This is a mechanism module, not a specific disease. It is the third of three sibling modules covering the epithelial CODE classes as the current nosology separates them (PMID:29654747), alongside diet_induced_osmotic_diarrhea (loss of a substrate-specific step handling an ingested nutrient; normal villus architecture; remits on dietary elimination) and electrolyte_transport_related_diarrhea (loss of an ion-transport step; normal villus architecture; low stool osmotic gap). The discriminator that assigns a disorder to this module rather than either sibling is the villus-to-crypt ratio: it is abnormal here and normal in both of the others, which is exactly the split PMID:29654747 draws. A disorder must not conform to this module and to either sibling for the same node. ARM SELECTION IS THE CURATOR'S FIRST DECISION. The module carries two molecularly distinct trigger arms as SEPARATE nodes - `#Loss of Apical Delivery Machinery` (MYO5B/STX3) and `#Loss of Junctional Adhesion Machinery` (EPCAM/SPINT2) - which converge on one rate-limiting node but are not interchangeable. They were originally curated as a single blended trigger; that structure let a conformer implicitly assert the other arm's lesion, so it was split to follow the separate-arm precedent of `defective_skeletal_mineralization` and `bilirubin_conjugation_transport`. A disorder must enter through exactly one arm and must NOT declare conformance to the other: MYO5B/STX3 disease and EPCAM/SPINT2 disease differ in histology (intracellular microvillus inclusions versus focal epithelial tufts), and apical vesicle delivery is intact in EpCAM disease. Note that a disorder may map more than one of its own nodes onto the central effector, because that node is deliberately coarser than the structural/functional split most conformers curate. Excluded: immune-mediated enteropathy (IPEX, autoimmune enteropathy), where epithelial damage is secondary to immune dysregulation rather than intrinsic to the enterocyte - PMID:29654747 separates epithelium-intrinsic from immune-mediated CODEs on exactly this basis; barrier injury and inflammatory villus blunting, covered by intestinal_barrier_dysfunction; and post-uptake intracellular metabolic defects such as DGAT1 deficiency, where the apical surface is intact and endoscopy is typically normal. Key disease-specific substitutions: microvillus inclusion disease substitutes MYO5B (or STX3/STXBP2) and the brush-border-loss-with-inclusions histology; congenital tufting enteropathy substitutes EpCAM (or SPINT2 acting through it) and the tuft-with-crypt-hyperplasia histology. Modules bind GO and CL terms only and do not use chemical (CHEBI) or disease (MONDO) term bindings.
Loss of Apical Delivery Machinery
trigger
ARM SELECTION IS THE CURATOR'S FIRST DECISION. This is the trafficking arm. Biallelic loss of the myosin Vb motor - or of syntaxin-3, the apical SNARE that receives its vesicles one step downstream - arrests delivery of recycling-endosome cargo to the apical membrane. Because basolateral cargo is mislocalized too, the defect is one of general epithelial polarity rather than of a single apical protein. A disorder entering the module through this arm must NOT declare conformance to the adhesion arm: the two are molecularly distinct and histologically distinguishable (intracellular microvillus inclusions here, focal epithelial tufts there), and conforming to both would assert a claudin-7 lesion that MYO5B disease does not have.
Downstream
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Loss of a Functionally Polarized Absorptive Epithelial Surface
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"mislocalization of transferrin receptor in MVID enterocytes suggests that MYO5B deficiency causes defective trafficking of apical and basolateral proteins in MVID"
Establishes the trafficking arm of this trigger as a general defect of polarized membrane traffic, affecting basolateral as well as apical cargo, rather than loss of one apical protein.
"Along with microvillus inclusion disease, a severe disorder belonging to the defective enterocyte trafficking and polarity category of CODEs is congenital tufting enteropathy (CTE)."
Supports treating the two arms as one CODE class even though they are curated as separate trigger nodes: both microvillus inclusion disease and congenital tufting enteropathy are assigned to the defective enterocyte trafficking and polarity category. Evidence source is OTHER because this is a review.
Loss of Junctional Adhesion Machinery
trigger
ARM SELECTION IS THE CURATOR'S FIRST DECISION. This is the adhesion arm. Loss of functional EpCAM at the epithelial cell surface - by EPCAM variants, or indirectly by SPINT2 variants that unleash matriptase to degrade it - removes the anchor that recruits claudin-7 to the tight junction, destabilizing the apical junctional complex that maintains polarity and cohesion across the sheet. A disorder entering through this arm must NOT declare conformance to the trafficking arm: apical vesicle delivery is intact in EpCAM disease, and the histology is focal epithelial tufts rather than intracellular microvillus inclusions.
Downstream
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Loss of a Functionally Polarized Absorptive Epithelial Surface
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"In CTE, the absence of EpCAM substantially reduces the recruitment of claudin-7 to TJs, leading to loss of TJ formation."
Establishes this arm - EpCAM loss removing claudin-7 from the tight junction so junction formation fails. Evidence source is OTHER because this is a review.
Loss of a Functionally Polarized Absorptive Epithelial Surface
central effector
The rate-limiting, disorder-agnostic node and the key conformance target. Whichever arm is taken, the epithelium can no longer present a correctly organized apical surface to the lumen. In the trafficking arm the brush border is sparse or absent and microvilli are internalized into cytoplasmic inclusions; in the adhesion arm the sheet becomes dysplastic, with disorganized enterocytes crowding into focal tufts on a background of villous atrophy and crypt hyperplasia. The functional consequence is the same and is what matters mechanistically: the apical surface carries the brush-border hydrolases, the nutrient carriers and the ion exchangers, so losing it removes absorptive capacity across the board rather than for any one substrate or ion. This is why conforming disorders cannot be treated by eliminating a dietary constituent or by replacing an ion - there is no single missing step to bypass.
Downstream
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Abnormal Villus Architecture
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Feeding-Independent Intractable Diarrhea
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"MVID is characterized by lack of microvilli on the surface of enterocytes and occurrence of intracellular vacuolar structures containing microvilli."
Documents the trafficking arm's version of this node: the apical surface is absent and its microvilli are internalized.
"The tufts are composed of disorganized enterocytes with focal crowding at villous tips and basement membrane abnormalities resulting in teardrop-like configurations."
Documents the adhesion arm's version of this node: the sheet itself becomes disorganized and dysplastic rather than the apical membrane being absent.
"The combined effect of decreased glucose transporters and disaccharidase expression result in compromised caloric uptake in this disease, which may contribute to weight loss and failure to thrive"
Supports the claim that losing the polarized surface removes several classes of absorptive machinery at once - transporters and disaccharidases together - rather than one substrate-specific step.
Abnormal Villus Architecture
effector
The histological signature of the class and its diagnostic discriminator. Unlike the digestive, absorptive and electrolyte-transport CODEs, where the villus-to-crypt ratio is normal, the enterocyte-structural disorders produce an abnormal ratio and abnormal morphology - villous atrophy in both arms, with crypt hyperplasia and focal tufts in the adhesion arm and subapical periodic-acid-Schiff-positive granules with intracytoplasmic microvillus inclusions in the trafficking arm. This node is what a biopsy-first diagnostic pathway detects, and it is the single feature that assigns a congenital diarrhea to this module rather than to either sibling.
Downstream
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Intestinal Failure and Parenteral Nutrition Dependence
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"Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt..."
States the discriminator this node encodes: enterocyte-structural defects give an abnormal villus-to-crypt ratio while the digestive, absorptive and electrolyte-transport defects give a normal one. Evidence source is OTHER because this is a review proposing the current CODE classification.
"CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely packed enterocytes."
Gives the adhesion arm's histology and confirms that diagnosis in this class rests on the mucosal architecture this node describes.
Feeding-Independent Intractable Diarrhea
effector
The functional output. Profuse watery diarrhea begins in the neonatal period and, critically, continues whether the infant is fed or fasted, because the lesion is in the absorptive surface itself rather than in the handling of anything ingested. This is the property that rules out the two non-structural CODE classes at the bedside: no dietary elimination abolishes it, no enzyme replacement bypasses it, and no ion substitution reduces stool volume. In the adhesion arm the loss of tight junctions adds a secretory component and the loss of glucose transporters and disaccharidases an osmotic one, so the diarrhea is mixed rather than cleanly of either type.
Downstream
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Intestinal Failure and Parenteral Nutrition Dependence
Show evidence (2 references)
"Watery diarrhea is abundant in CTE patients irrespective of whether the infant is fed or fasted"
States the feeding independence that defines this node and separates the class from the substrate-dependent diet-induced congenital diarrheas.
"Alteration in expression and localization of ion transporters and tight junction proteins explains the secretory nature of diarrhea found in CTE, whereas changes in glucose transporters explain osmotic diarrhea seen in these patients"
Supports the mixed secretory-plus-osmotic character of the diarrhea in this class, both components being downstream of the lost polarized surface rather than primary.
Intestinal Failure and Parenteral Nutrition Dependence
consequence
The clinical output, and the most severe of the three epithelial CODE classes. Because absorptive capacity is structurally absent, enteral feeding cannot sustain the child and parenteral nutrition is required from the neonatal period. The natural history is then dominated by the complications of that dependence - intestinal-failure-associated liver disease, catheter-related sepsis, growth failure, renal impairment and metabolic bone disease. Most patients never achieve enteral autonomy, and small-bowel transplantation, which replaces the epithelium with genotypically normal donor tissue, is the only definitive treatment. Severity is nonetheless heterogeneous within the class, and in the adhesion arm some patients improve substantially over time, so transplantation is not automatically first-line.
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"All of the patients completely depended on PN."
Documents universal parenteral-nutrition dependence in a 24-patient microvillus inclusion disease cohort, the trafficking arm's version of this node.
"Moreover, most patients never achieve enteral autonomy"
Documents the same outcome in the adhesion arm, supporting the claim that failure to achieve enteral autonomy characterises the class rather than one disorder.
"SBTx, despite being complicated, remains the only hope to improve the quality of life and long-term prognosis of these children."
Supports transplantation as the only definitive treatment for this node, which is what distinguishes the prognosis of this class from the dietarily and pharmacologically manageable sibling classes.
Parenteral Nutrition
Platform:
Other
The shared supportive mainstay of the class. Because the absorptive surface is structurally absent, nutrition must bypass the intestine entirely. It is not disease-modifying: it sustains the child while the polarity defect persists, and it carries substantial morbidity of its own. Its necessity here, as opposed to the dietary and ion-replacement strategies that work in the sibling classes, is a direct consequence of there being no single missing step to eliminate, replace or bypass.
Small-Bowel Transplantation
Platform:
Surgery
The only definitive treatment in this class, and the one that acts on the central effector rather than compensating for it: donor intestine carries genotypically normal epithelium that can build and hold a polarized apical surface. It is the therapeutic signature of the class - neither sibling module has a curative intervention of this kind, because in those classes the epithelium is intact and a single step can be replaced or avoided instead.