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Invited Review

Congenital Diarrheal Disorders: Improved Understanding of Gene Defects Is Leading to Advances in Intestinal Physiology and Clinical Management

Berni Canani, Roberto*; Terrin, Gianluca*; Cardillo, Giuseppe; Tomaiuolo, Rossella; Castaldo, Giuseppe

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Journal of Pediatric Gastroenterology and Nutrition: April 2010 - Volume 50 - Issue 4 - p 360-366
doi: 10.1097/MPG.0b013e3181d135ef
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Congenital diarrheal disorders (CDD, Online Mendelian Inheritance in Man [OMIM] 251850) are a group of rare chronic enteropathies characterized by a heterogeneous etiology, which in most cases is related to an identified or to an as yet unidentified genetic defect generally inherited as an autosomal recessive trait. CDD represent one of the most challenging clinical conditions for pediatric gastroenterologists because of the severity of the clinical picture and the broad range of conditions in its differential diagnosis (1–4). In the first weeks of life, patients affected by CDD usually present with severe diarrhea that within a few hours leads to a life-threatening condition secondary to massive dehydration and metabolic acidosis (1). Consequently, children affected by CDD require a prompt diagnosis and assistance. Milder forms with subtle clinical signs may remain undiagnosed until adulthood when patients may have developed irreversible complications. The number of conditions included within the CDD group has gradually increased (4–6). What is now clear is that CDD depend on defects in the structure and function of absorptive, enteroendocrine, or inflammatory cells of the gut, determined by mutations in genes expressed throughout the gastrointestinal tract involving different segments and different cells. Therefore, as shown in Figure 1, we suggest that CDD be classified into 4 groups in relation to the defect: absorption and transport of nutrients and electrolytes, enterocyte differentiation and polarization, enteroendocrine cell differentiation, and modulation of the intestinal immune response. The conditions included in these 4 groups are reported in Tables 1 to 4. The exact incidence of these disorders remains to be established and differs widely among populations and geographic areas (1,4,5,36). A study from the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition estimated that altered modulation of the intestinal immune response and altered enterocyte differentiation and polarization are the most common causes of CDD (37). In recent years, many new genes have been identified and functionally related to CDD, thereby opening new diagnostic and therapeutic perspectives. Such molecular techniques as positional candidate genes and genome-wide linkage analysis have clarified the role of these genes in the physiology of the gastrointestinal tract. Our review focuses on the recent advances made in the genetics of CDD that have contributed to a better understanding of intestinal physiology and clinical management of the more common diarrheal diseases (6).

The mechanisms involved in the pathogenesis of congenital diarrheal disorders.
Molecular basis of the main forms of congenital diarrheal diseases: defects of digestion, absorption, and transport of nutrients and electrolytes
Molecular basis of the main forms of congenital diarrheal diseases: defects of enterocyte differentiation and polarization
Molecular basis of the main forms of congenital diarrheal diseases: defects of enteroendocrine cells differentiation
Molecular basis of the main forms of congenital diarrheal diseases: defects of modulation of intestinal immune response


Congenital Chloride Diarrhea

Congenital chloride diarrhea (CLD, OMIM 214700) is a typical clinical model of the CDD subgroup that is due to the altered absorption and transport of nutrients and electrolytes. This rare genetic disease is caused by mutations in the gene encoding the solute-linked carrier family 26-member A3 (SLC26A3) protein, which acts as a plasma membrane anion exchanger for Cl and HCO3(10). The main clinical symptom is lifelong watery diarrhea with high Cl content and low pH, which causes dehydration and hypochloremic metabolic alkalosis (1). CLD may be fatal if not adequately treated. Long-term prognosis is generally favorable, but complications such as renal disease, hyperuricemia, inguinal hernias, spermatoceles, and subfertility are possible (38). The clinical picture of CLD varies from individual to individual, and 1 case has been diagnosed in an adult (39).

The genotype does not seem to be strictly related to the phenotype (40), and a discordant phenotype has been identified in an affected sibling pair (41). The SLC26A3 gene maps on chromosome 7, in region q31, close to the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and spans about 38 kb including 21 exons (10,41). In ethnic groups in which the disease is common, there is a single mutation: in Finns, the p.V317del mutation affects up to 90% of CLD alleles; in Saudi Arabians and Kuwaitis, p.G187X is present in more than 90% of altered chromosomes; in Poles, 50% of CLD alleles carry the I675–676ins mutation (official nomenclature c.2022_2024dup – p.I675dup). A wide genetic heterogeneity was found in about 100 patients affected by CLD from ethnic groups in which the disease is sporadic (40,42). In fact, about 30 mutations have been identified so far and they involve a large number of exons and several introns of the SLC26A3 gene. In addition, various types of mutations have been reported, namely, point mutations (nonsense, frameshift, and missense) and small and large gene rearrangements. Disease-causing mutations have not been identified in promoter or enhancer regions. All of the patients tested by us are homozygotes or compound heterozygotes for mutations in the coding region. This suggests that the entire coding region of the gene, and not just hotspots, should be scanned to obtain an accurate molecular diagnosis.

Little is known about the mechanism by which these mutations undermine function. The C-terminal conserved domain called the sulfate transporter and antisigma factor antagonist (STAS) has various functions (16,40). This domain ensures the correct location of the SLC26A3 protein on the apical membrane of enterocytes. In addition, it interacts with the R-domain of the CFTR gene (see below). Mutations in the STAS domain cause CLD by reducing the levels of the protein at the plasma membrane by at least 2 distinct mechanisms, both of which result in transporter mistrafficking and cytosol retention (16,40). Mutations p.I675dup and p.G702TfsX10 cause the STAS domain to misfold so that the mutant transporters cannot reach the native state. In contrast, mutations p.Y526_527del and p.I544N probably disrupt important intramolecular interactions that are critical for the formation of well-folded, functional transporters (16). Moreover, these mutations may affect other intermolecular interactions critical for correct folding.

The above-indicated mechanisms may have important therapeutic implications. Butyrate therapy is beneficial in patients affected by CLD (43,44). The mechanism underlying this therapeutic effect is unclear, but it could be related at least in part to stimulation of the Cl/butyrate exchanger activity (43). It is also possible that butyrate could reduce mistrafficking or misfolding of the SLC26A3 protein, as demonstrated in other conditions (45). Alternatively, butyrate may enhance gene expression: the SLC26A3 gene contains a 290-bp region between residues −398 and −688 that is crucial for high-level transcriptional activation induced by butyrate (Fig. 2). This may explain the variable response of patients affected by CLD to butyrate (44). In fact, depending on the patient's genotype, mutations in the above-mentioned regulatory regions of the SLC26A3 gene could affect gene transcription rate.

The rationale of the butyrate therapy in congenital chloride diarrhea. The most important process involved in intestinal absorption of Cl− is the NaCl cotransporter that is mediated by 2 coupled exchangers, Na+/H+ and Cl−/HCO3− (A). Congenital chloride diarrhea is caused by a defect in the Cl−/HCO3− exchanger (SLC26A3 protein) that leads to chloride malabsorption with consequent watery diarrhea determined by an osmotic mechanism (B). Butyrate, a short-chain fatty acid (SCFA), could limit diarrhea in these patients by stimulating Cl−/butyrate exchanger activity (C) and/or reducing the mistrafficking or misfolding of the SLC26A3 protein (D).

It is also conceivable that other channels are involved in the therapeutic effect of butyrate in CLD. SLC26A3, like other components of the SLC26 family, interacts with CFTR(46,47). The interaction between CFTR and these components is mediated by binding of the regulatory domain of CFTR to the STAS domain of SLC26. The interaction is enhanced by phosphorylation of the regulatory domain by protein kinase A (42) and is modulated by PDZ-binding scaffold proteins. An important consequence of this interaction is that SLC26 anion exchange activity is enhanced when CFTR is activated by phosphorylation. Moreover, the 2 genes regulate each other; that is, overexpression of SLC26A3 or -A6 causes upregulation of CFTR and vice versa (46–48). In patch-clamp experiments, protein kinase A–stimulated CFTR channel activity was 6-fold higher in HEK293 cells coexpressing both SLC26 exchanger and CFTR than in HEK293 cells expressing CFTR alone (16,44,46–48). Mutations may impair the interactions between channels and thus reduce the effect of butyrate therapy. Interestingly, it has recently been demonstrated that butyrate can act by different mechanisms in in vitro models of cystic fibrosis: it can increase the expression of the apical epithelial membrane of the CFTR, and it can act as a “chaperone-like” molecule, as shown in the deltaF508del CFTR cell line (49,50). Similar mechanisms could occur in CLD.

Congenital Sodium Diarrhea

Congenital sodium diarrhea (CSD, OMIM 270420) is a rare disorder characterized by perinatal onset of persistent severe diarrhea with increased sodium fecal excretion, and consequently hyponatremia and metabolic acidosis, with a high mortality because of electrolytic alterations. Few cases have been described so far (17,51,52). The disease gene is unknown, and a study based on the “candidate gene” approach failed to identify the disease gene among the 6 known isoforms of sodium-proton exchangers 1 to 6. There is a syndromic form of CSD, which is associated with choanal or anal atresia, hypertelorism and corneal erosions, double kidney, cleft palate, and digital anomalies, and a nonsyndromic (classic) form. The disease gene of the syndromic CSD form, serine peptidase inhibitor Kunitz type 2, which encodes a serine-protease inhibitor, was recently identified using genome-wide single nucleotide polymorphism linkage analysis in a large family (18). Mutations of the gene were identified in all of the other 4 syndromic patients studied. On the contrary, no mutations have been identified in the serine peptidase inhibitor Kunitz type 2 gene in patients bearing the classic form of the disease.


Microvillous Inclusion Disease

Microvillous inclusion disease (MID, OMIM 251850) is characterized by intractable secretory diarrhea that usually starts shortly after birth (1). A late-onset form (3–4 months of life) with a better outcome has been described (1,3). Pathology shows shortened microvilli and villous atrophy with an increased number of secretory granules within enterocytes and membrane-bound inclusions (53). Studies of specific transporters showed that apical, but not basolateral, membrane transport systems are defective (54). It has recently been demonstrated that Rab8, a small guanosine triphosphate–binding protein, and myosin Vb (MYO5B) are involved in the intracellular transport of proteins to the apical level of the intestinal epithelial cells (6). A deficit of Rab8 in mice results in a pathologic picture almost identical to that of MID (6). Interestingly, although Rab8 mRNA and protein were absent from 1 MID patient's biopsy specimen, no mutations were identified in the Rab8 gene in that patient or in 2 other patients (6). Mutations in the MYO5B gene have recently been found in 9 of 10 separate families that included MID-affected members (55). MYO5B is a good candidate gene for MID. It has been shown to interact with Rab proteins in various recycling systems (55,56). MYO5B forms a complex with Rab protein and vesicles, and is thus required for enterocyte polarization. MYO5B deficiency may block the apical traffic of intracellular vacuoles containing microvilli, thereby determining aggregation of apically bound vesicles (55,56). However, other genetic causes of MID are possible.

Congenital Tufting Enteropathy

Congenital tufting enteropathy (CTE; OMIM 613217) is a rare autosomal recessive diarrheal disorder that presents in the neonatal period and has significant morbidity and mortality (1). It has recently been reported that mutations in the epithelial cell adhesion molecule (EpCAM) gene are responsible for CTE (24). The identification of EpCAM as the disease gene for CTE not only will improve the diagnosis of this condition but is also an important step toward understanding the pathophysiology and mechanisms involved in normal and abnormal intestinal morphogenesis and differentiation. Like most CAMs, the primary function of EpCAM is to mediate cell-cell interaction (6,24). This is supported by studies with L929 fibroblasts, which are normally incapable of cellular adhesion but form multicellular aggregates when expressing EpCAM, which is indicative of homotypic cell-cell interactions (57). EpCAM is known to recruit intracellular actin to the sites of homophilic contacts. EpCAM also colocalizes with E-cadherin in areas of cell-cell junctions and directly associates with the tight junction protein claudin-7 (57). The identification of CTE mutations and of their effect on the protein will advance our understanding of this disorder and provide new avenues of research directions in this field.


Enteric Anendocrinosis

In 2006, Wang et al (26) described a new disorder that they called “enteric anendocrinosis” (OMIM 610370). This condition is characterized by severe malabsorptive diarrhea and a lack of intestinal enteroendocrine cells caused by loss of function of neurogenin-3 (NEUROG-3) (27). NEUROG-3 is a basic helix-loop-helix transcriptional factor that drives endocrine cell fate in both the pancreas and intestine (26). This transcriptional factor is located at the end of a complicated cascade that induces differentiation of stem cells located at the base of the crypt-villus axis into 4 functional cell types: epithelial cells, mucus-secreting goblet cells, antimicrobial Paneth cells, and hormone-secreting enteroendocrine cells. The gastrointestinal tract is populated by more than 10 types of enteroendocrine cells that can be characterized by the types of hormones and paracrine factors that they secrete, and their distribution along the rostrocaudal axis. The number of patients described so far is too small to draw reliable conclusions about the typical clinical picture of enteric anendocrinosis. However, the diarrhea in this condition is undoubtedly of an osmotic nature. Although water is well tolerated, glucose-based oral rehydration solution leads to diarrhea and the patients continue to experience diarrhea while receiving carbohydrate-free cow's milk or amino acid formulas. These infants may be optimally managed with lifelong parenteral nutrition and limited enteral nutrition (36). Because NEUROG-3 is critical in the development of pancreatic-islet cells, patients with enteric anendocrinosis develop clinical evidence of diabetes (without anti-islet antibodies) between 4 and 10 years of age (26,27). Extensive evaluation of intestinal biopsies from patients with enteric anendocrinosis with different histologic and ultrastructural tools has shown severe enteroendocrine cell dysgenesis revealed by chromogranin A staining, whereas the mucosa is otherwise normal with a normal villus structure and a crypt-villus axis without pathologic inflammatory cell infiltration (26,27). Staining with various antibodies toward multiple gut hormones confirmed the generalized absence of enteroendocrine cells. What remains unclear is the role that enteroendocrine cells have in facilitating the absorption of simple nutrients.


Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX; OMIM 304930) is usually a fatal disorder unless treated with immunosuppressive therapy and/or bone marrow transplantation (29–31). This severe autoimmune disease manifests as a secretory diarrhea associated with dermatitis, diabetes mellitus, thyroiditis, and hematological disorders (29,30). Diarrhea often starts within 3 months of life; however, a later onset has occasionally been described (29,30). Diarrhea is of an inflammatory nature sometimes accompanied by mucous or blood discharge. Most patients develop a protein-losing enteropathy with greatly enhanced α-1-antitrypsine clearance in stools and hypoalbuminemia (29–31).

Patients with IPEX syndrome were found to harbor mutations in the forkhead box P3 (FOXP3) gene (31,32), which is the gene altered in scurfy mice, a mouse strain with severe autoimmunity and lymphoproliferation (32). With the exception of the zinc-finger motif, mutations have been found in each of the functional domains of the FOXP3 gene in individuals affected by IPEX, which indicates that each of these regions is important for correct FOXP3 function (58). In particular, mutations that affect the forkhead domain of the gene seem to result in a more severe clinical course (59). The FOXP3 gene encodes scurfin, a protein predominantly expressed in CD4+/CD25+ T cells that regulates T-cell activation (T reg cells) (Fig. 3) (60,61). This regulatory T-cell population has been shown to dampen immune responses in a variety of settings, including autoimmune diseases (6,61). FOXP3 coordinates the assembly of multiple transcriptional regulators (including histones, chromatin remodeling enzymes, RNA binding proteins, molecular chaperones, and transcription factors) into a complex. Depending on the physiologic status of expression, activation, and subcellular localization of the binding partners, FOXP3 may form differential transcription-regulating complexes through combinatorial interactions with these partners in response to such physiological stimuli as T-cell receptor stimulation, cell surface receptor co-stimulation, and anti- or proinflammatory signaling. Structural and biochemical insights into these complex ensembles will increase our understanding of FOXP3 function and facilitate the development of potential applications under disease conditions (60,61).

The crucial role of theFOXP3 gene in the activity of CD4+/CD25+ regulatory T cells. Mutations in the FOXP3 gene result in abnormal nonsuppressed T-cell reactivity, thereby leading to an uncontrolled multiorgan inflammatory reaction through overproduction of proinflammatory cytokines.

A recently identified mutation within an upstream noncoding region of FOXP3 results in a variant of IPEX syndrome that is associated with autoimmune and severe immunoallergic symptoms (eg, food allergy, hyper-IgE, atopic dermatitis, hypereosinophila) (62). Ablation of FOXP3-expressing cells in mice results in severe autoimmunity and lymphoproliferation (61). The suppressive function of T reg cells appears to depend on their expression of cytotoxic T lymphocyte antigen-4 (63), because selective loss of cytotoxic T lymphocyte antigen-4 in FOXP3-expressing cells results in severe autoimmunity. Additionally, loss of expression of interleukin (IL)-10 by FOXP3-expressing cells results in inflammation in the gut and lung (64). A syndrome related to IPEX has been described in 2 patients with mutations in the IL-2 receptor alpha (CD25) gene (65,66). The FOXP3 gene was found to be wild-type in both of these patients. In 1 patient, homozygous mutations in CD25 resulted in defective secretion of IL-10 by CD4+ T lymphocytes (66). Because IL-10 is important in the downregulation of inflammation, this finding suggests a possible mechanism by which homozygous mutations in CD25 may phenocopy IPEX.


The identification of disease genes is a step forward in the diagnostic approach to a patient in whom CDD is strongly suspected. However, it is conceivable that faster, less expensive molecular procedures will, in the near future, become available. This approach could spare the patient invasive procedures and limit complications associated with a delay in diagnosis. It is also possible that a more widespread use of efficient diagnostic tests may reveal a higher prevalence of the disorders classified within CDD. Furthermore, carrier and prenatal molecular diagnosis may help pediatricians to better manage the condition in the early stages of life (67). However, molecular diagnostics does not mean only identifying or excluding gene mutations; in some cases, “second-level” approaches (including in vitro functional studies) are necessary to define the effect of a mutation and confirm that a novel variant is indeed disease causing. Clinical laboratories must be equipped for such studies. Thus far, no clear genotype-phenotype correlation has been established in cases of CDDs. Nevertheless, proteomic studies may, in the near future, predict the phenotype of congenital diarrhea and guide physicians in the prescription of treatment procedures. Thus, close collaboration between clinical laboratory professionals and physicians may improve both diagnostics and research in the field of CDD, and may also lead to novel therapeutic approaches (68).


We thank Jean Ann Gilder for text editing.


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        congenital chloride diarrhea; congenital sodium diarrhea; enteric anendocrinosis; enteropathy; immune dysregulation; microvillous inclusion disease; polyendocrinopathy; tufting enteropathy; X-linked syndrome

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