| Disorder | Gene | Protein function | Clinical characteristics | |||
| Name | Inheritance | Diarrhea type | Biopsy | Other characteristics | ||
| Epithelial electrolyte transport | ||||||
| Congenital chloride diarrhea (MIM #214700) | SLC26A3 | AR | Cl–/HCO3– exchanger | Severe watery, ETRD* | Normal | Polyhydramnios; high fecal Cl– (>90 mM); hypochloremic hypokalemic metabolic alkalosis. |
| Congenital sodium diarrhea (MIM #616868) | SLC9A3 | AR | Na+/H+ exchanger (NHE3) | Severe, watery, ETRD | Normal | Polyhydramnios; diarrhea features similar to above, but with high fecal Na+ content (typically >140 mM) and metabolic acidosis. |
| Familial GUCY2C diarrhea (MIM #614616) | GUCY2C (gain of function) | AD | Guanylate cyclase | Mild, watery, ETRD | Normal | Early-onset mild diarrhea, with increased intraluminal chloride, metabolic acidosis, and susceptibility to IBD. |
| Pseudohyperaldosteronism type 1 (MIM #264350) | SCNN1G | AR | Epithelial Na+ channel | Severe, watery, ETRD | Normal | Hypotension, Na+-wasting in urine and stools. Elevated serum aldosterone levels. Channels regulated by the renin-angiotensin-aldosterone system. |
| Epithelial nutrient transport | ||||||
| Glucose-galactose malabsorption (MIM #606824) | SLC5A1 | AR | Na+-glucose cotransporter | Severe, watery, diet-induced | Normal | Diarrhea resolves with fasting or with a glucose- and galactose-free diet; severe dehydration; metabolic acidosis. |
| Lysinuric protein intolerance (MIM #222700) | SLC7A7 | AR | Cationic amino acid transporter (intestine and kidney) | Watery diarrhea | Normal | Episodes of diarrhea, vomiting, and acute encephalopathy, with hyperammonemia induced by protein consumption. |
| Primary bile acid diarrhea (MIM #613291) | SLC10A2 | AR | Ileal bile salt transporters | Watery/fatty; both ETRD and diet-induced | Normal | Excessive colonic Cl– secretion; fat malabsorption due to lack of bile acid reuptake and insufficient intraluminal bile acids. Unlike other forms of ETRD, feedings worsen the diarrhea. Fat-soluble vitamin deficiency; cholestatic liver disease. |
| SLC51B | AR | Basolateral bile acid transporter | ||||
| Acrodermatitis enteropathica (MIM #201100) | SLC39A4 | AR | Zinc transporter | Watery | Normal | Erythematous vesiculobullous acrodermatitis (typically on cheeks and buttocks); diarrhea; alopecia; ophthalmic disorders; low serum zinc. |
| Epithelial enzymes and metabolism | ||||||
| Congenital lactase deficiency (MIM #223000) | LCT | AR | Disaccharidase | Watery, diet-induced | Normal | Diarrhea resolves with fasting or a lactose-free diet. Must be distinguished from secondary lactose intolerance, which is induced by mucosal injury (eg, after an enteric infection) and is transient. |
| Sucrase-isomaltase deficiency (MIM #222900) | SI | AR | Disaccharidase | Watery, diet-induced | Normal | Diarrhea resolves with fasting or a carbohydrate-free diet (no sucrose, maltose, or starch). Young infants are asymptomatic because sucrose is absent in breast milk and is not common in formulas. |
| Trehalase deficiency (MIM #612119) | TREH | AR | Disaccharidase | Watery | Normal | Diarrhea associated with a dose-dependent consumption of a trehalose-containing diet (eg, mushrooms or foods produced with bakers' yeast). Young infants are asymptomatic because trehalose is not typically in infant formula or breast milk. |
| Enterokinase deficiency (MIM #226200) | PRSS7 | AR | Pro-enterokinase | Watery, diet-induced | Normal | Diarrhea improves on an amino acid-based diet. |
| DGAT1 deficiency (MIM #615863) | DGAT1 | AR | Triglyceride synthesis | Watery, diet-induced | Abnormal villi; positive PAS stain. | Diarrhea induced by enteral lipids, with features of ETRD*; severe protein-losing enteropathy with hypoalbuminemia; emesis; growth failure. |
| Hennekam lymphangiectasia-lymphedema syndrome-1 (MIM #235510) | CCBE1 | AR | Budding of venous endothelium | Watery | Intestinal lymphangiectasia | Diarrhea; protein-losing enteropathy; facial dysmorphism; cognitive impairment. |
| PLVAP deficiency (MIM #226300) | PLVAP | AR | Endothelial fenestrae | Watery, diet-induced | Normal | Severe protein-losing enteropathy with hypoalbuminemia; hypertriglyceridemia. Very rare. |
| Abetalipoproteinemia (MIM #200100) | MTP | AR | Microsomal triglyceride transfer protein | Fatty, diet-induced | Fat-laden enterocytes | Low LDL with normal fecal elastase. |
| Hypobetalipoproteinemia (MIM #605019) | APOB | AR | Lipid absorption | Fatty, diet-induced | Fat-laden enterocytes | Low LDL with normal fecal elastase. |
| ANGPTL3 | AR | Inhibits lipoprotein lipase activity | ||||
| Chylomicron retention disease (MIM #246700) | SAR1B | AR | Intracellular chylomicron trafficking | Fatty, diet-induced | Fat-laden enterocytes | Low LDL with normal fecal elastase. |
| Dyskeratosis congenita (MIM #613989) | TERT | AR/AD | Maintenance of telomeres | Watery and/or bloody | Crypt apoptosis, increased intraepithelial lymphocytes, villus atrophy, and expanded lamina propria | Variable age of presentation, which may include enteropathy. Multiple syndromes and genes involved. |
| Kabuki syndrome (MIM #147920) | KMT2D | AD | Histone methyltransferase | Watery, but may be variable | Normal, but may be inflammatory | Syndromic disorder that may be associated with neonatal hypoglycemia, immunologic defects, and/or autoimmune diseases, including vitiligo. |
| Epithelial trafficking and polarity | ||||||
| Microvillus inclusion disease (MIM #251850) | MYO5B | AR | Cellular trafficking, polarity, and signaling | Severe watery ETRD | Villus atrophy; microvillus inclusions on electron microscopy; positive CD10/villin stain | Diarrhea improves but does not resolve with fasting. May include cholestatic liver disease. |
| STX3 | AR | |||||
| Tufting enteropathy (MIM #613217) | EPCAM | AR | Cell-cell adhesion and signaling | Severe watery ETRD | Villus atrophy and focal epithelial tufts in small and large bowel; positive MOC31 stain | Diarrhea persists with fasting. |
| Syndromic Na+ diarrhea (MIM #270420) | SPINT2 | AR | Serine protease inhibitor | Severe watery ETRD | Tufting enteropathy-like features | Choanal atresia; rarely, intestinal atresia. |
| Trichohepatoenteric syndrome 1 (THES1) (MIM #222470) | TTC37 | AR | Cell polarity and signaling | Watery/bloody | Villus atrophy, mononuclear infiltrates | Liver disease; immune defect; facial dysmorphism; abnormal hair. |
| Trichohepatoenteric syndrome 2 (THES2) (MIM #614602) | SKIV2L | AR | Helicase | |||
| Familial hemophagocytic lymphohistiocytosis 5 (MIM #613101) | STXBP2 | AR | Syntaxin-binding protein | Mild, diet-induced | Short apical microvilli | Hemophagocytic lymphohistiocytosis (excessive immune activation, hepatitis, cytopenias); mild chronic diarrhea. Diarrhea may not resolve after bone marrow transplant. |
| TTC7A deficiency (MIM #243150) | TTC7A | AR | Protein transport and trafficking | ETRD | Enterocolitis, villus atrophy; chronic inflammation | Intestinal atresias; underlying SCID. |
| UNC45A deficiency | UNC45A | AR | Cellular trafficking, polarity, and signaling | Severe watery ETRD | Villus atrophy; microvillus inclusions on electron microscopy; positive CD10/villin stain | Cholestasis; congenital diarrhea; impaired hearing; bone fragility. |
| MEDNIK syndrome (MIM #609313) | AP1S1 | AR | Required for sorting of late-Golgi/trans-Golgi network | Watery | Enteropathy | Intellectual disability; enteropathy; deafness; peripheral neuropathy; ichthyosis; keratoderma. |
| MIRAGE syndrome (MIM #617053) | SAMD9 | AR | Downstream target of TNF-alpha | Watery | Enteropathy | Enteropathy; myelodysplasia; infection; restriction of growth; adrenal hypoplasia; genital phenotypes. |
| Enteroendocrine cell dysfunction | ||||||
| Enteric anendocrinosis (MIM #610370) | NEUROG3 | AR | Transcription factor-cell fate | Watery, diet-induced | Normal villus architecture; selective loss of EECs (chromogranin or synaptophysin stains) | Later onset of insulin-dependent diabetes (without autoantibodies). |
| X-linked lissencephaly (MIM #300215) | ARX | X-linked | Transcription factor required for neuronal and EEC development | Diet-induced | Normal villus architecture; possible selective reduction of certain EECs | Lissencephaly (smooth cerebral cortex) and severe neurologic abnormalities; seizures; generalized malabsorptive diarrhea. |
| Enteric dysendocrinosis (MIM #600955) | PCSK1 | AR | Hormonal endopeptidase | Severe diet-induced | Normal villus architecture | Generalized malabsorption; multiple systemic endocrinopathies (adrenal insufficiency, hypothyroidism, diabetes insipidus); elevated pro-insulin. |
| Mitchell-Riley syndrome (MIM #615710) | RFX6 | AR | Transcription factor-cell fate | Generalized malabsorption | Normal villus architecture and EECs | May have intestinal atresia, malrotation, intrinsic and extrinsic biliary duct abnormalities, and neonatal diabetes. |
| Congenital malabsorptive diarrhea 11 (MIM #618662) | PERCC1 | AR | Required for EEC development | Generalized malabsorption | Normal villus architecture, reduced EECs | Diarrhea. |
| Immune dysregulation-associated enteropathy¶ | ||||||
| IPEX (MIM #304790) | FOXP3 | X-linked | Regulatory T cell | Watery, mucoid, or bloody | Villus atrophy; nonspecific features of autoimmune enteropathy; inflammation | Immune dysregulation; polyendocrinopathy (diabetes, thyroiditis); enteropathy X-linked (only males affected). Diarrhea persists with fasting. Food allergies common. |
| CD55 deficiency (MIM #226300) | CD55 | AR | Complement cascade inhibitor | Watery or bloody; generalized malabsorption | Inflammatory | Severe protein-losing enteropathy (low Igs and albumin, elevated stool AAT); thrombosis; mucosal ulcers. |
| Neonatal inflammatory skin and bowel disease-1 (NISBD1) (MIM #614328) | ADAM17 | AR | TNF-alpha-converting enzyme | Watery or bloody; generalized malabsorption | Focal villous atrophy; minimal crypt hyperplasia | Neonatal onset of severe inflammatory skin rash, diarrhea, and recurrent infections. |
| Neonatal inflammatory skin and bowel disease-2 (NISBD2) (MIM #616069) | EGFR | AR | EGF receptor | Watery | Normal | Similar to NISBD1. |
| Lymphoproliferative syndrome, X-linked (MIM #300635) | XIAP (BIRC4) | X-linked | Inhibitor of apoptosis | Bloody | Inflammatory | Associated with recurrent infections, hemophagocytic lymphohistiocytosis characteristics, and colitis. |
| Common variable immunodeficiency (CVID), type 1 (MIM #607594) | ICOS | AR | T cell receptor | Watery | Inflammatory; depletion of plasma cells | Form of CVID with low Igs and B cells. Severe diarrhea; recurrent infections (sinusitis, bronchitis); lymphadenopathy. Typically presents during childhood but occasionally in infants. |
| Autoimmune lymphoproliferative syndrome, type 5 (CTLA4 deficiency) (MIM #616100) | CTLA4 | AD | Costimulatory signaling | Watery or bloody | Inflammatory; lymphocytic infiltration | Interstitial lung disease; autoimmune thrombocytopenia; lymphocytic infiltration in various organs including the intestine. Some patients have features of CVID. |
| Common variable immunodeficiency (CVID), type 8 (LRBA deficiency) (MIM #614700) | LRBA | AR | Endosomal trafficking regulator | Watery or bloody | Inflammatory; loss of plasma cells | Form of CVID that may present with diarrheal symptoms during early infancy. Low Igs. |
| Common variable immunodeficiency (CVID), type 10 (NFKB2 deficiency) (MIM #615577) | NFKB2 | AD | Required for induction of secondary lymphoid tissue and for T helper and Treg function | Watery or bloody | Inflammatory; recurrent infections | Form of CVID that results in diarrheal symptoms and recurrent infections; may have associated central adrenal insufficiency. |
| Immunodeficiency, type 12 (MALT1 deficiency) (MIM #615468) | MALT1 | AR | Required for T and B cell activation | Watery or bloody | Inflammatory | Form of combined immunodeficiency that may present with diarrheal symptoms during early infancy; dysmorphic facies and poor growth. |
| Inflammatory bowel disease (IBD), type 28 (IL10RA deficiency) (MIM #613148) | IL10RA | AR | IL-10 receptor is required for antiinflammatory role of IL-10 | Watery or bloody | Inflammatory | Form of early-onset IBD with immune dysregulation that can result in enteric fistulas and perirectal abscess within several months of life. |
| Chronic granulomatous disease, X-linked (MIM #306400) | CYBB | X-linked | Impaired superoxide | Watery or bloody | Inflammatory; with granulomas | Severe recurrent infections. |
| Intestinal stem cell factors | ||||||
| Neonatal-onset chronic diarrhea-9 (MIM #618168) | WNT2B | AR | Cell-cell signaling factor | Watery | Crypt hypoplasia; enteroendocrine hyperplasia; atrophic gastritis | Occulo-intestinal syndrome (anterior chamber abnormalities such as corneal clouding). |
CODEs: congenital diarrheas and enteropathies; AR: autosomal recessive; AD: autosomal dominant; ETRD: electrolyte transport-related diarrhea; NHE3: sodium-hydrogen exchanger 3; IBD: inflammatory bowel disease; PAS: periodic acid-Schiff; LDL: low-density lipoprotein; SCID: severe combined immunodeficiency; TNF-alpha: tumor necrosis factor-alpha; EEC: endometrial echo complex; Igs: immunoglobulins; AAT: alpha-1 antitrypsin; EGF: epidermal growth factor; CVID: common variable immunodeficiency; Treg: regulatory T cells; IL: interleukin.
* ETRD is also known as secretory diarrhea. We prefer the term ETRD because this acknowledges that the pathology may include either abnormal secretion or abnormal absorption of electrolytes.
¶ Immune dysregulation-associated enteropathies include a group of disorders sometimes known as very early-onset IBD (VEO-IBD). For a discussion of the clinical presentation and evaluation of VEO-IBD, refer to UpToDate content on clinical presentation of IBD in children and Uhlig HH, et al[1].Original table modified for this publication. From: Thiagarajah JR, Kamin DS, Acra S, et al. Advances in evaluation of chronic diarrhea in infants. Gastroenterology 2018. Table used with the permission of Elsevier Inc. All rights reserved.
