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
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
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
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
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
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.