Paediatric Congenital Enteropathies: Clinical and Histological Review
Abstract
:1. Introduction
2. Intestinal Epithelial Structure and Function
3. Congenital Disorders Involving Epithelial Structure, Trafficking, Polarity, and Enteroendocrine Function
3.1. Microvillus Inclusion Disease
3.2. Congenital Tufting Enteropathy
3.3. IDEDNIK Syndrome
3.4. Enteroendocrine Cell Dysgenesis
3.5. Tricho-Hepato-Enteric Syndrome
4. Disorders of Immunomodulation
5. Very Early Onset Inflammatory Bowel Disease
- (1)
- A CD-like pattern characterized in the small bowel by irregular villus morphology, irregular inflammatory infiltrate, crypt hyperplasia, focal cryptitis, granulomas, lymphoid hyperplasia, and aphthous lesions over lymphoid aggregates. In the colon, it presents with a discontinuous and transmural mixed inflammatory infiltrate, deep ulceration of the mucosa, and crypt abscess formation and granulomas.
- (2)
- A UC-like pattern characterized by a continuous marked mixed inflammatory infiltrate, moderate-to-severe architectural gland atrophy/distortion, Paneth cell metaplasia, muco-depletion, foci of cryptitis, pseudo-abscesses, ulcerations, and focal detachment of superficial epithelium.
- (3)
- An enterocolitis-like pattern characterized in the small bowel by widespread villus atrophy and by a preserved glandular architecture, extensive detachment of superficial colonic epithelium, widespread lymphocytic and eosinophilic infiltrate, exudate and mucosal friability, oedema, and ischemic ulcers. Cytomegalovirus superinfection may also occur in UC and CD.
- (4)
- An apoptotic pattern characterized by scattered glands and severe glandular atrophy, increased mononuclear cells within the lamina propria, apoptotic cell death, extensive apoptosis, gland dropout, and “exploding crypts”.
6. Therapeutic Outlook
- (1)
- Nutritional strategies: exclusion of specific nutrients from the diet (e.g., in glucose-galactose malabsorption); electrolytes support (e.g., in congenital chloride diarrhoea); and low-fat diet, medium-chain triglycerides supplementation, high protein intake, vitamins, and electrolyte supplements in diseases associated with protein-losing enteropathy.
- (2)
- Non-nutritional strategies: hematopoietic stem cell transplantation, intestinal transplantation, steroids, immunosuppressants, and biologics can be employed in the defects of intestinal homeostasis according to the specific aetiology.
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADAM17 | A disintegrin and metalloprotease 17 |
AIE | Autoimmune enteropathy |
AIRE | Autoimmune Regulator |
AP1SP1 | Adaptor Related Protein Complex 1 Subunit Sigma 1 |
APECED | Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy syndrome |
APS-1 | autoimmune polyglandular syndrome type-1 |
CD | Crohn’s Disease |
CD25 | cluster of differentiation 25 |
CTE | Congenital Tufting Enteropathy |
CTLA-4 | cytotoxic T-lymphocyte-associated protein 4 |
EED | Enteroendocrine Cell Dysgenesis |
EM | Electron Microscopy |
EpCAM | Epithelial Cell Adhesion Molecule |
H&E | Haematoxylin and Eosin |
IDEDNIK | Intellectual disability, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia |
IELs | Intraepithelial Lymphocytes |
IPEX | Immune Dysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome |
ITCHY | Itchy E3 Ubiquitin Protein Ligase |
LRBA | Lipopolysaccharide-Responsive and Beige-like Anchor protein |
MEDNIK | Mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia |
MVID | Microvillus Inclusion Disease |
MYO5B | Myosin-Vb |
NEMO | Nuclear factor-kappa B Essential Modulator |
NEUROG3 | Neurogenin 3 |
PAS | Periodic Acid-Shiff |
PCEs | Paediatric Congenital Enteropathies |
PCSK1 | Proprotein Convertase Subtilisin/Kexin Type 1 |
PERCC1 | Proline and Glutamate Rich with Coiled Coil 1 (PERCC1) |
PN | Parenteral Nutrition |
SKIC2 | SKI2 subunit of the superkiller complex |
SKIC3 | SKI3 subunit of the superkiller complex |
SKIV2L | SKI2-like RNA helicase |
SPINT2 | Serine Peptidase Inhibitor Kunitz Type 2 |
STX3 | syntaxin 3 |
STAT5b | signal transducer and activator of transcription 5b |
STXBP2 | syntaxin-binding protein 2 |
THES | Tricho-hepato-enteric Syndrome |
TTC37 | tetratricopeptide repeat domain-containing protein 37 |
UC | Ulcerative Colitis |
UNCA-45 | unc-45 myosin chaperone A |
VEO-IBD | Very Early Onset Inflammatory Bowel Disease |
ZO-1 | Zonula occludens-1 |
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Condition | Mutation | Mechanism | Histopathology | Other Clinical Features |
---|---|---|---|---|
IPEX | FOXP3 | Impaired Treg | Villus atrophy, enteropathy | Endocrinopathies, dermatitis |
APECED/ APS-1 | AIRE | Impaired central tolerance | Villus blunting, absence of enteroendocrine cells | Candidiasis, endocrine dysfunction |
IPEX-LIKE Disorders | ||||
CD25 deficiency | IL2Rα | Impaired Treg functions | Villus atrophy | Recurrent infections |
STAT 5b deficiency | STAT5b | Impaired Treg functions | Villus atrophy | Growth failure, immunodeficiency, pulmonary disease |
CTLA-4 haploinsufficiency | CTLA-4 | Abnormal Treg function | Villus atrophy, ALPS-like proliferation | Recurrent infections, cytopenia |
ITCH mutation | ITCH | Abnormal T cell activity | IBD-like | Dysmorphism, short stature, pulmonary disease |
LRBA deficiency | LRBA | Abnormal function of CTLA-4 | Villus atrophy, IELs | Recurrent infections, lymphoproliferative disorders |
Criteria | Grade |
---|---|
Villus atrophy | normal/partial villus atrophy, subtotal total atrophy |
Goblet cells | present, reduced, absent |
Inflammatory infiltration | absent-mild-moderate-severe, IELs evaluated with CD3 |
Type of inflammatory cells | lymphocytes, plasma cells, neutrophils, eosinophils |
Glandular pathological features | cryptitis, crypt abscesses, necrosis, apoptosis |
Crypt epithelial apoptosis | >1/10 crypts |
Disease Type | Main Clinical Features | Diagnosis | Therapeutics | |
---|---|---|---|---|
Histopathology | Genetics | |||
Microvillus inclusion disease | intractable secretory diarrhoea
| severe villus atrophy EM microvillous inclusion | MYO5B STXBP2 STX3 UNC45A | PN; bowel transplantation; enteral feeding plus PN (1/2 per week) in late-onset form |
Congenital Tufting enteropathy | intractable secretory diarrhoea
| villus atrophy tufting appearance EM evidence of tufts; altered desmosomes | EpCAM SPINT2 | PN combined with a semi-elemental diet, if tolerated |
IDEDNIK Syndrome | intellectual disability, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia | mild/subtotal villus atrophy | AP1S1 | oral zinc acetate or oral zinc sulfato therapy; dietary modifications, feeding therapy, and parenteral supplementation; hearing aids; neurological treatment; supportive therapies |
Enteroendocrine cell dysgenesis | malabsorption and severe diarrhoea | absence of intestinal EEC (chromogranin negative) EM normal brush border | NEUROG3; ARX; PCSK1; RFX6 PERCC1 | PN and minimal enteral feeding, if tolerated |
Trichohepatoenteric syndrome (Phenotypic or Syndromic Diarrhoea) | chronic diarrhoea starting in the first 6 months of life, facial dysmorphism, and hair abnormalities | mild and subtotal villus atrophy | TTC37 SKIV2L | PN combined with a semi-elemental diet, if tolerated |
Autoimmune enteropathy | severe and prolonged diarrhoea, weight loss due to malabsorption, and extra-GI autoimmune disease | villous blunting; crypt hyperplasia; IELs; crypt apoptosis; absence of Paneth cells IF | FOXP3; AIRE; IL2Rα; STAT5b; CTLA-4; ITCH LRBA | immunosuppressive and immunomodulatory drugs combined with supportive PN and EN, if necessary |
Very early onset inflammatory bowel disease | GI and extra-GI symptoms | CD-like pattern; UC-like pattern; Enterocolitis-like pattern; apoptotic pattern | Multiple genes (Figure 6) | immunosuppressive and immunomodulatory drugs combined with supportive EN or, in some selected cases, EEN targeted pharmacologic agents and other therapies, such as hematopoietic stem cell transplantation, in selected cases |
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Arienzo, F.; Giovannoni, I.; Diamanti, A.; Trovato, C.M.; De Angelis, P.; Imondi, C.; Alaggio, R.; Francalanci, P. Paediatric Congenital Enteropathies: Clinical and Histological Review. Diagnostics 2025, 15, 946. https://doi.org/10.3390/diagnostics15080946
Arienzo F, Giovannoni I, Diamanti A, Trovato CM, De Angelis P, Imondi C, Alaggio R, Francalanci P. Paediatric Congenital Enteropathies: Clinical and Histological Review. Diagnostics. 2025; 15(8):946. https://doi.org/10.3390/diagnostics15080946
Chicago/Turabian StyleArienzo, Francesca, Isabella Giovannoni, Antonella Diamanti, Chiara Maria Trovato, Paola De Angelis, Chiara Imondi, Rita Alaggio, and Paola Francalanci. 2025. "Paediatric Congenital Enteropathies: Clinical and Histological Review" Diagnostics 15, no. 8: 946. https://doi.org/10.3390/diagnostics15080946
APA StyleArienzo, F., Giovannoni, I., Diamanti, A., Trovato, C. M., De Angelis, P., Imondi, C., Alaggio, R., & Francalanci, P. (2025). Paediatric Congenital Enteropathies: Clinical and Histological Review. Diagnostics, 15(8), 946. https://doi.org/10.3390/diagnostics15080946