Congenital Diarrheal Disorders (CODEs)

(see comparison table below)

A. Background

Rare but serious: Uncommon but high morbidity and mortality
Genetic basis:
- Mostly autosomal recessive (AR)
- Some X-linked or autosomal dominant
Frequently misdiagnosed: Leads to prolonged hospitalizations and delayed treatment
Diagnostic challenge in infants: Diarrhea may resemble urine due to watery consistency
Economic and clinical burden: High cost of care and risk of complications
Timing is critical:
- Diarrhea typically begins within the first few days of life
- Later onset suggests infectious, allergic, or acquired causes

B. Diagnostic Approach

1. Imaging

Upper GI-small bowel follow-through: rule out malrotation, intermittent volvulus, and congenital SBS

2. Dietary Challenges

Characterize diarrhea:
- Secretory vs osmotic/malabsorptive vs mixed
- If malabsorptive: selective vs generalized
Stool analysis:
- Volume, pH, reducing substances, electrolytes (fasting vs feeding)
Caloric challenge: bolus preferred over continuous feeds
Nutrient-specific testing:
- Glucose vs fructose
- Simple vs complex carbohydrates
- Carbohydrates vs amino acids vs fats

3. Intestinal Biopsy

Histology:
- H&E staining: crypt/villus axis, inflammation (acute vs chronic), location (intraepithelial vs lamina propria)
Functional assays: disaccharidase activity, breath hydrogen testing
Special stains and markers: PAS, anti-CD10, EpCAM, chromogranin A
Electron microscopy (EM) for ultrastructural defects

4. Laboratory Tests

Basic labs: electrolytes (acidosis, dehydration), albumin
Immune profiling: immunoglobulins, T and B cell subsets
Hormonal assays: proinsulin, systemic hormones

5. Genetic Testing

Gene-specific Sanger sequencing
Whole-exome or whole-genome sequencing for broader analysis

C. Categorization by Absorptive Capacity

1. Reduced Surface Area

Short bowel length: Congenital SBS
Villus atrophy: Autoimmune enteropathy
Microvillus defects: Microvillus inclusion disease (MVID)

2. Normal Surface Area with Assimilation Defects

Selective defects (not intestinal failure):
- Digestion: Pancreatic amylase deficiency, sucrase-isomaltase (SI) deficiency
- Absorption: Glucose/galactose malabsorption, chloride or sodium transport defects
Broad defects (intestinal failure): affect multiple nutrient and electrolyte pathways

Classification of Disorders

Selective Nutrient/Electrolyte Assimilation Disorders: Affect specific transporters or enzymes
Intestinal Failure Disorders:
- Immune-related: e.g., IPEX syndrome, severe combined immunodeficiency
- Structural/cytoskeletal: e.g., MVID, TTC7A deficiency
- Enteroendocrine cell defects: e.g., NEUROG3 mutations

Congenital Diarrhea Disorders – Section 2

Disorders Associated with Defects in Selective Nutrient or Electrolyte Assimilation

A. Glucose-Galactose Malabsorption (GGM)

Gene: SGLT1 | Inheritance: Autosomal Recessive

Neonatal onset with metabolic acidosis and dehydration
Stool: ↓ pH, ↑ osmolarity, ↑ osmotic gap; glycosuria common
Histology and disaccharidases: normal
Abnormal glucose/galactose breath H₂ test
Diarrhea resolves with glucose- and lactose-free diet
Treatment: Ross Carbohydrate-Free® formula + fructose

Pathogenesis: Loss-of-function in Na⁺/glucose cotransporter; fructose absorbed via GLUT5

B. Sucrase-Isomaltase (SI) Deficiency

Gene: SI | Inheritance: Autosomal Recessive

Symptoms upon introduction of sucrose, dextrins, or isomaltose
Distinguished from GGM by glucose tolerance
Stool: ↓ pH; reducing substances vary
Sucrose breath H₂ test: abnormal
Histology: normal; low SI enzyme activity
Founder variants in Native North Americans/Greenlanders
Treatment: sucrose-free diet; sacrosidase supplements

Pathogenesis: SI gene mutation impairs hydrolysis of sucrose to glucose and fructose

C. Congenital Lactase Deficiency

Gene: LCT | Inheritance: Autosomal Recessive

Rare; neonatal diarrhea with lactose exposure
Distinguished from acquired hypolactasia
Founder variant in Finland
Histology: ↓ lactase, normal sucrase; abnormal lactose breath H₂ test
Treatment: lactose-free diet; lactase supplements

Pathogenesis: Loss-of-function mutation in lactase gene

D. Congenital Chloride Diarrhea

Gene: SLC26A3 | Inheritance: Autosomal Recessive

Most common congenital secretory diarrhea
Prenatal polyhydramnios; metabolic alkalosis
Stool Cl⁻ >90 mmol/L
Diarrhea worsens with infections
Renal injury from hypovolemia
Treatment: oral NaCl and KCl; butyrate and PPIs may help

Pathogenesis: Defective Cl⁻/HCO₃⁻ exchanger; impaired Cl⁻ reabsorption

E. Congenital Sodium Diarrhea

Gene: SLC9A3 (NHE3) | Inheritance: Autosomal Recessive

Prenatal polyhydramnios; Na⁺-secreting diarrhea
No syndromic features (unlike SPINT2 cases)
Subset may develop IBD

Pathogenesis: Loss of Na⁺/H⁺ antiporter-3 function

F. Syndromic Sodium Secretory Diarrhea

Gene: SPINT2 | Inheritance: Autosomal Recessive

Mixed secretory and malabsorptive diarrhea
Tufted cells on histology; overlaps with CTE
Villous atrophy, crypt hyperplasia
Associated features: keratitis, choanal atresia, bone anomalies

Pathogenesis: Serine protease inhibitor dysfunction; ↑ tmprss13 activity inhibits ENaC

G. Enterokinase Deficiency

Gene: PRSS7 | Inheritance: Autosomal Recessive

Rare; diarrhea on protein-based diet
Edema, hypoproteinemia, vomiting
Histology: normal crypt-villus axis
Treatment: PERT for first 2 years; symptoms resolve
Low pancreatic enzyme levels

Pathogenesis: Defective activation of pancreatic enzymes (trypsin, chymotrypsin, carboxypeptidase A)

H. DGAT1 Deficiency

Gene: DGAT1 | Inheritance: Autosomal Recessive

Osmotic/malabsorptive diarrhea
Protein-losing enteropathy (PLE)
Hyperlipidemia (↑ triglycerides)
Histology: villous atrophy
Treatment: low-fat diet; not intestinal failure
Founder variant in Ashkenazi Jewish population

Pathogenesis: DGAT1 mutation disrupts final step of triglyceride synthesis

Section 3: Intestinal Failure Disorders

Section 3: Disorders Associated with Intestinal Failure

A. Microvillus Inclusion Disease (MVID)

Genes: MYO5B, STX3 | Inheritance: Autosomal Recessive

Diarrhea: Secretory + osmotic/malabsorptive
Histology: Villous atrophy, crypt hypoplasia
EM: Absent/reduced microvilli, apical inclusion bodies (CD10/PAS+)
Complications: Liver disease, TPN dependence (may improve in late-onset)

Pathogenesis: MYO5B regulates apical trafficking; STX3 variant causes atypical form

B. Congenital Tufting Enteropathy (CTE)

Gene: EpCAM | Inheritance: Autosomal Recessive

Diarrhea: Mixed type
Histology: Villous atrophy, crypt hyperplasia, tufted cells
Diagnosis: Negative EpCAM staining
Genetics: Arab and Mexican founder variants

Pathogenesis: EpCAM regulates tight junction integrity

C. Trichohepatoenteric Syndrome

Genes: TTC37, SKIV2L | Inheritance: Autosomal Recessive

Features: Diarrhea, woolly hair, dysmorphism, hepatomegaly, immune defects
Histology: Villous atrophy, inflammatory infiltrate

Pathogenesis: RNA degradation defect via exosome complex

D. Netherton Syndrome

Gene: SPINK5 | Inheritance: Autosomal Recessive

Features: Diarrhea, ichthyosis, bamboo hair, ↑ IgE, eosinophilia
Histology: Villous atrophy

Pathogenesis: LEKTI-1 loss → ↑ kallikrein and elastase activity

E. Kabuki Syndrome 1

Gene: MLL2 | Inheritance: Autosomal Dominant (de novo)

Features: Malabsorptive diarrhea, dysmorphism, seizures, GI malformations

Pathogenesis: Histone methylation defect affecting gene regulation

F. Enteric Anendocrinosis

Gene: NEUROG3 | Inheritance: Autosomal Recessive

Features: Osmotic diarrhea, absent enteroendocrine (EE) cells, diabetes risk
Histology: Normal architecture, absent chromogranin A staining

Pathogenesis: NEUROG3 drives EE cell differentiation

G. Enteric Dysendocrinosis

Gene: PCSK1 | Inheritance: Autosomal Recessive

Features: Osmotic diarrhea, ↑ proinsulin, multiple endocrinopathies
Histology: Normal EE cells

Pathogenesis: Impaired prohormone processing across endocrine organs

H. Mitchel-Riley Syndrome

Gene: RFX6 | Inheritance: Autosomal Recessive

Features: Diarrhea, neonatal diabetes, GI and biliary anomalies

Pathogenesis: RFX6 regulates EE cell development downstream of NEUROG3

I. IPEX Syndrome

Gene: FOXP3 | Inheritance: X-linked Recessive

Features: Severe diarrhea, dermatitis, neonatal diabetes, autoimmunity
Histology: Villous atrophy, mononuclear infiltrate
Labs: ↑ IgE, eosinophilia, ↓ Tregs
Treatment: Immunosuppression, bone marrow transplant

Pathogenesis: FOXP3 is master regulator of Treg cells

J. Neonatal Inflammatory Skin and Bowel Disease

Gene: ADAM17 | Inheritance: Autosomal Recessive

Features: Diarrhea (± bloody), rash, hepatitis, recurrent sepsis
Histology: Villus blunting, crypt hyperplasia, neutrophilic skin infiltrates

Pathogenesis: Defective TNFα activation and NOTCH signaling

K. IL-10 or IL-10R Deficiency

Genes: IL10, IL10R | Inheritance: Autosomal Recessive

Features: Early-onset enterocolitis, fistulas, folliculitis, arthritis
Refractory to: Steroids, anti-TNFα
Treatment: Stem cell transplant

Pathogenesis: Loss of anti-inflammatory IL-10 signaling → hyperinflammation

L. CD25/IL2RA Deficiency

Gene: IL2RA | Inheritance: Autosomal Recessive

Features: IPEX-like diarrhea, infections (CMV), eczema, lymphoid hypertrophy
Histology: Severe villous atrophy

Pathogenesis: IL-2 receptor defect → impaired Treg function despite normal FOXP3

M. STAT1 Deficiency

Gene: STAT1 | Inheritance: Autosomal Dominant

Features: Diarrhea, mucocutaneous candidiasis, autoimmune disease, vascular anomalies
Histology: Villous atrophy, lymphocytic/eosinophilic infiltrates
Other findings: Recurrent infections, diabetes, thyroiditis, alopecia
Vascular: Cerebral aneurysms, premature atherosclerosis, renal artery stenosis, hypertension

Pathogenesis: Gain-of-function mutation → ↑ STAT1 phosphorylation → impaired Th17 differentiation

Comparison Table – Congenital Diarrheal Disorders

Comparison Table of Congenital Diarrheal Disorders

*all disorders below are Autosomal Recessive (AR) unless stated otherwise*

Selective Nutrient/Electrolyte Assimilation Disorders
Name	Gene(s)	Key Features	Diagnosis	Treatment Notes
Glucose-Galactose Malabsorption (GGM)	SGLT1	Neonatal diarrhea, metabolic acidosis, glycosuria	↓ stool pH, ↑ osmolarity, abnormal glucose /galactose breath H₂ test	Glucose/lactose-free diet; fructose-based formula (Ross-carb free)
Sucrase-Isomaltase Deficiency (SI)	SI	Symptoms with sucrose/dextrins; tolerates glucose; greenland founder variant	↓ stool pH, variable reducing substances -since sucrose is a nonreducing sugar, abnormal sucrose breath H₂ test	Sucrose-free diet; sacrosidase supplements
Congenital Lactase Deficiency	LCT	Diarrhea with lactose; Finnish founder variant	↓ lactase, normal sucrase; abnormal lactose breath H₂ test	Lactose-free diet; lactase enzyme supplements
Congenital Chloride Diarrhea	SLC26A3	Secretory diarrhea, polyhydramnios, metabolic alkalosis Most common cause of congenital secretory diarrhea	↑ stool Cl⁻ (>90 mmol/L)	Oral NaCl/KCl; butyrate; PPIs
Congenital Sodium Diarrhea	SLC9A3	Na⁺-secreting diarrhea, polyhydramnios	Clinical features; no syndromic signs	Supportive care
Syndromic Na⁺ Diarrhea (SPINT2)	SPINT2	Mixed diarrhea, tufted cells, keratitis, choanal atresia, bone malformations	Villous atrophy, crypt hyperplasia, normal EpCAM staining indistinguishable from CTE	Nutritional support; symptom management
Enterokinase Deficiency	PRSS7	Protein malabsorption, edema, hypoproteinemia	Normal histology; low pancreatic enzymes. Diarrhea improves with elemental diet	PERT for first 2 years; symptoms resolve after 2yrs.
DGAT1 Deficiency	DGAT1	Osmotic diarrhea, PLE, hypertriglyceridemia	Villous atrophy; ↑ triglycerides	Low-fat diet; no TPN required

Intestinal Failure Disorders
Name	Gene(s)	Key Features	Diagnosis	Treatment Notes
Microvillus Inclusion Disease (MVID)	MYO5B, STX3	Secretory + osmotic diarrhea, liver disease, TPN dependence	Villous atrophy, crypt hypoplasia, EM: microvillus loss, inclusion bodies (CD10/PAS+)	TPN; possible weaning in late-onset cases
Congenital Tufting Enteropathy (CTE)	EpCAM	Mixed diarrhea, tufted cells, crypt hyperplasia	Negative EpCAM staining; villous atrophy	TPN; supportive care
Trichohepatoenteric Syndrome	TTC37, SKIV2L	Diarrhea, woolly hair, dysmorphism, hepatomegaly, immune defects	Villous atrophy, inflammatory infiltrate	Nutritional support; immune therapy
Netherton Syndrome	SPINK5	Diarrhea, ichthyosis, bamboo hair, ↑ IgE, eosinophilia	Villous atrophy	Allergy management; supportive care
Kabuki Syndrome 1	MLL2 AD	Malabsorptive diarrhea, dysmorphism, seizures, GI anomalies (malro, imperforate, stenosis, fistula)	Clinical features; genetic testing	Multidisciplinary care
Enteric Anendocrinosis	NEUROG3	Osmotic diarrhea, absent EE cells by antichromogranin stain, diabetes risk	Normal architecture; absent chromogranin A staining	Diarrhea persists indefinitely...but may wean off TPN after age 2–3
Enteric Dysendocrinosis	PCSK1	Osmotic diarrhea, ↑ proinsulin, multiple endocrinopathies	Normal EE cells; hormonal assays	Hormone replacement; supportive care
Mitchel-Riley Syndrome	RFX6	Diarrhea, neonatal diabetes, GI and biliary anomalies	Clinical features; genetic testing	Endocrine and nutritional support
IPEX Syndrome	FOXP3 x-linked	Severe diarrhea, dermatitis, neonatal diabetes, autoimmunity	Villous atrophy, mononuclear infiltrate, ↑ IgE, ↓ Tregs	Immunosuppression; bone marrow transplant
Neonatal Inflammatory Skin/Bowel Disease	ADAM17	Diarrhea (± bloody), rash, hepatitis, recurrent sepsis	Villus blunting, crypt hyperplasia, neutrophilic skin infiltrates	Immune therapy; supportive care
IL-10 or IL-10R Deficiency	IL10, IL10R	Early-onset enterocolitis, fistulas, folliculitis, arthritis	STAT3 phosphorylation assay; genetic sequencing	Hematopoietic stem cell transplant
CD25/IL2RA Deficiency	IL2RA	IPEX-like diarrhea, infections (CMV), eczema, lymphoid hypertrophy	Severe villous atrophy; immune profiling	Immunosuppression; antibiotics
STAT1 Deficiency	STAT1 AD	Diarrhea, candidiasis, autoimmune disease, vascular anomalies	Villous atrophy, lymphocytic/eosinophilic infiltrates; genetic testing	Targeted immune therapy; supportive care