INVITED REVIEW

Congenital Diarrheal Disorders: Improved Understanding

of Gene Defects Is Leading to Advances in Intestinal
Physiology and Clinical Management
Roberto Berni Canani, !Gianluca Terrin, yGiuseppe Cardillo, yRossella Tomaiuolo,
and yGiuseppe Castaldo

ABSTRACT
Congenital diarrheal disorders (CDD, Online Mendelian Inheritance in Man
[OMIM] 251850) represent one of the most challenging clinical conditions
for pediatric gastroenterologists because of the severity of the clinical
picture and the broad range of disorders in its differential diagnosis. The
number of conditions included within CDD has gradually increased. Recent
advances made in the pathophysiology of these conditions have led to a
better understanding of the more common diarrheal diseases. Based on the
body of data accumulated in recent years, we suggest that CDD be classified
in 4 categories depending on the alteration in absorption and transport of
nutrients and electrolytes, enterocyte differentiation and polarization, enteroendocrine cell differentiation, and modulation of the intestinal immune
response. Our knowledge of the genes responsible for CDD is also rapidly
increasing, thanks to linkage studies based on genome-wide analysis of
polymorphisms. In this context, 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. Furthermore, carrier and prenatal molecular
diagnosis may help pediatricians better manage the condition in the early
stages of life.
Key Words: congenital chloride diarrhea, congenital sodium diarrhea,
enteric anendocrinosis, enteropathy, immune dysregulation, microvillous
inclusion disease, polyendocrinopathy, tufting enteropathy, X-linked
syndrome

(JPGN 2010;50: 360366)

ongenital diarrheal disorders (CDD, Online Mendelian

Inheritance in Man [OMIM] 251850) are a group of rare
chronic enteropathies characterized by a heterogeneous etiology,

Received June 5, 2009; accepted December 22, 2009.

From the !Department of Pediatrics, and the yCEINGE-Biotecnologie
Avanzate, University of Naples Federico II, Naples, Italy.
Address correspondence and reprint requests to Roberto Berni Canani, MD,
PhD, Department of Pediatrics, University of Naples Federico II,
Via S Pansini 5, 80131 Naples, Italy (e-mail: berni@unina.it).
The study was supported by grants from Ministry of Health and Regione
Campania (L.229/99, 2004-05 and L.502/94, 2004, 2005); Regione
Campania (DGRG 2362/07); MiUR (Ministry of University and
Research), PS 35-126/Ind; Agenzia Italiana del Farmaco (AIFA) grant
code FARM6FJ728.
The authors report no conflicts of interest.
Copyright # 2010 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3181d135ef

360

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 (14). 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 (46). 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).

ABSORPTION AND TRANSPORT OF

NUTRIENTS AND ELECTROLYTES
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,
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Congenital Diarrheal Disorders

4
FIGURE 1. The mechanisms involved in the pathogenesis of congenital diarrheal disorders.
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 I675676ins
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
www.jpgn.org

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

361

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Berni Canani et al

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TABLE 1. Molecular basis of the main forms of congenital diarrheal diseases: defects of digestion, absorption, and transport of
nutrients and electrolytes
Disease
Disaccharidase deficiency
Congenital lactase deficiency
Sucrase-isomaltase deficiency
Maltase-glucoamylase deficiency
Ion and nutrient transport defects
Glucose-galactose malabsorption
Fructose malabsorption
Fanconi-Bickel syndrome
Cystic fibrosis
Acrodermatitis enteropathica
Congenital chloride diarrhea
Congenital sodium diarrhea
Lysinuric protein intolerance
Congenital bile acid diarrhea
Pancreatic insufficiency
Enterokinase deficiency
Trypsinogen deficiency
Pancreatic lipase deficiency
Lipid trafficking
Abetalipoproteinemia
Hypobetalipoproteinemia
Chylomicron retention disease

Gene

Location

Function

References

LCT
EC 3.2.1.48
MGAM

2q21
3q25-q26
7q34

Lactase-phlorizin hydrolase activity

Isomaltase-sucrase
Maltase-glucoamylase activity

(7)
(8)
(7,9)

SGLT1
GLUT5
GLUT2
CFTR
SLC39A4
DRA
SPINT2!
SLC7A7

22q13.1
1p36
3q26
7q31.2
8q24.3
7q22-q31.1
19q13.1
14q11

(10,11)
(10,12)
(13)
(14)
(15)
(16)
(17,18)
(18)

ABAT

13q3

Na/glucose cotransporter
Fructose transporter
Basolateral glucose transporter
cAMP-dependent Cl# channel
Zn2 transporter
Cl#/base exchanger
Serine-protease inhibitor
Hydrolyzes endo-/exopeptidases
Amino acid basolateral transport
Ileal Na/bile salt transporter

PRSS7
PRSS1
PNLIP

21q21
7q35
10q26.1

Proenterokinase
Trypsinogen synthesis
Hydrolyzes triglycerides to fatty acids

(20,21)
(20,21)
(21)

MTP
APOB
SAR1B

4q22
2p24
5q31.1

Transfer lipids to apolipoprotein B

Apolipoprotein that forms chylomicrons
Intracellular chylomicron trafficking

(22,23)
(22,23)
(23)

(19)

cAMP cyclic adenosine monophosphate.

!
This mutation has been associated with the syndromic form of congenital sodium diarrhea.

TABLE 2. Molecular basis of the main forms of congenital diarrheal diseases: defects of enterocyte differentiation and polarization
Disease
Microvillous inclusion disease
Congenital tufting enteropathy
Syndromic diarrhea

Gene

Location

Function

References

MY05B
EpCAM
Unknown

18q21
2p21
Unknown

Intracellular protein trafficking

Cell-cell interaction
Unknown

(55)
(24)
(25)

EpCAM epithelial cell adhesion molecule.

affected by CLD to butyrate (44). In fact, depending on the patients

genotype, mutations in the above-mentioned regulatory regions of
the SLC26A3 gene could affect gene transcription rate.
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 (4648). In patchclamp experiments, protein kinase Astimulated CFTR channel
activity was 6-fold higher in HEK293 cells coexpressing both
SLC26 exchanger and CFTR than in HEK293 cells expressing
CFTR alone (16,44,4648). Mutations may impair the interactions
between channels and thus reduce the effect of butyrate therapy.

TABLE 3. Molecular basis of the main forms of congenital diarrheal diseases: defects of enteroendocrine cells differentiation
Disease
Enteric anendocrinosis
Enteric dysendocrinosis
Proprotein convertase 1 deficiency

Gene

Location

Function

References

NEUROG3
Unknown
PCSK1

10q21.3
Unknown
5q15-q21

Enteroendocrine cell fate determination

Enteroendocrine cell function
Prohormone processing

(26,27)
(26,27)
(28)

NEUROG-3 neurogenin-3.

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TABLE 4. Molecular basis of the main forms of congenital diarrheal diseases: defects of modulation of intestinal immune response
Disease

Gene

Location

Function

References

IPEX
IPEX-like syndrome
Immunodeficiency-associated autoimmune enteropathy
APS-1
Autoimmune enteropathy with colitis-GAGD

FOXP3
Unknown
Unknown
AIRE
Unknown

Xp11.23-q13.3
Unknown
Unknown
21p22.3
Unknown

Transcription factor
Unknown
Unknown
Regulation gene transcription
Unknown

(2932)
(2932)
(33)
(34)
(35)

APS-1 autoimmune polyglandular syndrome-1; FOXP3 forkhead box P3; GAGD generalized autoimmune gut disorder; IPEX immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome.

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.

ENTEROCYTE DIFFERENTIATION AND

POLARIZATION
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 (34 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,

FIGURE 2. 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).
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363

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Berni Canani et al
but not basolateral, membrane transport systems are defective (54).
It has recently been demonstrated that Rab8, a small guanosine
triphosphatebinding 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 patients 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.

ENTEROENDOCRINE CELL DIFFERENTIATION

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 helixloop-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.

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Although water is well tolerated, glucose-based oral rehydration

solution leads to diarrhea and the patients continue to experience
diarrhea while receiving carbohydrate-free cows 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.

MODULATION OF THE INTESTINAL IMMUNE

RESPONSE
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 (2931). 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 a-1-antitrypsine clearance in stools and hypoalbuminemia (2931).
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 (Treg 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).
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Congenital Diarrheal Disorders

CONCLUSIONS
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, secondlevel 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).
Acknowledgments: We thank Jean Ann Gilder for text editing.

REFERENCES

FIGURE 3. The crucial role of the FOXP3 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 Treg 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.
www.jpgn.org

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