD-11 Foundation entity icd11f:235762608 defines FID as "the association of Fanconi anaemia, ichthyosis, musculo-skeletal anomalies, jaundice, and diarrhoea" and places it under Fanconi anaemia. The primary description (PMID:2206896), its MeSH synonym, and MONDO all use "Fanconi syndrome" in the renal proximal-tubulopathy sense; MONDO:0022948 is classified under MONDO:0001083 Fanconi renotubular syndrome. Nothing in the primary literature describes bone marrow failure, pancytopenia, chromosome breakage or cancer predisposition in these infants, and the molecular aetiology — biallelic VPS33B/VIPAS39 loss disrupting apical trafficking — has no relationship to the Fanconi anaemia DNA interstrand-crosslink repair pathway. The ICD-11 placement appears to be a homonym error between two unrelated Fanconi eponyms, and it propagates into any downstream system that inherits ICD-11 parentage. dismech records the mapping as a narrow match - the ICD-11 definition delimits the arthrogryposis-poor FID end of this entry's ARC spectrum - while flagging the parentage as incorrect.

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"No evidence of a recognised metabolic disorder was found in any of the six infants"

The primary series describes a renal tubulopathy phenotype and reports no haematological marrow-failure disorder, contradicting the ICD-11 parentage.

Were the six original Deal-Barratt-Dillon infants molecularly VPS33B- or VIPAS39-deficient, and does any FID-labelled case exist that is not explained by CHEVI complex loss?

KNOWLEDGE GAP OPEN fid_molecular_confirmation_gap

Attached to

pathophysiology#Biallelic Loss of VPS33B or VIPAS39 Function pathophysiology#Neurogenic Arthrogryposis and Musculoskeletal Anomalies

The 1990 FID series predates the identification of VPS33B (2004) and VIPAS39 (2010), so no proband from that series has a confirmed genotype. The assignment of FID to the ARC spectrum rests on the phenotypic argument made by Eastham and colleagues in 2001 (PMID:11668108) plus the subsequent demonstration that VPS33B-null patients can lack arthrogryposis (PMID:16492441). That argument is strong but is not the same as molecular proof for these specific families. Because the assignment determines whether FID should be retired as an independent entity or retained as a distinct locus, the gap is worth stating explicitly rather than papering over.

Proposed experiments

Retrospective genotyping of archival FID material

fid_archival_genotyping

Where archival DNA or fixed tissue from the 1990 Great Ormond Street cohort or surviving relatives can be located and consented, sequence VPS33B and VIPAS39 (with copy-number analysis) to test directly whether the FID probands carry biallelic CHEVI-complex variants.

Would support

FID is a phenotypic variant of VPS33B/VIPAS39-related ARC-spectrum disease and should be retired as an independent entity

Would refute

FID represents a distinct, still-unidentified locus that phenocopies the ARC spectrum

Exome/genome sequencing of ARC-phenotype, CHEVI-negative infants

fid_phenotype_negative_cohort_sequencing

Sequence infants presenting with renal Fanconi syndrome, low-GGT cholestasis, ichthyosis and diarrhoea but no VPS33B or VIPAS39 variant, to determine whether a third locus exists that would correspond to a genuinely separate FID entity.

Would support

A distinct FID locus exists outside the CHEVI complex

Would refute

VPS33B and VIPAS39 account for the entire phenotypic spectrum, as suggested when VIPAR mutations explained all VPS33B-negative classical ARC cases

Show evidence (2 references)

PMID:11668108 SUPPORT Human Clinical

"The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum."

The phenotypic, pre-molecular basis on which FID was subsumed into the ARC spectrum — strong, but not genotype-confirmed for the FID probands themselves.

PMID:20190753 SUPPORT Human Clinical

"Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."

Evidence bearing on whether a third locus is likely: VIPAS39 closed the residual gap in classical ARC, arguing against an unidentified FID locus.

Should a "CHEVI-complex apical trafficking failure" mechanism module be factored out of this entry and its allelic relatives?

CURATION TODO OPEN fid_chevi_trafficking_module_candidate

Attached to

pathophysiology#Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex

The mechanism curated here — CHEVI/RAB11A-dependent apical recycling failure producing simultaneous epithelial polarity loss and defective biogenesis of two lysosome-related organelles (lamellar body, platelet alpha-granule) — is shared across ARC syndrome, this FID presentation, and the allelic ARKID syndrome, and is conceptually adjacent to other lysosome-related-organelle disorders (Hermansky-Pudlak, Chediak-Higashi). No existing dismech module covers it: the `epithelial_barrier_dysfunction` and `intestinal_barrier_dysfunction` modules model allergic and inflammatory barrier loss, not a constitutive trafficking lesion. No `conforms_to` edge is asserted in this entry for that reason. If ARC syndrome and ARKID are curated as separate entries, a shared module becomes worthwhile.

Show evidence (1 reference)

PMID:27555442 SUPPORT Other

"corroborate its role in the specialized delivery of cargo in different cell types"

Frames CHEVI as a general cargo-delivery mechanism operating across cell types, which is the recurrence criterion a dismech mechanism module requires.

Should MONDO:0022948 (Deal Barratt Dillon syndrome) be obsoleted and merged into, or asserted as a subclass of, MONDO:0017123 arthrogryposis-renal dysfunction-cholestasis syndrome?

OPEN QUESTION OPEN mondo_deal_barratt_dillon_unreconciled_stub

Attached to

pathophysiology#Biallelic Loss of VPS33B or VIPAS39 Function

MONDO:0022948 is an unreconciled legacy class. It has no textual definition, no gene association, and no OMIM xref - only GARD, MEDGEN, MeSH and UMLS cross-references - and it is classified under MONDO:0001083 Fanconi renotubular syndrome. By contrast MONDO:0017123 has an Orphanet-sourced definition, an OMIMPS xref, and two gene-defined children (MONDO:0008822 VPS33B, MONDO:0013255 VIPAS39). The primary literature closed this gap in 2001: PMID:11668108 concluded that the Fanconi syndrome-ichthyosis-dysmorphism-jaundice-diarrhoea association "is part of the ARC spectrum", and the molecular basis was established in 2004 and 2010. So the two MONDO classes denote the same patients, one of them without any mechanistic grounding. dismech anchors on MONDO:0017123 and records MONDO:0022948 as a close match; the ontology-side fix is out of scope here but worth filing upstream.

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

The published statement that the two labels denote one entity, which is what MONDO has not yet reflected in its class hierarchy.

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Pathophysiology

Biallelic Loss of VPS33B or VIPAS39 Function

Germline biallelic loss-of-function variants in VPS33B (15q26.1) or, in VPS33B-negative families, in VIPAS39/VIPAR abolish production of functional protein. VPS33B is a Sec1/Munc18-family protein containing a Sec1-like domain that regulates vesicle-to-target SNARE complex formation and subsequent membrane fusion; VIPAR is its obligate binding partner. Nearly all reported VPS33B alleles are null (nonsense, frameshift, splice), and no VPS33B protein is detectable in tissues from classical ARC cases. VPS33B accounts for roughly three-quarters of ARC-spectrum cases, with VIPAS39 explaining the remainder.

VPS33B hgnc:12712 ↓ DECREASED VIPAS39 hgnc:20347 ↓ DECREASED

syntaxin binding (Sec1/Munc18-type SNARE regulation) GO:0019905 ↓ DECREASED

Downstream

Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex Absence of either subunit prevents assembly of the heterodimeric tethering complex, since the two proteins function only together.

Show evidence (3 references)

PMID:15052268 SUPPORT Human Clinical

"we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"

Original identification of VPS33B as the ARC-spectrum disease gene.

PMID:15052268 SUPPORT Human Clinical

"VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion."

Defines the molecular function lost when VPS33B is inactivated.

PMID:20190753 SUPPORT Human Clinical

"We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects."

Establishes VIPAS39/VIPAR as the second ARC-spectrum locus.

Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex

VPS33B and VIPAR are the two known components of the CHEVI (class C Homologues in Endosome-Vesicle Interaction) complex, a metazoan endosomal tethering complex distinct from the better-characterised HOPS and CORVET complexes. The complex interacts with the active, GTP-bound form of RAB11A, placing it on the apical recycling endosome pathway. Loss of either subunit therefore removes a tethering step required for delivery of specific cargo to apical membranes and to specialised lysosome-related organelles.

vesicle-mediated transport (endosomal vesicle tethering) GO:0016192 ↓ DECREASED SNARE complex assembly GO:0035493 ↓ DECREASED

recycling endosome GO:0055037

Downstream

Disrupted RAB11A-Dependent Apical Recycling and Cargo Sorting Without CHEVI tethering, RAB11A-dependent delivery of apical cargo fails and cargo is diverted to the basolateral membrane or to lysosomal degradation.

Defective Epidermal Lamellar Body Biogenesis and Secretion The same tethering function is required for the biogenesis and exocytosis of epidermal lamellar bodies, a lysosome-related organelle.

Failed Platelet Alpha-Granule Biogenesis CHEVI is likewise required for construction of the platelet alpha-granule, another lysosome-related organelle.

Neurogenic Arthrogryposis and Musculoskeletal Anomalies Arthrogryposis in this disorder is neurogenic, so CHEVI loss must reach the motor unit, but the intermediates are not established. No published work identifies the neuronal cargo, cell type, or developmental window through which VPS33B/VIPAS39 deficiency produces anterior horn involvement, and the mouse models characterised to date address the cutaneous and platelet arms rather than the neuromuscular one. The edge is therefore asserted as indirect with unknown intermediates rather than left implicit.

Show evidence (1 reference)

PMID:27555442 SUPPORT Other

"VPS33B and VIPAR comprise the two known components of the recently christened class C Homologues in Endosome-Vesicle Interaction (CHEVI) complex, thought to act as a tethering complex in endosomal trafficking distinct from the HOPS and CORVET complexes in mammalian cells."

Names and defines the complex whose loss underlies the disease.

Disrupted RAB11A-Dependent Apical Recycling and Cargo Sorting

Apical membrane cargo that normally traverses RAB11A-positive apical recycling endosomes is mis-sorted: some proteins reach the basolateral membrane instead, and others (e.g., CEACAM5) are diverted into late endosomes and lysosomes for degradation. Cargo that bypasses the apical recycling endosome (e.g., MRP2) is spared, which is what makes the defect cargo-selective rather than a global secretory block.

ABCB11 hgnc:42 ⚠ ABNORMAL

apical protein localization GO:0045176 ↓ DECREASED endosomal transport GO:0016197 ⚠ ABNORMAL

recycling endosome GO:0055037

Downstream

Loss of Apical-Basolateral Epithelial Polarity Cargo mis-sorting, compounded by transcriptional downregulation of E-cadherin, degrades the apical junctional complex and with it epithelial polarity and lumen formation.

Show evidence (2 references)

PMID:20190753 SUPPORT Human Clinical

"Mis-sorting of some BSEP to the basolateral hepatocyte membrane was seen in the livers of individuals with ARC"

Direct human tissue evidence of apical cargo mis-sorting.

PMID:20190753 SUPPORT Human Clinical

"Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation"

Documents the second fate of mis-sorted apical cargo — lysosomal destruction.

Loss of Apical-Basolateral Epithelial Polarity

The final shared cellular lesion in liver, kidney and gut: polarised epithelia can no longer establish or maintain distinct apical and basolateral membrane domains, and the apical junctional complexes required to build lumenal structures (bile canaliculi, renal tubules) are destabilised. Reduced E-cadherin, secondary to transcriptional downregulation rather than mis-sorting, contributes independently.

hepatocyte CL:0000182 proximal tubular epithelial cell CL:0002306 enterocyte CL:0000584

CDH1 hgnc:1748 ↓ DECREASED

establishment or maintenance of apical/basal cell polarity GO:0035088 ↓ DECREASED

liver UBERON:0002107 kidney UBERON:0002113

Downstream

Low-GGT Intrahepatic Cholestasis Mis-sorted canalicular transporters and hypoplastic peripheral biliary radicles abolish intrahepatic bile flow despite a patent biliary tree.

Proximal Tubular Apical Transport Failure The same polarity failure in the proximal nephron prevents apical reabsorptive transport, producing urinary wasting of sugars, amino acids, phosphate and bicarbonate.

Intestinal Malabsorption and Intractable Diarrhoea Enterocyte polarity failure impairs brush-border absorptive function, contributing to the diarrhoea and failure to thrive that are near-universal in the ARC spectrum.

Show evidence (2 references)

PMID:20190753 SUPPORT In Vitro

"The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney."

States the shared hepatic and renal polarity lesion.

PMID:20190753 SUPPORT In Vitro

"Reduced expression of E-cadherin underlies disordered formation of the AJCs essential for generation and maintenance of lumenal structures such as bile ducts and renal tubules."

Mechanism linking E-cadherin loss to failed bile duct and renal tubule lumen formation.

Low-GGT Intrahepatic Cholestasis

Non-obstructive cholestatic jaundice with a characteristically normal or low serum gamma-glutamyltransferase — the combination that separates ARC-spectrum liver disease from biliary atresia and most other neonatal cholestases. Radionuclide imaging shows that labelled compounds normally secreted into bile do not reach the duodenum despite biliary tract patency, and peripheral biliary radicles are hypoplastic. Histology shows intrahepatocyte pigment accumulation including lipofuscin, with hepatocyte giant-cell transformation.

hepatocyte CL:0000182

bile acid and bile salt transport GO:0015721 ↓ DECREASED

bile canaliculus UBERON:0001283

Downstream

Severe Failure to Thrive Cholestasis impairs fat and fat-soluble vitamin absorption, compounding the nutritional failure driven by diarrhoea and renal solute loss.

Show evidence (2 references)

PMID:15052268 SUPPORT Human Clinical

"neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity"

Defines the low-GGT cholestasis with bile duct hypoplasia characteristic of the spectrum.

PMID:20190753 SUPPORT Human Clinical

"labeled compounds normally secreted into bile do not enter the duodenum despite biliary tract patency, reflecting absent or severely reduced intrahepatic bile flow"

Demonstrates the intrahepatic, non-obstructive nature of the cholestasis.

Proximal Tubular Apical Transport Failure

Generalised failure of apical reabsorptive transport in the proximal tubule produces renal Fanconi syndrome: aminoaciduria, glycosuria, phosphaturia and bicarbonate wasting (proximal renal tubular acidosis). In some ARC-spectrum patients the renal presentation dominates and precedes recognition of the hepatic and cutaneous features; a minority present instead with nephrogenic diabetes insipidus.

proximal tubular epithelial cell CL:0002306

apical protein localization GO:0045176 ↓ DECREASED

proximal tubule UBERON:0004134

Downstream

Bicarbonate Wasting and Metabolic Acidosis Failure of apical bicarbonate reclamation produces proximal (type 2) renal tubular acidosis with an obligatory high alkali requirement.

Volume Depletion and Dehydration Osmotic solute wasting drives obligatory water loss and a high fluid requirement, compounded by diarrhoeal losses.

Show evidence (2 references)

PMID:11668108 SUPPORT Human Clinical

"Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."

Establishes renal Fanconi syndrome as near-universal, with a nephrogenic DI variant.

PMID:29907094 SUPPORT Human Clinical

"A 6 year old girl presented during the first year of life with severe renal Fanconi as the first manifestation of ARC-Syndrome."

Documents a renal-predominant presentation, the pattern that produced the FID label.

Bicarbonate Wasting and Metabolic Acidosis

Proximal (type 2) renal tubular acidosis from obligatory urinary bicarbonate loss, compounded by diarrhoeal alkali losses. Requires high alkali intake; uncorrected it was a direct terminal event in the index series.

Downstream

Death in Infancy

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"Their progress was poor: they required high fluid and bicarbonate intakes"

Documents the alkali requirement created by bicarbonate wasting.

Volume Depletion and Dehydration

Osmotic diuresis from proximal solute wasting, compounded by diarrhoeal fluid losses, produces volume depletion requiring high obligatory fluid intake. Failure to keep pace was a direct terminal event in the index series.

Downstream

Death in Infancy

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"they required high fluid and bicarbonate intakes"

Documents the fluid requirement created by renal and gastrointestinal losses.

Intestinal Malabsorption and Intractable Diarrhoea

Persistent diarrhoea is one of the five cardinal FID features and is present in essentially all ARC-spectrum infants. It reflects enterocyte apical trafficking and polarity failure, compounded by cholestatic fat malabsorption, and drives fluid and electrolyte loss on top of the renal losses.

enterocyte CL:0000584

small intestine UBERON:0002108

Downstream

Severe Failure to Thrive

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

Diarrhoea is a defining component of the FID phenotype.

Defective Epidermal Lamellar Body Biogenesis and Secretion

Lamellar bodies (lamellar granules) are keratinocyte lysosome-related organelles that are normally exocytosed at the boundary between the granular and cornified layers, delivering the lipids that build the stratum corneum permeability barrier. In ARC-spectrum skin, ultrastructural examination shows lamellar granules entombed within cornified cells rather than secreted; their internal structure is normal, distinguishing the defect from CEDNIK syndrome. Vps33b- and Vipar-deficient mice reproduce the abnormal lamellar body morphology and cargo mislocalisation.

keratinocyte CL:0000312

epidermal lamellar body GO:0097209

skin epidermis UBERON:0001003

Downstream

Stratum Corneum Lipid Barrier Failure and Ichthyosis Undelivered lamellar body lipid cargo leaves a defective cornified envelope and reduced intercellular lipid lamellae.

Show evidence (2 references)

PMID:18347289 SUPPORT Human Clinical

"ultrastructural examination of the skin in ARC syndrome revealed many entombed lamellar granules in the cornified cells"

Direct human ultrastructural evidence of failed lamellar granule secretion.

PMID:29409756 SUPPORT Model Organism

"Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype."

Model-organism confirmation that the lamellar body lesion is sufficient for ichthyosis.

Stratum Corneum Lipid Barrier Failure and Ichthyosis

The end result of failed lamellar body exocytosis is a structurally abnormal stratum corneum — increased corneocyte thickness, a thinner cornified envelope and reduced deposition of intercellular lipids — manifesting clinically as ichthyosis. Skin biopsy typically shows mild hyperkeratosis without parakeratosis. Impaired absorption of free fatty acids, secondary to cholestasis and intestinal disease, has been proposed as an additional contributor.

establishment of skin barrier GO:0061436 ↓ DECREASED

stratum corneum of epidermis UBERON:0002027

Show evidence (2 references)

PMID:29409756 SUPPORT Model Organism

"Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids."

Quantifies the stratum corneum abnormality underlying the ichthyosis.

PMID:29409756 SUPPORT Model Organism

"These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome."

States the causal chain from lamellar body defect to skin phenotype.

Failed Platelet Alpha-Granule Biogenesis

VPS33B colocalises with alpha-granule markers in normal megakaryocytes and is required to build the alpha-granule, which is a lysosome-related organelle like the lamellar body. Its loss produces platelets that are large, pale on blood films, deficient in both soluble and membrane-bound alpha-granule proteins, and that show compensatorily increased delta-granules. This is the mechanistic basis of the "grey platelet syndrome" morphology reported in two of the six original FID infants — a phenocopy of, not an instance of, true NBEAL2/GFI1B grey platelet syndrome.

megakaryocyte CL:0000556 platelet CL:0000233

platelet alpha granule organization GO:0070889 ↓ DECREASED

platelet alpha granule GO:0031091

Downstream

Bleeding Diathesis and Procedural Haemorrhage Risk Alpha-granule-deficient platelets aggregate poorly, producing a bleeding tendency that makes diagnostic liver or kidney biopsy hazardous.

Show evidence (3 references)

PMID:16123220 SUPPORT Human Clinical

"Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules."

Defines the platelet ultrastructural phenotype matching the FID "grey platelet" observation.

PMID:16123220 SUPPORT In Vitro

"VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes."

Localises VPS33B to the alpha-granule biogenesis compartment.

PMID:25947942 SUPPORT Model Organism

"is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis"

Confirms the bleeding diathesis attributable to the alpha-granule defect.

Bleeding Diathesis and Procedural Haemorrhage Risk

Self-limiting intra-abdominal haemorrhage is common, and liver or kidney biopsy carries a reported risk of fatal bleeding exceeding 50%. Critically, routine platelet count and morphology can be normal and therefore cannot be used to exclude the bleeding risk — a management trap that makes molecular rather than histological diagnosis the safer route.

Show evidence (2 references)

PMID:25239142 SUPPORT Human Clinical

"or liver biopsies result in a risk of fatal bleeding"

Fragment of the review's statement that kidney or liver biopsies carry >50% risk of fatal bleeding; "kidney" is hyphen-broken across a line in the cached full text, so the quote starts at the next clean word boundary.

PMID:25239142 SUPPORT Human Clinical

"therefore, normal routine platelet analysis cannot assess"

States that normal routine platelet analysis cannot assess bleeding risk in ARC; the sentence continues across a hyphenated line break so only the verifiable fragment is quoted.

Neurogenic Arthrogryposis and Musculoskeletal Anomalies

Congenital joint contractures in the ARC spectrum are neurogenic rather than primarily myopathic or connective-tissue in origin. In the FID series this component was described as "musculoskeletal abnormalities" rather than frank arthrogryposis, and its relative mildness is precisely why FID was initially separated from ARC. Complete loss-of-function VPS33B alleles have since been shown to produce ichthyosis, cholestasis and renal dysfunction without arthrogryposis, so its absence does not exclude the diagnosis. Reported skeletal features across the spectrum include congenital hip dislocation and vertical talus.

Show evidence (2 references)

PMID:15052268 SUPPORT Human Clinical

"an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita"

Establishes the neurogenic basis of the contractures.

PMID:16492441 SUPPORT Human Clinical

"although homozygous for the novel VPS33B mutation 971delA/K324fs, predicted to abolish VPS33B function, did not exhibit arthrogryposis"

Demonstrates that a null VPS33B genotype can present without arthrogryposis, reconciling the FID phenotype with the ARC molecular aetiology.

Severe Failure to Thrive

Combined renal solute wasting, diarrhoeal loss and cholestatic fat malabsorption produce severe, near-universal growth failure. Failure to thrive is listed among the cardinal features of the spectrum.

Downstream

Recurrent Infection and Sepsis Malnutrition and multiorgan failure predispose to the recurrent febrile illnesses that were universal in the ARC cohort.

Death in Infancy

Show evidence (2 references)

PMID:22753090 SUPPORT Human Clinical

"Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis."

Establishes severe failure to thrive as a cardinal feature.

PMID:15052268 SUPPORT Human Clinical

"Affected infants do not thrive and usually die in the first year of life."

Links growth failure to the infantile-lethal course.

Recurrent Infection and Sepsis

Recurrent febrile illnesses were universal in the ARC cohort, and sepsis was one of the named terminal events in the index series.

Downstream

Death in Infancy

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"All had recurrent febrile illnesses, diarrhoea, and failed to thrive."

Recurrent febrile illness in all six cohort patients.

Death in Infancy

The convergent endpoint. Death follows in infancy from dehydration, acidosis, sepsis, or internal haemorrhage. Every infant in the original FID series died by 6 months; across the ARC spectrum most die within the first year, with survival beyond infancy essentially restricted to patients retaining partial VPS33B function.

Show evidence (3 references)

PMID:2206896 SUPPORT Human Clinical

"all died by the age of 6 months of dehydration, acidosis and sepsis"

The terminal common pathway documented in the index FID series.

PMID:22753090 SUPPORT Human Clinical

"Most patients with ARC do not survive past the first year of life."

Confirms infantile lethality across the molecularly defined spectrum.

PMID:22753090 SUPPORT In Vitro

"cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function)"

Residual VPS33B-VIPAR interaction is what permits survival beyond infancy.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 1

Abnormal bleeding Abnormal bleeding HP:0001892

Show evidence (3 references)

PMID:16123220 SUPPORT Human Clinical

"We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP)."

Human patient platelets show impaired aggregation - the functional defect underlying the bleeding tendency. This is the primary, human-derived support for the phenotype.

PMID:25239142 SUPPORT Human Clinical

"abdominal hemorrhage often occurs in patients with"

Human clinical corroboration that self-limiting intra-abdominal haemorrhage is common in ARC patients; the sentence wraps across a line in the cached full text, so only the verifiable span is quoted.

PMID:25947942 SUPPORT Model Organism

"is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis"

Background framing from a Vps33b-conditional mouse study, retained as secondary support only. Tagged MODEL_ORGANISM to match the same snippet's classification on the Failed Platelet Alpha-Granule Biogenesis node.

Digestive 3

Cholestasis Cholestasis HP:0001396

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."

Documents the severe low-GGT cholestasis of the spectrum.

Jaundice Jaundice HP:0000952

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

Jaundice is a defining component of FID.

Diarrhea VERY_FREQUENT Diarrhea HP:0002014

Temporal: CHRONIC

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"All had recurrent febrile illnesses, diarrhoea, and failed to thrive."

All six patients in the ARC cohort had diarrhoea, supporting the VERY_FREQUENT band.

Ear 1

Sensorineural hearing impairment OCCASIONAL Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:16492441 SUPPORT Human Clinical

"We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness"

Deafness in the FID-like arthrogryposis-negative phenotype.

Genitourinary 1

Renal Fanconi syndrome VERY_FREQUENT Renal Fanconi syndrome HP:0001994

Show evidence (2 references)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

Renal Fanconi syndrome is a defining component of FID.

PMID:11668108 SUPPORT Human Clinical

"Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."

Supports the VERY_FREQUENT frequency band — 5 of 6 patients (83%) in the ARC cohort that subsumed FID.

Head and Neck 1

Dysmorphic facial features Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"Many of our patients showed dysmorphic features or ichthyosis."

Documents dysmorphic features in the cohort that subsumed FID.

Immune 1

Recurrent febrile illness and sepsis Sepsis HP:0100806

Show evidence (2 references)

PMID:11668108 SUPPORT Human Clinical

"All had recurrent febrile illnesses, diarrhoea, and failed to thrive."

Recurrent febrile illness in all cohort patients.

PMID:2206896 SUPPORT Human Clinical

"all died by the age of 6 months of dehydration, acidosis and sepsis"

Sepsis as a terminal event in the FID series.

Integument 1

Ichthyosis Ichthyosis HP:0008064

Show evidence (2 references)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

Ichthyosis is a defining component of FID.

PMID:18347289 SUPPORT Human Clinical

"Neurological signs and ichthyosis almost invariably accompany the disease."

Confirms ichthyosis as a near-constant feature of the spectrum.

Metabolism 1

Dehydration Dehydration HP:0001944

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"all died by the age of 6 months of dehydration, acidosis and sepsis"

Dehydration was a proximate cause of death in the FID series.

Nervous System 1

Corpus callosum abnormality OCCASIONAL Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

PMID:16492441 SUPPORT Human Clinical

"in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities"

CNS malformation as a variable spectrum feature.

Growth 1

Failure to thrive VERY_FREQUENT Failure to thrive HP:0001508

Show evidence (2 references)

PMID:11668108 SUPPORT Human Clinical

"All had recurrent febrile illnesses, diarrhoea, and failed to thrive."

All six patients failed to thrive, supporting the VERY_FREQUENT band.

PMID:22753090 SUPPORT Human Clinical

"Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis."

Lists severe failure to thrive among cardinal spectrum features.

Other 7

Renal tubular acidosis Renal tubular acidosis HP:0001947

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"the association of arthrogryposis, renal tubular acidosis, and cholestasis"

Renal tubular acidosis is one of the three defining ARC-spectrum features.

Aminoaciduria Aminoaciduria HP:0003355

Show evidence (1 reference)

PMID:16492441 SUPPORT Human Clinical

"We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness"

Documents aminoaciduria in the arthrogryposis-negative (FID-like) presentation.

Nephrogenic diabetes insipidus OCCASIONAL Nephrogenic diabetes insipidus HP:0009806

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."

One of six patients (17%) presented with nephrogenic diabetes insipidus, supporting the OCCASIONAL band.

Conjugated hyperbilirubinemia Conjugated hyperbilirubinemia HP:0002908

Show evidence (1 reference)

PMID:16492441 SUPPORT Human Clinical

"Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype"

Conjugated hyperbilirubinaemia is a core-phenotype element.

Arthrogryposis multiplex congenita VARIABLE Arthrogryposis multiplex congenita HP:0002804

Show evidence (2 references)

PMID:11668108 SUPPORT Human Clinical

"All patients had the typical pattern of arthrogryposis."

Arthrogryposis was universal in the classical ARC cohort.

PMID:16492441 PARTIAL Human Clinical

"The phenotypes associated with VPS33B mutation may include incomplete ARC."

Counter-evidence for obligate arthrogryposis — supports the VARIABLE band and explains why the FID cases were not recognised as ARC at the time.

Reduced platelet alpha granules Reduced platelet alpha granules HP:0033536

Show evidence (2 references)

PMID:16123220 SUPPORT Human Clinical

"Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets"

Documents alpha-granule protein deficiency in patient platelets.

PMID:2206896 SUPPORT Human Clinical

"two of the infants were found to have abnormal platelet morphology--the grey platelet syndrome"

The original FID observation this phenotype term formalises.

Increased mean platelet volume Increased mean platelet volume HP:0011877

Show evidence (1 reference)

PMID:11668108 SUPPORT Human Clinical

"Blood films revealed abnormally large platelets."

Large platelets on blood film in the ARC cohort that subsumed FID.

🧬

Genetic Associations

VPS33B

Gene: VPS33B hgnc:12712 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (5 references)

PMID:15052268 SUPPORT Human Clinical

"we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"

Establishes VPS33B as causative and localises it to 15q26.1.

PMID:20190753 SUPPORT Human Clinical

"Germline mutations in VPS33B are found in approximately 75% of individuals with ARC"

Quantifies the VPS33B share of ARC-spectrum cases.

PMID:20190753 SUPPORT Human Clinical

"only one (T89C; L30P) of 31 VPS33B-proven pathogenic mutations detected so far in ARC is a missense mutation"

Documents the null-dominated allelic spectrum.

+ 2 more references

VIPAS39

Gene: VIPAS39 hgnc:20347 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:20190753 SUPPORT Human Clinical

"Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."

Establishes VIPAS39 as the second and apparently only other ARC-spectrum locus.

PMID:20190753 SUPPORT Human Clinical

"We detected no differences in clinical symptoms, signs or disease course between subjects in VPS33B- and VIPAR-mutated ARC subsets."

Documents locus-independence of the clinical phenotype.

💊

Medical Actions

Fluid, alkali and electrolyte replacement

Category: Therapeutic Action: fluid and electrolyte replacement Ontology label: Supportive Care NCIT:C15747

The cornerstone of care. High fluid and bicarbonate intakes are required to offset proximal tubular bicarbonate and solute wasting compounded by diarrhoeal losses; failure to keep pace results in fatal dehydration and acidosis. Phosphate supplementation addresses renal phosphate wasting.

Mechanism Target:

INHIBITS Bicarbonate Wasting and Metabolic Acidosis — Exogenous alkali offsets the obligatory renal bicarbonate loss; this compensates for, rather than corrects, the upstream tubular transport failure.

INHIBITS Volume Depletion and Dehydration — Exogenous fluid offsets the obligatory renal and gastrointestinal water loss.

Target Phenotypes: Renal tubular acidosis HP:0001947 Dehydration HP:0001944

Show evidence (2 references)

PMID:2206896 SUPPORT Human Clinical

"they required high fluid and bicarbonate intakes"

Documents the fluid and alkali requirement in the index FID series.

PMID:25239142 SUPPORT Human Clinical

"including fluid infusion, anti-infection, supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"

Enumerates the supportive-care regimen used across the ARC spectrum.

Ursodeoxycholic acid for cholestasis

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: ursodeoxycholic acid CHEBI:9907

Used as part of supportive management of the cholestatic liver disease. As with all ARC-spectrum therapy this is symptomatic; no agent modifies the underlying trafficking defect.

Target Phenotypes: Cholestasis HP:0001396

Show evidence (1 reference)

PMID:25239142 SUPPORT Human Clinical

"supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"

Names ursodeoxycholic acid within the standard supportive regimen.

Nutritional support with fat-soluble vitamin supplementation

Category: Therapeutic Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Cholestatic fat malabsorption plus diarrhoeal and renal losses make aggressive nutritional support and fat-soluble vitamin replacement necessary, though failure to thrive typically persists.

Mechanism Target:

INHIBITS Severe Failure to Thrive — Caloric and fat-soluble vitamin replacement partially offsets malabsorptive and renal losses; growth failure typically persists.

Target Phenotypes: Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:25239142 SUPPORT Human Clinical

"supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"

Fat-soluble vitamin and mineral supplementation within the supportive regimen.

Avoidance of liver and kidney biopsy

Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747

A management decision rather than an intervention, but arguably the highest-value one. Percutaneous liver or kidney biopsy carries a reported risk of fatal bleeding above 50% because of the platelet alpha-granule defect, and routine platelet analysis cannot identify who is at risk. Diagnosis should proceed via clinical features, blood film, fibroblast VPS33B expression and sequencing instead.

Show evidence (1 reference)

PMID:25239142 SUPPORT Human Clinical

"or liver biopsies result in a risk of fatal bleeding"

Quantifies the biopsy bleeding risk (>50% in the source sentence) that motivates avoidance; "kidney" is hyphen-broken across a line in the cached full text.

LDL apheresis and biliary diversion for intractable cholestatic pruritus

Category: Therapeutic Action: therapeutic apheresis Ontology label: Therapeutic Apheresis NCIT:C173286

Reported in a single ARC-spectrum patient with a renal-predominant presentation, combining LDL apheresis with biliodigestive derivation for cholestatic pruritus, with encouraging results. This is anecdotal rescue therapy, not established practice.

Show evidence (1 reference)

PMID:29907094 SUPPORT Human Clinical

"we report on the successful use of LDL-Apheresis and biliodigestive derivation for treatment of cholestatic pruritus with encouraging results"

Single-case report of this rescue approach.

Genetic counseling and prenatal diagnosis

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Given autosomal recessive inheritance with a 25% recurrence risk, high consanguinity in affected families and near-uniform infantile lethality, genetic counselling with the option of prenatal or preimplantation genetic diagnosis is a central part of care once the family's variants are known.

Show evidence (1 reference)

PMID:25239142 SUPPORT Human Clinical

"provide genetic counseling and prenatal or preimplantation genetic diagnosis"

Recommends genetic counselling and prenatal/preimplantation diagnosis for affected families.

Palliative and supportive care

Category: Therapeutic Action: palliative care Ontology label: Palliative Therapy NCIT:C15292

No specific or disease-modifying treatment exists. Care is directed at quality of life, infection control and symptom relief; aggressive orthopaedic intervention for contractures is generally not recommended because poor general status and low survival compromise surgical outcomes.

Show evidence (2 references)

PMID:25239142 SUPPORT Human Clinical

"However, no specific treatment currently exists for this syndrome."

States the absence of disease-modifying therapy.

PMID:25239142 SUPPORT Human Clinical

"orthopedic management is still not recommended, since poor general status and low survival rates may affect the outcome of the surgery"

Advises against aggressive orthopaedic surgery; the sentence continues past a line break in the cached full text so only the verifiable span is quoted.

🔬

Biochemical Markers

Serum gamma-glutamyltransferase (NORMAL)

Show evidence (3 references)

PMID:11668108 SUPPORT Human Clinical

"Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."

Documents normal GGT despite severe cholestasis in all cohort patients.

PMID:15052268 SUPPORT Human Clinical

"neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity"

Low GGT is part of the defining biochemical signature.

PMID:24782640 PARTIAL Human Clinical

"this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found"

Counter-evidence bounding the low-GGT rule. A genotype-confirmed ARC patient (compound heterozygous VPS33B c.403+2T>A / c.1509-1510insG) had a HIGH GGT on three consecutive tests alongside otherwise typical arthrogryposis, renal involvement and ichthyosis. A high GGT therefore does not exclude ARC.

Urinary amino acids (INCREASED)

Show evidence (1 reference)

PMID:20190753 SUPPORT Human Clinical

"resulting in cholestasis and in urinary wasting of sugars and amino acids"

Documents urinary amino acid and sugar wasting as a consequence of the trafficking defect.

Urinary glucose (INCREASED)

Show evidence (1 reference)

PMID:20190753 SUPPORT Human Clinical

"urinary wasting of sugars and amino acids"

Documents urinary sugar wasting.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome:

Fanconi Renotubular Syndrome

Overlapping Features The isolated renal phenotype. ARC-spectrum disease includes renal Fanconi syndrome as one component of a multisystem disorder, so an infant presenting first with proximal tubulopathy can be mistaken for isolated FRTS. The distinguishing move is to look for the extrarenal components — cholestasis, ichthyosis, contractures, platelet defect — none of which belong to FRTS. This is also the entity MONDO places MONDO:0022948 (the Deal-Barratt-Dillon stub) under, which is why the nomenclatural argument in `discussions` turns on it.

Distinguishing Features

Isolated FRTS lacks low-GGT cholestasis, ichthyosis, neurogenic arthrogryposis and the platelet alpha-granule defect
Renal Fanconi syndrome in ARC-spectrum disease is one component of a CHEVI-trafficking multisystem disorder, not the whole phenotype

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

The index description presents renal Fanconi syndrome as one component of a multisystem association, not as isolated renotubular disease.

Arthrogryposis Multiplex Congenita

Overlapping Features The isolated musculoskeletal phenotype. AMC is an aetiologically heterogeneous endpoint of reduced fetal movement; the ARC spectrum is one specific neurogenic cause of it, and MONDO parents ARC under MONDO:0008823 arthrogryposis multiplex congenita 2, neurogenic type. An infant with contractures should be evaluated for the renal and hepatic components before AMC is called isolated.

Distinguishing Features

ARC-spectrum arthrogryposis is neurogenic and accompanied by renal tubular dysfunction and low-GGT cholestasis; isolated AMC has neither
Arthrogryposis is not obligate in the ARC spectrum, so its absence does not exclude ARC while its presence does not establish isolated AMC

Show evidence (1 reference)

PMID:15052268 SUPPORT Human Clinical

"an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita"

Establishes that ARC-spectrum contractures are neurogenic AMC occurring within a multisystem disorder, distinguishing them from isolated AMC.

Fanconi anemia

Overlapping Features Not a clinical mimic but a persistent nomenclatural trap, entered through this entry's historical FID synonym. The "Fanconi" in Fanconi-ichthyosis-dysmorphism syndrome denotes renal Fanconi syndrome (proximal tubulopathy), not Fanconi anaemia (the DNA interstrand-crosslink repair and bone marrow failure disorder). The ICD-11 Foundation entry for FID both defines it as an association with "Fanconi anaemia" and classifies it as a child of Fanconi anaemia; MONDO instead places the same entity under Fanconi renotubular syndrome, which matches the primary literature.

Distinguishing Features

ARC-spectrum disease has proximal renal tubulopathy with no reported DNA crosslinker sensitivity; Fanconi anemia is defined by chromosome breakage on diepoxybutane/mitomycin C testing
ARC-spectrum disease causes early-infantile death from acidosis, dehydration and sepsis; Fanconi anemia presents with progressive bone marrow failure and cancer predisposition over years
ARC-spectrum disease has low-GGT cholestasis and ichthyosis, neither of which is characteristic of Fanconi anemia

Show evidence (1 reference)

PMID:2206896 SUPPORT Human Clinical

"a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"

The primary description names the renal "Fanconi syndrome", not Fanconi anaemia, establishing which entity the eponym refers to.

Progressive familial intrahepatic cholestasis

Overlapping Features The low-GGT PFIC types (notably PFIC1/ATP8B1 and PFIC2/ABCB11) share severe conjugated hyperbilirubinaemia with normal GGT, diarrhoea and failure to thrive, and are the principal hepatic differential. They lack the renal Fanconi syndrome, ichthyosis, arthrogryposis and alpha-granule defect.

Distinguishing Features

PFIC lacks renal proximal tubulopathy, ichthyosis and the platelet alpha-granule defect
Mechanistically related — ARC-spectrum cholestasis arises partly from mis-sorting of BSEP/ABCB11, the protein mutated in PFIC2

Show evidence (2 references)

PMID:25239142 SUPPORT Human Clinical

"similar clinical and laboratory findings could be observed both in ARC syndrome and progressive"

States the clinical and laboratory overlap with progressive familial intrahepatic cholestasis; the sentence is hyphen-broken across a line in the cached full text, so only the verifiable fragment is quoted.

PMID:20190753 SUPPORT Human Clinical

"Mis-sorting of some BSEP to the basolateral hepatocyte membrane was seen in the livers of individuals with ARC"

The mechanistic link between the two entities — BSEP is the PFIC2 protein.

Biliary atresia

Overlapping Features The dominant differential for any infant with conjugated hyperbilirubinaemia. Distinguished by an elevated GGT and by hepatobiliary imaging showing obstruction; in ARC-spectrum disease the biliary tree is patent but intrahepatic bile flow is absent, and GGT is normal. Misdirection towards biliary atresia risks a hazardous laparotomy or biopsy in a child with a bleeding diathesis.

Distinguishing Features

GGT is usually elevated in biliary atresia and normal or low in ARC-spectrum cholestasis, but a high-GGT ARC case is documented, so GGT does not reliably rule ARC out
Biliary tract is patent in ARC-spectrum disease despite absent intrahepatic bile flow

Show evidence (2 references)

PMID:20190753 SUPPORT Human Clinical

"labeled compounds normally secreted into bile do not enter the duodenum despite biliary tract patency"

Documents biliary patency, the anatomical feature distinguishing this from biliary atresia.

PMID:24782640 PARTIAL Human Clinical

"this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found"

CEDNIK syndrome

Overlapping Features Cerebral dysgenesis-neuropathy-ichthyosis-keratoderma syndrome (SNAP29) is the closest dermatological mimic: another SNARE-machinery disorder with ichthyosis from abnormal lamellar granule handling. It is distinguished ultrastructurally — in ARC-spectrum disease the entombed lamellar granules have normal internal structure, whereas in CEDNIK the granule structure itself is abnormal — and clinically by the absence of cholestasis and renal tubulopathy.

Distinguishing Features

Lamellar granule internal structure is normal in ARC-spectrum disease and abnormal in CEDNIK
CEDNIK lacks low-GGT cholestasis and renal Fanconi syndrome

Show evidence (1 reference)

PMID:25239142 SUPPORT Human Clinical

"lamellar granule internal structure is normal in ARC syndrome while it is abnormal in"

States the ultrastructural discriminator between the two lamellar-granule ichthyoses; "CEDNIK" is hyphen-broken across a line in the cached full text.

Gray platelet syndrome

Overlapping Features True grey platelet syndrome (NBEAL2, and the GFI1B-related form) is an isolated platelet alpha-granule deficiency with macrothrombocytopenia and myelofibrosis. Two of the six original FID infants were labelled as having "the grey platelet syndrome" on morphology alone; the ARC-spectrum alpha-granule defect is a phenocopy arising from a different trafficking lesion and is accompanied by multisystem disease.

Distinguishing Features

Gray platelet syndrome is confined to the platelet lineage, without cholestasis, renal tubulopathy or ichthyosis
In the ARC spectrum, delta-granules are increased rather than normal

Show evidence (2 references)

PMID:2206896 SUPPORT Human Clinical

"two of the infants were found to have abnormal platelet morphology--the grey platelet syndrome"

The original morphological attribution that this differential resolves.

PMID:16123220 SUPPORT Human Clinical

"elevated numbers of delta-granules, and completely absent alpha-granules"

The increased delta-granule count distinguishing the ARC-spectrum platelet from classical grey platelet syndrome.

{ }

Source YAML

click to show

name: Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome
creation_date: "2026-08-02T00:00:00Z"
category: Mendelian
synonyms:
- ARC syndrome
- arthrogryposis, renal dysfunction, and cholestasis
- ARCS1
- ARCS2
- Fanconi-ichthyosis-dysmorphism syndrome
- FID syndrome
- Deal-Barratt-Dillon syndrome
- Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea
- Fanconi syndrome-ichthyosis-dysmorphism-jaundice-diarrhoea syndrome
description: >
  Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a lethal
  autosomal recessive multisystem disorder caused by biallelic loss-of-function
  variants in VPS33B (ARCS1) or its obligate partner VIPAS39/VIPAR (ARCS2).
  These two proteins form the CHEVI (class C Homologues in Endosome-Vesicle
  Interaction) tethering complex, which acts with RAB11A on the apical recycling
  endosome pathway. Loss of CHEVI function destroys apical-basolateral polarity
  in hepatocytes and renal proximal tubular cells and cripples the biogenesis of
  two specialised lysosome-related organelles - the epidermal lamellar body and
  the platelet alpha-granule. The cardinal triad is neurogenic arthrogryposis
  multiplex congenita, renal tubular dysfunction (usually renal Fanconi
  syndrome), and neonatal cholestasis with a characteristically normal or low
  serum gamma-glutamyltransferase; ichthyosis, intractable diarrhoea, severe
  failure to thrive, dysmorphism, central nervous system malformation,
  sensorineural deafness and an alpha-granule-deficient bleeding diathesis are
  common. Most affected infants die within the first year of life.

  Nomenclature. This entry deliberately carries the ARC name and MONDO:0017123
  because that is the entity whose mechanism is curated here. Two historical
  clinical labels resolve into it and are retained as synonyms. The first is
  Fanconi-ichthyosis-dysmorphism (FID) syndrome, also called Deal-Barratt-Dillon
  syndrome, described in 1990 in six infants of consanguineous parentage who
  shared renal Fanconi syndrome, ichthyosis, musculoskeletal abnormalities,
  jaundice and diarrhoea, two of them with grey-platelet-like platelet
  morphology, all dead before 6 months of age. A 2001 multicentre ARC series
  concluded explicitly that this association "is part of the ARC spectrum", and
  the molecular basis was then established as VPS33B (2004) and VIPAS39 (2010).
  The FID presentation is the arthrogryposis-poor end of the spectrum:
  arthrogryposis is not obligate, and patients with complete loss-of-function
  VPS33B alleles have been reported with ichthyosis, cholestasis and renal
  dysfunction but no contractures. Note that the "Fanconi" in the FID label
  refers to the renal proximal tubulopathy, NOT to Fanconi anaemia - a
  conflation that persists in some classifications (see `discussions` and
  `notes`).

  Management is supportive; no disease-modifying therapy exists. Liver and
  kidney biopsy carry a very high risk of fatal bleeding from the platelet
  alpha-granule defect, so molecular diagnosis is preferred over tissue
  sampling.
disease_term:
  preferred_term: arthrogryposis-renal dysfunction-cholestasis syndrome
  term:
    id: MONDO:0017123
    label: arthrogryposis-renal dysfunction-cholestasis syndrome
parents:
- Renal tubular transport disease
- inborn disorder of bilirubin metabolism
- hereditary disease
- Intracellular trafficking disorder
mappings:
  icd11f_mappings:
  - term:
      id: icd11f:235762608
      label: Fanconi-ichthyosis-dysmorphism syndrome
    mapping_predicate: skos:narrowMatch
    mapping_justification: >-
      The ICD-11 Foundation entity for the historical FID label. Recorded as a
      narrow match now that this entry targets the ARC spectrum
      (MONDO:0017123) on the strength of PMID:11668108, which concluded the FID
      association "is part of the ARC spectrum": FID denotes the
      arthrogryposis-poor end of this entry's extension rather than the whole of
      it. The narrow match rests on that ARC-spectrum literature and not on the
      ICD-11 definition, because the ICD-11 text does not faithfully reproduce
      the original Deal-Barratt-Dillon description — it substitutes the homonym
      error, reading "the association of Fanconi anaemia, ichthyosis,
      musculo-skeletal anomalies, jaundice, and diarrhoea" where PMID:2206896
      says "the Fanconi syndrome". The ICD-11 parentage propagates the same
      misreading (see the `fid_icd11_fanconi_anaemia_misparent` discussion).
  mondo_mappings:
  - term:
      id: MONDO:0022948
      label: Deal Barratt Dillon syndrome
    mapping_predicate: skos:closeMatch
    mapping_justification: >-
      MONDO:0022948 is the historical Deal-Barratt-Dillon / FID clinical label,
      carrying "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and
      diarrhoea" as a synonym (from MESH:C538206). Deliberately recorded as a
      close rather than narrow match, unlike the ICD-11 FID class: MONDO:0022948
      is an unreconciled stub - no textual definition, no gene association, no
      OMIM xref - and it sits under MONDO:0001083 Fanconi renotubular syndrome
      rather than under MONDO:0017123, so its intended extension is not
      formally recoverable from MONDO. Asserting a hierarchical narrowMatch
      would over-claim knowledge of a class that has not been given an
      extension; closeMatch states the association without the subset claim.
      MONDO's placement does at least get the "Fanconi" homonym right. See the
      `mondo_deal_barratt_dillon_unreconciled_stub` discussion.
  - term:
      id: MONDO:0008822
      label: arthrogryposis, renal dysfunction, and cholestasis 1
    mapping_predicate: skos:narrowMatch
    mapping_justification: >-
      The VPS33B-defined child class, curated here as the ARCS1 subtype.
  - term:
      id: MONDO:0013255
      label: arthrogryposis, renal dysfunction, and cholestasis 2
    mapping_predicate: skos:narrowMatch
    mapping_justification: >-
      The VIPAS39-defined child class, curated here as the ARCS2 subtype.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    All six infants in the original FID series were born to consanguineous
    couples, consistent with autosomal recessive inheritance of a rare founder
    or private allele. ARC-spectrum disease, to which FID belongs, is an
    established autosomal recessive disorder caused by biallelic VPS33B or
    VIPAS39 variants.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six infants, from consanguineous marriages, with a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: Consanguinity in all six index families supports recessive inheritance of the FID phenotype.
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene."
    explanation: Establishes autosomal recessive inheritance for the ARC spectrum that subsumes FID.
has_subtypes:
- name: ARCS1
  display_name: ARCS1 (VPS33B-related)
  subtype_term:
    preferred_term: arthrogryposis, renal dysfunction, and cholestasis 1
    term:
      id: MONDO:0008822
      label: arthrogryposis, renal dysfunction, and cholestasis 1
  description: >
    ARC syndrome caused by biallelic VPS33B variants at 15q26.1, accounting for
    roughly three-quarters of cases. VPS33B is the Sec1/Munc18-family subunit of
    the CHEVI complex. The allelic spectrum is dominated by null variants, and no
    VPS33B protein is detectable in tissues from classical cases; rare hypomorphic
    alleles retaining partial VPS33B-VIPAR interaction produce attenuated
    phenotypes with survival into childhood.
  genes:
  - preferred_term: VPS33B
    term:
      id: hgnc:12712
      label: VPS33B
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"
    explanation: Establishes VPS33B as the ARCS1 disease gene.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline mutations in VPS33B are found in approximately 75% of individuals with ARC"
    explanation: Quantifies the ARCS1 share of the spectrum.
- name: ARCS2
  display_name: ARCS2 (VIPAS39/VIPAR-related)
  subtype_term:
    preferred_term: arthrogryposis, renal dysfunction, and cholestasis 2
    term:
      id: MONDO:0013255
      label: arthrogryposis, renal dysfunction, and cholestasis 2
  description: >
    ARC syndrome caused by biallelic VIPAS39 (formerly C14orf133, protein VIPAR)
    variants, accounting for the cases without VPS33B lesions. VIPAR is the
    obligate binding partner of VPS33B within the CHEVI complex. Reported alleles
    are predicted null, and no clinical differences distinguish ARCS2 from ARCS1,
    consistent with the two proteins acting as a single functional complex.
  genes:
  - preferred_term: VIPAS39
    term:
      id: hgnc:20347
      label: VIPAS39
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."
    explanation: Establishes VIPAS39 as the ARCS2 locus.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected no differences in clinical symptoms, signs or disease course between subjects in VPS33B- and VIPAR-mutated ARC subsets."
    explanation: Documents locus-independence of the clinical phenotype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    ARC-spectrum disease has no accurately defined population prevalence and is
    over-represented in populations with high consanguinity rates (Saudi Arabia,
    Pakistan), with sporadic reports from Turkey, North Africa, Italy, Portugal
    and Asia. The historical FID label rests on a single 1990 series of six
    infants; no further cases were published under that name because subsequent
    cases were reported as ARC syndrome.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe six infants, from consanguineous marriages, with a new syndrome"
    explanation: The complete published FID case series is six infants.
- population: Infants with neonatal cholestasis
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: UNKNOWN
  notes: >
    An indirect indication of how often ARC-spectrum disease underlies neonatal
    cholestasis: in a series of 90 infants with neonatal cholestasis, the relative
    incidence rate ratio of ARC was estimated at one-seventh that of biliary
    atresia. This is a ratio within a referral cohort, not a population rate, so
    no rate_per_100000 is asserted.
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "that of biliary atresia in 90 patients with neonatal cholestasis"
    explanation: >
      Fragment of the review's statement that the relative incidence rate ratio of
      ARC was suggested to be 1/7 that of biliary atresia in 90 patients with
      neonatal cholestasis; the sentence is hyphen-broken across a line in the
      cached full text, so only the verifiable span is quoted.
clinical_burden:
  burden_level: HIGH
  rationale: >
    Uniformly lethal in the index FID series — all six infants died by 6 months
    of age — and ARC-spectrum disease more broadly kills most affected infants
    within the first year of life. The burden combines multiorgan failure (renal
    solute wasting with acidosis and dehydration, cholestatic liver disease,
    malabsorptive diarrhoea, failure to thrive), a bleeding diathesis that makes
    diagnostic biopsy hazardous, recurrent sepsis, and the absence of any
    disease-modifying therapy.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they required high fluid and bicarbonate intakes and all died by the age of 6 months of dehydration, acidosis and sepsis"
    explanation: Documents uniform early mortality and intensive supportive-care requirement in the FID series.
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients with ARC do not survive past the first year of life."
    explanation: Confirms the high mortality burden across the ARC spectrum.
pathophysiology:
- name: Biallelic Loss of VPS33B or VIPAS39 Function
  biological_scale: MOLECULAR
  description: >
    Germline biallelic loss-of-function variants in VPS33B (15q26.1) or, in
    VPS33B-negative families, in VIPAS39/VIPAR abolish production of functional
    protein. VPS33B is a Sec1/Munc18-family protein containing a Sec1-like domain
    that regulates vesicle-to-target SNARE complex formation and subsequent
    membrane fusion; VIPAR is its obligate binding partner. Nearly all reported
    VPS33B alleles are null (nonsense, frameshift, splice), and no VPS33B protein
    is detectable in tissues from classical ARC cases. VPS33B accounts for
    roughly three-quarters of ARC-spectrum cases, with VIPAS39 explaining the
    remainder.
  genes:
  - preferred_term: VPS33B
    modifier: DECREASED
    term:
      id: hgnc:12712
      label: VPS33B
  - preferred_term: VIPAS39
    modifier: DECREASED
    term:
      id: hgnc:20347
      label: VIPAS39
  molecular_functions:
  - preferred_term: syntaxin binding (Sec1/Munc18-type SNARE regulation)
    modifier: DECREASED
    term:
      id: GO:0019905
      label: syntaxin binding
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"
    explanation: Original identification of VPS33B as the ARC-spectrum disease gene.
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion."
    explanation: Defines the molecular function lost when VPS33B is inactivated.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects."
    explanation: Establishes VIPAS39/VIPAR as the second ARC-spectrum locus.
  downstream:
  - target: Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex
    causal_link_type: DIRECT
    description: >
      Absence of either subunit prevents assembly of the heterodimeric tethering
      complex, since the two proteins function only together.
    evidence:
    - reference: PMID:20190753
      reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A."
      explanation: Demonstrates that the two disease proteins act as one complex.
- name: Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex
  biological_scale: MOLECULAR
  description: >
    VPS33B and VIPAR are the two known components of the CHEVI (class C Homologues
    in Endosome-Vesicle Interaction) complex, a metazoan endosomal tethering
    complex distinct from the better-characterised HOPS and CORVET complexes. The
    complex interacts with the active, GTP-bound form of RAB11A, placing it on the
    apical recycling endosome pathway. Loss of either subunit therefore removes a
    tethering step required for delivery of specific cargo to apical membranes and
    to specialised lysosome-related organelles.
  cellular_components:
  - preferred_term: recycling endosome
    term:
      id: GO:0055037
      label: recycling endosome
  biological_processes:
  - preferred_term: vesicle-mediated transport (endosomal vesicle tethering)
    modifier: DECREASED
    term:
      id: GO:0016192
      label: vesicle-mediated transport
  - preferred_term: SNARE complex assembly
    modifier: DECREASED
    term:
      id: GO:0035493
      label: SNARE complex assembly
  evidence:
  - reference: PMID:27555442
    reference_title: "The CHEVI tethering complex: facilitating special deliveries."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VPS33B and VIPAR comprise the two known components of the recently christened class C Homologues in Endosome-Vesicle Interaction (CHEVI) complex, thought to act as a tethering complex in endosomal trafficking distinct from the HOPS and CORVET complexes in mammalian cells."
    explanation: Names and defines the complex whose loss underlies the disease.
  downstream:
  - target: Disrupted RAB11A-Dependent Apical Recycling and Cargo Sorting
    causal_link_type: DIRECT
    description: >
      Without CHEVI tethering, RAB11A-dependent delivery of apical cargo fails and
      cargo is diverted to the basolateral membrane or to lysosomal degradation.
    evidence:
    - reference: PMID:20190753
      reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We suggest that the VPS33B-VIPAR complex is involved in stabilization of apical membrane protein content, possibly via the RAB11A-dependent apical recycling pathway"
      explanation: Places the complex on the apical recycling pathway whose failure is the proximal cellular lesion.
  - target: Defective Epidermal Lamellar Body Biogenesis and Secretion
    causal_link_type: DIRECT
    description: >
      The same tethering function is required for the biogenesis and exocytosis of
      epidermal lamellar bodies, a lysosome-related organelle.
    evidence:
    - reference: PMID:29409756
      reference_title: VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "epidermal lamellar bodies, which are essential for skin barrier function, had abnormal morphology and the localisation of lamellar body cargo was disrupted"
      explanation: Links CHEVI loss directly to lamellar body failure.
  - target: Failed Platelet Alpha-Granule Biogenesis
    causal_link_type: DIRECT
    description: >
      CHEVI is likewise required for construction of the platelet alpha-granule,
      another lysosome-related organelle.
    evidence:
    - reference: PMID:16123220
      reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion"
      explanation: Assigns alpha-granule biogenesis to the same trafficking complex.
  - target: Neurogenic Arthrogryposis and Musculoskeletal Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Arthrogryposis in this disorder is neurogenic, so CHEVI loss must reach the
      motor unit, but the intermediates are not established. No published work
      identifies the neuronal cargo, cell type, or developmental window through
      which VPS33B/VIPAS39 deficiency produces anterior horn involvement, and the
      mouse models characterised to date address the cutaneous and platelet arms
      rather than the neuromuscular one. The edge is therefore asserted as
      indirect with unknown intermediates rather than left implicit.
    evidence:
    - reference: PMID:15052268
      reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita"
      explanation: >
        Establishes that the contractures are neurogenic and part of the same
        VPS33B-determined disorder; it does not establish the intervening mechanism.
- name: Disrupted RAB11A-Dependent Apical Recycling and Cargo Sorting
  biological_scale: CELLULAR
  description: >
    Apical membrane cargo that normally traverses RAB11A-positive apical recycling
    endosomes is mis-sorted: some proteins reach the basolateral membrane instead,
    and others (e.g., CEACAM5) are diverted into late endosomes and lysosomes for
    degradation. Cargo that bypasses the apical recycling endosome (e.g., MRP2) is
    spared, which is what makes the defect cargo-selective rather than a global
    secretory block.
  cellular_components:
  - preferred_term: recycling endosome
    term:
      id: GO:0055037
      label: recycling endosome
  biological_processes:
  - preferred_term: apical protein localization
    modifier: DECREASED
    term:
      id: GO:0045176
      label: apical protein localization
  - preferred_term: endosomal transport
    modifier: ABNORMAL
    term:
      id: GO:0016197
      label: endosomal transport
  genes:
  - preferred_term: ABCB11
    modifier: ABNORMAL
    term:
      id: hgnc:42
      label: ABCB11
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mis-sorting of some BSEP to the basolateral hepatocyte membrane was seen in the livers of individuals with ARC"
    explanation: Direct human tissue evidence of apical cargo mis-sorting.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation"
    explanation: Documents the second fate of mis-sorted apical cargo — lysosomal destruction.
  downstream:
  - target: Loss of Apical-Basolateral Epithelial Polarity
    causal_link_type: DIRECT
    description: >
      Cargo mis-sorting, compounded by transcriptional downregulation of
      E-cadherin, degrades the apical junctional complex and with it epithelial
      polarity and lumen formation.
    evidence:
    - reference: PMID:20190753
      reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Vipar- and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects."
      explanation: Connects cargo mis-sorting to junctional and polarity failure.
- name: Loss of Apical-Basolateral Epithelial Polarity
  biological_scale: CELLULAR
  description: >
    The final shared cellular lesion in liver, kidney and gut: polarised epithelia
    can no longer establish or maintain distinct apical and basolateral membrane
    domains, and the apical junctional complexes required to build lumenal
    structures (bile canaliculi, renal tubules) are destabilised. Reduced
    E-cadherin, secondary to transcriptional downregulation rather than
    mis-sorting, contributes independently.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: proximal tubular epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: establishment or maintenance of apical/basal cell polarity
    modifier: DECREASED
    term:
      id: GO:0035088
      label: establishment or maintenance of apical/basal cell polarity
  genes:
  - preferred_term: CDH1
    modifier: DECREASED
    term:
      id: hgnc:1748
      label: CDH1
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney."
    explanation: States the shared hepatic and renal polarity lesion.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reduced expression of E-cadherin underlies disordered formation of the AJCs essential for generation and maintenance of lumenal structures such as bile ducts and renal tubules."
    explanation: Mechanism linking E-cadherin loss to failed bile duct and renal tubule lumen formation.
  downstream:
  - target: Low-GGT Intrahepatic Cholestasis
    causal_link_type: DIRECT
    description: >
      Mis-sorted canalicular transporters and hypoplastic peripheral biliary
      radicles abolish intrahepatic bile flow despite a patent biliary tree.
    evidence:
    - reference: PMID:20190753
      reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consequences of disordered apical protein restriction in ARC include mis-sorting of some apical proteins to basolateral membrane and into late endosomes and lysosomes, resulting in cholestasis and in urinary wasting of sugars and amino acids."
      explanation: Directly attributes both the cholestasis and the renal solute wasting to apical mis-sorting.
  - target: Proximal Tubular Apical Transport Failure
    causal_link_type: DIRECT
    description: >
      The same polarity failure in the proximal nephron prevents apical
      reabsorptive transport, producing urinary wasting of sugars, amino acids,
      phosphate and bicarbonate.
    evidence:
    - reference: PMID:20190753
      reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "resulting in cholestasis and in urinary wasting of sugars and amino acids"
      explanation: Attributes proximal tubular solute wasting to the polarity defect.
  - target: Intestinal Malabsorption and Intractable Diarrhoea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Enterocyte polarity failure impairs brush-border absorptive function,
      contributing to the diarrhoea and failure to thrive that are near-universal
      in the ARC spectrum.
    intermediate_mechanisms:
    - Brush-border transporter mis-sorting and reduced absorptive surface function
    - Cholestatic fat malabsorption from loss of intraluminal bile acids
    evidence:
    - reference: PMID:11668108
      reference_title: "ARC syndrome: an expanding range of phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
      explanation: Documents diarrhoea and failure to thrive as universal in the ARC cohort.
- name: Low-GGT Intrahepatic Cholestasis
  biological_scale: TISSUE
  description: >
    Non-obstructive cholestatic jaundice with a characteristically normal or low
    serum gamma-glutamyltransferase — the combination that separates ARC-spectrum
    liver disease from biliary atresia and most other neonatal cholestases.
    Radionuclide imaging shows that labelled compounds normally secreted into bile
    do not reach the duodenum despite biliary tract patency, and peripheral biliary
    radicles are hypoplastic. Histology shows intrahepatocyte pigment accumulation
    including lipofuscin, with hepatocyte giant-cell transformation.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bile acid and bile salt transport
    modifier: DECREASED
    term:
      id: GO:0015721
      label: bile acid and bile salt transport
  locations:
  - preferred_term: bile canaliculus
    term:
      id: UBERON:0001283
      label: bile canaliculus
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity"
    explanation: Defines the low-GGT cholestasis with bile duct hypoplasia characteristic of the spectrum.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "labeled compounds normally secreted into bile do not enter the duodenum despite biliary tract patency, reflecting absent or severely reduced intrahepatic bile flow"
    explanation: Demonstrates the intrahepatic, non-obstructive nature of the cholestasis.
  downstream:
  - target: Severe Failure to Thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Cholestasis impairs fat and fat-soluble vitamin absorption, compounding the
      nutritional failure driven by diarrhoea and renal solute loss.
    intermediate_mechanisms:
    - Fat and fat-soluble vitamin malabsorption from absent intraluminal bile acids
    evidence:
    - reference: PMID:11668108
      reference_title: "ARC syndrome: an expanding range of phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."
      explanation: Documents severe cholestasis with normal GGT in the cohort that subsumed FID.
- name: Proximal Tubular Apical Transport Failure
  biological_scale: CELLULAR
  description: >
    Generalised failure of apical reabsorptive transport in the proximal tubule
    produces renal Fanconi syndrome: aminoaciduria, glycosuria, phosphaturia and
    bicarbonate wasting (proximal renal tubular acidosis). In some ARC-spectrum
    patients the renal presentation dominates and precedes recognition of the
    hepatic and cutaneous features; a minority present instead with nephrogenic
    diabetes insipidus.
  cell_types:
  - preferred_term: proximal tubular epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: apical protein localization
    modifier: DECREASED
    term:
      id: GO:0045176
      label: apical protein localization
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."
    explanation: Establishes renal Fanconi syndrome as near-universal, with a nephrogenic DI variant.
  - reference: PMID:29907094
    reference_title: "Severe renal Fanconi and management strategies in Arthrogryposis-Renal dysfunction-Cholestasis syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 6 year old girl presented during the first year of life with severe renal Fanconi as the first manifestation of ARC-Syndrome."
    explanation: Documents a renal-predominant presentation, the pattern that produced the FID label.
  downstream:
  - target: Bicarbonate Wasting and Metabolic Acidosis
    causal_link_type: DIRECT
    description: >
      Failure of apical bicarbonate reclamation produces proximal (type 2) renal
      tubular acidosis with an obligatory high alkali requirement.
    evidence:
    - reference: PMID:2206896
      reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "they required high fluid and bicarbonate intakes"
      explanation: Documents the obligatory alkali requirement created by bicarbonate wasting.
  - target: Volume Depletion and Dehydration
    causal_link_type: DIRECT
    description: >
      Osmotic solute wasting drives obligatory water loss and a high fluid
      requirement, compounded by diarrhoeal losses.
    evidence:
    - reference: PMID:2206896
      reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "they required high fluid and bicarbonate intakes"
      explanation: Documents the obligatory fluid requirement created by renal solute wasting.
- name: Bicarbonate Wasting and Metabolic Acidosis
  biological_scale: ORGANISM
  description: >
    Proximal (type 2) renal tubular acidosis from obligatory urinary bicarbonate
    loss, compounded by diarrhoeal alkali losses. Requires high alkali intake;
    uncorrected it was a direct terminal event in the index series.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their progress was poor: they required high fluid and bicarbonate intakes"
    explanation: Documents the alkali requirement created by bicarbonate wasting.
  downstream:
  - target: Death in Infancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2206896
      reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
      explanation: Acidosis is named as a direct cause of death in the index series.
- name: Volume Depletion and Dehydration
  biological_scale: ORGANISM
  description: >
    Osmotic diuresis from proximal solute wasting, compounded by diarrhoeal fluid
    losses, produces volume depletion requiring high obligatory fluid intake.
    Failure to keep pace was a direct terminal event in the index series.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they required high fluid and bicarbonate intakes"
    explanation: Documents the fluid requirement created by renal and gastrointestinal losses.
  downstream:
  - target: Death in Infancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2206896
      reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
      explanation: Dehydration is named as a direct cause of death in the index series.
- name: Intestinal Malabsorption and Intractable Diarrhoea
  biological_scale: TISSUE
  description: >
    Persistent diarrhoea is one of the five cardinal FID features and is present in
    essentially all ARC-spectrum infants. It reflects enterocyte apical trafficking
    and polarity failure, compounded by cholestatic fat malabsorption, and drives
    fluid and electrolyte loss on top of the renal losses.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: Diarrhoea is a defining component of the FID phenotype.
  downstream:
  - target: Severe Failure to Thrive
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11668108
      reference_title: "ARC syndrome: an expanding range of phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
      explanation: Links diarrhoea to growth failure.
- name: Defective Epidermal Lamellar Body Biogenesis and Secretion
  biological_scale: CELLULAR
  description: >
    Lamellar bodies (lamellar granules) are keratinocyte lysosome-related
    organelles that are normally exocytosed at the boundary between the granular
    and cornified layers, delivering the lipids that build the stratum corneum
    permeability barrier. In ARC-spectrum skin, ultrastructural examination shows
    lamellar granules entombed within cornified cells rather than secreted; their
    internal structure is normal, distinguishing the defect from CEDNIK syndrome.
    Vps33b- and Vipar-deficient mice reproduce the abnormal lamellar body
    morphology and cargo mislocalisation.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  cellular_components:
  - preferred_term: epidermal lamellar body
    modifier: ABNORMAL
    term:
      id: GO:0097209
      label: epidermal lamellar body
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:18347289
    reference_title: "Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ultrastructural examination of the skin in ARC syndrome revealed many entombed lamellar granules in the cornified cells"
    explanation: Direct human ultrastructural evidence of failed lamellar granule secretion.
  - reference: PMID:29409756
    reference_title: VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype."
    explanation: Model-organism confirmation that the lamellar body lesion is sufficient for ichthyosis.
  downstream:
  - target: Stratum Corneum Lipid Barrier Failure and Ichthyosis
    causal_link_type: DIRECT
    description: >
      Undelivered lamellar body lipid cargo leaves a defective cornified envelope
      and reduced intercellular lipid lamellae.
    evidence:
    - reference: PMID:18347289
      reference_title: "Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "VPS33B deficiency results in abnormal secretion of lamellar granules, which underlies ichthyosis in ARC syndrome"
      explanation: Explicitly assigns the ichthyosis to defective lamellar granule secretion.
- name: Stratum Corneum Lipid Barrier Failure and Ichthyosis
  biological_scale: TISSUE
  description: >
    The end result of failed lamellar body exocytosis is a structurally abnormal
    stratum corneum — increased corneocyte thickness, a thinner cornified envelope
    and reduced deposition of intercellular lipids — manifesting clinically as
    ichthyosis. Skin biopsy typically shows mild hyperkeratosis without
    parakeratosis. Impaired absorption of free fatty acids, secondary to cholestasis
    and intestinal disease, has been proposed as an additional contributor.
  locations:
  - preferred_term: stratum corneum of epidermis
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  biological_processes:
  - preferred_term: establishment of skin barrier
    modifier: DECREASED
    term:
      id: GO:0061436
      label: establishment of skin barrier
  evidence:
  - reference: PMID:29409756
    reference_title: VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids."
    explanation: Quantifies the stratum corneum abnormality underlying the ichthyosis.
  - reference: PMID:29409756
    reference_title: VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome."
    explanation: States the causal chain from lamellar body defect to skin phenotype.
- name: Failed Platelet Alpha-Granule Biogenesis
  biological_scale: CELLULAR
  description: >
    VPS33B colocalises with alpha-granule markers in normal megakaryocytes and is
    required to build the alpha-granule, which is a lysosome-related organelle like
    the lamellar body. Its loss produces platelets that are large, pale on blood
    films, deficient in both soluble and membrane-bound alpha-granule proteins, and
    that show compensatorily increased delta-granules. This is the mechanistic basis
    of the "grey platelet syndrome" morphology reported in two of the six original
    FID infants — a phenocopy of, not an instance of, true NBEAL2/GFI1B grey platelet
    syndrome.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  cellular_components:
  - preferred_term: platelet alpha granule
    modifier: ABSENT
    term:
      id: GO:0031091
      label: platelet alpha granule
  biological_processes:
  - preferred_term: platelet alpha granule organization
    modifier: DECREASED
    term:
      id: GO:0070889
      label: platelet alpha granule organization
  evidence:
  - reference: PMID:16123220
    reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules."
    explanation: Defines the platelet ultrastructural phenotype matching the FID "grey platelet" observation.
  - reference: PMID:16123220
    reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes."
    explanation: Localises VPS33B to the alpha-granule biogenesis compartment.
  - reference: PMID:25947942
    reference_title: "VPS33B regulates protein sorting into and maturation of alpha-granule progenitor organelles in mouse megakaryocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis"
    explanation: Confirms the bleeding diathesis attributable to the alpha-granule defect.
  downstream:
  - target: Bleeding Diathesis and Procedural Haemorrhage Risk
    causal_link_type: DIRECT
    description: >
      Alpha-granule-deficient platelets aggregate poorly, producing a bleeding
      tendency that makes diagnostic liver or kidney biopsy hazardous.
    evidence:
    - reference: PMID:16123220
      reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP)."
      explanation: Functional platelet defect underlying the bleeding risk.
- name: Bleeding Diathesis and Procedural Haemorrhage Risk
  biological_scale: ORGANISM
  description: >
    Self-limiting intra-abdominal haemorrhage is common, and liver or kidney biopsy
    carries a reported risk of fatal bleeding exceeding 50%. Critically, routine
    platelet count and morphology can be normal and therefore cannot be used to
    exclude the bleeding risk — a management trap that makes molecular rather than
    histological diagnosis the safer route.
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "or liver biopsies result in a risk of fatal bleeding"
    explanation: >
      Fragment of the review's statement that kidney or liver biopsies carry >50%
      risk of fatal bleeding; "kidney" is hyphen-broken across a line in the cached
      full text, so the quote starts at the next clean word boundary.
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "therefore, normal routine platelet analysis cannot assess"
    explanation: >
      States that normal routine platelet analysis cannot assess bleeding risk in
      ARC; the sentence continues across a hyphenated line break so only the
      verifiable fragment is quoted.
- name: Neurogenic Arthrogryposis and Musculoskeletal Anomalies
  biological_scale: TISSUE
  description: >
    Congenital joint contractures in the ARC spectrum are neurogenic rather than
    primarily myopathic or connective-tissue in origin. In the FID series this
    component was described as "musculoskeletal abnormalities" rather than frank
    arthrogryposis, and its relative mildness is precisely why FID was initially
    separated from ARC. Complete loss-of-function VPS33B alleles have since been
    shown to produce ichthyosis, cholestasis and renal dysfunction without
    arthrogryposis, so its absence does not exclude the diagnosis. Reported
    skeletal features across the spectrum include congenital hip dislocation and
    vertical talus.
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita"
    explanation: Establishes the neurogenic basis of the contractures.
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although homozygous for the novel VPS33B mutation 971delA/K324fs, predicted to abolish VPS33B function, did not exhibit arthrogryposis"
    explanation: >
      Demonstrates that a null VPS33B genotype can present without arthrogryposis,
      reconciling the FID phenotype with the ARC molecular aetiology.
- name: Severe Failure to Thrive
  biological_scale: ORGANISM
  description: >
    Combined renal solute wasting, diarrhoeal loss and cholestatic fat
    malabsorption produce severe, near-universal growth failure. Failure to
    thrive is listed among the cardinal features of the spectrum.
  evidence:
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis."
    explanation: Establishes severe failure to thrive as a cardinal feature.
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected infants do not thrive and usually die in the first year of life."
    explanation: Links growth failure to the infantile-lethal course.
  downstream:
  - target: Recurrent Infection and Sepsis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Malnutrition and multiorgan failure predispose to the recurrent febrile
      illnesses that were universal in the ARC cohort.
    intermediate_mechanisms:
    - Malnutrition-associated impairment of host defence
    evidence:
    - reference: PMID:11668108
      reference_title: "ARC syndrome: an expanding range of phenotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
      explanation: Co-occurrence of growth failure and recurrent febrile illness in all cohort patients.
  - target: Death in Infancy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cumulative nutritional and multiorgan failure
    evidence:
    - reference: PMID:15052268
      reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected infants do not thrive and usually die in the first year of life."
      explanation: Directly couples failure to thrive to death in the first year.
- name: Recurrent Infection and Sepsis
  biological_scale: ORGANISM
  description: >
    Recurrent febrile illnesses were universal in the ARC cohort, and sepsis was
    one of the named terminal events in the index series.
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
    explanation: Recurrent febrile illness in all six cohort patients.
  downstream:
  - target: Death in Infancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2206896
      reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
      explanation: Sepsis is named as a direct cause of death in the index series.
- name: Death in Infancy
  biological_scale: ORGANISM
  description: >
    The convergent endpoint. Death follows in infancy from dehydration, acidosis,
    sepsis, or internal haemorrhage. Every infant in the original FID series died
    by 6 months; across the ARC spectrum most die within the first year, with
    survival beyond infancy essentially restricted to patients retaining partial
    VPS33B function.
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
    explanation: The terminal common pathway documented in the index FID series.
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients with ARC do not survive past the first year of life."
    explanation: Confirms infantile lethality across the molecularly defined spectrum.
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function)"
    explanation: Residual VPS33B-VIPAR interaction is what permits survival beyond infancy.
phenotypes:
- category: Renal
  name: Renal Fanconi syndrome
  description: >
    Generalised proximal tubular dysfunction with urinary loss of amino acids,
    glucose, phosphate and bicarbonate. The defining renal component of FID, and
    the origin of the "Fanconi" in the syndrome name.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Renal Fanconi syndrome
    term:
      id: HP:0001994
      label: Renal Fanconi syndrome
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: Renal Fanconi syndrome is a defining component of FID.
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."
    explanation: >
      Supports the VERY_FREQUENT frequency band — 5 of 6 patients (83%) in the ARC
      cohort that subsumed FID.
- category: Renal
  name: Renal tubular acidosis
  description: >
    Proximal (type 2) renal tubular acidosis from bicarbonate wasting, requiring
    high alkali intake.
  phenotype_term:
    preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the association of arthrogryposis, renal tubular acidosis, and cholestasis"
    explanation: Renal tubular acidosis is one of the three defining ARC-spectrum features.
- category: Renal
  name: Aminoaciduria
  phenotype_term:
    preferred_term: Aminoaciduria
    term:
      id: HP:0003355
      label: Aminoaciduria
  evidence:
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness"
    explanation: Documents aminoaciduria in the arthrogryposis-negative (FID-like) presentation.
- category: Renal
  name: Nephrogenic diabetes insipidus
  description: >
    An alternative renal presentation reported in a minority of ARC-spectrum
    infants in place of renal Fanconi syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nephrogenic diabetes insipidus
    term:
      id: HP:0009806
      label: Nephrogenic diabetes insipidus
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus."
    explanation: >
      One of six patients (17%) presented with nephrogenic diabetes insipidus,
      supporting the OCCASIONAL band.
- category: Dermatologic
  name: Ichthyosis
  description: >
    Generalised scaling skin disease from failed lamellar body secretion and
    consequent stratum corneum lipid barrier failure. Skin biopsy shows mild
    hyperkeratosis without parakeratosis.
  diagnostic: true
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: Ichthyosis is a defining component of FID.
  - reference: PMID:18347289
    reference_title: "Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological signs and ichthyosis almost invariably accompany the disease."
    explanation: Confirms ichthyosis as a near-constant feature of the spectrum.
- category: Hepatic
  name: Cholestasis
  description: >
    Severe non-obstructive intrahepatic cholestasis with characteristically normal
    or low serum gamma-glutamyltransferase and bile duct hypoplasia.
  diagnostic: true
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."
    explanation: Documents the severe low-GGT cholestasis of the spectrum.
- category: Hepatic
  name: Jaundice
  description: >
    Conjugated hyperbilirubinaemia from intrahepatic cholestasis; one of the five
    cardinal FID features.
  diagnostic: true
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: Jaundice is a defining component of FID.
- category: Hepatic
  name: Conjugated hyperbilirubinemia
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia
  evidence:
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype"
    explanation: Conjugated hyperbilirubinaemia is a core-phenotype element.
- category: Gastrointestinal
  name: Diarrhea
  description: >
    Persistent, often intractable diarrhoea contributing to fluid loss and failure
    to thrive; one of the five cardinal FID features.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
    explanation: >
      All six patients in the ARC cohort had diarrhoea, supporting the
      VERY_FREQUENT band.
- category: Growth
  name: Failure to thrive
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
    explanation: >
      All six patients failed to thrive, supporting the VERY_FREQUENT band.
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis."
    explanation: Lists severe failure to thrive among cardinal spectrum features.
- category: Craniofacial
  name: Dysmorphic facial features
  description: >
    The "dysmorphism" of the FID acronym. Dysmorphic features are reported in a
    substantial proportion of ARC-spectrum infants but have not been reduced to a
    consistent recognisable gestalt, and no specific facial HPO terms can be
    supported from the primary sources.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many of our patients showed dysmorphic features or ichthyosis."
    explanation: Documents dysmorphic features in the cohort that subsumed FID.
- category: Musculoskeletal
  name: Arthrogryposis multiplex congenita
  description: >
    Neurogenic congenital joint contractures. Present in classical ARC but
    conspicuously mild or absent in the FID presentation, where the original
    description recorded "musculoskeletal abnormalities" instead. Its absence does
    not exclude biallelic VPS33B loss of function.
  frequency: VARIABLE
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had the typical pattern of arthrogryposis."
    explanation: Arthrogryposis was universal in the classical ARC cohort.
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypes associated with VPS33B mutation may include incomplete ARC."
    explanation: >
      Counter-evidence for obligate arthrogryposis — supports the VARIABLE band and
      explains why the FID cases were not recognised as ARC at the time.
- category: Hematologic
  name: Reduced platelet alpha granules
  description: >
    Complete or near-complete absence of platelet alpha-granules with loss of both
    soluble and membrane-bound alpha-granule proteins — the mechanistic basis of the
    "grey platelet syndrome" morphology described in two of the six FID infants.
  diagnostic: true
  phenotype_term:
    preferred_term: Reduced platelet alpha granules
    term:
      id: HP:0033536
      label: Reduced platelet alpha granules
  evidence:
  - reference: PMID:16123220
    reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets"
    explanation: Documents alpha-granule protein deficiency in patient platelets.
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of the infants were found to have abnormal platelet morphology--the grey platelet syndrome"
    explanation: The original FID observation this phenotype term formalises.
- category: Hematologic
  name: Increased mean platelet volume
  description: >
    Abnormally large, pale platelets on blood film — a low-cost diagnostic clue.
  phenotype_term:
    preferred_term: Increased mean platelet volume
    term:
      id: HP:0011877
      label: Increased mean platelet volume
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood films revealed abnormally large platelets."
    explanation: Large platelets on blood film in the ARC cohort that subsumed FID.
- category: Hematologic
  name: Abnormal bleeding
  description: >
    Bleeding diathesis from dysfunctional alpha-granule-deficient platelets;
    self-limiting intra-abdominal haemorrhage is common and biopsy carries a high
    risk of fatal bleeding.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:16123220
    reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP)."
    explanation: >
      Human patient platelets show impaired aggregation - the functional defect
      underlying the bleeding tendency. This is the primary, human-derived support
      for the phenotype.
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abdominal hemorrhage often occurs in patients with"
    explanation: >
      Human clinical corroboration that self-limiting intra-abdominal haemorrhage
      is common in ARC patients; the sentence wraps across a line in the cached
      full text, so only the verifiable span is quoted.
  - reference: PMID:25947942
    reference_title: "VPS33B regulates protein sorting into and maturation of alpha-granule progenitor organelles in mouse megakaryocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis"
    explanation: >
      Background framing from a Vps33b-conditional mouse study, retained as
      secondary support only. Tagged MODEL_ORGANISM to match the same snippet's
      classification on the Failed Platelet Alpha-Granule Biogenesis node.
- category: Metabolic
  name: Dehydration
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
    explanation: Dehydration was a proximate cause of death in the FID series.
- category: Immunologic
  name: Recurrent febrile illness and sepsis
  description: >
    Recurrent febrile illnesses were universal in the ARC cohort, and sepsis was a
    terminal event in the FID series.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had recurrent febrile illnesses, diarrhoea, and failed to thrive."
    explanation: Recurrent febrile illness in all cohort patients.
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all died by the age of 6 months of dehydration, acidosis and sepsis"
    explanation: Sepsis as a terminal event in the FID series.
- category: Neurologic
  name: Sensorineural hearing impairment
  description: >
    Reported in the arthrogryposis-negative VPS33B presentation and, more
    prominently, in the allelic ARKID syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness"
    explanation: Deafness in the FID-like arthrogryposis-negative phenotype.
- category: Neurologic
  name: Corpus callosum abnormality
  description: >
    Partial callosal agenesis and other central nervous system malformations occur
    in a subset of the spectrum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:16492441
    reference_title: "VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities"
    explanation: CNS malformation as a variable spectrum feature.
biochemical:
- name: Serum gamma-glutamyltransferase
  presence: NORMAL
  notes: >
    Usually the most useful discriminating laboratory finding, but not an absolute
    rule. Severe conjugated hyperbilirubinaemia with a NORMAL or low serum GGT
    separates ARC-spectrum cholestasis from biliary atresia, Alagille syndrome and
    most other causes of neonatal cholestasis, in which GGT is elevated, and it
    overlaps with the low-GGT PFIC types, which are the principal differential.
    Important exception: a genotype-confirmed ARC patient has been reported with a
    persistently HIGH GGT, so a raised GGT does not exclude the diagnosis.
  biomarker_term:
    preferred_term: serum gamma-glutamyltransferase (normal or low despite cholestasis)
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."
    explanation: Documents normal GGT despite severe cholestasis in all cohort patients.
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity"
    explanation: Low GGT is part of the defining biochemical signature.
  - reference: PMID:24782640
    reference_title: "ARC syndrome with high GGT cholestasis caused by VPS33B mutations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found"
    explanation: >
      Counter-evidence bounding the low-GGT rule. A genotype-confirmed ARC patient
      (compound heterozygous VPS33B c.403+2T>A / c.1509-1510insG) had a HIGH GGT on
      three consecutive tests alongside otherwise typical arthrogryposis, renal
      involvement and ichthyosis. A high GGT therefore does not exclude ARC.
- name: Urinary amino acids
  presence: INCREASED
  notes: >
    Generalised aminoaciduria as part of proximal tubular solute wasting.
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in cholestasis and in urinary wasting of sugars and amino acids"
    explanation: Documents urinary amino acid and sugar wasting as a consequence of the trafficking defect.
- name: Urinary glucose
  presence: INCREASED
  notes: >
    Glycosuria with normal blood glucose, reflecting proximal tubular transport
    failure rather than hyperglycaemia.
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "urinary wasting of sugars and amino acids"
    explanation: Documents urinary sugar wasting.
genetic:
- name: VPS33B
  subtype: ARCS1
  gene_term:
    preferred_term: VPS33B
    term:
      id: hgnc:12712
      label: VPS33B
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: approximately 75% of ARC-spectrum cases
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >
    VPS33B lies at 15q26.1 and encodes a Sec1/Munc18-family protein. The reported
    allelic spectrum is dominated by null variants — nonsense, frameshift and
    splice-site changes — with only rare missense alleles; no VPS33B protein is
    detectable in tissues from classical ARC cases. A curated locus-specific
    database (LOVD) collates known VPS33B and VIPAS39 variants. Rare hypomorphic
    alleles that retain partial VPS33B-VIPAR interaction (e.g., the splice variant
    c.1225+5G>C) produce attenuated phenotypes with survival into childhood, giving
    the first genotype-phenotype correlation in the spectrum. VPS33B is also
    allelic with autosomal recessive keratoderma-ichthyosis-deafness (ARKID)
    syndrome, in which missense variants impair Rab11a/Rab25 interaction and
    trafficking of the collagen-modifying enzyme LH3 without producing the full ARC
    picture. No molecular testing was available at the time of the 1990 FID report,
    so no FID proband has a confirmed genotype (see `discussions`).
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC"
    explanation: Establishes VPS33B as causative and localises it to 15q26.1.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline mutations in VPS33B are found in approximately 75% of individuals with ARC"
    explanation: Quantifies the VPS33B share of ARC-spectrum cases.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only one (T89C; L30P) of 31 VPS33B-proven pathogenic mutations detected so far in ARC is a missense mutation"
    explanation: Documents the null-dominated allelic spectrum.
  - reference: PMID:22753090
    reference_title: "Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study provides the first evidence of genotype-phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype."
    explanation: Establishes the hypomorphic-allele basis of attenuated phenotypes.
  - reference: PMID:28017832
    reference_title: "Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations were found in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein that interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen-modifying enzyme LH3."
    explanation: Documents the allelic ARKID phenotype and an additional VPS33B cargo (LH3).
- name: VIPAS39
  subtype: ARCS2
  gene_term:
    preferred_term: VIPAS39
    term:
      id: hgnc:20347
      label: VIPAS39
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: the minority of ARC-spectrum cases without VPS33B variants
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >
    VIPAS39 (formerly C14orf133, protein name VIPAR) encodes the obligate binding
    partner of VPS33B. Biallelic VIPAS39 variants accounted for every classical ARC
    case in which VPS33B mutation and linkage were excluded, and the reported
    alleles (six nonsense, one frameshift, one start-codon change) are predicted
    null. No clinical differences distinguish VPS33B- from VIPAS39-mutated
    patients, consistent with the two proteins acting as a single functional
    complex.
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."
    explanation: Establishes VIPAS39 as the second and apparently only other ARC-spectrum locus.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected no differences in clinical symptoms, signs or disease course between subjects in VPS33B- and VIPAR-mutated ARC subsets."
    explanation: Documents locus-independence of the clinical phenotype.
diagnosis:
- name: Molecular genetic testing of VPS33B and VIPAS39
  description: >
    Sequencing of VPS33B and VIPAS39 is the preferred confirmatory test and is
    explicitly safer than tissue diagnosis, because liver or kidney biopsy carries a
    reported risk of fatal bleeding above 50% from the platelet alpha-granule
    defect. Limitations are turnaround time and the possibility of false negatives.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with VPS33B and VIPAR sequencing analyses constitute an apparently safer diagnostic procedure"
    explanation: >
      Recommends sequencing over biopsy as the safer diagnostic route; the sentence
      begins with a hyphen-broken word ("presenta-tions") in the cached full text, so
      the quote starts at the verifiable boundary.
- name: Peripheral blood film and platelet morphology
  description: >
    Examination of platelet morphology on a peripheral blood smear is a proposed
    low-cost screening tool: large, pale, alpha-granule-deficient platelets are
    characteristic. It must not be used to exclude bleeding risk, since routine
    platelet analysis can be normal in patients who nonetheless bleed. Assay of
    VPS33B protein expression in cultured skin fibroblasts is the paired
    non-invasive alternative.
  diagnosis_term:
    preferred_term: peripheral blood smear examination
    term:
      id: NCIT:C49286
      label: Hematology Test
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in skin fibroblasts and platelet morphology in peripheral blood smears are two alternative techniques that have"
    explanation: >
      Fragment of the review's statement that VPS33B expression in skin fibroblasts
      and platelet morphology on blood smears are proposed screening alternatives to
      biopsy; the sentence is line-wrapped in the cached full text.
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood films revealed abnormally large platelets."
    explanation: Documents the blood-film finding this test detects.
- name: Serum GGT with conjugated bilirubin
  description: >
    A normal or low serum gamma-glutamyltransferase in the face of severe conjugated
    hyperbilirubinaemia is the pivotal biochemical clue that redirects a neonatal
    cholestasis workup away from biliary atresia and towards the low-GGT
    cholestases, including ARC-spectrum disease. It is a rule-in rather than a
    rule-out test: a genotype-confirmed ARC patient has been reported with
    persistently high GGT, so a raised GGT does not exclude ARC and should not stop
    the workup if the arthrogryposis / renal / cutaneous features are present.
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal."
    explanation: Establishes the discriminating normal-GGT-with-severe-cholestasis pattern.
  - reference: PMID:24782640
    reference_title: "ARC syndrome with high GGT cholestasis caused by VPS33B mutations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found"
    explanation: >
      Counter-evidence bounding the low-GGT rule. A genotype-confirmed ARC patient
      (compound heterozygous VPS33B c.403+2T>A / c.1509-1510insG) had a HIGH GGT on
      three consecutive tests alongside otherwise typical arthrogryposis, renal
      involvement and ichthyosis. A high GGT therefore does not exclude ARC.
- name: Skin biopsy with electron microscopy
  description: >
    Ultrastructural examination of skin shows lamellar granules entombed within
    cornified cells with normal internal granule structure — the finding that
    separates ARC-spectrum ichthyosis from CEDNIK syndrome, where the granules are
    themselves structurally abnormal. Light microscopy shows mild hyperkeratosis
    without parakeratosis. Skin is a far safer biopsy site than liver or kidney.
  diagnosis_term:
    preferred_term: skin biopsy with electron microscopy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:18347289
    reference_title: "Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ultrastructural examination of the skin in ARC syndrome revealed many entombed lamellar granules in the cornified cells"
    explanation: The diagnostic ultrastructural finding on skin biopsy.
differential_diagnoses:
- name: Fanconi Renotubular Syndrome
  description: >
    The isolated renal phenotype. ARC-spectrum disease includes renal Fanconi
    syndrome as one component of a multisystem disorder, so an infant presenting
    first with proximal tubulopathy can be mistaken for isolated FRTS. The
    distinguishing move is to look for the extrarenal components — cholestasis,
    ichthyosis, contractures, platelet defect — none of which belong to FRTS.
    This is also the entity MONDO places MONDO:0022948 (the Deal-Barratt-Dillon
    stub) under, which is why the nomenclatural argument in `discussions` turns
    on it.
  distinguishing_features:
  - Isolated FRTS lacks low-GGT cholestasis, ichthyosis, neurogenic arthrogryposis and the platelet alpha-granule defect
  - Renal Fanconi syndrome in ARC-spectrum disease is one component of a CHEVI-trafficking multisystem disorder, not the whole phenotype
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: >
      The index description presents renal Fanconi syndrome as one component of a
      multisystem association, not as isolated renotubular disease.
- name: Arthrogryposis Multiplex Congenita
  description: >
    The isolated musculoskeletal phenotype. AMC is an aetiologically
    heterogeneous endpoint of reduced fetal movement; the ARC spectrum is one
    specific neurogenic cause of it, and MONDO parents ARC under
    MONDO:0008823 arthrogryposis multiplex congenita 2, neurogenic type. An
    infant with contractures should be evaluated for the renal and hepatic
    components before AMC is called isolated.
  distinguishing_features:
  - ARC-spectrum arthrogryposis is neurogenic and accompanied by renal tubular dysfunction and low-GGT cholestasis; isolated AMC has neither
  - Arthrogryposis is not obligate in the ARC spectrum, so its absence does not exclude ARC while its presence does not establish isolated AMC
  evidence:
  - reference: PMID:15052268
    reference_title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita"
    explanation: >
      Establishes that ARC-spectrum contractures are neurogenic AMC occurring
      within a multisystem disorder, distinguishing them from isolated AMC.
- name: Fanconi anemia
  description: >
    Not a clinical mimic but a persistent nomenclatural trap, entered through this
    entry's historical FID synonym. The "Fanconi" in Fanconi-ichthyosis-dysmorphism
    syndrome denotes renal Fanconi syndrome (proximal tubulopathy), not Fanconi
    anaemia (the DNA interstrand-crosslink repair and bone marrow failure disorder).
    The ICD-11 Foundation entry for FID both defines it as an association with
    "Fanconi anaemia" and classifies it as a child of Fanconi anaemia; MONDO instead
    places the same entity under Fanconi renotubular syndrome, which matches the
    primary literature.
  distinguishing_features:
  - ARC-spectrum disease has proximal renal tubulopathy with no reported DNA crosslinker sensitivity; Fanconi anemia is defined by chromosome breakage on diepoxybutane/mitomycin C testing
  - ARC-spectrum disease causes early-infantile death from acidosis, dehydration and sepsis; Fanconi anemia presents with progressive bone marrow failure and cancer predisposition over years
  - ARC-spectrum disease has low-GGT cholestasis and ichthyosis, neither of which is characteristic of Fanconi anemia
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea"
    explanation: >
      The primary description names the renal "Fanconi syndrome", not Fanconi
      anaemia, establishing which entity the eponym refers to.
- name: Progressive familial intrahepatic cholestasis
  description: >
    The low-GGT PFIC types (notably PFIC1/ATP8B1 and PFIC2/ABCB11) share severe
    conjugated hyperbilirubinaemia with normal GGT, diarrhoea and failure to thrive,
    and are the principal hepatic differential. They lack the renal Fanconi
    syndrome, ichthyosis, arthrogryposis and alpha-granule defect.
  distinguishing_features:
  - PFIC lacks renal proximal tubulopathy, ichthyosis and the platelet alpha-granule defect
  - Mechanistically related — ARC-spectrum cholestasis arises partly from mis-sorting of BSEP/ABCB11, the protein mutated in PFIC2
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "similar clinical and laboratory findings could be observed both in ARC syndrome and progressive"
    explanation: >
      States the clinical and laboratory overlap with progressive familial
      intrahepatic cholestasis; the sentence is hyphen-broken across a line in the
      cached full text, so only the verifiable fragment is quoted.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mis-sorting of some BSEP to the basolateral hepatocyte membrane was seen in the livers of individuals with ARC"
    explanation: The mechanistic link between the two entities — BSEP is the PFIC2 protein.
- name: Biliary atresia
  description: >
    The dominant differential for any infant with conjugated hyperbilirubinaemia.
    Distinguished by an elevated GGT and by hepatobiliary imaging showing obstruction;
    in ARC-spectrum disease the biliary tree is patent but intrahepatic bile flow is
    absent, and GGT is normal. Misdirection towards biliary atresia risks a
    hazardous laparotomy or biopsy in a child with a bleeding diathesis.
  distinguishing_features:
  - GGT is usually elevated in biliary atresia and normal or low in ARC-spectrum cholestasis, but a high-GGT ARC case is documented, so GGT does not reliably rule ARC out
  - Biliary tract is patent in ARC-spectrum disease despite absent intrahepatic bile flow
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "labeled compounds normally secreted into bile do not enter the duodenum despite biliary tract patency"
    explanation: Documents biliary patency, the anatomical feature distinguishing this from biliary atresia.
  - reference: PMID:24782640
    reference_title: "ARC syndrome with high GGT cholestasis caused by VPS33B mutations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found"
    explanation: >
      Counter-evidence bounding the low-GGT rule. A genotype-confirmed ARC patient
      (compound heterozygous VPS33B c.403+2T>A / c.1509-1510insG) had a HIGH GGT on
      three consecutive tests alongside otherwise typical arthrogryposis, renal
      involvement and ichthyosis. A high GGT therefore does not exclude ARC.
- name: CEDNIK syndrome
  description: >
    Cerebral dysgenesis-neuropathy-ichthyosis-keratoderma syndrome (SNAP29) is the
    closest dermatological mimic: another SNARE-machinery disorder with ichthyosis
    from abnormal lamellar granule handling. It is distinguished ultrastructurally —
    in ARC-spectrum disease the entombed lamellar granules have normal internal
    structure, whereas in CEDNIK the granule structure itself is abnormal — and
    clinically by the absence of cholestasis and renal tubulopathy.
  distinguishing_features:
  - Lamellar granule internal structure is normal in ARC-spectrum disease and abnormal in CEDNIK
  - CEDNIK lacks low-GGT cholestasis and renal Fanconi syndrome
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lamellar granule internal structure is normal in ARC syndrome while it is abnormal in"
    explanation: >
      States the ultrastructural discriminator between the two lamellar-granule
      ichthyoses; "CEDNIK" is hyphen-broken across a line in the cached full text.
- name: Gray platelet syndrome
  description: >
    True grey platelet syndrome (NBEAL2, and the GFI1B-related form) is an isolated
    platelet alpha-granule deficiency with macrothrombocytopenia and myelofibrosis.
    Two of the six original FID infants were labelled as having "the grey platelet
    syndrome" on morphology alone; the ARC-spectrum alpha-granule defect is a
    phenocopy arising from a different trafficking lesion and is accompanied by
    multisystem disease.
  distinguishing_features:
  - Gray platelet syndrome is confined to the platelet lineage, without cholestasis, renal tubulopathy or ichthyosis
  - In the ARC spectrum, delta-granules are increased rather than normal
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of the infants were found to have abnormal platelet morphology--the grey platelet syndrome"
    explanation: The original morphological attribution that this differential resolves.
  - reference: PMID:16123220
    reference_title: "Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated numbers of delta-granules, and completely absent alpha-granules"
    explanation: The increased delta-granule count distinguishing the ARC-spectrum platelet from classical grey platelet syndrome.
treatments:
- name: Fluid, alkali and electrolyte replacement
  description: >
    The cornerstone of care. High fluid and bicarbonate intakes are required to
    offset proximal tubular bicarbonate and solute wasting compounded by diarrhoeal
    losses; failure to keep pace results in fatal dehydration and acidosis.
    Phosphate supplementation addresses renal phosphate wasting.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fluid and electrolyte replacement
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Bicarbonate Wasting and Metabolic Acidosis
    treatment_effect: INHIBITS
    description: >
      Exogenous alkali offsets the obligatory renal bicarbonate loss; this
      compensates for, rather than corrects, the upstream tubular transport failure.
  - target: Volume Depletion and Dehydration
    treatment_effect: INHIBITS
    description: >
      Exogenous fluid offsets the obligatory renal and gastrointestinal water loss.
  target_phenotypes:
  - preferred_term: Renal tubular acidosis
    term:
      id: HP:0001947
      label: Renal tubular acidosis
  - preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they required high fluid and bicarbonate intakes"
    explanation: Documents the fluid and alkali requirement in the index FID series.
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including fluid infusion, anti-infection, supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"
    explanation: Enumerates the supportive-care regimen used across the ARC spectrum.
- name: Ursodeoxycholic acid for cholestasis
  description: >
    Used as part of supportive management of the cholestatic liver disease. As with
    all ARC-spectrum therapy this is symptomatic; no agent modifies the underlying
    trafficking defect.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  target_phenotypes:
  - preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"
    explanation: Names ursodeoxycholic acid within the standard supportive regimen.
- name: Nutritional support with fat-soluble vitamin supplementation
  description: >
    Cholestatic fat malabsorption plus diarrhoeal and renal losses make aggressive
    nutritional support and fat-soluble vitamin replacement necessary, though failure
    to thrive typically persists.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Severe Failure to Thrive
    treatment_effect: INHIBITS
    description: >
      Caloric and fat-soluble vitamin replacement partially offsets malabsorptive
      and renal losses; growth failure typically persists.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supplement with ursodeoxycholic acid, fat-soluble vitamins, calcium glubionate, L-thyroxine and phosphate"
    explanation: Fat-soluble vitamin and mineral supplementation within the supportive regimen.
- name: Avoidance of liver and kidney biopsy
  description: >
    A management decision rather than an intervention, but arguably the highest-value
    one. Percutaneous liver or kidney biopsy carries a reported risk of fatal bleeding
    above 50% because of the platelet alpha-granule defect, and routine platelet
    analysis cannot identify who is at risk. Diagnosis should proceed via clinical
    features, blood film, fibroblast VPS33B expression and sequencing instead.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "or liver biopsies result in a risk of fatal bleeding"
    explanation: >
      Quantifies the biopsy bleeding risk (>50% in the source sentence) that motivates
      avoidance; "kidney" is hyphen-broken across a line in the cached full text.
- name: LDL apheresis and biliary diversion for intractable cholestatic pruritus
  description: >
    Reported in a single ARC-spectrum patient with a renal-predominant presentation,
    combining LDL apheresis with biliodigestive derivation for cholestatic pruritus,
    with encouraging results. This is anecdotal rescue therapy, not established
    practice.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic apheresis
    term:
      id: NCIT:C173286
      label: Therapeutic Apheresis
  evidence:
  - reference: PMID:29907094
    reference_title: "Severe renal Fanconi and management strategies in Arthrogryposis-Renal dysfunction-Cholestasis syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report on the successful use of LDL-Apheresis and biliodigestive derivation for treatment of cholestatic pruritus with encouraging results"
    explanation: Single-case report of this rescue approach.
- name: Genetic counseling and prenatal diagnosis
  description: >
    Given autosomal recessive inheritance with a 25% recurrence risk, high
    consanguinity in affected families and near-uniform infantile lethality, genetic
    counselling with the option of prenatal or preimplantation genetic diagnosis is a
    central part of care once the family's variants are known.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "provide genetic counseling and prenatal or preimplantation genetic diagnosis"
    explanation: Recommends genetic counselling and prenatal/preimplantation diagnosis for affected families.
- name: Palliative and supportive care
  description: >
    No specific or disease-modifying treatment exists. Care is directed at quality of
    life, infection control and symptom relief; aggressive orthopaedic intervention
    for contractures is generally not recommended because poor general status and low
    survival compromise surgical outcomes.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: palliative care
    term:
      id: NCIT:C15292
      label: Palliative Therapy
  evidence:
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, no specific treatment currently exists for this syndrome."
    explanation: States the absence of disease-modifying therapy.
  - reference: PMID:25239142
    reference_title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "orthopedic management is still not recommended, since poor general status and low survival rates may affect the outcome of the surgery"
    explanation: >
      Advises against aggressive orthopaedic surgery; the sentence continues past a
      line break in the cached full text so only the verifiable span is quoted.
animal_models:
- species: Mus musculus
  genotype: Vps33b knockout (constitutive and tamoxifen-inducible Vps33b-fl/fl-ERT2); Vipas39 knockout
  category: KNOCKOUT
  genes:
  - preferred_term: VPS33B
    term:
      id: hgnc:12712
      label: VPS33B
  - preferred_term: VIPAS39
    term:
      id: hgnc:20347
      label: VIPAS39
  description: >
    Vps33b and Vipas39 knockout mice reproduce the ichthyotic skin phenotype with
    histologically similar changes to human ARC-spectrum skin, abnormal epidermal
    lamellar body morphology, disrupted lamellar body cargo localisation, and reduced
    stratum corneum lipid deposition. The tamoxifen-inducible Vps33b model also
    reproduces the platelet alpha-granule defect. These are good models of the
    cutaneous and haematological arms specifically; fidelity to the renal and hepatic
    arms is not established by these papers.
  evidence:
  - reference: PMID:29409756
    reference_title: VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate that the skin manifestations in Vps33b and Vipar deficient mice are histologically similar to those of patients with ARC syndrome."
    explanation: Establishes fidelity of the mouse skin phenotype to human disease.
  - reference: PMID:25947942
    reference_title: "VPS33B regulates protein sorting into and maturation of alpha-granule progenitor organelles in mouse megakaryocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a tamoxifen-inducible mouse model of VPS33B deficiency, Vps33b(fl/fl)-ER(T2), and studied the platelet phenotype"
    explanation: Describes the inducible model used to dissect the platelet phenotype.
- species: Danio rerio
  genotype: vipar morpholino knockdown
  category: KNOCKDOWN
  genes:
  - preferred_term: VIPAS39
    term:
      id: hgnc:20347
      label: VIPAS39
  description: >
    Morpholino knockdown of vipar in zebrafish produces biliary excretion and
    E-cadherin defects mirroring those in human ARC-spectrum disease, supporting the
    causal role of the polarity defect in cholestasis.
  evidence:
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC."
    explanation: Zebrafish model recapitulating the biliary and junctional phenotype.
discussions:
- discussion_id: fid_icd11_fanconi_anaemia_misparent
  kind: INTERPRETATION
  status: OPEN
  prompt: >
    Should the ICD-11 Foundation classification of Fanconi-ichthyosis-dysmorphism
    syndrome as a child of Fanconi anaemia be corrected to renal Fanconi syndrome?
  rationale: >
    The ICD-11 Foundation entity icd11f:235762608 defines FID as "the association of
    Fanconi anaemia, ichthyosis, musculo-skeletal anomalies, jaundice, and
    diarrhoea" and places it under Fanconi anaemia. The primary description
    (PMID:2206896), its MeSH synonym, and MONDO all use "Fanconi syndrome" in the
    renal proximal-tubulopathy sense; MONDO:0022948 is classified under
    MONDO:0001083 Fanconi renotubular syndrome. Nothing in the primary literature
    describes bone marrow failure, pancytopenia, chromosome breakage or cancer
    predisposition in these infants, and the molecular aetiology — biallelic
    VPS33B/VIPAS39 loss disrupting apical trafficking — has no relationship to the
    Fanconi anaemia DNA interstrand-crosslink repair pathway. The ICD-11 placement
    appears to be a homonym error between two unrelated Fanconi eponyms, and it
    propagates into any downstream system that inherits ICD-11 parentage. dismech
    records the mapping as a narrow match - the ICD-11 definition delimits the
    arthrogryposis-poor FID end of this entry's ARC spectrum - while flagging the
    parentage as incorrect.
  attaches_to:
  - pathophysiology#Proximal Tubular Apical Transport Failure
  evidence:
  - reference: PMID:2206896
    reference_title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No evidence of a recognised metabolic disorder was found in any of the six infants"
    explanation: >
      The primary series describes a renal tubulopathy phenotype and reports no
      haematological marrow-failure disorder, contradicting the ICD-11 parentage.
- discussion_id: fid_molecular_confirmation_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Were the six original Deal-Barratt-Dillon infants molecularly VPS33B- or
    VIPAS39-deficient, and does any FID-labelled case exist that is not explained by
    CHEVI complex loss?
  rationale: >
    The 1990 FID series predates the identification of VPS33B (2004) and VIPAS39
    (2010), so no proband from that series has a confirmed genotype. The assignment
    of FID to the ARC spectrum rests on the phenotypic argument made by Eastham and
    colleagues in 2001 (PMID:11668108) plus the subsequent demonstration that
    VPS33B-null patients can lack arthrogryposis (PMID:16492441). That argument is
    strong but is not the same as molecular proof for these specific families.
    Because the assignment determines whether FID should be retired as an
    independent entity or retained as a distinct locus, the gap is worth stating
    explicitly rather than papering over.
  attaches_to:
  - pathophysiology#Biallelic Loss of VPS33B or VIPAS39 Function
  - pathophysiology#Neurogenic Arthrogryposis and Musculoskeletal Anomalies
  proposed_experiments:
  - experiment_id: fid_archival_genotyping
    name: Retrospective genotyping of archival FID material
    description: >
      Where archival DNA or fixed tissue from the 1990 Great Ormond Street cohort or
      surviving relatives can be located and consented, sequence VPS33B and VIPAS39
      (with copy-number analysis) to test directly whether the FID probands carry
      biallelic CHEVI-complex variants.
    would_support:
    - FID is a phenotypic variant of VPS33B/VIPAS39-related ARC-spectrum disease and should be retired as an independent entity
    would_refute:
    - FID represents a distinct, still-unidentified locus that phenocopies the ARC spectrum
  - experiment_id: fid_phenotype_negative_cohort_sequencing
    name: Exome/genome sequencing of ARC-phenotype, CHEVI-negative infants
    description: >
      Sequence infants presenting with renal Fanconi syndrome, low-GGT cholestasis,
      ichthyosis and diarrhoea but no VPS33B or VIPAS39 variant, to determine whether
      a third locus exists that would correspond to a genuinely separate FID entity.
    would_support:
    - A distinct FID locus exists outside the CHEVI complex
    would_refute:
    - VPS33B and VIPAS39 account for the entire phenotypic spectrum, as suggested when VIPAR mutations explained all VPS33B-negative classical ARC cases
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum."
    explanation: >
      The phenotypic, pre-molecular basis on which FID was subsumed into the ARC
      spectrum — strong, but not genotype-confirmed for the FID probands themselves.
  - reference: PMID:20190753
    reference_title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in VIPAR accounted for all cases of classical ARC in whom mutations in and linkage to VPS33B were excluded."
    explanation: >
      Evidence bearing on whether a third locus is likely: VIPAS39 closed the
      residual gap in classical ARC, arguing against an unidentified FID locus.
- discussion_id: fid_chevi_trafficking_module_candidate
  kind: CURATION_TODO
  status: OPEN
  prompt: >
    Should a "CHEVI-complex apical trafficking failure" mechanism module be factored
    out of this entry and its allelic relatives?
  rationale: >
    The mechanism curated here — CHEVI/RAB11A-dependent apical recycling failure
    producing simultaneous epithelial polarity loss and defective biogenesis of two
    lysosome-related organelles (lamellar body, platelet alpha-granule) — is shared
    across ARC syndrome, this FID presentation, and the allelic ARKID syndrome, and
    is conceptually adjacent to other lysosome-related-organelle disorders
    (Hermansky-Pudlak, Chediak-Higashi). No existing dismech module covers it: the
    `epithelial_barrier_dysfunction` and `intestinal_barrier_dysfunction` modules
    model allergic and inflammatory barrier loss, not a constitutive trafficking
    lesion. No `conforms_to` edge is asserted in this entry for that reason. If
    ARC syndrome and ARKID are curated as separate entries, a shared module becomes
    worthwhile.
  attaches_to:
  - pathophysiology#Loss of the VPS33B-VIPAR (CHEVI) Tethering Complex
  evidence:
  - reference: PMID:27555442
    reference_title: "The CHEVI tethering complex: facilitating special deliveries."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "corroborate its role in the specialized delivery of cargo in different cell types"
    explanation: >
      Frames CHEVI as a general cargo-delivery mechanism operating across cell types,
      which is the recurrence criterion a dismech mechanism module requires.
- discussion_id: mondo_deal_barratt_dillon_unreconciled_stub
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    Should MONDO:0022948 (Deal Barratt Dillon syndrome) be obsoleted and merged
    into, or asserted as a subclass of, MONDO:0017123 arthrogryposis-renal
    dysfunction-cholestasis syndrome?
  rationale: >
    MONDO:0022948 is an unreconciled legacy class. It has no textual definition, no
    gene association, and no OMIM xref - only GARD, MEDGEN, MeSH and UMLS
    cross-references - and it is classified under MONDO:0001083 Fanconi renotubular
    syndrome. By contrast MONDO:0017123 has an Orphanet-sourced definition, an
    OMIMPS xref, and two gene-defined children (MONDO:0008822 VPS33B, MONDO:0013255
    VIPAS39). The primary literature closed this gap in 2001: PMID:11668108
    concluded that the Fanconi
    syndrome-ichthyosis-dysmorphism-jaundice-diarrhoea association "is part of the
    ARC spectrum", and the molecular basis was established in 2004 and 2010. So the
    two MONDO classes denote the same patients, one of them without any mechanistic
    grounding. dismech anchors on MONDO:0017123 and records MONDO:0022948 as a
    close match; the ontology-side fix is out of scope here but worth filing
    upstream.
  attaches_to:
  - pathophysiology#Biallelic Loss of VPS33B or VIPAS39 Function
  evidence:
  - reference: PMID:11668108
    reference_title: "ARC syndrome: an expanding range of phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum."
    explanation: >
      The published statement that the two labels denote one entity, which is what
      MONDO has not yet reflected in its class hierarchy.
notes: >
  Nosological status. This entry is anchored on the ARC entity (MONDO:0017123)
  because dismech is a pathograph resource: the name should correspond to the
  mechanism curated, and the mechanism here is CHEVI-complex (VPS33B/VIPAS39)
  apical-trafficking failure, which is ARC. It was originally drafted under the
  historical label Fanconi-ichthyosis-dysmorphism syndrome, seeded from ICD-11
  icd11f:235762608 and bound to MONDO:0022948; that was a mismatch between the
  bound term and the content, since MONDO:0022948 is a clinical-gestalt stub with
  no gene association. FID and Deal-Barratt-Dillon are retained as synonyms and as
  a `mappings` entry so the historical labels still resolve here. Discoverability
  by the old names is MONDO's concern, not this resource's.

  Synonyms vs mappings. The `synonyms` list is a deliberately broad lookup aid and
  is not a co-denotation claim: it carries historical labels
  (Fanconi-ichthyosis-dysmorphism syndrome, Deal-Barratt-Dillon syndrome) and
  gene-level labels (ARCS1, ARCS2) that `mappings` separately records as
  `skos:narrowMatch`, and that ARCS1/ARCS2 additionally appear in `has_subtypes`.
  Where the two disagree, `mappings` carries the formal claim and `synonyms` is
  the search surface. MONDO likewise does not list ARCS1/ARCS2 as exact synonyms
  of MONDO:0017123.

  Eponym collision. "Fanconi" in the FID label refers to renal Fanconi syndrome
  (Guido Fanconi's proximal tubulopathy), not Fanconi anaemia. The ICD-11
  Foundation entry propagates the wrong reading in both its definition and its
  parentage; see the `fid_icd11_fanconi_anaemia_misparent` discussion. MONDO's
  placement of MONDO:0022948 under Fanconi renotubular syndrome gets the homonym
  right but still does not connect it to ARC; see
  `mondo_deal_barratt_dillon_unreconciled_stub`.

  Subtypes. ARCS1 (VPS33B, MONDO:0008822) and ARCS2 (VIPAS39, MONDO:0013255) are
  curated as `has_subtypes` following MONDO's disease-series-by-gene pattern. No
  clinical differences distinguish them, so the pathograph is shared rather than
  split per subtype.

  Mortality. All six infants in the index FID series died by 6 months of age, and
  most ARC-spectrum infants die within the first year. Following repository convention
  (see Cardiomyopathy-Hypotonia-Lactic_Acidosis_Syndrome), this is not curated as a
  `phenotypes` entry, because HP:0001522 (Death in infancy) sits in the HPO
  mortality/clinical-modifier branch rather than under HP:0000118 Phenotypic
  abnormality and so is outside the PhenotypeTerm enum. It is instead captured on
  the `Death in Infancy` pathophysiology node and in `clinical_burden`.

  Evidence provenance. In the absence of a GeneReviews chapter (see "GeneReviews
  baseline" below for the check and its provenance), the phenotype baseline is
  drawn from the primary FID series (PMID:2206896), the multicentre ARC
  phenotype series that subsumed it (PMID:11668108), the two gene-discovery papers
  (PMID:15052268, PMID:20190753), and the ARC review (PMID:25239142). Several
  snippets are quoted from the full text of PMID:25239142 and PMID:20190753 rather
  than their abstracts; because that cached full text is hard-wrapped with
  hyphenated word breaks, some snippets begin or end mid-sentence at the nearest
  verifiable boundary. Each such snippet's `explanation` states what the complete
  sentence says.

  Frequency bands. VERY_FREQUENT and OCCASIONAL bands are derived from the
  six-patient ARC cohort of PMID:11668108 (6/6 for diarrhoea, febrile illness and
  failure to thrive; 5/6 for renal Fanconi syndrome; 1/6 for nephrogenic diabetes
  insipidus). These are small denominators from referral series and should be read
  as order-of-magnitude indications, not population frequencies. Phenotypes with no
  defensible denominator carry no `frequency`.

  GGT is not an absolute rule. The low/normal-GGT signature is the standard
  discriminator and is used as such throughout this entry, but PMID:24782640
  reports a genotype-confirmed ARC patient with high GGT on three consecutive
  tests. That paper is cited as PARTIAL counter-evidence on the biochemical,
  diagnosis and biliary-atresia-differential blocks so the rule is not read as
  exclusionary. The mechanism of the raised GGT in that patient is unexplained.

  GeneReviews baseline. Verified 2026-08-02 by searching the GeneReviews
  bookshelf: no dedicated chapter exists for ARC syndrome, VPS33B, VIPAS39 or the
  historical FID label. (An earlier revision of this entry asserted the same thing
  before the check had actually been run; the PR reviewer correctly flagged it as
  author-attested, and it has since been confirmed.)

  Deep research. No deep-research provider artifact underlies this entry; it was
  curated directly from primary literature (the index series, the multicentre ARC
  phenotype series, the two gene-discovery papers, and the ARC review), which is
  why there is no `research/*-deep-research-*.md` file in the change.

  Not curated. The allelic autosomal recessive keratoderma-ichthyosis-deafness
  (ARKID) syndrome, which shares the VPS33B locus but not the full ARC phenotype,
  does not yet have a dismech entry; when it is added, this entry should be
  cross-referenced from it and the shared mechanism considered for a module (see
  `fid_chevi_trafficking_module_candidate`).
references:
- reference: PMID:2206896
  title: "Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome."
- reference: PMID:11668108
  title: "ARC syndrome: an expanding range of phenotypes."
- reference: PMID:15052268
  title: "Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome."
- reference: PMID:20190753
  title: "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization."
- reference: PMID:25239142
  title: "Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features."

📚

References & Deep Research

References

PMID:2206896

Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhoea--a new syndrome.

No top-level findings curated for this source.

PMID:11668108

ARC syndrome: an expanding range of phenotypes.

No top-level findings curated for this source.

PMID:15052268

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.

No top-level findings curated for this source.

PMID:20190753

Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.

No top-level findings curated for this source.

PMID:25239142

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features.

No top-level findings curated for this source.

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