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Approach to chronic diarrhea in neonates

and young infants (<6 months)
Approach to chronic diarrhea in neonates and young infants (<6 months)
Authors:
Jay R Thiagarajah, MD, PhD
Martin G Martin, MD, MPP
Section Editor:
B UK Li, MD

Deputy Editor:
Alison G Hoppin, MD

Literature review current through: Dec 2022. | This topic last updated: Jul 06, 2022.

INTRODUCTION — Diarrhea in young infants (<6 months) is relatively

common, generally mild, and often self-limited. Most cases in this age group are acquired,
caused by infection or a food protein intolerance.

When diarrhea begins within days of birth and is persistent (lasting more than two weeks)
or severe, several uncommon causes must be considered. These include congenital
anatomic anomalies of the intestine and a group of rare genetic disorders collectively
known as "congenital diarrheas and enteropathies" (CODEs) [1].

This topic review will outline a clinical approach to infants presenting with chronic diarrhea
before six months of age and particularly during the first six weeks of life. The acquired
causes will be outlined briefly, with links to more detailed discussions. The congenital
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causes, including CODEs, will be discussed in more detail. An overview of etiology for
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diarrhea in children of all ages is discussed separately. (See "Overview of the causes of
chronic diarrhea in children in resource-rich settings".)

OVERVIEW OF THE CAUSES OF DIARRHEA

DURING INFANCY — In resource-rich countries, a wide variety of
disorders cause chronic diarrheas in neonates and young infants (table 1) [2]. Most
frequently, chronic diarrhea is of allergic or infectious origin and is usually not associated
with any significant long-term sequelae. Less common causes of diarrhea in infants include
anatomic disorders such as gastroschisis or inflammatory disorders such as necrotizing
enterocolitis, which can require surgical resection that may be complicated by short bowel
syndrome and chronic diarrhea. In resource-limited countries, chronic diarrhea is usually
associated with serial enteric infections and environmental enteric dysfunction [3]. (See
"Persistent diarrhea in children in resource-limited countries".)

Congenital diarrheas and enteropathies (CODEs) are rare genetic disorders characterized by
persistent and often severe diarrhea presenting in the first weeks of life, often associated
with feeding intolerance, malabsorption, and growth failure [1]. Most CODEs are monogenic
and can be categorized into genetic variants that directly affect the intestinal epithelium or
those that affect the immune system, which secondarily impair epithelial function (table 2).

INITIAL EVALUATION
Assessment of the diarrhea — The first step is to determine the
presence and severity of the diarrhea using either qualitative or quantitative measures, as
appropriate to the clinical setting. Diarrhea in infancy is difficult to define based on stool
frequency or consistency since the normal range for these parameters can vary greatly. In
outpatient settings, the presence and severity of diarrhea can be inferred by the significant
deviation from the daily stool pattern and by the level of dehydration, presence of
electrolyte abnormalities, and poor weight gain. In inpatient settings, it may be possible to
quantify the stool output, in which case, diarrhea can be defined as stool volume of more
than 20 g/kg/day in a young infant. In children with ostomies, output of greater than 30
g/kg/day is considered excessive. (See "Pathogenesis of acute diarrhea in children".)

In infants, diarrhea is typically defined as acute if it lasts less than two weeks or chronic
when it persists for longer than two weeks.

Clinical features that suggest a cause — The second step is to do

a thorough history and physical examination to identify the most likely cause(s) of the
diarrhea (table 1), focusing on the following considerations:
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Acquired diarrheas Your activity: 11 p.v.

●Timing and severity – Acquired diarrheas can present at any time during infancy, usually
after the first few weeks of life. They vary in severity but are usually mild or moderate. By
contrast, diarrhea presenting immediately postnatally or requiring critical care intervention
is more likely to represent a congenital diarrhea or enteropathy (CODE). (See 'Congenital
diarrheas and enteropathies' below.)

●Triggers and associated features – Acquired diarrheas often have characteristic features
that permit a provisional diagnosis. Important causes to consider in an infant are listed
below; details of diagnosis and management are available in the linked topic reviews.

•Infections – Infections are the most common cause of diarrhea in either resource-rich or
resource-poor settings. Clues to enteric infections are sudden onset of symptoms, ill
contacts, and sometimes fever or vomiting. While most infectious diarrheas resolve within
two weeks and are therefore considered acute diarrheas, they occasionally persist,
especially in immunocompromised individuals. In some cases, persistent diarrhea after an
acute infection is caused by lingering mucosal injury with malabsorption, termed
"postinfectious enteropathy."

Most infectious diarrheas are caused by viruses, including rotavirus, cytomegalovirus,

adenovirus, and norovirus. Less common in resource-rich countries, but a significant factor
globally, are enteric bacterial pathogens, such as Salmonella enterica, Shigella spp,
Campylobacter jejuni, and pathogenic Escherichia coli [4]. (See "Diagnostic approach to
diarrhea in children in resource-rich countries" and "Approach to the child with acute
diarrhea in resource-limited countries".)

•Food-induced – Food protein-induced allergic proctocolitis is a common cause of bloody,

loose stools in young infants [5]. The infant is otherwise healthy, and there is no associated
vomiting or weight loss. In most cases, the triggering protein is cow's milk, ingested
through either breast milk or cow's milk-based formula. It can be induced by soy protein as
well. (See "Food protein-induced allergic proctocolitis of infancy".)

Food protein-induced enterocolitis syndrome (FPIES) is an uncommon gastrointestinal food

hypersensitivity that manifests as profuse, repetitive vomiting, sometimes with diarrhea,
leading to dehydration and lethargy in the acute setting or weight loss and failure to thrive
in a chronic form [6,7]. Symptoms of classic FPIES usually begin in early infancy, within one
to four weeks following introduction of cow's milk or soy protein. In extreme cases,
symptoms may begin within the first days of life. FPIES may present later in infancy if the
exposure is delayed, eg, when the trigger is a solid food. (See "Food protein-induced
enterocolitis syndrome (FPIES)".)

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•Prematurity or medical illness – Necrotizing enterocolitis usually presents in hospitalized

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premature infants with symptoms of watery or bloody diarrhea, abdominal distension,
feeding intolerance, and temperature instability [8,9]. Abdominal radiographs show dilated
bowel loops, often with intramural gas (pneumatosis intestinalis). Occasionally, necrotizing
enterocolitis develops in full-term infants, usually in the setting of an underlying medical
illness (eg, congenital heart disease or sepsis). (See "Neonatal necrotizing enterocolitis:
Clinical features and diagnosis".)

If necrotizing enterocolitis, intestinal atresias, or other congenital bowel malformations

require resection of substantial portions of bowel, this may lead to short bowel syndrome,
with associated malabsorption and diarrhea. (See "Management of short bowel syndrome
in children".)

Any medication or herbal supplement given to the infant should be reviewed as a possible
cause of diarrhea. As examples, antibiotics or products with high concentrations of fructose
commonly induce diarrhea [10].

Congenital diarrheas and enteropathies — CODEs are rare genetic

disorders with diverse mechanisms, characterized by persistent and often severe diarrhea
presenting in the first weeks of life (table 2).

●Timing and severity – Infants with CODEs typically have severe diarrhea from birth;
although, in some cases, diarrhea may start after the neonatal period, particularly when
caused by immune dysregulation. By contrast, acquired diarrheas due to infectious and
allergic conditions generally have a symptom-free postnatal period of at least a few weeks
before the diarrhea develops. In some CODEs, the volume of diarrhea may be so high that
less experienced parents, caregivers, and clinicians may confuse watery diarrhea for urine,
delaying recognition and appropriate consultation. In these cases, the infant may come to
medical attention because of dehydration or a persistent metabolic acidosis.

●Other features – Other clinical features that raise the possibility of CODEs include
polyhydramnios, multisystemic disease (eg, dysmorphism or other congenital anomalies or
immune deficiencies), and consanguinity or membership in a higher-risk population (eg,
Navajo) [11-16].

Other congenital disorders that may present with

diarrhea — Congenital abnormalities of the intestine sometimes present with diarrhea
in young infants. These usually can be diagnosed by fluoroscopic imaging, guided by the
characteristic clinical features of each disorder (table 1):

●Hirschsprung disease – Infants with Hirschsprung disease occasionally present with

Hirschsprung-associated enterocolitis, a potentially life-threatening illness with a sepsis-like
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picture including fever, vomiting, diarrhea, and abdominal distension. It can also present
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with subacute diarrhea and poor weight gain. More often, Hirschsprung disease presents
with symptoms of distal intestinal obstruction, including bilious emesis, abdominal
distension, delayed passage of meconium or stool, and constipation. An important clue is
explosive release of gas and stool during digital examination of the rectum ("squirt sign").
Infants with Down syndrome have a high risk of having Hirschsprung disease. (See
"Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Suspected
enterocolitis'.)

●Intestinal malrotation with intermittent volvulus – Intestinal malrotation with

intermittent volvulus occasionally presents with diarrhea, which may be bloody, and
intermittent abdominal pain. However, obstructive symptoms and vomiting are more
common presenting features. (See "Intestinal malrotation in children" and "Lower
gastrointestinal bleeding in children: Causes and diagnostic approach", section on
'Malrotation with midgut volvulus'.)

●Pseudo-obstruction – Chronic intestinal pseudo-obstruction (CIPO) is characterized by

impaired intestinal motility without anatomic obstruction, leading to diffuse bowel dilation,
abdominal distension, (usually) vomiting and constipation, and (sometimes) diarrhea [17].
Fluoroscopic imaging often reveals very dilated bowel loops and malrotation (similar to
congenital short bowel syndrome). It is rare in infants and is caused by congenital defects in
myopathies, neuropathies, or mitochondrial disorders. Some cases are associated with
dilated but unobstructed bladder (known as megacystis, microcolon, and hypoperistalsis
syndrome) [18,19]. (See "Chronic intestinal pseudo-obstruction: Etiology, clinical
manifestations, and diagnosis", section on 'Genetic'.)

●Congenital short bowel syndrome – This is a rare congenital defect that usually presents
during the first few days of life with generalized malabsorptive diarrhea and dilated bowel
loops despite lack of abdominal distension, often with bile-stained vomiting and failure to
thrive [20]. Fluoroscopic imaging often reveals malrotation (similar to CIPO), as well as the
abnormally shortened small bowel. Genetic and in utero developmental causes have been
identified. The presentation can be very similar to many CODE disorders.

EVALUATION FOR SUSPECTED CONGENITAL

DIARRHEAS AND ENTEROPATHIES — If the initial
evaluation suggests an acquired diarrhea, further evaluation depends on the suspected
type (see 'Acquired diarrheas' above). If the initial evaluation suggests the possibility of a
congenital diarrhea and enteropathy (CODE), an approach to further evaluation is described
below.

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Initial tests — For most patients with a suspected CODE, the initialYour

evaluation
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includes a battery of serum tests, stool tests, fluoroscopic upper gastrointestinal series, and
upper endoscopy and sigmoidoscopy (with colonoscopy for selected patients). A typical
sequence of testing is outlined below, but the order may vary depending on the patient's
presentation and clinical suspicion for a particular disorder (table 2).

Serum testing — Initial testing for all infants with a suspected CODE should include:
●Complete blood count with differential – Low hemoglobin suggests iron deficiency anemia
(eg, due to blood loss), leukocytosis suggests an infectious diarrhea, and low total
lymphocyte counts suggest a possible T or B cell deficiency.

●Electrolytes and trace elements (sodium [Na+], potassium [K+], chloride [Cl-], bicarbonate
[HCO3-], and glucose) – Hypokalemic metabolic acidosis (low K+ and HCO3-) is the most
common electrolyte pattern associated with most diarrheas. However, congenital chloride
diarrhea presents with a hypochloremic metabolic alkalosis [15]. Some of these disorders
are associated with hyperglycemia or diabetes that develop during infancy (Mitchell-Riley
syndrome [RFX6 gene mutation]) or later in life (immune dysregulation,
polyendocrinopathy, enteropathy, X-linked [IPEX] syndrome, intestinal anendocrinosis
[NEUROG3 gene mutation]).

●Systemic inflammatory biomarkers – Elevated levels of C-reactive protein or erythrocyte

sedimentation rate suggest an acute or chronic inflammatory condition, especially if the
diarrhea is bloody. In a young infant with chronic diarrhea, there are several possible causes
of inflammatory diarrhea, which are often categorized as very early-onset inflammatory
bowel disease, a congenital immunodeficiency, or both. (See "Clinical presentation and
diagnosis of inflammatory bowel disease in children", section on 'Very early-onset
inflammatory bowel disease'.)

●Liver function tests (alanine aminotransferase [ALT], aspartate transaminase [AST], alkaline
phosphatase) – The primary purpose of measuring AST and ALT is to screen for cholestatic
liver disease, which can cause chronic diarrhea due to bile acid insufficiency. In infants
receiving parenteral nutrition, abnormalities in these tests are often due to intestinal
failure-associated liver disease (see "Intestinal failure-associated liver disease in infants").
However, some monogenic CODEs are also associated with liver disease, including
microvillus inclusion disease, trichohepatoenteric syndrome, familial hemophagocytic
lymphohistiocytosis, and some autoimmune enteropathies.

●Albumin – Low serum albumin associated with diarrhea may suggest insufficient caloric
absorption or excessive protein loss, indicative of protein-losing enteropathy. (See "Protein-
losing gastroenteropathy".)

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The following tests also may be included in the initial evaluation if suggestive clinical
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features are present (table 2) or may be selected later in the evaluation based on the type of
diarrhea.

●If fat malabsorption is suspected (due to grossly fatty diarrhea, positive fecal fat screening,
abnormal serum lipids, or clinical features of cystic fibrosis):

•Lipid panel (triglycerides, cholesterol, high-density lipoprotein, low-density lipoprotein

[LDL]) – Very low LDL suggests abetalipoproteinemia. Elevated triglycerides and cholesterol
suggest cholestatic liver disease. (See "Low LDL-cholesterol: Etiologies and approach to
evaluation".)

•Fat-soluble vitamins (vitamin A, 25-hydroxyvitamin D, vitamin E [alpha-tocopherol],

prothrombin time [or international normalized ratio]) – Abnormally low concentrations of
fat-soluble vitamins in the absence of cholestasis suggests either exocrine pancreatic
insufficiency or impairment of enterocyte absorption of fat-containing nutrients (eg, due to
short bowel syndrome or disorders of fat transport and metabolism, such as
abetalipoproteinemia).

●If an immunodeficiency is suspected, the following tests should be included. Signs and
symptoms of an immunodeficiency may include bloody diarrhea, recurrent severe
infections, desquamating rash, diabetes mellitus, syndromic appearance, other congenital
anomalies, complete blood count abnormalities, an inflammatory infiltrate on endoscopic
biopsies, abnormal results of tests for severe combined immunodeficiency on newborn
screening, or family history of immunodeficiency (table 3). (See "Recognition of
immunodeficiency in the first three months of life".)

•Serum immunoglobulin G and A (IgG and IgA) level – Hypogammaglobulinemia suggests

either a primary humoral immunodeficiency or a globulin loss, as may occur in a protein-
losing enteropathy. The results should be interpreted using age-specific reference ranges
provided by the laboratory since there is a physiologic nadir during the first six months of
life (figure 1). (See "Primary humoral immunodeficiencies: An overview".)

•Specific T, B, and natural killer (NK) cell subset analysis by flow cytometry – To evaluate for
primary immunodeficiencies. (See "Flow cytometry for the diagnosis of primary
immunodeficiencies".)

●If an eczematous dermatitis is present (picture 1):

•Evaluate for IPEX syndrome. (See "IPEX: Immune dysregulation, polyendocrinopathy,

enteropathy, X-linked".)

●If acral or periorificial dermatitis (picture 2) is present:

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•Zinc concentration – A low zinc concentration suggests acrodermatitis enteropathica, a

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recessively inherited defect in intestinal zinc absorption. (See "Zinc deficiency and
supplementation in children", section on 'Acrodermatitis enteropathica'.)

Stool testing — Stool testing is a key component of the diagnostic evaluation for

infantile diarrheas. The first step is to evaluate for the most common infectious diarrheas, if
these have not already been excluded. This testing should include standard assessment of
enteric bacterial pathogens by culture and/or by polymerase chain reaction. Viral pathogens
such as rotavirus, cytomegalovirus, norovirus, and adenovirus should be tested by
polymerase chain reaction and/or enzyme-linked immunosorbent assay (ELISA).
Cytomegalovirus and adenovirus can also be assessed on the intestinal biopsy if performed
later in the evaluation.

The following tests require special stool-collection procedures and should be performed
during feeds with a full caloric challenge, as well as during fasting (unless the diarrhea
abates completely during fasting). The infant's dietary intake at the time of testing should
be recorded in detail to permit accurate interpretation of the stool test results.

Collection of accurate stool samples can be challenging because the diaper rapidly absorbs
stool water and stool is often mixed with urine in the diaper. To avoid loss of stool water in
an absorbent diaper, either reverse the diaper so that the nonabsorbent surface is on the
inside or line the diaper with a nonabsorbent surface, such as an adhesive wound dressing.
In addition, the stool must be separated from urine to allow for accurate stool sampling and
volume measurement. For boys, this usually can be accomplished by using an adhesive bag
to catch the urine. For girls (or for boys if the adhesive bag is not successful), a urine
catheter may be needed but should only be used for a few days to reduce the risk a of
secondary urinary tract infection. The stool samples should be packaged and sent for
testing as soon as possible after excretion.

Samples of stool should be sent for the following tests:

●Electrolytes – This is a key test in evaluating the nature of the diarrhea and for calculation
of the stool osmotic gap. Results are interpreted as follows (see "Pathogenesis of acute
diarrhea in children", section on 'Diarrhea classification'):

•High stool Na+ or Cl- suggests an electrolyte transport-related diarrhea. These include
congenital chloride diarrhea, congenital sodium diarrhea, hormone diarrhea (due to
VIPoma or serotonin-secreting tumor), or primary bile acid diarrhea (due to a defect in ileal
bile acid reuptake transporters [eg, SLC10A2]). In congenital chloride diarrhea, stool Cl- is
typically >120 mM [15]. In congenital sodium diarrhea, stool Na+ is typically >145 mM.

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•Stool osmotic gap – The stool osmotic gap can be calculated from the stool electrolytes
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using this calculator (calculator 1) or the following formula:

Stool osmotic gap = 290 – 2 × (stool Na+ + K+)

Results are expressed in mOsm/kg stool weight.

-A stool osmotic gap >100 mOsm/kg is high, suggesting diet-induced (osmotic) diarrhea,
usually due to unabsorbed carbohydrate moieties

-A stool osmotic gap <50 mOsm/kg is low, suggesting electrolyte transport-related

(secretory) diarrhea

-Intermediate results (50 to 100 mOsm/kg) are equivocal; they may be caused by a mixed
mechanism for diarrhea or artifact of the stool collection

●Osmolarity – Stool osmolarity should be measured if there is suspicion of improper

collection (eg, delay in collection or contamination with urine or water). This is also valuable
for any infant with profuse watery diarrhea to validate the other stool tests. Proper stool
collection is confirmed if the stool osmolality is isoosmolar to serum (approximately 290
mOsm). Stool osmolarity that is well above this threshold suggests contamination with
urine (or delay in sample processing, with evaporation of water or fermentation). Stool
osmolarity below this threshold suggests contamination with water (eg, factitious diarrhea).

●Reducing substances and pH – These tests serve as an initial screen for carbohydrate
malabsorption. They must be interpreted in the context of the infant's diet and age.
Neonates normally have some degree of carbohydrate malabsorption because of
immaturity of the disaccharidase enzymes (eg, lactase) on the intestinal brush border.

•Reducing substances >0.5 percent suggests possible malabsorption of disaccharides or

monosaccharides (although up to 0.75 percent can be normal in neonates and young
infants).

Glucose, lactose, and fructose are reducing sugars. Therefore, this test accurately reflects
carbohydrate malabsorption if the infant is breastfed or on a formula that contains these
sugars (eg, any cow's milk-based formula). By contrast, reducing substances may be
negative if the infant is on a formula that contains only sucrose (a nonreducing sugar).
However, malabsorbed sucrose is sometimes degraded by colonic bacteria to glucose and
fructose, resulting in a positive test for reducing substances.

•Low pH (<5.3) also suggests carbohydrate malabsorption; this finding is caused by

fermentation of malabsorbed carbohydrates by colonic bacteria, resulting in an abundance
of short-chain fatty acids.

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●Alpha-1 antitrypsin – Elevated alpha-1 antitrypsin in the stool reflects intestinal protein
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loss; patients with this finding may have low serum albumin and IgG as well. Causes include
a protein-losing enteropathy (eg, lymphangiectasia, diacylglycerol acyltransferase 1 [DGAT1]
deficiency, or complement decay-accelerating factor [CD55] deficiency) or an inflammatory
enteropathy (eg, immune dysregulation-associated enteropathies [autoimmune or
immunodeficiency] or postinfectious enteropathy). Alpha-1 antitrypsin is a protein that is
largely resistant to the action of intestinal proteases, unless it is secreted in the stomach.

●Fat – A qualitative or spot fecal fat (neutral or split) is a helpful initial screen for fat
malabsorption, although the sensitivity and specificity of this test are limited. Elevation in
neutral fat reflects increased unhydrolyzed mono-, di-, or triglyceride content in the stool
and is consistent with pancreatic insufficiency. Elevation in split fat reflects increased free
fatty acids in stool and correlates with fat malabsorption from injury to or loss of the
mucosal surface.

If fat malabsorption is suspected (eg, due to fatty-appearing stools or positive spot test), a
quantitative 72-hour fecal fat collection should be performed for a more accurate
assessment of fat malabsorption. The test requires a complete collection of all stools passed
during the collection period, as well as a record of dietary fat intake, to permit calculation of
the percentage of fat absorbed. Normal neonates and young infants absorb 75 to 80
percent of dietary fat, and this proportion increases with age; a healthy six-month-old infant
absorbs 80 to 95 percent of dietary fat.

●Elastase – Stool elastase should be measured to screen for pancreatic insufficiency.

Elastase is secreted by the pancreas, and low values (<200 mcg/g) suggest pancreatic
insufficiency. Abnormal results also may be seen in any type of high-volume diarrhea due to
the effects of dilution.

●Inflammation – The following tests serve to screen for an inflammatory process:

•Occult blood – A positive test for occult blood (Hemoccult) indicates or confirms the
presence of blood in the stool and could indicate an inflammatory process. However,
positive tests are common in infants with severe diarrhea of any cause, due to skin
irritation. Therefore, the results should only be used as supportive evidence for an
inflammatory process.

•Inflammatory markers – Elevated calprotectin or lactoferrin are correlated with the

presence of mucosal intestinal inflammation.

Imaging — Infants with suspected CODEs should be evaluated with a fluoroscopic

upper gastrointestinal series with small bowel follow-through (UGI/SBFT). This is particularly
important for infants presenting with any signs or symptoms of obstruction, including

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vomiting and abdominal distension, or with signs of proximal bowel obstruction on

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conventional abdominal radiograph. The main purpose is to evaluate for malrotation,
congenital short bowel syndrome, and chronic intestinal pseudo-obstruction (CIPO).
Congenital short bowel syndrome and CIPO are characterized by very dilated bowel loops
and are often associated with malrotation. (See 'Other congenital disorders that may
present with diarrhea' above.)

If distal bowel obstruction is suspected based on the conventional radiograph or other

clinical features (eg, Hirschsprung disease), an unprepped contrast enema is indicated. (See
"Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Contrast enema'.)

Endoscopy/histology — Endoscopic evaluation of the bowel is almost always

needed in the evaluation of an infant for a suspected CODE. Regardless of the nature of the
diarrhea, evaluation of endoscopic biopsies is a key step, allowing prioritization of further
testing (see 'Diagnostic algorithm' below). In general, at least an upper endoscopy
(esophagogastroduodenoscopy) should be performed to assess small intestinal structure.
Sigmoidoscopy is often performed as well to assess colonic changes, especially if there is
any suspicion of colitis. Samples should be sent for histologic examination and a sample
prepared for electron microscopy.

Interpretation — Initial evaluation of hematoxylin and eosin (H&E)-stained biopsy

sections should focus on overall intestinal epithelial architecture, namely villus-to-crypt
ratio, abundance of the epithelial cell types and microscopic structure, and immune cell
composition in the lamina propria and intraepithelial compartments [21]. Findings of note
for infants with suspected CODEs are (table 2):

●Normal villus and crypt architecture and ratio – Normal villus architecture is seen in several
different conditions in which diarrhea is caused by intracellular abnormalities that affect
digestion or absorption of nutrients. These include specific carbohydrate malabsorption
disorders or defects in electrolyte transport, such as congenital chloride or sodium
diarrheas. Normal villus and crypt architecture are also seen in diarrhea caused by defects
of enteroendocrine cell development or function (eg, enteric anendocrinosis [NEUROG3
deficiency], proprotein convertase type 1 [PCSK1] deficiency, or Mitchell-Riley syndrome
[RFX6]).

●Abnormal villus and crypt architecture and villus-to-crypt ratio – Villi that are short or
flattened may be associated with either crypt hyperplasia or crypt hypoplasia; these
findings may be seen in defects of enterocyte structure, vesicular trafficking, differentiation,
and immune-mediated conditions. Specifically, villus blunting and apoptosis at the crypt
base suggests an immune-mediated disorder. Epithelial crowding and disorganization at
the top of the villus is found in tufting enteropathy and is associated with crypt hyperplasia.

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●The relative abundance and distribution of cells in the stem cell-based compartment and
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differentiated cells of the epithelium can be appreciated by H&E and by cell type-specific
staining. Selective depletion of differentiated cell types may be associated with autoimmune
enteropathies and endocrinopathies. Enteroendocrine cell loss is seen in enteric
anendocrinosis (NEUROG3 deficiency).

●Abnormal abundance or absence of mononuclear cells in the lamina propria and

intraepithelial compartments suggest an immune-mediated disorder. A dominance of
eosinophilic infiltrates within the mucosa and lamina propria, associated with villus
blunting, may be an indicator of eosinophilic gastroenteritis.

●Electron microscopy is performed to assess the presence, relative size, and location of the
microvilli and to identify intracellular microvillus inclusions (characteristic of microvillus
inclusion disease) or abnormal vesicular structures suggestive of disorders of intracellular
trafficking (eg, due to mutations in the STX3 gene, or TTC37). For practical reasons, electron
microscopy is usually ordered for all patients with suspected CODEs, but it is most relevant
for patients with abnormal villus architecture on H&E stain and lack of inflammatory
infiltrate. One practical option is to prepare a sample for electron microscopy but defer the
actual test until the H&E results are available.

Immunohistochemical staining — Further evaluation of the endoscopic

biopsies depends upon the suspected disorder (table 2). In particular, infants with watery
diarrhea and abnormal villus architecture should be evaluated with special stains and
electron microscopy to assess for microvillus inclusion disease or tufting enteropathy.

●If the H&E stain shows normal villus architecture, stain for enteroendocrine cells
(chromogranin A) to evaluate for enteric anendocrinosis (NEUROG3 deficiency).

●If the H&E stain showed abnormal villus architecture, perform the following [22,23]:

•CD10/villin immunostaining (to evaluate for microvillus inclusion disease)

•MOC-31 immunostaining (to evaluate for congenital tufting enteropathy)

•Frozen sections-staining with oil red O if lipid trafficking disorders are under consideration

•Electron microscopy to evaluate for abnormalities of the microvilli if not already performed
(see 'Interpretation' above)

●If an immunodeficiency is suspected clinically or if there is an abundance or paucity of

immune cells on the initial biopsy, further evaluation may include further specific markers
for immune cell subtypes.

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Diagnostic algorithm — The evaluation for CODEs is initiated following

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exclusion of more commonly acquired diarrhea [1]. (See 'Acquired diarrheas' above.)

For an infant with a suspected CODE, the sequence and interpretation of the initial serum
and stool tests and endoscopic findings is facilitated by categorizing the stool by its general
appearance into one of three categories, which help to narrow the diagnostic possibilities
(table 2):

●Watery stool is characterized by a high liquid content, often with very little form, which can
be mistaken for urine.

●Fatty stools are usually foul smelling, can have a bulky or "fluffy" appearance, are pale in
color, and/or are spot fecal fat-positive.

●Bloody stools contain gross blood mixed in with stools. The presence of large volumes of
bright red blood or melena should trigger evaluation of vascular or anatomic
gastrointestinal bleeding as well as bacterial infection.

Genetic testing can be performed after the diagnostic possibilities are narrowed down by
initial testing. Alternatively, these tests can be performed earlier in the evaluation, especially
if the infectious work-up is negative and there are clear factors to suspect a monogenic
diarrheal disease, such as significant consanguinity, a family history of gastrointestinal
disease in infancy, and clinical indicators such as diarrhea severity and neonatal onset. (See
'Genomic testing' below.)

Evaluation of watery diarrhea

●Trial of fasting – Following documentation of diarrheal output with normal feeding,
evaluation should include a trial of withholding feeds for a minimum of 24 hours, with
assessment of stool output and stool electrolytes (if possible), preferably while receiving
intravenous fluids.

•If diarrheal volume is unchanged or is minimally changed following fasting, this suggests
electrolyte transport-related diarrhea (also known as secretory diarrhea). These disorders
are usually associated with elevated stool electrolytes with a low osmotic gap. They include
congenital chloride diarrhea, congenital sodium diarrhea, hormone diarrhea (due to
VIPoma or serotonin-secreting tumors), or primary bile acid diarrhea. (See 'Stool testing'
above.)

•If diarrheal volume significantly improves during fasting, this suggests diet-induced
diarrhea (also known as osmotic diarrhea).

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•Other types of diarrhea have mixed mechanisms, and the fasting trial may result in no
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change, improvement, or equivocal results. This is true for disorders with epithelial
structural defects (eg, microvillus inclusion disease, tufting enteropathy).

●If diet-induced diarrhea is present, the next step is to determine if this is due to
unabsorbed carbohydrates, which are the most common cause. Carbohydrate
malabsorption is supported by the presence of reducing substances in the stool and a low
pH. Further support comes from a trial of feeds with a carbohydrate-free formula (eg, Ross
Carbohydrate Free); significant improvement on this diet supports the diagnosis of
carbohydrate malabsorption. If the child is clinically stable, the dietary trial should be done
with bolus feeds of full-strength formula administered at a full caloric load.

If diarrhea persists on a carbohydrate-free diet, consider the disorders associated with a

generalized malabsorption, which include enteric endocrinopathies (eg, enteric
anendocrinosis or dysendocrinosis) and congenital short gut. In this setting, challenges with
glucose (eg, Pedialyte) alone would also exacerbate the diarrhea.

●If carbohydrate malabsorption is present, the next step is to determine if there is

selective malabsorption of a specific carbohydrate:

•The specificity of carbohydrate absorption can be evaluated by dietary challenges with

various disaccharides (sucrose, lactose, and maltose) and monosaccharides (glucose and
fructose) and assessed by changes in stool volume. Breath hydrogen testing also could
identify the specific carbohydrate, but the use of this test is limited because accurate breath
collection is very challenging in infants [24].

•If an endoscopy is performed, disaccharidase activity assays for lactase, sucrase, maltase,
palatinase, and trehalase can be measured in biopsies of the proximal small bowel in an
attempt to diagnose disaccharidase deficiency. However, these enzymatic assays can be
unreliable due to poor sampling or specimen handling. In the setting of inflammation or
villus atrophy, the loss of mucosal epithelium results in secondary and generalized
disaccharidase deficiency.

●If there is no clear evidence of a selective carbohydrate malabsorption, the next steps are:

•Esophagogastroduodenoscopy and flexible sigmoidoscopy with biopsies for histologic

analysis if not contraindicated by the clinical status of the infant [25]. Biopsies should
include samples for both routine histology and electron microscopy. (See
'Endoscopy/histology' above.)

•In addition, the patient should be evaluated for a possible protein-losing enteropathy,
which is suggested by elevated levels of alpha-1 antitrypsin in the stool, often in conjunction
with low serum albumin, low IgG, and lymphopenia.

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A protein-losing enteropathy may be caused by a compromised epithelial barrier, as in an

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immune dysregulation-associated enteropathy (autoimmune or immunodeficiency-related);
lymphangiectasia; or certain enterocyte-specific monogenic disorders, including DGAT1 or
CD55 deficiency. (See 'Initial tests' above.)

●Alternatively, the endoscopy can be performed earlier in the diagnostic sequence (before
the dietary trials). Early endoscopy and biopsy helps to narrow the diagnostic categories by
identifying abnormalities in villus architecture and determining if an inflammatory infiltrate
is present. These findings often streamline the remaining steps in the diagnostic evaluation,
including dietary trials and genetic testing.

Evaluation of fatty diarrhea — The first step in evaluation of fatty diarrhea is

to confirm the presence of excessive fat in the stool by spot testing for neutral and split
(hydrolyzed) fat. If possible, a 72-hour stool fat collection should be performed for
quantitative evaluation of fecal fat. Stool elastase also should be measured.

●The combination of elevated fecal fat and low fecal elastase suggests exocrine pancreatic
insufficiency, such as cystic fibrosis, although fecal elastase can be falsely low (false-positive)
with high-volume diarrhea. Pancreatic insufficiency is confirmed by the responsiveness of
diarrheal symptoms to enzyme replacement therapy [26]. (See "Cystic fibrosis: Assessment
and management of pancreatic insufficiency", section on 'Fecal elastase'.)

●The combination of elevated fecal fat and normal fecal elastase suggests intestinal fat
malabsorption due to mucosal abnormalities or a disorder of fat transport and metabolism,
such as chylomicron retention disease and abetalipoproteinemia. These disorders of fat
transport and metabolism are also characterized by fat-laden enterocytes in histologic
sections and serum lipid abnormalities, especially low LDL.

Patients with suspected or confirmed fat malabsorption also should be evaluated for
associated fat-soluble vitamin deficiencies. (See 'Serum testing' above.)

Evaluation of bloody diarrhea — The presence of gross blood implies

significant colitis, and further evaluation should include stool inflammatory markers
(calprotectin or lactoferrin), colonoscopy, and esophagogastroduodenoscopy. The presence
of inflammatory changes in histologic sections should precipitate further investigation for
immune dysregulation-associated enteropathies, which include autoimmune enteropathies
and primary immunodeficiencies. Some of these disorders are classified as infantile very
early-onset inflammatory bowel disease. (See "Approach to the child with recurrent
infections" and "Primary humoral immunodeficiencies: An overview" and "Laboratory
evaluation of the immune system" and "Genetic testing in patients with a suspected primary
immunodeficiency or autoinflammatory syndrome" and "Clinical presentation and diagnosis

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of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel

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disease'.)

It should be noted that not all forms of immune dysregulation-related enteropathies are
associated with bloody stools. Some of these disorders present with watery diarrhea or with
diet-induced characteristics (improves with fasting, low stool Na+, and high osmolar gap),
and others present with an intermediate osmolar gap [27].

Genomic testing — Advances in sequencing technologies have allowed

diagnosis of new and unknown genetic causes of diarrhea. In cases where there is a high
suspicion of a CODE diagnosis but the specific etiology requires confirmation, either
targeted genetic testing (Sanger sequencing) or whole-exome sequencing (WES) can
identify the genetic cause and potentially direct management. Trio WES that includes the
proband and biologic parents is considerably more informative and should be encouraged
whenever possible. (See "Next-generation DNA sequencing (NGS): Principles and clinical
applications".)

In cases of a suspected CODE where the diagnosis based on clinical evaluation is unclear,
WES should be performed to identify a possible causative genetic mutation. However, WES
may not detect genetic defects in genes due to technical reasons (eg, regions with poor
coverage, large insertions and deletions, and mutations in regulatory and splice or intronic
regions). Moreover, interpretation of WES can be challenging because it provides data
regarding "variants" in multiple genes, many of which are unexpected, outside the gene(s)
of interest and of unknown significance. These findings require interpretation by a clinical
geneticist and functional confirmation by tertiary centers before a diagnosis can be
confirmed. In cases where a monogenic disorder is likely despite a normal or inconclusive
WES, whole-genome sequencing should be considered.

SOCIETY GUIDELINE LINKS — Links to society and government-

sponsored guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Chronic diarrhea".)

SUMMARY AND RECOMMENDATIONS

●Definitions – During infancy, stool volumes of >20 g/kg/day are considered diarrhea. If
symptoms persist for more than two weeks, it is classified as chronic. (See 'Assessment of
the diarrhea' above.)

●Acquired diarrheas – Acquired forms of chronic diarrhea result from infectious, allergic,
or underlying congenital anomalies or medical disorders (table 1). If the latter require
resection of significant portions of the bowel, they may lead to short bowel syndrome, with
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associated malabsorption and chronic diarrhea. Some cases of persistent or recurrent

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infectious diarrhea are caused by a primary immunodeficiency. Food protein-induced
allergic proctocolitis (due to cow's milk protein) is a common benign cause of bloody stools
in young infants. (See 'Acquired diarrheas' above.)

●Congenital diarrheas and enteropathies (CODEs) – CODEs are uncommon but serious
causes of chronic diarrhea in neonates and young infants. Most CODEs are monogenic and
can be categorized into genetic variants that directly affect the intestinal epithelium and
impair absorption of nutrients or electrolyte flux, or those that affect the immune system,
which, due to inflammation, secondarily impair epithelial function (table 2).

•Clinical presentation – Most CODEs present with severe diarrheal symptoms that begin
within the first weeks of life, although some CODEs, particularly those caused by immune
dysregulation, may present after the neonatal period. Other clinical features that raise the
possibility of a CODE include membership in a population with a high frequency of certain
genetic variants or consanguinity, multisystemic disease (eg, dysmorphism or other
congenital anomalies or immune deficiencies), and polyhydramnios. (See 'Congenital
diarrheas and enteropathies' above.)

•Evaluation – For most patients with a suspected CODE, the initial evaluation includes a
battery of serum tests, stool tests, and upper endoscopy (with colonoscopy for selected
patients). A few of these tests may be selected later in the evaluation based on the type of
diarrhea.

-Standard serum testing includes complete blood count, electrolytes, erythrocyte

sedimentation rate or C-reactive protein, liver function tests, and albumin. Additional
testing for selected patients includes a lipid panel, immunoglobulin G and A (IgG and IgA),
and T and B cell subsets. (See 'Serum testing' above.)

-Standard stool tests consist of electrolytes (to calculate an osmotic gap), reducing
substance and pH, alpha-1 antitrypsin, elastase, calprotectin, and culture and/or
polymerase chain reaction techniques to rule out bacterial or other infectious causes. Some
of these tests require special collection procedures to ensure an accurate result. (See 'Stool
testing' above.)

The results of these tests inform the diagnostic steps used to determine the most likely type
of CODE. For watery diarrhea, trials of fasting or carbohydrate-free formula help to narrow
the diagnostic possibilities. Once the likely category of CODE is identified, functional testing
or genomic testing can be used to confirm the specific diagnosis. (See 'Diagnostic algorithm'
above and 'Genomic testing' above.)
1. Thiagarajah JR, Kamin DS, Acra S, et al. Advances in Evaluation of Chronic Diarrhea in
Infants. Gastroenterology 2018; 154:2045.

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2. Bhutta ZA, Ghishan F, Lindley K, et al. Persistent and chronic diarrhea and
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malabsorption: Working Group report of the second World Congress of Pediatric
Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39
Suppl 2:S711.
3. Guerrant RL, DeBoer MD, Moore SR, et al. The impoverished gut--a triple burden of
diarrhoea, stunting and chronic disease. Nat Rev Gastroenterol Hepatol 2013; 10:220.
4. Kotloff KL, Nataro JP, Blackwelder WC, et al. Burden and aetiology of diarrhoeal disease
in infants and young children in developing countries (the Global Enteric Multicenter
Study, GEMS): a prospective, case-control study. Lancet 2013; 382:209.
5. Koletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of
cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical
guidelines. J Pediatr Gastroenterol Nutr 2012; 55:221.
6. Caubet JC, Szajewska H, Shamir R, Nowak-Węgrzyn A. Non-IgE-mediated
gastrointestinal food allergies in children. Pediatr Allergy Immunol 2017; 28:6.
7. Leonard SA, Nowak-Węgrzyn A. Food Protein-Induced Enterocolitis Syndrome. Pediatr
Clin North Am 2015; 62:1463.
8. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364:255.
9. Frost BL, Modi BP, Jaksic T, Caplan MS. New Medical and Surgical Insights Into Neonatal
Necrotizing Enterocolitis: A Review. JAMA Pediatr 2017; 171:83.
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11. Pohl JF, Shub MD, Trevelline EE, et al. A cluster of microvillous inclusion disease in the
Navajo population. J Pediatr 1999; 134:103.
12. Little BB, Malina RM. Inbreeding avoidance in an isolated indigenous Zapotec
community in the valley of Oaxaca, southern Mexico. Hum Biol 2005; 77:305.
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Congenital Tufting Enteropathy in the Arabic Gulf. Eur J Med Genet 2011; 54:319.
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2019; 214:151.
16. Macraigne L, Allaf B, Buffat C, et al. Prenatal biochemical diagnosis of two forms of
congenital diarrheal disorders (congenital chloride diarrhea and congenital sodium
diarrhea): A series of 12 cases. Prenat Diagn 2021; 41:434.
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Gastroenterol Nutr 1997; 24:102.
18. Gosemann JH, Puri P. Megacystis microcolon intestinal hypoperistalsis syndrome:
systematic review of outcome. Pediatr Surg Int 2011; 27:1041.

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19. Prathapan KM, King DE, Raghu VK, et al. Megacystis Microcolon Intestinal
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Hypoperistalsis Syndrome: A Case Series With Long-term Follow-up and Prolonged
Survival. J Pediatr Gastroenterol Nutr 2021; 72:e81.
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Topic 117487 Version 15.0

References

1 : Advances in Evaluation of Chronic Diarrhea in Infants.

2 : Persistent and chronic diarrhea and malabsorption: Working Group report of the second
World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

3 : The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease.

4 : Burden and aetiology of diarrhoeal disease in infants and young children in developing
countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.

5 : Diagnostic approach and management of cow's-milk protein allergy in infants and children:
ESPGHAN GI Committee practical guidelines.

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3/19/23, 10:20 AM Approach to chronic diarrhea in neonates and young infants (&lt;6 months) - Uptodate Free

6 : Non-IgE-mediated gastrointestinal food allergies in children. Your activity: 11 p.v.

7 : Food Protein-Induced Enterocolitis Syndrome.

8 : Necrotizing enterocolitis.

9 : New Medical and Surgical Insights Into Neonatal Necrotizing Enterocolitis: A Review.

10 : Drug-induced diarrhoea.

11 : A cluster of microvillous inclusion disease in the Navajo population.

12 : Inbreeding avoidance in an isolated indigenous Zapotec community in the valley of

Oaxaca, southern Mexico.

13 : A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf.

14 : Clustering of private mutations in the congenital chloride diarrhea/down-regulated in

adenoma gene.

15 : Clinical Features, Molecular Genetics, and Long-Term Outcome in Congenital Chloride

Diarrhea: A Nationwide Study in Japan.

16 : Prenatal biochemical diagnosis of two forms of congenital diarrheal disorders (congenital

chloride diarrhea and congenital sodium diarrhea): A series of 12 cases.

17 : Diagnosis and treatment of chronic intestinal pseudo-obstruction in children: report of

consensus workshop.

18 : Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review of outcome.

19 : Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: A Case Series With Long-

term Follow-up and Prolonged Survival.

20 : Congenital Short Bowel Syndrome: from clinical and genetic diagnosis to the molecular
mechanisms involved in intestinal elongation.

21 : Newcomers in paediatric GI pathology: childhood enteropathies including very early onset

monogenic IBD.

https://pro.uptodatefree.ir/show/117487 20/21
3/19/23, 10:20 AM Approach to chronic diarrhea in neonates and young infants (&lt;6 months) - Uptodate Free

22 : Evaluation of intestinal biopsies for pediatric enteropathy: a proposed Your activity: 11 p.v.
immunohistochemical panel approach.

23 : Villin immunohistochemistry is a reliable method for diagnosing microvillus inclusion

disease.

24 : Quantitative assay of disaccharidase activities of small intestinal mucosal biopsy

specimens in infancy and childhood.

25 : Complications of pediatric EGD: a 4-year experience in PEDS-CORI.

26 : Enzyme replacement therapy of exocrine pancreatic insufficiency in man. Relations

between in vitro enzyme activities and in vivo potency in commercial pancreatic extracts.

27 : Autoimmunity and Primary Immunodeficiency Disorders.

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