Congenital Tufting Enteropathy

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Inheritance

1

Autosomal recessive inheritance HP:0000007

CTE is inherited in an autosomal recessive manner. Affected individuals are homozygous or compound heterozygous; parents are unaffected carriers, and consanguinity is common in reported families.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Analysis of the family history of CTE patients reveals that, as expected, siblings or cousins of CTE patients may be affected though parents/ancestors of the patients are often unaffected with no similar family history"

Describes the sibling-recurrence-with-unaffected-parents pattern characteristic of recessive inheritance. Evidence source is OTHER because this is a review.

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Subtypes

2

EPCAM-associated tufting enteropathy (non-syndromic)

EPCAM hgnc:11529

The commoner form, accounting for about three-quarters of reported cases. Intestinal disease predominates; extraintestinal features, when present, are more often arthritis and other systemic manifestations.

SPINT2-associated syndromic tufting enteropathy

SPINT2 hgnc:11247

About a quarter of reported cases. Intestinal pathology is indistinguishable from the EPCAM form, but extraintestinal features are prominent - ophthalmological disease (punctate keratitis, corneal erosion, cataract) and atresias (anal, intestinal, choanal). Mechanistically it converges on EpCAM loss via unrestrained matriptase activity.

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Pathophysiology

5

Loss of Functional EpCAM at the Epithelial Cell Surface

The initiating lesion. EpCAM is a transmembrane glycoprotein localized to the tight junctions, adherens junctions and lateral membrane of intestinal epithelial cells. Biallelic EPCAM variants reduce its abundance or mislocalize it, and the syndromic SPINT2 form reaches the same endpoint indirectly: without HAI-2 to restrain matriptase, EpCAM is proteolytically depleted. The node is therefore defined by loss of functional EpCAM at the cell surface, not by the identity of the mutated gene - which is why the two genotypes produce indistinguishable intestinal histology.

Intestinal epithelial cell CL:0002563

Homotypic cell-cell adhesion GO:0034109 ↓ DECREASED

Small intestine UBERON:0002108

Downstream

Apical Junctional Complex Disassembly and Barrier Failure

Show evidence (1 reference)

PMID:18572020 SUPPORT Human Clinical

"Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM."

Demonstrates reduced EpCAM protein in patient intestinal tissue, the protein-level lesion defining this node.

Apical Junctional Complex Disassembly and Barrier Failure

The rate-limiting step. EpCAM's transmembrane and intracellular regions recruit claudin-7 to the tight junction, so loss of EpCAM substantially reduces claudin-7 at the junction and prevents normal tight-junction formation. Other claudins (2, 3, 15) and the tight-junction proteins ZO-1 and occludin are also reduced. Because adherens junctions govern tight-junction assembly, the whole apical junctional complex is destabilised, and with it epithelial barrier function and the apical-basal polarity that the complex maintains. Claudin-15 loss is of particular functional consequence: it mediates paracellular sodium permeability, whose failure impairs the sodium-coupled glucose absorption that normally drives fluid uptake.

Intestinal epithelial cell CL:0002563

Tight junction assembly GO:0120192 ↓ DECREASED

Tight junction GO:0070160

Downstream

Epithelial Dysplasia and Focal Tuft Formation

Loss of Absorptive and Ion-Transport Function

Show evidence (2 references)

PMID:33374714 SUPPORT Other

"In CTE, the absence of EpCAM substantially reduces the recruitment of claudin-7 to TJs, leading to loss of TJ formation."

States the mechanism of this node directly: EpCAM loss removes claudin-7 from the tight junction and tight-junction formation fails. Evidence source is OTHER because this is a review.

PMID:33374714 SUPPORT Model Organism

"Another study using mutant EpCAM mice, based on a CTE patient mutation, demonstrated growth retardation and CTE-like pathology, including impaired barrier function and decreases in the tight junction proteins zonula occludins-1 (ZO-1) and occludin"

Model-organism evidence that a patient-derived EpCAM mutation is sufficient to impair barrier function and reduce tight-junction proteins in vivo.

Epithelial Dysplasia and Focal Tuft Formation

The morphological signature that names the disease. Loss of EpCAM-dependent adhesion at bicellular junctions shifts the mechanical balance of the epithelium: myosin IIa/IIb accumulates at tricellular junctions, which become hypercontractile, while the apical domain of individual cells expands abnormally. The result is focal crowding of disorganised enterocytes at the villus tips forming teardrop-shaped "tufts", on a background of partial or total villous atrophy and crypt hyperplasia, characteristically without inflammatory infiltration. Basement-membrane abnormalities (increased heparan sulfate proteoglycan and collagen IV, decreased laminin) and abnormal alpha-2-beta-1 integrin distribution accompany the dysplasia.

Small-intestinal enterocyte CL:0000584

Small intestine UBERON:0002108

Downstream

Intractable Diarrhea and Intestinal Failure

Show evidence (2 references)

PMID:33374714 SUPPORT Other

"The loss of EpCAM-dependent cell-cell adhesion at bicellular junctions in CTE leads to tricellular junction hypercontractility due to accumulation of myosin IIa/IIb."

Gives the mechanical mechanism by which adhesion loss produces the tuft lesion, linking this node to its upstream junctional cause.

PMID:33374714 SUPPORT Other

"The tufts are composed of disorganized enterocytes with focal crowding at villous tips and basement membrane abnormalities resulting in teardrop-like configurations."

Describes the histological appearance of the tuft lesion that defines this node.

Loss of Absorptive and Ion-Transport Function

The functional arm, running in parallel with the morphological one and explaining why the diarrhea of CTE has both a secretory and an osmotic component. Ion transporters are differentially affected - NKCC1 is mislocalized and reduced while CFTR is unchanged, and NHE3 is affected in murine models - which together with tight-junction loss accounts for the secretory component. Separately, the glucose transporters SGLT1 and GLUT2 and the brush-border glycoside hydrolases (maltase, sucrase, lactase) are disrupted, which accounts for the osmotic component and for the compromised caloric uptake driving weight loss. This dual mechanism is why enteral feeding worsens CTE and why parenteral nutrition is usually the only reliable route.

Small-intestinal enterocyte CL:0000584

Intestinal absorption GO:0050892 ↓ DECREASED

Downstream

Intractable Diarrhea and Intestinal Failure

Show evidence (2 references)

PMID:33374714 SUPPORT Other

"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"

States the dual secretory-plus-osmotic mechanism this node models and attributes each component to a distinct transporter defect.

PMID:33374714 SUPPORT Other

"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"

Links the transporter and disaccharidase defects to the nutritional consequences, connecting this node to the downstream clinical outcome.

Intractable Diarrhea and Intestinal Failure

The clinical output. Profuse watery diarrhea, present whether the infant is fed or fasted, produces electrolyte imbalance, dehydration, weight loss and impaired growth, progressing to intestinal failure that requires parenteral nutrition and in some cases intestinal transplantation. Severity is heterogeneous - some patients need total parenteral nutrition while others need little parenteral support, and some improve substantially over time - but most never achieve enteral autonomy.

Small intestine UBERON:0002108

Show evidence (2 references)

PMID:33374714 SUPPORT Other

"Congenital tufting enteropathy (CTE) is an autosomal recessive disease of infancy that causes severe intestinal failure with electrolyte imbalances and impaired growth."

States the clinical output of the chain - intestinal failure with electrolyte imbalance and impaired growth.

PMID:33374714 SUPPORT Other

"Moreover, most patients never achieve enteral autonomy"

Documents the long-term dependence on parenteral support that characterises the outcome.

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Pathograph

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Phenotypes

5

Digestive 1

Intractable Watery Diarrhea OBLIGATE HP:0002014

Temporal: CHRONIC

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Watery diarrhea is abundant in CTE patients irrespective of whether the infant is fed or fasted"

Documents the feeding-independent diarrhea that distinguishes CTE from the substrate-dependent diet-induced congenital diarrheas.

Musculoskeletal 1

Arthritis HP:0001369

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Arthritis is more common in patients with EPCAM mutations who have extra-intestinal manifestations"

Supports the genotype association of arthritis with EPCAM variants. No frequency band is adopted, for the same reason as the ophthalmological phenotype above: the source is comparative ("more common"), not quantitative, and is measured over reported CTE patients as a whole.

Growth 1

Failure to Thrive HP:0001508

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Nutrient malabsorption and intractable diarrhea lead infants to become irritable and develop dehydration as well as weight loss"

Attributes the weight loss and dehydration to malabsorption and diarrhea.

Other 2

Villous Atrophy with Epithelial Tufts VERY_FREQUENT HP:0011473

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely packed enterocytes."

Describes the diagnostic triad of villous atrophy, crypt hyperplasia and epithelial tufts.

Punctate Keratitis HP:0011859

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"ophthalmological symptoms and atresia are more common in patients with SPINT2 mutations"

Supports the genotype association of ophthalmological features with SPINT2 rather than EPCAM variants. No frequency band is adopted: the source states only that these features are "more common" with SPINT2 variants, a comparative claim measured over reported CTE patients as a whole with no figure for either genotype, so it cannot support a quantitative band on this subtype-scoped record.

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Genetic Associations

2

EPCAM loss-of-function variants (Causative)

Gene: EPCAM hgnc:11529 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:18572020 SUPPORT Human Clinical

"Mutations in the gene for EpCAM are responsible for CTE."

The gene-discovery report establishing EPCAM as the cause of congenital tufting enteropathy.

PMID:18572020 SUPPORT Human Clinical

"Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients."

Specifies the original causative variant and its homozygous state, supporting the recessive coding-level lesion described in this block.

SPINT2 variants (syndromic form) (Causative)

Gene: SPINT2 hgnc:11247 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:33374714 SUPPORT Other

"Mutant HAI-2 results in the decrease/loss of EpCAM through matriptase activity"

States the mechanistic convergence of the SPINT2 form onto EpCAM loss via unrestrained matriptase activity. Evidence source is OTHER because this is a review summarising model-system studies.

PMID:33374714 SUPPORT Other

"a recent review suggests 74% of those reported have mutations in EPCAM, while 26% have mutations in SPINT2"

Quantifies the relative contribution of the two loci to reported CTE cases.

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Medical Actions

2

Parenteral Nutrition

Action: Total Parenteral Nutrition NCIT:C29484

Parenteral nutrition is the mainstay of supportive care, required because enteral feeding worsens the diarrhea and the epithelium cannot absorb adequately. The degree of dependence varies: some patients require total parenteral nutrition indefinitely while others need only limited parenteral support. It carries the usual burden of long-term intravenous nutrition - liver disease, infection and vascular complications.

Mechanism Target:

BYPASSES Loss of Absorptive and Ion-Transport Function — Intravenous nutrition bypasses the failed absorptive epithelium; it does not act on EpCAM loss or restore junctional integrity.

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"These findings provide a rationale as to why parenteral nutrition is often the only reliable source of nutrients in these patients and the clinical observation that enteral feeding has been shown to worsen CTE"

Explains why parenteral nutrition is required and ties that requirement to the absorptive and disaccharidase defects of this node.

Intestinal Transplantation

Action: Small Bowel Transplantation NCIT:C157985

Small-bowel transplantation is the only accepted cure, but is not a first-line treatment: the natural history is variable and some patients improve substantially over time, so the decision must weigh transplant morbidity against that possibility.

Mechanism Target:

RESTORES Loss of Absorptive and Ion-Transport Function — Donor intestine carrying functional EPCAM restores an intact epithelium with normal junctions and absorptive capacity.

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Although small bowel transplantation is the only accepted cure for CTE to date, transplantation should not be the first line of treatment given the varied natural history of the disease, with some patients showing significant improvement over time."

States both that transplantation is the only cure and the clinical caveat against using it first-line.

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Diagnosis

2

Duodenal biopsy with histology

Esophagogastroduodenoscopy with duodenal biopsy is the diagnostic mainstay, showing villous atrophy, crypt hyperplasia and focal epithelial tufts. EpCAM immunohistochemistry showing reduced or mislocalized protein supports the diagnosis.

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"CTE is generally diagnosed by esophagogastroduodenoscopy, noting duodenal histological abnormalities."

States the diagnostic procedure and the tissue on which the diagnosis rests.

EPCAM and SPINT2 sequencing

Molecular confirmation by sequencing EPCAM and SPINT2. With broader access to genomic testing, patients may now be identified genetically before mucosal findings are available.

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"Given the recent advancement in genetic technologies and improved access to whole-genome testing, patients may be identified by genetics even prior to the identification of mucosal findings."

Supports genomic testing as an increasingly primary diagnostic route.

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Prevalence

1

Western Europe

Birth Prevalence 1.0–2.0 per 100,000 1–9 per 100,000

Reported incidence of 1/50,000-100,000 live births in western Europe, i.e. 1-2 per 100,000 births; higher in the Middle East. Recorded here as a birth prevalence because the source reports incidence per live birth.

Show evidence (1 reference)

PMID:33374714 SUPPORT Other

"with an incidence estimated at 1/50,000-100,000 live births in western Europe"

Source for the western European birth-incidence estimate.

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Source YAML

click to show

name: Congenital Tufting Enteropathy
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
synonyms:
- CTE
- intestinal epithelial dysplasia
- congenital diarrhea 5 with tufting enteropathy
- familial enteropathy
description: >-
  Congenital tufting enteropathy (CTE) is a rare autosomal recessive congenital
  enteropathy of infancy and, with microvillus inclusion disease, one of the two
  prototypes of the "defective enterocyte trafficking and polarity" class of
  congenital diarrheas and enteropathies (CODEs). Biallelic variants in EPCAM,
  encoding the epithelial cell adhesion molecule, account for roughly
  three-quarters of reported cases; variants in SPINT2, encoding the serine
  protease inhibitor HAI-2, cause a syndromic form and act through the same final
  pathway, since loss of functional HAI-2 permits unrestrained matriptase
  activity that in turn destroys EpCAM. EpCAM is required to recruit claudin-7
  to the tight junction, so its loss disassembles the apical junctional complex,
  degrades barrier function and disorganises epithelial polarity. The
  histological signature is focal crowding of disorganised enterocytes at the
  villus tips - the "tufts" - on a background of villous atrophy and crypt
  hyperplasia without an inflammatory infiltrate. Affected infants have profuse
  watery diarrhea with both secretory and osmotic components, electrolyte
  disturbance and impaired growth, leading to intestinal failure and dependence
  on parenteral nutrition; most never achieve enteral autonomy. Extraintestinal
  features segregate with genotype: arthritis and other systemic features are
  more common with EPCAM variants, whereas ophthalmological disease (punctate
  keratitis, corneal erosions, cataract) and atresias (anal, intestinal,
  choanal) are more common with SPINT2 variants.
disease_term:
  preferred_term: congenital tufting enteropathy
  term:
    id: MONDO:0013184
    label: congenital diarrhea 5 with tufting enteropathy
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    CTE is inherited in an autosomal recessive manner. Affected individuals are
    homozygous or compound heterozygous; parents are unaffected carriers, and
    consanguinity is common in reported families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Analysis of the family history of CTE patients reveals that, as expected,
      siblings or cousins of CTE patients may be affected though
      parents/ancestors of the patients are often unaffected with no similar
      family history
    explanation: >-
      Describes the sibling-recurrence-with-unaffected-parents pattern
      characteristic of recessive inheritance. Evidence source is OTHER because
      this is a review.
genetic:
- name: EPCAM loss-of-function variants
  gene_term:
    preferred_term: EPCAM
    term:
      id: hgnc:11529
      label: EPCAM
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Biallelic EPCAM variants are the primary cause of CTE. Reported variants
    include deletions, splice-site changes, frameshifts, truncations and
    missense substitutions; the originally described variant was a homozygous
    donor-splice-site change in exon 4. Most produce a mutant or truncated EpCAM
    protein that is reduced in abundance and/or mislocalized rather than absent.
    Frameshift and truncating variants are associated with a more severe
    phenotype.
  evidence:
  - reference: PMID:18572020
    reference_title: "Identification of EpCAM as the gene for congenital tufting enteropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the gene for EpCAM are responsible for CTE.
    explanation: >-
      The gene-discovery report establishing EPCAM as the cause of congenital
      tufting enteropathy.
  - reference: PMID:18572020
    reference_title: "Identification of EpCAM as the gene for congenital tufting enteropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Direct sequencing of genes in this region revealed homozygous G>A
      substitution at the donor splice site of exon 4 in epithelial cell adhesion
      molecule (EpCAM) of affected patients.
    explanation: >-
      Specifies the original causative variant and its homozygous state,
      supporting the recessive coding-level lesion described in this block.
- name: SPINT2 variants (syndromic form)
  gene_term:
    preferred_term: SPINT2
    term:
      id: hgnc:11247
      label: SPINT2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    SPINT2 encodes HAI-2, an inhibitor of the membrane serine protease
    matriptase. Biallelic SPINT2 variants cause a syndromic form of CTE with
    intestinal pathology indistinguishable from the EPCAM form plus
    extraintestinal features. Mechanistically this is not a parallel disease but
    the same pathway entered one step upstream: loss of HAI-2 inhibition allows
    matriptase to cleave and deplete EpCAM, so the SPINT2 form converges on
    EpCAM loss.
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutant HAI-2 results in the decrease/loss of EpCAM through matriptase
      activity
    explanation: >-
      States the mechanistic convergence of the SPINT2 form onto EpCAM loss via
      unrestrained matriptase activity. Evidence source is OTHER because this is
      a review summarising model-system studies.
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a recent review suggests 74% of those reported have mutations in EPCAM,
      while 26% have mutations in SPINT2
    explanation: >-
      Quantifies the relative contribution of the two loci to reported CTE cases.
  case_fractions:
  - population: Reported CTE cases in the literature
    case_fraction_percent: 26.0
    notes: >-
      SPINT2 share of reported CTE cases; the complementary 74% carry EPCAM
      variants.
    evidence:
    - reference: PMID:33374714
      reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        a recent review suggests 74% of those reported have mutations in EPCAM,
        while 26% have mutations in SPINT2
      explanation: >-
        Source for the per-gene case fractions among reported CTE patients.
pathophysiology:
- name: Loss of Functional EpCAM at the Epithelial Cell Surface
  conforms_to: "enterocyte_polarity_trafficking_failure#Loss of Junctional Adhesion Machinery"
  description: >-
    The initiating lesion. EpCAM is a transmembrane glycoprotein localized to the
    tight junctions, adherens junctions and lateral membrane of intestinal
    epithelial cells. Biallelic EPCAM variants reduce its abundance or mislocalize
    it, and the syndromic SPINT2 form reaches the same endpoint indirectly:
    without HAI-2 to restrain matriptase, EpCAM is proteolytically depleted. The
    node is therefore defined by loss of functional EpCAM at the cell surface,
    not by the identity of the mutated gene - which is why the two genotypes
    produce indistinguishable intestinal histology.
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: Homotypic cell-cell adhesion
    term:
      id: GO:0034109
      label: homotypic cell-cell adhesion
    modifier: DECREASED
  locations:
  - preferred_term: Small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:18572020
    reference_title: "Identification of EpCAM as the gene for congenital tufting enteropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry and Western blot of patient intestinal tissue revealed
      decreased expression of EpCAM.
    explanation: >-
      Demonstrates reduced EpCAM protein in patient intestinal tissue, the
      protein-level lesion defining this node.
  downstream:
  - target: Apical Junctional Complex Disassembly and Barrier Failure
    causal_link_type: DIRECT
- name: Apical Junctional Complex Disassembly and Barrier Failure
  conforms_to: "enterocyte_polarity_trafficking_failure#Loss of a Functionally Polarized Absorptive Epithelial Surface"
  description: >-
    The rate-limiting step. EpCAM's transmembrane and intracellular regions
    recruit claudin-7 to the tight junction, so loss of EpCAM substantially
    reduces claudin-7 at the junction and prevents normal tight-junction
    formation. Other claudins (2, 3, 15) and the tight-junction proteins ZO-1 and
    occludin are also reduced. Because adherens junctions govern tight-junction
    assembly, the whole apical junctional complex is destabilised, and with it
    epithelial barrier function and the apical-basal polarity that the complex
    maintains. Claudin-15 loss is of particular functional consequence: it
    mediates paracellular sodium permeability, whose failure impairs the
    sodium-coupled glucose absorption that normally drives fluid uptake.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: Tight junction assembly
    term:
      id: GO:0120192
      label: tight junction assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: Tight junction
    term:
      id: GO:0070160
      label: tight junction
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In CTE, the absence of EpCAM substantially reduces the recruitment of
      claudin-7 to TJs, leading to loss of TJ formation.
    explanation: >-
      States the mechanism of this node directly: EpCAM loss removes claudin-7
      from the tight junction and tight-junction formation fails. Evidence source
      is OTHER because this is a review.
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Another study using mutant EpCAM mice, based on a CTE patient mutation,
      demonstrated growth retardation and CTE-like pathology, including impaired
      barrier function and decreases in the tight junction proteins zonula
      occludins-1 (ZO-1) and occludin
    explanation: >-
      Model-organism evidence that a patient-derived EpCAM mutation is sufficient
      to impair barrier function and reduce tight-junction proteins in vivo.
  downstream:
  - target: Epithelial Dysplasia and Focal Tuft Formation
    causal_link_type: DIRECT
  - target: Loss of Absorptive and Ion-Transport Function
    causal_link_type: DIRECT
- name: Epithelial Dysplasia and Focal Tuft Formation
  conforms_to: "enterocyte_polarity_trafficking_failure#Abnormal Villus Architecture"
  description: >-
    The morphological signature that names the disease. Loss of EpCAM-dependent
    adhesion at bicellular junctions shifts the mechanical balance of the
    epithelium: myosin IIa/IIb accumulates at tricellular junctions, which become
    hypercontractile, while the apical domain of individual cells expands
    abnormally. The result is focal crowding of disorganised enterocytes at the
    villus tips forming teardrop-shaped "tufts", on a background of partial or
    total villous atrophy and crypt hyperplasia, characteristically without
    inflammatory infiltration. Basement-membrane abnormalities (increased
    heparan sulfate proteoglycan and collagen IV, decreased laminin) and
    abnormal alpha-2-beta-1 integrin distribution accompany the dysplasia.
  role: effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Small-intestinal enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: Small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The loss of EpCAM-dependent cell-cell adhesion at bicellular junctions in
      CTE leads to tricellular junction hypercontractility due to accumulation of
      myosin IIa/IIb.
    explanation: >-
      Gives the mechanical mechanism by which adhesion loss produces the tuft
      lesion, linking this node to its upstream junctional cause.
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The tufts are composed of disorganized enterocytes with focal crowding at
      villous tips and basement membrane abnormalities resulting in teardrop-like
      configurations.
    explanation: >-
      Describes the histological appearance of the tuft lesion that defines this
      node.
  downstream:
  - target: Intractable Diarrhea and Intestinal Failure
    causal_link_type: DIRECT
- name: Loss of Absorptive and Ion-Transport Function
  conforms_to: "enterocyte_polarity_trafficking_failure#Loss of a Functionally Polarized Absorptive Epithelial Surface"
  description: >-
    The functional arm, running in parallel with the morphological one and
    explaining why the diarrhea of CTE has both a secretory and an osmotic
    component. Ion transporters are differentially affected - NKCC1 is
    mislocalized and reduced while CFTR is unchanged, and NHE3 is affected in
    murine models - which together with tight-junction loss accounts for the
    secretory component. Separately, the glucose transporters SGLT1 and GLUT2 and
    the brush-border glycoside hydrolases (maltase, sucrase, lactase) are
    disrupted, which accounts for the osmotic component and for the compromised
    caloric uptake driving weight loss. This dual mechanism is why enteral
    feeding worsens CTE and why parenteral nutrition is usually the only reliable
    route.
  role: effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Small-intestinal enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: Intestinal absorption
    term:
      id: GO:0050892
      label: intestinal absorption
    modifier: DECREASED
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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
    explanation: >-
      States the dual secretory-plus-osmotic mechanism this node models and
      attributes each component to a distinct transporter defect.
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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
    explanation: >-
      Links the transporter and disaccharidase defects to the nutritional
      consequences, connecting this node to the downstream clinical outcome.
  downstream:
  - target: Intractable Diarrhea and Intestinal Failure
    causal_link_type: DIRECT
- name: Intractable Diarrhea and Intestinal Failure
  conforms_to: "enterocyte_polarity_trafficking_failure#Intestinal Failure and Parenteral Nutrition Dependence"
  description: >-
    The clinical output. Profuse watery diarrhea, present whether the infant is
    fed or fasted, produces electrolyte imbalance, dehydration, weight loss and
    impaired growth, progressing to intestinal failure that requires parenteral
    nutrition and in some cases intestinal transplantation. Severity is
    heterogeneous - some patients need total parenteral nutrition while others
    need little parenteral support, and some improve substantially over time -
    but most never achieve enteral autonomy.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: Small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital tufting enteropathy (CTE) is an autosomal recessive disease of
      infancy that causes severe intestinal failure with electrolyte imbalances
      and impaired growth.
    explanation: >-
      States the clinical output of the chain - intestinal failure with
      electrolyte imbalance and impaired growth.
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Moreover, most patients never achieve enteral autonomy
    explanation: >-
      Documents the long-term dependence on parenteral support that characterises
      the outcome.
phenotypes:
- name: Intractable Watery Diarrhea
  category: Gastrointestinal
  description: >-
    Profuse watery diarrhea of early onset, with both secretory and osmotic
    components. It is present whether the infant is fed or fasted, though fasting
    improves stool output in some cases.
  phenotype_term:
    preferred_term: Intractable watery diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  frequency: OBLIGATE
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Watery diarrhea is abundant in CTE patients irrespective of whether the
      infant is fed or fasted
    explanation: >-
      Documents the feeding-independent diarrhea that distinguishes CTE from the
      substrate-dependent diet-induced congenital diarrheas.
- name: Villous Atrophy with Epithelial Tufts
  category: Histopathological
  description: >-
    Duodenal biopsy shows partial or total villous atrophy with crypt
    hyperplasia and the characteristic focal epithelial tufts of densely packed,
    disorganised enterocytes at the villus tips, typically without inflammatory
    infiltration.
  phenotype_term:
    preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CTE is typically diagnosed by its characteristic histological features,
      including villous atrophy, crypt hyperplasia and focal epithelial tufts
      consisting of densely packed enterocytes.
    explanation: >-
      Describes the diagnostic triad of villous atrophy, crypt hyperplasia and
      epithelial tufts.
- name: Failure to Thrive
  category: Growth
  description: >-
    Impaired growth from nutrient malabsorption and chronic fluid and electrolyte
    loss, present from infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nutrient malabsorption and intractable diarrhea lead infants to become
      irritable and develop dehydration as well as weight loss
    explanation: >-
      Attributes the weight loss and dehydration to malabsorption and diarrhea.
- name: Punctate Keratitis
  category: Ophthalmological
  description: >-
    Superficial punctate keratitis, corneal erosions and cataract occur in a
    subset of patients and are more common in the SPINT2-associated syndromic
    form than in the EPCAM form.
  phenotype_term:
    preferred_term: Punctate keratitis
    term:
      id: HP:0011859
      label: Punctate keratitis
  subtype: SPINT2 syndromic form
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ophthalmological symptoms and atresia are more common in patients with
      SPINT2 mutations
    explanation: >-
      Supports the genotype association of ophthalmological features with SPINT2
      rather than EPCAM variants. No frequency band is adopted: the source states
      only that these features are "more common" with SPINT2 variants, a
      comparative claim measured over reported CTE patients as a whole with no
      figure for either genotype, so it cannot support a quantitative band on
      this subtype-scoped record.
- name: Arthritis
  category: Musculoskeletal
  description: >-
    Chronic arthritis occurs as an extraintestinal manifestation, reported more
    often in patients with EPCAM variants who have extraintestinal features.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  subtype: EPCAM form
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Arthritis is more common in patients with EPCAM mutations who have
      extra-intestinal manifestations
    explanation: >-
      Supports the genotype association of arthritis with EPCAM variants. No
      frequency band is adopted, for the same reason as the ophthalmological
      phenotype above: the source is comparative ("more common"), not
      quantitative, and is measured over reported CTE patients as a whole.
has_subtypes:
- name: EPCAM form
  display_name: EPCAM-associated tufting enteropathy (non-syndromic)
  genes:
  - preferred_term: EPCAM
    term:
      id: hgnc:11529
      label: EPCAM
  review_notes: >-
    No subtype_term is bound. MONDO has no term for the EPCAM form distinct from
    the entry's own disease_term (MONDO:0013184, whose causal gene is EPCAM), so
    binding one would be circular. Per the project's term guidance, no term beats
    a bad one; the subtype is identified by its gene instead.
  description: >-
    The commoner form, accounting for about three-quarters of reported cases.
    Intestinal disease predominates; extraintestinal features, when present, are
    more often arthritis and other systemic manifestations.
- name: SPINT2 syndromic form
  display_name: SPINT2-associated syndromic tufting enteropathy
  genes:
  - preferred_term: SPINT2
    term:
      id: hgnc:11247
      label: SPINT2
  review_notes: >-
    No subtype_term is bound. MONDO's nearest term, MONDO:0034204 syndromic
    congenital sodium diarrhea, is a different disease that happens to share the
    SPINT2 gene and some extraintestinal features; binding it here would assert a
    false identity. Left unbound deliberately rather than forced.
  description: >-
    About a quarter of reported cases. Intestinal pathology is indistinguishable
    from the EPCAM form, but extraintestinal features are prominent -
    ophthalmological disease (punctate keratitis, corneal erosion, cataract) and
    atresias (anal, intestinal, choanal). Mechanistically it converges on EpCAM
    loss via unrestrained matriptase activity.
diagnosis:
- name: Duodenal biopsy with histology
  description: >-
    Esophagogastroduodenoscopy with duodenal biopsy is the diagnostic mainstay,
    showing villous atrophy, crypt hyperplasia and focal epithelial tufts. EpCAM
    immunohistochemistry showing reduced or mislocalized protein supports the
    diagnosis.
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CTE is generally diagnosed by esophagogastroduodenoscopy, noting duodenal
      histological abnormalities.
    explanation: >-
      States the diagnostic procedure and the tissue on which the diagnosis
      rests.
- name: EPCAM and SPINT2 sequencing
  description: >-
    Molecular confirmation by sequencing EPCAM and SPINT2. With broader access to
    genomic testing, patients may now be identified genetically before mucosal
    findings are available.
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Given the recent advancement in genetic technologies and improved access to
      whole-genome testing, patients may be identified by genetics even prior to
      the identification of mucosal findings.
    explanation: >-
      Supports genomic testing as an increasingly primary diagnostic route.
treatments:
- name: Parenteral Nutrition
  description: >-
    Parenteral nutrition is the mainstay of supportive care, required because
    enteral feeding worsens the diarrhea and the epithelium cannot absorb
    adequately. The degree of dependence varies: some patients require total
    parenteral nutrition indefinitely while others need only limited parenteral
    support. It carries the usual burden of long-term intravenous nutrition -
    liver disease, infection and vascular complications.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Total Parenteral Nutrition
    term:
      id: NCIT:C29484
      label: Total Parenteral Nutrition
  target_mechanisms:
  - target: Loss of Absorptive and Ion-Transport Function
    treatment_effect: BYPASSES
    description: >-
      Intravenous nutrition bypasses the failed absorptive epithelium; it does
      not act on EpCAM loss or restore junctional integrity.
    evidence:
    - reference: PMID:33374714
      reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These findings provide a rationale as to why parenteral nutrition is
        often the only reliable source of nutrients in these patients and the
        clinical observation that enteral feeding has been shown to worsen CTE
      explanation: >-
        Explains why parenteral nutrition is required and ties that requirement
        to the absorptive and disaccharidase defects of this node.
- name: Intestinal Transplantation
  description: >-
    Small-bowel transplantation is the only accepted cure, but is not a
    first-line treatment: the natural history is variable and some patients
    improve substantially over time, so the decision must weigh transplant
    morbidity against that possibility.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Small Bowel Transplantation
    term:
      id: NCIT:C157985
      label: Small Bowel Transplantation
  target_mechanisms:
  - target: Loss of Absorptive and Ion-Transport Function
    treatment_effect: RESTORES
    description: >-
      Donor intestine carrying functional EPCAM restores an intact epithelium
      with normal junctions and absorptive capacity.
    evidence:
    - reference: PMID:33374714
      reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Although small bowel transplantation is the only accepted cure for CTE to
        date, transplantation should not be the first line of treatment given the
        varied natural history of the disease, with some patients showing
        significant improvement over time.
      explanation: >-
        States both that transplantation is the only cure and the clinical
        caveat against using it first-line.
prevalence:
- population: Western Europe
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 2.0
  notes: >-
    Reported incidence of 1/50,000-100,000 live births in western Europe, i.e.
    1-2 per 100,000 births; higher in the Middle East. Recorded here as a birth
    prevalence because the source reports incidence per live birth.
  evidence:
  - reference: PMID:33374714
    reference_title: "Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with an incidence estimated at 1/50,000-100,000 live births in western
      Europe
    explanation: >-
      Source for the western European birth-incidence estimate.
notes: >-
  CTE belongs to the defective enterocyte trafficking and polarity class of
  congenital diarrheas and enteropathies, with microvillus inclusion disease, and
  is curated as a conformer of the enterocyte_polarity_trafficking_failure
  module. CTE enters that module through its junctional-adhesion arm (EpCAM
  loss), microvillus inclusion disease through its apical-trafficking arm
  (MYO5B/STX3); the two arms converge on loss of a functionally polarized
  absorptive surface but are molecularly distinct and histologically
  distinguishable, so each entry substitutes its own lesion. It
  deliberately does NOT conform to the diet_induced_osmotic_diarrhea module:
  although CTE has an osmotic component, the module requires a normal
  villus-to-crypt ratio and substrate-dependent diarrhea remitting on dietary
  withdrawal, whereas CTE has villous atrophy and diarrhea that persists when the
  infant is fasted. The osmotic component here is a downstream consequence of
  junctional and transporter loss, not a primary substrate-specific digestive
  defect. The prevalence figure is recorded with rate_low/rate_high because the
  source gives a range; the prevalence_class band is assigned from the upper end
  of the reported range.

Congenital Tufting Enteropathy

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