PATHOLOGY OF
INTESTINAL MOTOR
D I S O R D E R S IN
CHILDREN
Raj P. Kapur, MD, PhD
KEYWORDS
 Intestinal pseudo-obstruction  Hirschsprung disease  Hypoganglionosis  Neuronal dysplasia
 Visceral myopathy  Visceral neuropathy  Dysmotility  Rectal biopsy
ABSTRACT
V
aried intestinal neuromuscular pathologies
are responsible for Hirschsprung disease
and other forms of chronic pseudo-
obstruction that are encountered in pediatrics.
Pathologically distinct subtypes discussed in this
review include aganglionosis, hypoganglionosis,
neuronal intranuclear inclusion disease, ganglioni-
tis, degenerative neuropathy, diffuse ganglioneur-
omatosis, neuronal dysplasia, malformations of
the muscularis propria, degenerative leiomyop-
athy, leiomyositis, and mitochondriopathies.
Emphasis is given to the histopathologic features
that distinguish these conditions and their differen-
tial diagnoses.
OVERVIEW
Propulsion of contents through the intestinal tract
is effected by the muscularis propria and enteric
nervous system. Dysfunction of these tissues
causes abnormal intestinal motility and contrib-
utes to common clinical problems (eg, diarrhea,
constipation) as well as chronic intestinal
pseudo-obstruction (CIPO). CIPO denotes signs
and symptoms of intestinal obstruction (abdominal
distension, constipation, vomiting, and failure to
gain weight) in the absence of a mechanical
obstructive lesion.1
This review focuses on pathology of severe con-
stipation or CIPO in children, although many of the
entities discussed can also be applied to adults.
Although patients with these disorders may
Department of Laboratories, Seattle Children’s Hospital University of Washington, A6901, 4800 Sand Point Way
North East, Seattle, WA 98105, USA
E-mail address: raj.kapur@seattlechildrens.org
Surgical Pathology 3 (2010) 711–741
doi:10.1016/j.path.2010.06.005
1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
experience episodes of diarrhea (often secondary
to stasis and luminal bacterial overgrowth), motor
disorders characterized principally by increased
motility (eg, congenital deficiency of enteroendo-
crine cells) are not discussed. The author uses
the London Classification of Gastrointestinal
Neuromuscular Pathology (GINMP),2 which was
established recently by an international working
group (IWG) as an organizational framework for
histopathologic diagnoses associated with intes-
tinal dysmotility. In keeping with the London Clas-
sification emphasis is placed on pathologic
findings that the IWG considered diagnostic of
a well-characterized disease or involved in disease
pathogenesis. For the purpose of this review,
neither isolated gastroesophageal lesions (eg,
achalasia) nor conditions that present primarily in
adults (eg, diabetic visceropathy) are discussed.
CIPO is often subcategorized into myopathic,
neuropathic, mixed, and idiopathic forms on the
basis of clinical and pathologic data. Manometry
or other studies of bowel physiology can some-
times help with this discrimination. In general,
myopathies alter the amplitude of contractions,
whereas neuropathies affect the coordination of
enteric reflexes and the migration of contractions.
Myopathic or neuropathic etiologies can affect the
bladder, and megacystis, hydronephrosis, and/or
recurrent urinary tract infections are common in
some patients with CIPO.3,4 Histopathologic eval-
uation of biopsies or resection specimens is inte-
gral to the evaluation CIPO, and an effort to
surgpath.theclinics.com
standardize the approach to these specimens is
provided elsewhere.5 It is not uncommon, despite
712 Kapur
thorough microscopic analysis, to find no diag-
nostic alterations, in which case the cause of
CIPO is most appropriately deemed idiopathic.6
The severity and course of pediatric CIPO are
highly variable. Some of these conditions are
hereditary, and it is not uncommon to encounter
multiple affected family members with heteroge-
neous clinical severity. At the mild end of the spec-
trum are patients with chronic constipation, who
can be managed medically. At the other extreme
are severe cases that require parenteral nutrition,
for which intestinal transplantation is sometimes
a therapeutic option. Symptoms frequently wax
and wane and, for an individual patient, it can be
difficult to prognosticate. Laxatives, prokinetic
medications, enemas, diversion stomas, and
hyperalimentation are part of an escalating arsenal
used to manage these patients. Apart from
intestinal transplantation or resection of segmental
malformations, surgery is not curative. Severe
symptoms, however, often lead to exploratory
laparotomy to exclude a true obstructive lesion,
with subsequent potential for postoperative adhe-
sions and additional procedures in the future.
HIRSCHSPRUNG DISEASE
OVERVIEW
Hirschsprung disease (HSCR) is congenital absence
of ganglion cells in the myenteric and submucosal
plexuses of the terminal rectum and a highly variable
length of contiguous proximal bowel. This birth
defect affects 1 of every 5000 newborns. HSCR
is subdivided based on the rostral extent of
aganglionosis into ultrashort- (distalmost rectum),
Key Features
HIRSCHSPRUNG DISEASE
 Diagnosis of HSCR by suction rectal biopsy
requires an adequate sample of submucosa
and thorough sectioning. It may be facili-
tated by enzymo- or immunohistochemistry.
 Partially aganglionic or severely hypogan-
glionic portions of transitional zone should
be identified intraoperatively by frozen
section and resected.
 Biopsies of the neorectum occasionally iden-
tify a cause for persistent symptoms after
a pull-through procedure.
short- (rectosigmoid), colonic- (descending colon),
and long-segment (proximal to splenic flexure) vari-
ants, although some refer only to short- and long-
segment subtypes.7 Short-segment disease affects
80% of patients, who exhibit a 4:1 male-to-female
gender bias. In contrast, males and females are
more equally likely to have long-segment disease.
Rarely, total colonic HSCR is interrupted by
a segment of large intestine that contains ganglion
cells (skip area), in which case proximal agangliono-
sis can cause persistent symptoms after resection of
the distal aganglionic segment.8
HSCR results from failure of neural crest cells to
fully colonize the gut during embryogenesis.9,10
Most, if not all, cases have a genetic basis, but
risk of the malformation is determined by muta-
tions of one of many HSCR-susceptibility genes
or, more often, coincident alterations of multiple
such genetic loci.11 Mutations in more than 11
genes have been implicated in the pathogenesis
of HSCR.10 Although aganglionosis is usually an
isolated birth defect, some of the genetic alter-
ations associated with HSCR also cause extraen-
teric malformations (syndromic HSCR); therefore,
consideration of physical findings and family
history are important components of patient eval-
uation. Despite progress made in defining genetic
susceptibility factors, mutational examination has
a limited role in the management of most HSCR
patients and their families, with the possible
exception of targeted analysis of exons in the
RET gene to exclude mutations associated with
multiple endocrine neoplasia, type 2A.11
SUCTION RECTAL BIOPSY
Diagnosis of HSCR by suction rectal biopsy is
based the observation that submucosal ganglion
cells are invariably absent and generally correlate
with absence of adjacent myenteric ganglion cells.
In older patients, the procedure is more prone to
produce inadequate specimens, probably
because the submucosa is more fibrous. A deep
biopsy with forceps or another instrument is
a reasonable alternative.
Several studies have demonstrated that enteric
ganglia in the distal 1 to 2 cm of rectum are nor-
mally sparse, and justifiable concern exists that
sampling of this area may lead to a false impres-
sion of aganglionosis.12–15 Therefore, clinicians
are taught to biopsy 2 to 3 cm proximal to the den-
tate line (transition between rectal and squamous
mucosa). Ganglion cells can often be found,
however, in even a terminal rectal biopsy from
a patient who does not have HSCR, if the biopsy
size is adequate and sectioned thoroughly (in
rare patients, more than 100 histologic sections

are needed to find a single unequivocal ganglion
cell).
With contemporary rectal biopsy methods, it is
not uncommon to find that a biopsy was obtained
at or below the squamo-columnar junction.
Conversely, deviation may occur in the oral direc-
tion, in which case biopsy may miss very short
segment aganglionosis. To increase the likelihood
that adequate tissue is obtained and reduce the
probability that very short segment disease is
overlooked, some groups favor routine biopsies
from multiple levels (eg, 1, 2, and 3 cm proximal
to the dentate line).16
Two different approaches have evolved for the
evaluation of rectal biopsies. The first relies solely
on enzyme histochemistry using frozen sections to
identify ganglion cells and acetylcholinesterase
(AChE)-positive nerves17 and is used by a few
laboratories in Europe and other parts of the world.
AChE histochemistry is performed on sections
from an unfixed frozen biopsy.5 In biopsies from
aganglionic rectum, the diagnosis is based on
the increased density and thicknesses of AChE-
positive nerves in the muscularis mucosae with
or without lamina propria (Fig. 1). The changes
are quantitative and qualitative, not absolute, and
most reliable in 15 mm–thick sections. Positive (es-
tablished HSCR) and negative (ganglionic)
controls should be performed with each case for
comparison. Histochemical reactions that high-
light neuronal cell bodies (eg, lactate dehydroge-
nase, succinate dehydrogenase, and NADPH
diaphorase) are sometimes used in conjunction
with AChE histochemistry to facilitate diagnosis.18
The more widely used approach relies on
paraffin sections stained with hematoxylin-eosin
(H&E), although some laboratories complement
the latter with AChE histochemistry and/or
paraffin-based immunohistochemistry.16,19 In
H&E-stained sections, HSCR is excluded if one
or more ganglion cells are identified in the submu-
cosa of a distal rectal biopsy. Given the spacing of
submucosal ganglion cells, many sections must
be examined to be confident that ganglion cells
are present or absent. We routinely cut and
examine a minimum of 5 slides with 12 to 20
sections per slide from every paraffin-embedded
HSCR biopsy. The diagnosis of HSCR is estab-
lished with confidence when hypertrophic nerves
and no ganglion cells are identified in an
adequately sectioned biopsy (Fig. 2). Hypertrophic
submucosal nerves are greater than or equal to
40 mm in diameter and are generally accompanied
by an increased density of smaller nerves in agan-
glionic submucosa.20 In long-segment aganglio-
nosis (eg, total colonic), hypertrophic nerves may
be absent in the aganglionic bowel or restricted
Intestinal Motor Disorders in Children 713
to the terminal rectum.21 Biopsies from premature
infants offer a particular challenge, in that ganglion
cells mature cytologically at the end of gestation
and beyond. Immature ganglion cells tend to
cluster in primitive ganglia, but they lack the abun-
dant cytoplasm and prominent nucleoli that char-
acterize their mature counterparts. Helpful
features to identify immature neurons include
a background of neuropil, eccentric nuclear place-
ment, and a granular chromatin unlike that of
lymphocytes.
Immunolocalization of any one of a group of
neuronal markers has been proposed as a poten-
tially useful adjunct to H&E-stained sections in the
diagnosis of HSCR.22 Although these antibodies
are specific, none is used widely in practice
because pathologists who regularly search for
ganglion cells in H&E-stained sections are good
at discriminating neuronal cell bodies without the
need for costly special stains. In contrast, calreti-
nin immunohistochemistry has begun to be used
in many laboratories as an adjunct to H&E staining
in addition to, or in place of, AChE histochem-
istry.23 Calretinin immunoreactivity is normally
present in small intrinsic nerves located in the
muscularis mucosae and lamina propria
(Fig. 3).24 In the mucosa of aganglionic bowel,
expression is completely absent. Case-control
studies suggest that calretinin immunohistochem-
istry is at least as sensitive and specific as AChE
histochemistry for the diagnosis/exclusion of
HSCR from suction rectal biopsies.23,25 In contrast
with AChE staining, which requires a second
frozen biopsy and specialized methods, calretinin
immunostaining can be performed on paraffin
sections of formalin-fixed biopsies with methods
that are available in most pathology laboratories.
Independent of the approach used, assessment
of specimen adequacy and recognition of ganglion
cells, hypertrophic nerves, and/or abnormal
(immuno)histochemical results is influenced by
experience and regular practice. Even the most
experienced pathologists encounter biopsies that
yield equivocal results, usually because inade-
quate submucosa is present. A pathologist must
have the confidence to distinguish diagnostic
from equivocal findings and clearly communicate
the results to the clinician. In some instances, re-
biopsy is necessary.
INTRAOPERATIVE FROZEN SECTIONS
Intraoperative seromuscular biopsies are essential
to determine that ganglion cells are present at the
level where the ostomy or anastomosis is placed.
Seromuscular biopsies should be a minimum
of 5 to 10 mm long and extend for a depth of
714 Kapur

Fig. 1. AChE histochem-

istry in HSCR. The density
and thickness of nerves
(dark brown) in the mus-
cularis mucosae and la-
mina propria are increased
in a suction rectal biopsy
from a patient with HSCR
(A), in contrast with
normal bowel (B). Insets
show portions of muscu-
laris mucosae and deep
lamina propria at higher
magnification. Scale bars:
40 mm.

3 to 5 mm, so as to include the longitudinal and
most of the circular layers of the muscularis prop-
ria. The biopsy should be oriented to cut perpen-
dicular to the serosal surface, thereby visualizing
both muscle layers and their interface in the histo-
logic sections. With a well-oriented biopsy, 10 or
fewer sections are generally sufficient to confirm/
exclude aganglionosis. Frozen sections are
stained with H&E or Diff-Quik (Siemens Healthcare
Diagnostics, Newark, NJ, USA). The latter usually
imparts a reddish-purple hue to the cytoplasm of
ganglion cells, which eases their identification.
Recognition of ganglion cells is usually not difficult,
although inflammation sometimes obscures their
cytologic features.
It is important to know that the interface between
ganglionic and aganglionic gut is often irregular,
such that ganglion cells may extend 2 to 3 cm farther
 Intestinal Motor Disorders in Children 715

Fig. 2. Hypertrophic ex-

trinsic nerves in agan-
glionic rectum of HSCR.
Large nerves (arrows) are
present in the submucosal
(A) and myenteric (B)
plexuses, along with
a complete absence of
ganglion cells. The
density of hypertrophic
nerves is greatest in the
distal rectum and dissi-
pates proximally in long-
segment aganglionosis.
Scale bars: 40 mm.

distally along a portion of the bowel circumference,
usually on the antimesenteric side (Fig. 4).26,27 Prox-
imal to this interface is a transition zone in which the
myenteric plexus is hypoganglionic and the submu-
cosal plexus is hyper-, eu-, or hypoganglionic.
Abnormalities in the density and distribution of
myenteric ganglion cells typically extend several
centimeters proximal to the aganglionic zone and
occasionally are present over a length of more
than 10 cm.13,28,29 A body of literature, based largely
on uncontrolled studies, suggests that incorporation
of transitional zone (usually defined as hypogan-
glionic with or without large nerves or partially agan-
glionic) increases the risk for persistent
postoperative obstructive symptoms.30,31 For this
reason, most surgeons strive to resect the transi-
tional zone and perform an anastomosis or ostomy
with euganglionic bowel.
In practice, assessment of myenteric ganglion
cell density by examination of histologic sections
is insensitive and has not been shown to be reli-
able.5,32 Therefore, only severe hypoganglionosis
716 Kapur

Fig. 3. Calretinin immu-

noreactivity in HSCR. (A)
Calretinin immunoreac-
tive nerves are completely
absent from the superfi-
cial submucosa, muscula-
ris mucosae, and lamina
propria in a suction rectal
biopsy from a patient
with HSCR. (B) In contrast,
abundant nerves in mus-
cularis mucosae and
adjacent tissue (eg,
arrowheads) and a subset
of submucosal ganglion
cells (arrow) show strong
calretinin immunoreac-
tivity in a biopsy that
contains ganglion cells
(arrowhead). Scale bars:
40 mm.

(discussed later) or aganglionosis of large takedown, we freeze and examine a full-

portions of the bowel circumference can be
deduced intraoperatively from intraoperative
frozen sections. Our practice is to perform sero-
muscular biopsies at successively more proximal
sites until ganglion cells are identified. Then I
advise resection/ostomy at least 3 cm proximal
to this site. At the time of resection or ostomy
circumference section from the proximal margin
of the pull-through specimen. If a large contig-
uous portion of the bowel circumference is agan-
glionic with or without hypertrophic nerves, or if
the majority of myenteric ganglia are tiny (one or
two ganglion cells without significant neuropil),
resection of additional bowel is advised.

Fig. 4. Diagram illus-
trating the transitional
zone between eugan-
glionic and aganglionic
bowel in HSCR. The tran-
sitional zone includes
two parts: a distal
portion (typically <3 cm
in length), in which large
portions of the circum-
ference may be agan-
glionic, and a proximal
portion of variable
length, in which the
myenteric plexus is hypo-
ganglionic. Intraoperative frozen sections are used to localize the transitional zone and guide resection of
portions that are partially aganglionic or severely hypoganglionic.
DISTAL COLONIC RESECTION
The goals when evaluating a resection from a patient
with HSCR disease are to document (1) the distribu-
tion of myenteric and submucosal ganglion cells
around the entire circumference of the proximal
margin, (2) the length of the aganglionic zone,
(3) the distance between the aganglionic zone and
the proximal margin (which may vary around the
circumference of the bowel), and (4) other patho-
logic changes that may potentially correlate with
pre- or postoperative clinical behavior (eg, inflam-
mation). This type of comprehensive examination
is best accomplished by fixing the specimen before
histologic samples are obtained. No standard
exists, but the IWG recommends examination of
the complete circumference of the proximal margin
and mapping the transitional zone with transverse
sections spaced 1 cm apart.
A comprehensive approach is to examine
a transverse section of the proximal margin (usually
the residual tissue from an intraoperative frozen
section), a longitudinal full-thickness strip from
the entire length of the remaining bowel, and
closely spaced transverse sections of the transi-
tional zone at 1 cm intervals. The longitudinal strip
provides a general guide as to the distribution of
ganglion cells and discloses potential skip areas.8
The transitional zone is often demarcated grossly
because the bowel diameter tapers between
dilated ganglionic bowel and narrow aganglionic
bowel. In some specimens, however, in particular
those with long-segment aganglionosis, a gross
transition is not evident. Thorough mapping of the
transitional zone may require resampling of the
resection, so it is advisable to store intestinal frag-
ments in order until the case is completed.
In addition to aganglionosis and hypertrophic
nerves, several other secondary changes have
Intestinal Motor Disorders in Children 717
been reported in HSCR resections.10 Most of
these changes are not specific to HSCR, can be
observed in other forms of CIPO, and are not
useful diagnostically. Included in this list is defi-
cient or absent CD117-positive interstitial cells of
Cajal, the pacemaker cells that serve as an inter-
face between enteric nerves and smooth
muscle.33,34 At this time, it is unnecessary to incor-
porate immunohistochemical investigations into
the routine handling of HSCR resections, because
insufficient data exist to know whether or not any
of these secondary changes or their location in
the resection specimen (eg, proximal margin) influ-
ences the risk for postoperative complications.
DIFFERENTIAL DIAGNOSIS
The clinical differential diagnosis for HSCR is
broad but includes functional constipation,
extrinsic or intrinsic forms of intestinal obstruction,
and the other entities discussed in this article. In
practice, identification in a distal rectum suction
biopsy of even a single submucosal or myenteric
ganglion cell excludes HSCR and should lead to
consideration of other disorders. Overlap between
the distributions of submucosal and myenteric
ganglion cells is imperfect, particularly in the tran-
sitional zone, and it is possible that clinically signif-
icant, rectal myenteric aganglionosis may occur
despite a normal suction rectal biopsy. If such
cases do exist, they have not been well docu-
mented and may constitute a subset of patients
with so-called ultrashort-segment HSCR.
PROGNOSIS
The long-term outcome for most patients who
undergo a pull-through procedure for isolated
HSCR is good, although pre- and postoperative
718 Kapur
Pitfalls
HIRSCHSPRUNG DISEASE
! Failure to examine as many sections as
possible from rectal biopsies may lead to
a false-positive diagnosis of HSCR.
! Hypertrophic submucosal nerves are not
present in all aganglionic biopsies from
HSCR patients.
! Recognition of immature ganglion cells in
H&E-stained sections requires experience.
complications are common. Enterocolitis is among
the most serious complications affecting these
patients. Enterocolitis occurs before or after
surgery and can pursue a waxing and waning
course or present as a fulminant fatal disease.
Postoperative persistent obstructive symptoms
are observed in a significant subset of HSCR
patients. Explanations include anastomotic stric-
tures, failure to resect all of the anatomically
abnormal bowel (transitional zone pull-through),
skip areas, poorly understood physiologic defects
of the euganglionic bowel, intestinal neuronal
dysplasia (discussed later), and acquired agan-
glionosis. Acquired aganglionosis refers to loss
of ganglion cells from bowel proximal to the anas-
tomosis of a pull-through procedure for HSCR.35–38
The pathogenesis is unknown but may involve
regional ischemia and/or underlying genetic
defects that influence the activity of neurotrophic
factors.39,40 Other long-term complications
include incontinence or soiling, which in some
instances may be due to damage to the anal
sphincter during surgery.
CONGENITAL HYPOGANGLIONOSIS
OVERVIEW
Patients with congenital hypoganglionosis (CH)
exhibit symptoms similar to HSCR, which begin
typically just after birth or early infancy. Most
undergo a rectal biopsy that excludes HSCR and
are diagnosed based on full-thickness biopsies
or intestinal resections performed for recurrent
CIPO. The incidence of CH is difficult to establish
because the diagnostic criteria are poorly defined
and are influenced by varied histologic methods
used to characterize the condition. The etiology
is unknown. Although the myenteric plexus
pathology is similar to the transitional zone of
HSCR, mutational studies have failed to identify
a genetic relationship and the majority of CH cases
are sporadic. Megacystis is found in a subset of
patients, which suggests a more global pattern
of visceral neuropathy,41 but malformations in
other organ systems are usually absent and hypo-
ganglionosis is not a described part of a specific
malformation syndrome.
GROSS FEATURES
Like HSCR, most examples of CH involve the
distal rectum and a variable length of contiguous
intestine. Hypoganglionosis of the distal colon is
most common, but extension into or throughout
the small intestine has been observed. No reliable
diagnostic radiographic or manometric findings
exist and, the colon and/or small intestine may
be distended or normal. In contrast to HSCR,
a tapered transitional zone is not found. Therefore,
boundaries of CH have to be defined histopatho-
logically, usually based on examination of perma-
nent sections from biopsies, as opposed to
intraoperative frozen sections.
MICROSCOPIC FEATURES
CH is characterized by an abnormally low density of
myenteric ganglion cells. Although submucosal hy-
poganglionosis is a theoretic consideration and has
been reported in a few examples of hypogangliono-
sis, concordance between myenteric and submu-
cosal ganglion cell density is poor, and normal or
increased submucosal neurons are present in most
patients. Therefore, submucosal biopsies are inade-
quate to establish the diagnosis. Instead, a generous
sample of myenteric plexus is required.32
Most quantitative studies of patients with symp-
tomatic CH report reductions in the density of
myenteric ganglion cells to at least 50% of
normal.41–44 Severe cases are easy to recognize
in H&E-stained sections from adequate samples
of myenteric plexus. Key features are small widely
spaced ganglia composed of one or two ganglion
cells with markedly depleted neuropil (Fig. 5).
Usually the interganglionic nerves are sparse and
thin, although nerve hypertrophy has been
observed in some patients.45 Less severe exam-
ples require special sectioning and staining
methods with rigorous morphometric analysis
that is not practical in routine laboratory practice.
Silver-stained preparations of en face thick
sections or enzyme histochemistry are among
the favored approaches.41,43 It has been specu-
lated that some or all cases of CH may reflect
arrested or abnormal neuronal maturation, as
opposed to an absolute reduction of neurons.46
This could explain the insensitivity of diagnosis
 Intestinal Motor Disorders in Children 719

Fig. 5. Congenital hypo-

ganglionosis. (A) The myen-
teric plexus in the colon
from a patient with hypo-
ganglionosis shows close
apposition of the external
and internal lamina of the
muscularis propria, with
minimal intervening nerve
tissue (arrowhead) and no
myenteric ganglia. In this
case, an ectopic ganglion
cell (arrow) is present in
the serosa, but ectopic
neurons are not a general-
ized feature of hypogan-
glionosis. (B) Another field
from the same specimen
illustrates one (arrow) of
rare, widely spaced, myen-
teric ganglion cells, which
resided in isolation with no
adjacent ganglion cells or
significant neuropil. Scale
bars: 40 mm.

from H&E sections, because many alternatives
(eg, silver stains) resolve cytologic features of
mature neurons.41
DIFFERENTIAL DIAGNOSIS
The transitional zone in HSCR can be indistin-
guishable from CH, but the presence of ganglion
cells in the terminal rectum excludes the former.
Apart from CH, myenteric hypoganglionosis has
been described in pediatric patients in a variety
of other contexts in which symptoms develop later
and/or other factors suggest an acquired loss of
ganglion cells.47 In contrast with CH, acquired
hypoganglionoses are frequently familial, often
segmental or multifocal, and may involve the
small intestine and spare the colon.48 Most can
be grouped as postinfectious or degenerative
720 Kapur
neuropathies (discussed later). Some investigators
regard intestinal neuronal dysplasia, type A, as
a form of CH.48 The basis for this assertion is
unclear, because the diagnosis of intestinal
neuronal dysplasia, type A, is predicated on loss
of extrinsic adrenergic innervation, not enteric
ganglion cell density.49
PROGNOSIS
Patients with severe CH suffer from intestinal
pseudo-obstruction from infancy. Failure to thrive,
enterocolitis, and multiple surgeries to exclude
obstruction are common, and infants or young
children have died from impaired motility. Many
survivors are partially or completely dependent
on parenteral nutrition, and some have been
treated by intestinal transplantation.
NEURONAL INTRANUCLEAR INCLUSION
DISEASE
OVERVIEW
Neuronal intranuclear inclusion disease (NIID) is
a rare and probably etiologically heterogeneous
neurodegenerative disorder that affects the central
and peripheral nervous systems.50 Clinical and path-
ologic features vary, but CIPO is common, along with
ataxia, dysautonomia, dementia, and extrapyra-
midal symptoms. Infantile, juvenile, and adult forms
have been described. NIID has been classified by
some as autosomal recessive NIID, because the first
familial reports involved siblings with unaffected
parents. Multigenerational examples have since
been observed, however, and the pattern of clinical
and histopathologic shows similarities to hereditary
trinucleotide repeat disorders (discussed later), sug-
gesting autosomal dominant inheritance. A specific
gene has not been implicated.
GROSS FEATURES
A paucity of gross descriptions of the intestinal
tract in NIID patients with CIPO has been pub-
lished. At autopsy, two adult siblings with the
disorder showed dilatation of the proximal small
intestine and numerous colonic diverticulae, with
normal bowel wall thickness throughout.
MICROSCOPIC FEATURES
Progressive ganglion cell loss occurs in patients
with NIID, the severity of which depends on the
stage of the disease. In its terminal phase, hypogan-
glionosis is obvious, and residual ganglion cells
often show degenerative cytologic features that
include vacuolization, nuclear pyknosis, and irreg-
ular cytoplasmic contours. Large eosinophilic inclu-
sions in nuclei of enteric ganglion cells (as well as
extraenteric neurons) are the pathognomonic histo-
pathologic finding in NIID (Fig. 6). These circular
inclusions are larger than normal nucleoli and range
from 5 to 10 mm in diameter.51 Inclusions, usually
singular but sometimes multiple, are present in
a subset of neurons, sometimes a small minority
Fig. 6. Neuronal intranu-
clear inclusion disease.
Large azurophilic inclu-
sions (arrow) in a subset of
myenteric and/or submu-
cosal neurons are charac-
teristic of this progressive
neurologic disorder, which
also affects the autonomic
and central nervous systems.
Scale bars: 40 mm.

of the ganglion cell population. Myenteric and
submucosal ganglion cells are both affected. Ultra-
structurally, the inclusions comprise compact nests
of filamentous and granular electron-dense mate-
rial.52,53 A variety of antigens, including SUMO-1,
ubiquitin, ataxin-1, ataxin-3, and polyglutamine-
rich peptides, have been immunolocalized to these
inclusions, although the results from different
laboratories have been inconsistent.54–57 Their
structural and immunohistochemical properties
resemble nuclear inclusions observed in a variety
of dominant neurodegenerative disorders caused
by expansions of polyglutamine tracts in various
genes (eg, forms of spinal cerebellar ataxia). Unlike
NIID, however, the inclusions in the latter disorders
are generally not as easily visualized in H&E-stained
sections.50
DIFFERENTIAL DIAGNOSIS
Apart from intranuclear inclusions, the pathologic
features of NIID are identical to other forms of
degenerative intestinal neuropathy. The clinical
overlap between NIID and spinal cerebellar ataxia
or other hereditary neurodegenerative conditions
with polyglutamine tract expansions is significant,
although CIPO is infrequently described in the latter.
Although intranuclear inclusions have been reported
in extraenteric neurons in many of these hereditary
conditions, nuclear inclusions in enteric ganglion
cells is not as well established as with NIID. Muta-
tional analysis of genes associated with spinal cere-
bellar ataxias has yielded negative results.57
PROGNOSIS
The severity of enteric and extraenteric symptoms
in patients with NIID is variable but usually
progressive and debilitating. No effective therapy
exists, apart from supportive measures.
INFLAMMATORY INTESTINAL NEUROPATHY/
ENTERIC GANGLIONITIS
OVERVIEW
Enteric ganglionitis (EG) denotes inflammation
within enteric ganglia and often along enteric
nerves. This process may be associated with
neuronal loss and/or intestinal dysmotility.58 The
inflammatory infiltrate is lymphoplasmacytic or
eosinophilic. Lymphoplasmacytic EG is an
immune-mediated process that occurs as an idio-
pathic disorder,59 a paraneoplastic phenomenon
(ie, with neuroblastoma),60,61 or as a part of diverse
primary lesions, such as infection (ie, Chagas
disease),62 generalized encephalomyeloneurop-
athy,63 cystic fibrosis,64 or inflammatory bowel
Intestinal Motor Disorders in Children 721
disease.65 Neuron-specific antibodies (eg, anti-
Hu) have been demonstrated in many patients
with lymphoplasmacytic EG.58 Eosinophilic EG
has been described less frequently, in conjunction
with eosinophilic enterocolitis,66,67 connective
tissue disease,68 or patients with HSCR.69 The clin-
ical findings of EG differ depending in part on the
regions of bowel involved, but CIPO is one presen-
tation. In HSCR, the significance of eosinophilic EG
is unclear, and no current data indicate that gan-
glionitis affects pre- or postoperative physiology.
GROSS FEATURES
EG affects small intestine, colon, or both. Depend-
ing on the stage of the disease and underlying
etiology, the bowel may be distended, narrow, or
normal, although distension (megacolon) is
a common finding with advanced disease. In
inflammatory bowel disease or eosinophilic
enterocolitis, EG is part of more generalized
inflammation, and the bowel wall is edematous,
thick, and noncompliant. Many patients never
undergo resection but are diagnosed by full-
thickness biopsy alone.
MICROSCOPIC FEATURES
The common element of EG in all of its clinical
contexts is inflammation within myenteric ganglia.
Inflammatory infiltrates may be restricted to myen-
teric ganglia or radiate along nerves in the myenter-
ic plexus, intramuscular plexus, and even involve
submucosal ganglia and nerves (Fig. 7). Normally
neither lymphocytes nor eosinophils are found
within the basement membrane that separates
ganglia from surrounding stroma, and perigan-
glionic lymphocytes are rarely observed in contact
with the perimeter of the ganglion. According to the
IWG, the presence of any lymphocyte in a ganglion
and/or greater than 5 lymphocytes around
a ganglion are sufficient for a diagnosis of ganglio-
nitis.5 Lymphocytes within periganglionic
lymphatics or blood vessels should be disre-
garded. The significance of periganglionic eosino-
phils is less clear, and their presence alone
probably is not sufficient to warrant the diagnosis
of EG, especially in the context of eosinophilic
gastroenteritis. Immunohistochemistry shows that
T cells, either CD4- or CD8-positive, predominate
in most forms of lymphoplasmacytic EG, although
plasma cells and macrophages are sometimes
present as well.58 In chagasic EG, CD3-negative,
CD57-positive natural killer cells predominate.62
Progressive loss of neurons is a frequent histo-
pathologic feature in patients with lymphoplasma-
cytic EG.58 Early in the course, the density and
722 Kapur

Fig. 7. Enteric ganglioni-

tis. (A) A representative
myenteric ganglion from
a patient with lymphocytic
ganglionitis demonstrates
many small lymphocytes
(T cells) intimately associ-
ated with ganglion cell
bodies and adjacent neu-
ropil. A degenerating
neuron with condensed
hyperchromatic cytoplasm
(arrow) is also present in
this trichrome-stained
section. (B) In this biopsy
from a child with eosino-
philic ganglionitis, a myen-
teric ganglion and
presumed intramuscular
nerve fibers (lower right
corner) in the adjacent
muscularis propria are in-
filtrated by eosinophils.
HSCR was excluded by
suction rectal biopsy,
although eosinophilic
ganglionitis can occur
proximal to congenital
aganglionosis. Scale bars:
40 mm.

morphology of neurons in inflamed ganglia may be
normal or obscured by inflammatory cells. In some
cases, neurodegenerative cytologic changes can
be recognized, although silver stains or other
sophisticated techniques may be required to iden-
tify these with confidence.61 Neuron loss seems to
be nonselective; different subtypes of enteric
ganglion cells are affected equally.58 Later, neuron
loss (acquired hypoganglionosis) is readily
apparent, although patients are typically symp-
tomatic before this stage. Intraganglionic fibrosis
does not occur, although fibrous tissue may accu-
mulate in the stroma surrounding atrophic ganglia.
Enteric glial cells are probably also affected, but

histopathologic changes in glial cells are not
usually resolved.
Inflammation in idiopathic EG is usually confined
to the enteric nervous system, whereas many of
the other conditions associated with EG (ie,
connective tissue disease, inflammatory bowel
disease, cystic fibrosis, and eosinophilic enteroco-
litis) are characterized by inflammation elsewhere
in the bowel wall. Coexistent leiomyositis or myo-
cyte atrophy and fibrosis may indicate an under-
lying connective tissue disorder. Combined
leiomyositis/ganglionitis also occurs in the distal
ileal obstruction syndrome of cystic fibrosis.64 In
HSCR disease, eosinophilic inflammation can be
present in the nervous systems of both ganglionic
and aganglionic bowel.
DIFFERENTIAL DIAGNOSIS
It is important to distinguish EG from nonspecific
periganglionic infiltrates that accompany a wide
variety of enteric diseases. Many patients with
CIPO develop enterocolitis due to stasis and
bacterial overgrowth. Mixed inflammation is
usually concentrated in the mucosa, and although
inflammatory cells (especially eosinophils) often
permeate the full-thickness of the bowel wall and
may come into contact with ganglia, truly intra-
ganglionic eosinophils (or lymphocytes) are diffi-
cult to find. Serologic studies for antineuronal
antibodies are helpful when lymphocytic EG is
considered.58
In pediatric patients, paraneoplastic EG is rare
and has only been reported in a teenager whose
persistent symptoms began 1.5 years after resec-
tion of her ganglioneuroblastoma.60 CIPO in
patients with neuroblastoma may not be due to
EG but rather to hormonal or other paraneoplastic
effects, because dysmotility disappears when the
tumor is treated.70,71
PROGNOSIS
Most forms of EG seem to have an immune basis,
and many cases are associated with circulating
antineuronal antibodies. Immunosuppressive ther-
apies have proved beneficial, particularly if
ganglion cell loss can be arrested.58 No evidence
exists for spontaneous regeneration of enteric
ganglion cells with or without treatment.
DEGENERATIVE INTESTINAL NEUROPATHY
OVERVIEW
Degenerative neuropathy (DN) refers to a hetero-
geneous group of hereditary and sporadic
diseases in which enteric neurons exhibit cytologic
Intestinal Motor Disorders in Children 723
features and progressive loss. The cytologic
changes in DN are not specific and overlap with
neurodegenerative findings in other conditions
(eg, mitochondrial disorders, inflammatory
neuropathies, and NIID). DN is distinguished NIID
because ganglion cell inclusions are absent and
ganglionitis is not observed.
DN has been subdivided into familial and
sporadic visceral neuropathies, either of which
may have extraenteric manifestations, including
urinary bladder dysfunction.48,72 Familial forms
include autosomal recessive, autosomal domi-
nant, and X-linked variants. Specific genes have
not been implicated for most of these conditions,
except a form of X-linked IPO caused by mutations
in FILAMIN-A.73,74 Some investigators classify
NIID as an autosomal recessive subtype of familial
DN as opposed to a distinct neuropathy. DN is
more frequently diagnosed in adolescents or
adults than in infants or young children.
GROSS FEATURES
DN is usually reported in the context of intestinal
dilatation, which may be segmental (ie, megaduo-
denum or megarectum) or diffuse.
MICROSCOPIC FEATURES
Neurodegenerative ganglion cell cytology is the
hallmark of DN.Qualitative changes that constitute
cytologic atypia, however, are relative, not abso-
lute, and, therefore, are interpreted subjectively.
The IWG states that the cytologic abnormalities in
DN ‘‘include hypertrophy, central chromatolysis,
(swollen/ballooning degeneration), hypoxic alter-
ations, inclusions or coarse granules, and occa-
sionally, oxyphilic change.’’2 Lindberg and
colleagues75 subclassified DN as ‘‘either swollen
degeneration or shrunken degeneration, accompa-
nied by chromatolysis and sometimes karyolysis.’’
Cytoplasmic and/or axonal vacuoles can occur in
either form. In swollen degeneration, immunohisto-
chemical staining for perikaryal antigens (NSE,
PGP9.5, bcl2) is reduced, whereas immunoreac-
tivity is accentuated in shrunken degeneration.
Instead of immunohistochemistry, some rely on
silver stain preparations to visualize swelling, frag-
mentation, or other irregularities in argyrophilic or
argyrophobic myenteric neurons.72,76,77 Neuronal
loss is sometimes obvious but may require formal
counts.
DIFFERENTIAL DIAGNOSIS
The diagnosis of DN is challenging and perhaps
best left to experts, unless neuronal loss is severe.
The neurodegenerative features of DN overlap
724 Kapur
with artifacts introduced by tissue trauma, autol-
ysis, or delayed or inadequate fixation. Careful
attention to intra- and postoperative tissue
handling is important in patients with CIPO to mini-
mize artifacts. Even so, discrimination of DN from
artifact requires experience and may not be
possible in some cases.
PROGNOSIS
DN is usually progressive but may be confined to
intestinal segments that can be removed. More
often, IPO is managed medically with hyperali-
mentation as needed. If surgery is considered,
radiologic imaging, manometry, and/or laparo-
scopic biopsies can guide the extent of resection,
but recurrence is common.47,78 Many forms of DN
are associated with central or autonomic neuropa-
thology, which complicate patient management.
DIFFUSE INTESTINAL
GANGLIONEUROMATOSIS
OVERVIEW
Diffuse intestinal ganglioneuromatosis (DIG) refers
to widely distributed, transmural hamartomatous
lesions composed of benign ganglion cells and
associated glia.79 DIG is one manifestation of
multiple endocrine neoplasia, type IIB,80 type I
neurofibromatosis,81 and Cowden disease (PTEN
mutations).82 None of these syndromes, however,
can be proved in a subset of patients. The diffuse
infiltrative nature of DIG and distinguishes it from
solitary ganglioneuromas and ganglioneuroma-
tous polyposis, which are characterized by
polypoid or sessile mucosa and/or submucosal
lesions that form discrete masses and are not
strongly associated with the aforementioned
syndromes. DIG can be associated with constipa-
tion, diarrhea, and occasional CIPO. The patho-
genesis of dysmotility is unclear; possible
mechanisms include derangements of enteric
neural physiology, physical constraints imposed
by the hamartomas on contraction or relaxation
of the bowel wall, and effects of hormones
produced by the ganglioneuromas.83
GROSS FEATURES
The neuroglial hyperplasia in DIG is poorly demar-
cated but can produce a variety of gross alterations,
such as sessile or endophytic mucosal masses or
segmental thickening of the bowel wall with vague
nodularity in cut surfaces. Megacolon is common,
and diverticuli have been observed.79,84
MICROSCOPIC FEATURES
DIG usually involves all layers of the bowel wall,
but the distribution of lesions is patchy.85 In
some areas, the pathology resembles enlarge-
ment of the normal enteric ganglioneuronal plex-
uses, which displace adjacent muscle or
mucosal tissue while preserving some normal rela-
tionships (Fig. 8A). At the other extreme, nodular
or multinodular masses of neuroglial tissue fill the
full thickness of the intestinal wall and/or project
into the lumen. Cytologically, the neural and glial
cells that compose these lesions resemble age-
appropriate enteric ganglion development. The
hamartomatous elements comprise cytologically
mature ganglioneuromas with large ganglion cells,
Nissl substance, and eccentric nuclei with
moderate-size nucleoli in a background of enteric
nerve-like neuropil (Fig. 8B). Immature neuroblasts
are generally not found, and mitotic figures are
scarce. Neither immunohistochemistry nor elec-
tron microscopic studies are necessary to diag-
nose DIG, although such investigations indicate
a variety of neurochemically distinct neuronal
phenotypes in the hyperplastic process, similar
to normal enteric ganglia.
DIFFERENTIAL DIAGNOSIS
Solitary ganglioneuroma and polypoid ganglio-
neuromatosis may be histologically indistinguish-
able from DIG, but they differ in their discrete
nature and location in the mucosa and submucosa
without extension into the myenteric plexus.85
Polypoid ganglioneuromatosis may be more
frequent in adults than children, can be a manifes-
tation of syndromes associated with DIG, and may
confer an increased risk for adenocarcinoma.81,86
Neurofibromas can occur in the gut wall, where
they probably arise from the enteric nervous
system.87–89 In contrast with DIG, the predominant
cell type in neurofibromas is a glial cell, and the
stroma has a fibromyxoid quality that resembles
peripheral nerve more than the neuropil of enteric
ganglia. In a patient with type I neurofibromatosis,
DIG and intestinal neurofibromas may coexist.
DIG, a benign hamartomatous process, should
be distinguished from neuroblastoma, a malignant
neoplasm that rarely arises or invades the gut
wall.90,91 In addition to any differentiated ganglion
cells, the latter lesion harbors immature neuro-
blasts in a background of glial cell–depleted
neuropil.
PROGNOSIS
Dysmotility or obstruction caused by DIG can be
so severe that surgical removal of intestinal
 Intestinal Motor Disorders in Children 725

Fig. 8. Diffuse intestinal

ganglioneuromatosis. (A)
Ganglioneuromatous hy-
perplasia of the myenteric
plexus in the appendix of
a patient with multiple
endocrine neoplasia, type
2B. (B) Mucosal ganglio-
neuroma. Scale bars: 40 mm.

segments is required. An exceptional patient with INTESTINAL NEURONAL DYSPLASIA

nonsyndromic congenital ganglioneuromatosis
may have an intestinal tumor that secretes asoac-
tive intestinal peptide, so that the diarrhea
improves with somatostatin analog therapy.83
The kinetics of pediatric ganglioneuroma growth
have not been defined, although slow enlargement
of existing lesions and the evolution of new lesions
occurs in many patients throughout life. All of the
named syndromes associated with DIG harbor
an increased risk for malignant neoplasms (eg,
medullary thyroid carcinoma, adenocarcinoma)
that arise independent of DIG per se.
OVERVIEW
Intestinal neuronal dysplasia, type B (IND) is one of
the most controversial and confusing topics in
enteric neuropathology. IND was described origi-
nally almost four decades ago by Meier-Ruge92
on the basis of histochemical findings in rectal
biopsies. Over the years, he and others refined
the diagnostic criteria, but submucosal hypergan-
glionosis, as represented by large submucosal
ganglia that contain increased numbers of ganglion
726 Kapur
Key Features
INTESTINAL NEURONAL DYSPLASIA
 Diagnosis is based on quantitative changes
valid only for frozen sections and enzyme
histochemistry.
 The diagnostic criteria are based on submu-
cosal, not myenteric, hyperganglionosis.
 IND may be a secondary response to chronic
dysmotility, as opposed to a primary cause
of constipation.
cells, has remained a prerequisite.93–95 Many have
arbitrarily extrapolated the findings to H&E-stained
sections, other parts of the intestinal tract, and/or
myenteric ganglia, without justification.
IND has been reported as an isolated disorder or
in the bowel proximal to a variety of conditions that
are known to produce chronic obstructive symp-
toms (ie, HSCR).94,96 In some series, isolated IND
is cited as the most frequent cause of pediatric
HSCR-like symptoms,97 and IND of the transitional
zone has been touted as a cause for persistent
obstructive symptoms after surgery for HSCR.98–102
Other investigators challenge the validity of the
diagnostic criteria and assert that IND is a myth
or an adaptive response with no proved clinical
significance.103–107 In more contemporary articles,
Meier-Ruge indicates that IND is less common
than previously thought, should not be diagnosed
without histochemical stains of frozen sections or
before age 1 year, and usually resolves spontane-
ously by age 4 years.95 At present, insufficient
compelling data exist to suggest that IND-like
changes in HSCR predict a poor outcome or
should be managed any differently from isolated
HSCR.
GROSS FEATURES
No consistent gross pathology is associated with
isolated IND, although some patients may have
dilated rectums. When IND-like changes are
present proximal to other lesions (eg, postis-
chemic strictures or HSCR), the gross pathology
of the distal bowel conforms to that of the under-
lying primary disease.
MICROSCOPIC FEATURES
The most recently revised histopathologic criteria
for the diagnosis of IND allow diagnosis only on
the basis of quantitative abnormalities in submu-
cosal ganglion cell number, assessed in enzyme–
histochemically stained (lactate dehydrogenase),
15 mm–thick frozen sections.95 With this type of
analysis, the only diagnostic criterion is greater
than 8 ganglion cells (giant ganglia) in more than
20% of at least 25 submucosal ganglia. Rare, if
any, descriptions of the counting procedure
describe how neurons are counted (eg, does
a nucleus need to be present in the plane of section
or can a small fragment of enzymatically stained
cytoplasm be counted as an individual neuron).
IND should not be diagnosed in patients under
the age of 1 year, because a high proportion of
giant ganglia may be normal in infants, which
disappears along with HSCR-like symptoms by
age 4 years. Previous diagnostic features of IND
included HSCR-like changes in AChE-positive
mucosal innervation, prominent perivascular
submucosal nerves, and ‘‘ectopic’’ ganglion cells
in the lamina propria.93 All of the these findings
are no longer considered necessary or sufficient
for diagnosis.95
DIFFERENTIAL DIAGNOSIS
The contemporary definition of IND is based on
objective quantitative criteria, which should elimi-
nate diagnostic confusion. It is still unclear,
however, whether or not IND is a histopathologic
phenotype (possibly a secondary response to
impaired motility) as opposed to a primary enteric
neuropathy. Awareness of this controversy should
prompt diagnosticians to consider other
dysmotility-producing lesions that may not be
evident in submucosal biopsies (eg, hypoganglio-
nosis or myopathy).
PROGNOSIS
IND-like submucosal ganglion cell hyperplasia and
clinical symptoms disappear in most infants by
age 4 years.108,109 Limited follow-up data have
been published for patients older than 4 years
with IND. One such study found that approxi-
mately 75% of isolated patients with IND
continued to have significant constipation at
a mean age of 7 years after conservative medical
management.110 Whether or not failure to resect
transitional zone IND influences the long- or
short-term prognosis for HSCR patients is contro-
versial. Some studies suggest that retained prox-
imal bowel with IND correlates with postsurgical
complications and advocate prophylactic resec-
tion96,99,111,112 or delayed anastomosis until the
enteric nervous system matures and IND disap-
pears.113 Others find no difference in postoperative

Pitfalls
INTESTINAL NEURONAL DYSPLASIA
! Quantitative criteria used to diagnose IND
have not been established for myenteric
ganglia, sites other than the distal colon, or
H&E-stained paraffin sections.
! IND should not be diagnosed in patients less
than 1 year of age.
! Diagnosis of IND should not end the search
for another primary cause of dysmotility.
complication rates between HSCR alone versus
HSCR plus proximal IND.107
MALFORMATIONS OF THE MUSCULARIS
PROPRIA
OVERVIEW
Malformations of enteric smooth muscle are
another potential cause of intestinal pseudo-
obstruction, which, like Hirschsprung, disease
often present in infancy but may not be recog-
nized for months or years. The muscularis propria
of the intestinal tract is normally composed of two
layers, externa (longitudinal) and interna (circular),
which are oriented perpendicular to one another.
Only two forms of primary muscular malformation
have been described: segmental additional
muscle coat and diffuse abnormal muscle
layering.114–116 These conditions may be rare;
only a handful of patients with each type have
been reported. An etiology has not been defined
for either entity, although segmental additional
muscle coat has been reported in a patient with
Mowat-Wilson syndrome (microcephaly,
abnormal facies, and HSCR).117 Other patients
with segmental additional muscle coat have had
mild intellectual impairment or other central
nervous system findings.115,116 X-linked inheri-
tance has been suggested for diffuse abnormal
muscle layering based largely on a single family
with three affected male relatives.114 The patho-
genesis of these conditions is presumed to reflect
abnormal radial patterning of gut mesenchyme
during embryogenesis and possibly involve
abnormal intercellular signals between the endo-
derm and surrounding mesoderm.115
GROSS FEATURES
Segmental additional muscle coat has been asso-
ciated with profound segmental dilatation of the
Intestinal Motor Disorders in Children 727
colon (megacolon), primarily in teens or young
adults with lifelong constipation. Small intestinal
involvement has not been described. Careful
gross inspection may reveal irregularities in the
thickness of the bowel wall, but usually the diag-
nosis is not suspected until microscopic sections
are reviewed. Diffuse abnormal muscle layering
has primarily been described in the small intestine
as a patchy process throughout the length of the
organ. The small intestine is short, dilated, or
normal caliber; often malrotated; and may have
a thick-walled appearance.
MICROSCOPIC FEATURES
Segmental additional muscle coat is character-
ized by a prominent separate band of smooth
muscle located internal to the muscularis interna
and external to the muscularis mucosae of an
otherwise normal muscularis propria (Fig. 9A).
The supernumerary musculature is less thick
than the muscularis interna and is surrounded
by submucosal stroma, including neural and
vascular elements. As the name suggests, the
malformation is segmental or patchy and gener-
ally does not surround the entire circumference
of the bowel wall. In contrast with tunics of the
muscularis propria, myocyte fascicles in the extra
muscle layer are oriented haphazardly and, in at
least one case, lacked intramuscular interstitial
cells of Cajal. Myenteric ganglia and nerves retain
their normal spatial relationships to the tunica of
the muscularis propria and are neither displaced
nor duplicated in conjunction with the additional
smooth muscle.
In diffuse abnormal muscular layering, portions
of the muscularis propria retain their normal bilay-
ered architecture, but malformed regions harbor
broad fascicles of smooth muscle that course
obliquely or perpendicularly to their appropriate
orientations (Fig. 9B). In some sites, the muscula-
ris propria appears trilayered, but in contrast to
segmental additional muscle coat, any additional
muscle coat is intimately associated with the mus-
cularis propria. Nerves and ganglia of the myenter-
ic plexus occupy various planes in the muscularis
propria, much like the pattern of the normal
appendix, where the muscular tunica are less
distinct.
DIFFERENTIAL DIAGNOSIS
In well-oriented histologic sections, both types of
intestinal muscle malformation are easily identified.
Smooth muscle hyperplasia in response to chronic
injury (eg, fibrosing colonopathy or Crohn colitis)
can sometimes occupy much of the submucosa.
728 Kapur

Fig. 9. Malformations of
the muscularis propria.
(A) A segmental addi-
tional muscle coat (as-
terisk) is present internal
to and separate from
the muscularis interna.
(B) Diffuse abnormal
muscle layering is exempli-
fied by this field from the
small intestine of a boy
with pseudo-obstruction.
Muscle fascicles are orga-
nized in at least three
distinct layers that appear
perpendicular to one
another. In other sites, the
arrangement of fascicles
was more haphazard.
Arrows indicate myenteric
ganglia. Scale bars: 40 mm.

Smooth muscle fibers in the latter are more
diffusely distributed, often merge with the muscula-
ris mucosae, and do not form compact muscularis
propria-like bundles, which typify segmental addi-
tional muscle coat. Diffuse abnormal layering of
intestinal smooth muscle must be distinguished
from tangential sections of normal bowel wall.
This is particularly challenging in small biopsies,
which tend to roll-up and appear multilayered if
they are not oriented appropriately. Additional
levels or reorientation of the biopsy can usually
eliminate confusion.

PROGNOSIS
Few cases of either type of muscular malformation
have been reported, and no published long-term
follow-up data exist. Among patients with
segmental additional muscle coat, isolated colonic
involvement has been the rule, and persistent
problems after partial or complete colectomy
have not been described. In contrast, patients
with diffuse abnormal muscle layering have died
because of malformations in other organ systems
or survived with persistent CIPO. For survivors,
the extent of small intestinal involvement is seldom
completely defined. Intestinal transplantation for
diffuse abnormal muscle layering has not been
reported.
DEGENERATIVE LEIOMYOPATHY
OVERVIEW
Progressive loss of enteric smooth muscle and
replacement by fibrous tissue are the hallmarks
of degenerative leiomyopathy (DL), which is
synonymous with visceral myopathy or hollow
visceral myopathy. CIPO is usually present, but
age at presentation (birth-to-adulthood), involve-
ment of the urinary bladder (megacystis), inheri-
tance pattern (sporadic, autosomal dominant, or
autosomal recessive), and severity of intestinal
dilatation (minimal, segmental, or diffuse) are all
highly variable. In contrast with most pediatric
enteric neuropathies, many patients with DL do
not develop symptoms until adolescence. Mega-
duodenum or segmental dilatation of jejunum is
also common. Apart from bladder involvement,
extraenteric problems are less common than
with enteric neuropathies, and their absence may
help distinguish DL from enteric manifestations
of more global connective tissue disorders (eg,
muscular dystrophy or progressive systemic
sclerosis).118–120
Key Features
DEGENERATIVE LEIOMYOPATHY
 The distribution is often patchy; portions of
one or both layers of the muscularis propria
may be spared.
 Urinary bladder involvement is common.
 Degenerative cytologic changes in myocytes
and prominent interstitial fibrosis.
Intestinal Motor Disorders in Children 729
GROSS FEATURES
Although the bowel may appear normal grossly,
dilatation (segmental or diffuse) is more common.
If inspected closely, the cut surface of the muscu-
laris propria may be irregularly thick or thin de-
pending on the amount of muscular atrophy and
compensatory hypertrophy.121 Zones of pale
discoloration, which correspond to fibrous
replacement of smooth muscle, may blur the
normal sharp distinction between the muscularis
externa and interna. Diverticulae are rare and
only observed with severe muscular atrophy.
MICROSCOPIC FEATURES
The two consistent histopathologic alterations of
DL are myocyte degeneration and intramuscular
fibrosis (Fig. 10).121–123 These changes often are
more severe in the muscularis externa or the mus-
cularis interna, but occasionally both layers are
affected.124 Myocyte degeneration manifests as
cell shrinkage (typically with some pericellular
fibrosis), moderate-to-severe anisocytosis,
nuclear atypia (enlargement, hyperchromasia,
pyknosis, or binucleation), and vacuolar degenera-
tion.123,124 Vacuolar degeneration is touted to be
a reliable feature to distinguish between DL and
enteric involvement by progressive systemic scle-
rosis.120 Myocytes contain either mutiple small
vacuoles or perinuclear halos. Fibrosis seems to
begin as pericellular deposition of connective
tissue between degenerating myocytes, possibly
due to myofibroblastic transformation of smooth
muscle cells.125 With progression, confluent zones
of fibrosis replace contiguous myocytes, and
eventually the entire muscular tunic may be lost.
As muscular tissue is lost, the relative amount of
neural tissue increases passively. Absolute neural
hyperplasia, however, has been reported as
well.126,127
All of these changes are frequently patchy, even
through the length of a grossly dilated segment of
intestine. Vascular involvement is rare but has
been described.128,129 The muscularis mucosae
is usually unaffected. Therefore, histopathologic
diagnosis requires one or more seromuscular or
full-thickness biopsies. Reliance on a rectal biopsy
is inappropriate.
DIFFERENTIAL DIAGNOSIS
In the author’s opinion, the most frequent histo-
pathologic differential for DL is artifactual change
introduced by surgery and tissue manipulation.
730 Kapur

Fig. 10. Degenerative leio-

myopathy. (A) At low
magnification loss of myo-
cytes in the muscularis
externa (me) is apparent,
along with thinning and
pericellular fibrosis of
the muscularis interna
(mi). (B) A Movat
pentachrome-stained se-
ction from the same case
highlights fibrosis (yellow)
and glycosaminoglycan
(blue) deposition in the
muscularis interna (mi)
and externa (me).
(C) Another field from the
same case illustrates vacu-
olar myocyte degenera-
tion with pericellular
fibrosis, which are hall-
marks of degenerative
leiomyopathy. Scale bars:
40 mm.

Differential Diagnosis
ATROPHY
Degenerative leiomyopathy
 Connective tissue disorders (eg, progressive
systemic sclerosis) may produce similar
fibrosis without overt degenerative changes
in myocytes.
 Artifacts associated with tissue manipulation
or poor fixation can mimic cytologic changes
but do not produce fibrosis.
 DL can be a consequence of mitochondrial
disorders or inflammatory leiomyopathy.
Contraction bands, autolysis, intercellular edema,
crush, and other changes in smooth muscle cells
are forms of acute cellular degeneration that may
be misinterpreted as DL. Important features that
should be present before the diagnosis of DL is
established include the nuclear atypia and cyto-
plasmic vacuolization (described previously) along
with unequivocal fibrosis. Alone, muscular atrophy
and fibrosis may represent enteric manifestations
of progressive systemic sclerosis, but cytologic
myocyte degeneration and clinical history are
helpful discriminators. Similarly, extraintestinal
findings distinguish cases of myotonic or
Duchenne muscular dystrophy with intestinal
involvement from DL, even though the enteric
pathology may be similar. Some mitochondrial
disorders (discussed later) affect neurons and
smooth muscle and cause DL. It is possible that
some patients with ophthalmoplegia and ptosis,
who have been classified traditionally as a subtype
of autosomal recessive familiar visceral myop-
athy,48 may actually have mitochondrial disease.
Moore and colleagues130 have written extensively
about an African form of sporadic DL, which they
think can be distinguished from other types of DL
based on a variety of clinical and histopathologic
grounds, but the morphologic overlap is
significant.
PROGNOSIS
DL is progressive. The pace varies, but most
patients require prokinetic drugs and/or hyperali-
mentation. Diversion ileostomy may reduce
morbidity, but resection of dilated segments of
bowel usually is not curative.131
Intestinal Motor Disorders in Children 731
Pitfalls
DEGENERATIVE LEIOMYOPATHY
! Contraction bands, perinuclear halos, and
irregular cell shrinkage can occur secondary
to tissue manipulation or poor fixation, and
should not be misinterpreted as DL unless
significant fibrosis is present.
INTESTINAL LEIOMYOSITIS
OVERVIEW
Intestinal leiomyositis (IL) denotes inflammation of
the muscularis propria, which is the only histopath-
ologic finding in some patients with CIPO. IL is
rare. In a review published in 2005, Oton and
colleagues132 identified only 12 reported patients,
including nine cases in which inflammation was
transmural and therefore not pure leiomyositis.
All patients with isolated IL have been children
(ages 6 months, 2 years, and 16 years).
GROSS FEATURES
Limited gross pathologic information is available
because most reports only include biopsy
pathology. Radiographically, diffuse small intes-
tinal dilatation is the rule; the colon is spared or
slightly dilated.
MICROSCOPIC FEATURES
The isolated form of IL reported in pediatric
patients is characterized by dense, diffuse
lymphocytic infiltrates in the muscularis propria,
with limited extension into the myenteric plexus,
submucosa, or lamina propria (Fig. 11).132,133 My-
ocyte degeneration and fibrosis, identical to DL,
appear in the inflammatory milieu and probably
increase with time. In one patient, the infiltrate
was pleomorphic and included eosinophils and
neutrophils, in addition to lymphocytes.134 IL also
can occur in patients with CIPO as part of a trans-
mural lymphoplasmacytic infiltrate, which over-
runs the enteric nervous system as well, but
causes minimal cytologic damage to myocytes,
neurons, or glial cells. The latter has been
described almost exclusively in adults and inter-
preted as an atypical lymphoproliferative
disorder.135 Finally, rare examples of eosinophilic
IL have been reported in patients with intestinal
dysmotility, and eosinophilic IL is regarded as
a distinct entity from lymphocytic IL.136
732 Kapur

Fig. 11. Intestinal leio-

myositis. (A) Lympho-
cytes are present in both
the external (me) and
internal (mi) layers of
the muscularis propria.
(B) In this case, myocyte
loss and fibrosis are
most conspicuous in
the muscularis interna.
Scale bars: 40 mm.

DIFFERENTIAL DIAGNOSIS history, immunohistochemistry, and in situ hybrid-

Some inflammation in the muscularis propria is
not uncommon with luminal stasis, but the latter
produces transmural mixed inflammation
(lymphocytes and eosinophils) that is not concen-
trated in the muscularis propria. Epstein-Barr
virus–related lymphoproliferative disease or
lymphoma must also be kept in mind, particularly
with transmural IL. Cytologic atypia, clinical
ization for virus may be helpful in difficult cases.
PROGNOSIS
A variety of approaches have been used to treat
lymphocytic leiomyositis (eg, antibiotics and im-
munosupression) with variable success. Some
patients require parenteral nutrition.
 Intestinal Motor Disorders in Children 733

MITOCHONDRIAL INTESTINAL central and peripheral nervous systems and skel-

NEUROMUSCULAR DISEASE
OVERVIEW
CIPO is a common, although not universally
present, manifestation of a variety of mitochondrial
myopathies (Table 1).48,137 As a group, these
disorders are due to mutations in nuclear or mito-
chondrial genes that are necessary for mitochon-
drial replication and/or oxidative respiration.
Extraenteric manifestations, particularly in the
etal muscle, are usually present and may dominate
the clinical presentation. CIPO is a prominent
finding in mitochondrial neurogastrointestinal en-
cephalomyopathy (MNGIE) and the synonymous
disorders POLIP (polyneuropathy ophthalmople-
gia, leukoencephalopathy, and intestinal pseudo-
obstruction), MEPOP (mitochondrial sensorimotor
polyneuropathy, ophthalmoplegia, and pseudo-
obstruction), and OGIMD (oculogastrointestinal
muscular dystrophy).142 MNGIE is an autosomal
recessive condition caused by mutations in the

Table 1
Mitochondrial disorders associated with chronic intestinal pseudo-obstruction

Disorder Extraenteric Findings Enteric Histopathology Gene References

MNGIE  Polyneuropathy  Segmental atrophy  TYMP (nuclear) Amiot A,
 Progressive external  Vacuolization and  RRM2B (nuclear) Tchikviladze M,
ophthalmoplegia fibrosis of muscularis Joly F, et al.137
 Leukoencephalopathy externa Blondon H,
 Deafness  Megamitochondria Polivka M,
in smooth muscle and Joly F, et al.138
ganglion cells Perez-Atayde AR,
 Vacuolization and Fox V,
dropout of myenteric Teitelbaum JE,
ganglion cells et al.139
Simon LT,
Horoupian DS,
Dorfman LJ,
et al.140
Giordano C,
Sebastiani M,
Plazzi G, et al.141
MELAS  Myopathy  mtDNA Amiot A,
 Ophthalmoplegia tRNAleu(UUR) Tchikviladze M,
 Pigmentary (mitochondrial) Joly F, et al.137
retinopathy
 Cardiomyopathy
 Ataxia
 Deafness
 Lactic acidemia
 Dementia
 Proximal renal tubular
dysfunction
 Stroke-like episodes
Alpers  Spongiform cerebral  POLG (nuclear) Amiot A,
disease degeneration Tchikviladze M,
 Developmental delay Joly F, et al.137
 Seizures
 Liver
 Dysfunction/cirrhosis

Abbreviations: mtDNA tRNAleu(UUR), mitochondrial DNA-encoded transfer RNA for leucine; POLG, mitochondrial DNA
polymerase gamma; RRM2B, p53-inducible ribonucleoside reductase small subunit; TYMP, thymidine phosphorylase.
734 Kapur
THYMIDINE PHOSPHORYLASE gene, which
encodes an enzyme required for normal mitocho-
drial DNA synthesis. CIPO is also found in patients
with Alpers disease (POLG mutations) or mito-
chondrial encephalopathy, lactic acidosis, and
stroke-like episodes syndrome (MELAS). Definitive
diagnosis of one of these conditions typically
requires biopsies from other tissues (eg, skeletal
muscle) with biochemical studies of respiratory
enzyme activities, histochemistry, and/or electron
microscopy, as well as mutational analysis for
specific genes.
GROSS FEATURES
CIPO in mitochondrial disorders results in bowel
distension, especially the small intestine. Small
intestinal diverticulae have been reported in 53%
of patients with MNGIE.138 Intestinal resections
are uncommon and usually occur only because
of adhesions related to prior laparotomy.
MICROSCOPIC FEATURES
Light and electron microscopic studies of intes-
tinal samples from patients with MNGIE have
yielded diverse impressions as to whether or not
CIPO results from myopathic, neuropathic, or
mixed effects.138 The most consistent finding is
atrophy and fibrosis of the outer longitudinal
smooth muscle layer in the muscularis propria
with vacuolization and other neurodegenerative
features in the residual myocytes (Fig. 12A). The
inner circular muscle layer and muscularis
mucosae are spared, at least at the light micro-
scopic level.138,141,143 Ultrastructurally, myocyte
vacuoles correspond to lipid or swollen mitochon-
dria, which are often increased in number and size.
Sometimes giant mitochondria can be resolved in
H&E-stained sections as hyalinized eosinophilic
globules several micrometers in diameter (see
Fig. 12B). In a few reported cases, the muscularis
propria appeared normal, but loss of neurons,
ultrastructural alterations of myenteric axons,
and/or perikaryal megamitochondria were
observed.140,144 When present, megamitochon-
dria are only in a subset of neurons, so careful
inspection of many ganglia may be required.
Combined muscular and neural changes have
also been identified.139 In at least one instance,
the diagnosis was confirmed based on megamito-
chondria in ganglion cells from a rectal biopsy.139
DIFFERENTIAL DIAGNOSIS
From a histopathologic perspective, the myopathic
changes described in patients with CIPO due to
a primary mitochondrial disorder are identical to
the muscular atrophy, myocyte vacuolar degenera-
tion, and fibrosis to that encountered in degenera-
tive leiomyopathy. Although the latter can also be
patchy and involve only one layer of the muscularis
propria, visceral myopathies more frequently affect
the muscularis internus. Light or electron micro-
scopic resolution of megamitochondria or
abnormal mitochondrial ultrastructure strongly
suggests a mitochondrial basis, but biochemical
or genetic testing is necessary to confirm the
diagnosis.
PROGNOSIS
CIPO associated with mitochondrial disorders
usually assumes a protracted course. Medical
therapies aimed at improving an underlying meta-
bolic problem have not been shown to be of
value.138 Bone marrow transplantation may offer
some improvement for patients with MNGIE,145
but most patients are managed with prokinetic
drugs (with variable success) and/or parenteral
nutrition.
OTHER PEDIATRIC DYSMOTILITY DISORDERS
Other disorders of pediatric intestinal motility are
recognized clinically, but do not have well-
established anatomic pathologies. Two entities in
this group are slow transit constipation (STC) and
megacystis microcolon intestinal hypoperistalsis
syndrome (MMIHS). The clinical features of STC
are reduced stooling frequency, abdominal disten-
sion, and soiling.146 STC is best known as an idio-
pathic condition that predominantly affects young
women and is often treated empirically by colec-
tomy after years of symptoms (often dating to
childhood) and failed medical management.147 In
children with STC, no gender bias exists, and it
is unclear how STC in adults relates, if at all, to
pediatric STC.148 STC is distinguished from func-
tional fecal retention by transit studies usually
using radio-opaque markers, which move at
a normal rate through the small intestine but
show significantly delayed transit through the
entire colon. Pediatric STC has been investigated
primarily by Hutson and colleagues146 in Australia,
who find immunohistochemical changes in the
density of myenteric nerve fibers that express
specific neurotransmitters, with little or no associ-
ated histopathology. It remains uncertain whether
or not the reported changes actually contribute
to the pathogenesis of STC. The pathology of adult
STC is also poorly established, because a variety
of inconsistent and/or subtle microscopic alter-
ations have been reported by various groups,
many of which required special methods
 Intestinal Motor Disorders in Children 735

Fig. 12. Mitochondrial dis-

order (Alpers disease).
(A) Degeneration of the
muscularis externa, with
relative preservation of
the muscularis interna
and myenteric ganglia
(arrows) is a frequent
finding in patients with
pseudo-obstruction due
to a primary mitochondrial
disorder. (B) Large eosino-
philic inclusions (megami-
tochondria) in the
perikarya of a subset of
enteric neurons is another
characteristic feature.
Scale bars: 40 mm.

(eg, silver stain and immunohistochemistry) to
demonstrate.147,149,150
MMIHS is a form of severe neonatal pseudo-
obstruction with a probable genetic basis.151 In
addition to the phenotypic features specified by
MMIHS, the gut is malrotated and short, and mi-
croileum exists along with microcolon. The bowel
of affected infants has been described as
aperistaltic, and signs of pseudo-obstruction with
or without bladder distension can be recognized
prenatally by ultrasound examination. MMIHS is
more common in females (4:1) and affected
siblings, including twins, have been observed.
Inconsistent pathologic findings, including
myopathic and neuropathic features, have been
reported in intestinal tissues from patients with
736 Kapur
MMIHS, which may be a phenotype produced by
multiple etiologies.152–154 The prognosis for
MMIHS is poor with 80% to 90% mortality by
age 2 years.
ACKNOWLEDGMENTS
The editorial comments of Dr Clarissa Fauth are
greatly appreciated.
REFERENCES
1. Rudolph CD, Hyman PE, Altschuler SM, et al.
Diagnosis and treatment of chronic intestinal pseudo-
obstruction in children: report of a consensus work-
shop. J Pediatr Gastroenterol Nutr 1997;24:102–12.
2. Knowles CH, De Georgio R, Kapur RP, et al. The
London classification of gastrointestinal neuromus-
cular pathology (GINMP): report on behalf of the
Gastro 2009 International Working Group. Gut
2010;59:882–7.
3. Vargas JH, Sachs P, Ament ME. Chronic intestinal
pseudo-obstruction syndrome in pediatrics.
J Pediatr Gastroenterol Nutr 1988;7:323–32.
4. Faure C, Goulet O, Ategbo S, et al. Chronic intes-
tinal pseudoobstruction syndrome. Dig Dis Sci
1999;44:953–9.
5. Knowles CH, De Giorgio R, Kapur RP, et al. Gastro-
intestinal neuromuscular pathology: guidelines for
histological techniques and reporting on behalf of
the Gastro 2009 International Working Group.
Acta Neuropathol 2009;118(2):271–301.
6. Anuras S, Mitros FA, Soper RT, et al. Chronic intes-
tinal pseudoobstruction in young children. Gastro-
enterology 1986;91(1):62–70.
7. Chakravarti A, Lyonnet S. Hirschsprung disease. In:
Scriver CR, Beaudet AL, Sly WS, et al, editors, The
metabolic & molecular bases of inherited disease,
vol. 1. New York: McGraw-Hill; 2001. p. 931–42.
8. Kapur RP, deSa DJ, Luquette M, et al. Hypothesis:
pathogenesis of skip areas in long-segment Hirsch-
sprung’s disease. Pediatr Pathol Lab Med 1995;
15(1):23–37.
9. Burns AJ, Roberts RR, Bornstein JC, et al. Develop-
ment of the enteric nervous system and its role in
intestinal motility during fetal and early postnatal
stages. Semin Pediatr Surg 2009;18(4):196–205.
10. Kapur RP. Practical pathology and genetics of
Hirschsprung’s disease. Semin Pediatr Surg 2009;
18(4):212–23.
11. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al.
Hirschsprung disease, associated syndromes and
genetics: a review. J Med Genet 2008;45(1):1–14.
12. Aldridge RT, Cambell PE. Ganglion cell distribution
in the normal rectum and anal canal: a basis for the
diagnosis of Hirschsprung’s disease by anorectal
biopsy. J Pediatr Surg 1968;3:475–89.
13. Weinberg AG. The anorectal myenteric plexus: its
relation to hypoganglionosis of the colon. Am
J Clin Pathol 1970;54:637–42.
14. Leutenegger F. Untersuchungen des M. sphincter
ani internus auf Ganglienzellen. Schweiz Med Wo-
chenschr 1969;99(40):1431–2 [in German].
15. Venugopal S, Mancer K, Shandling B. The validity of
rectal biopsy in relation to morphology and distribu-
tion of ganglion cells. J Pediatr Surg 1981;16:433–7.
16. Qualman SJ, Jaffe R, Bove KE, et al. Diagnosis of
Hirschsprung disease using the rectal biopsy:
multi-institutional survey. Pediatr Dev Pathol 1999;
2:588–96.
17. Feichter S, Meier-Ruge WA, Bruder E. The histopa-
thology of gastrointestinal motility disorders in chil-
dren. Semin Pediatr Surg 2009;18(4):206–11.
18. Meier-Ruge W, Bruder E. Pathology of chronic con-
stipation in pediatric and adult coloproctology.
Pathobiology 2005;72:1–102.
19. Martin JE, Hester TW, Aslam H, et al. Discordant
practice and limited histopathological assessment
in gastrointestinal neuromuscular disease. Gut
2009;58(12):1703–5.
20. Monforte-Munoz H, Gonzales-Gomez I,
Rowland JM, et al. Increased submucosal nerve
trunk caliber in aganglionosis. A ‘‘positive’’ and
objective finding in suction biopsies and segmental
resections in Hirschsprung’s disease. Arch Pathol
Lab Med 1998;122:721–5.
21. Meier-Ruge W, Hunziger O, Tobler H-J, et al.
The pathophysiology of aganglionosis of the
entire colon (Zuelzer-Wilson syndrome): morpho-
metric investigations of the extent of sacral
parasympathetic innervation of the circular
muscles of the aganglionic colon. Beitr Pathol
1972;147:228–36.
22. Kapur RP. Can we stop looking? Immunohisto-
chemistry and the diagnosis of Hirschsprung
disease. Am J Clin Pathol 2006;126(1):9–12.
23. Kapur RP, Reed RC, Finn LS, et al. Calretinin immu-
nohistochemistry versus acetylcholinesterase
histochemistry in the evaluation of suction rectal
biopsies for Hirschsprung disease. Pediatr Dev
Pathol 2009;12(1):6–15.
24. Barshack I, Fridman E, Goldberg I, et al. The loss of
calretinin expression indicates aganglionosis in
Hirschsprung’s disease. J Clin Pathol 2004;57(7):
712–6.
25. Guinard-Samuel V, Bonnard A, De Lagausie P, et al.
Calretinin immunohistochemistry: a simple and effi-
cient tool to diagnose Hirschsprung disease. Mod
Pathol 2009;22(10):1379–84.
26. Gherardi GJ. Pathology of the ganglionic-
aganglionic junction in congenital megacolon.
Arch Pathol 1960;69:520–8.
27. White FV, Langer JC. Circumferential distribution of
ganglion cells in the transition zone of children with

Hirschsprung disease. Pediatr Dev Pathol 2000;3:
216–22.
28. Whitehouse FR, Kernohan JW. Myenteric plexus in
congenital megacolon. Arch Intern Med 1948;82:
75–111.
29. Doi T, Kobayashi H, Yamataka A, et al. Complete
innervation profile of whole bowel resected at
pull-through for Hirschsprung’s disease. Unex-
pected findings. Pediatr Surg Int 2005;21(11):
889–98.
30. Langer JC. Persistent obstructive symptoms after
surgery for Hirschsprung’s disease: development
of a diagnostic and therapeutic algorithm. J Pediatr
Surg 2004;39:1458–62.
31. Boman R, Sfeir R, Preso R, et al. Advantages of intra-
operative semiquantitative evaluation of myenteric
nervous plexuses in patients with Hirschsprung
disease. J Pediatr Surg 2007;42:1089–94.
32. Swaminathan M, Kapur RP. Counting myenteric
ganglion cells in histologic sections: an empirical
approach. Hum Pathol 2010. [Epub ahead of print].
33. Yamataka A, Kato Y, Tibboel D, et al. A lack of
intestinal pacemaker (c-kit) in aganglionic bowel
of patients with Hirschsprung’s disease. J Pediatr
Surg 1995;30:441–4.
34. Vanderwinden J-M, Rumessen JJ, Liu H, et al. Inter-
stitial cells of cajal in human colon and in Hirsch-
sprung’s disease. Gastroenterology 1996;111:
901–10.
35. West KW, Grosfeld JL, Rescorla FJ, et al. Acquired
aganglionosis: a rare occurrence following pull-
through procedures for Hirschsprung’s disease.
J Pediatr Surg 1990;25(1):104–8 [discussion: 108–9].
36. Cogbill TH, Lilly JR. Acquired aganglionosis after
Soave’s procedure for Hirschsprung’s disease.
Arch Surg 1982;117(10):1346–7.
37. Langer JC. Repeat pull-through surgery for
complicated Hirschsprung’s disease: indications,
techniques, and results. J Pediatr Surg 1999;34:
1136–41.
38. Cohen MC, Moore SW, Neveling U, et al. Acquired
aganglionosis following surgery for Hirschsprung’s
disease: a report of five cases during a 33-year
experience with pull-through procedures. Histopa-
thology 1993;22(2):163–8.
39. Uesaka T, Jain S, Yonemura S, et al. Conditional
ablation of GFR{alpha}1 in postmigratory enteric
neurons triggers unconventional neuronal death
in the colon and causes a Hirschsprung’s
disease phenotype. Development 2007;134(11):
2171–81.
40. Crone SA, Negro A, Trumpp A, et al. Colonic
epithelial expression of ErbB2 is required for post-
natal maintenance of the enteric nervous system.
Neuron 2003;37(1):29–40.
41. Krishnamurthy S, Heng Y, Schuffler MD. Chronic
intestinal pseudo-obstruction in infants and
Intestinal Motor Disorders in Children 737
children caused by diverse abnormalities of the
myenteric plexus. Gastroenterology 1993;104:
1398–408.
42. Scharli AF, Sossai R. Hypoganglionosis. Semin
Pediatr Surg 1998;7:187–91.
43. Meier-Ruge WA, Brunner LA, Engert J, et al.
A correlative morphometric and clinical investiga-
tion of hypoganglionosis of the colon in children.
Eur J Pediatr Surg 1999;9:67–74.
44. Kubota A, Yamauchi K, Yonekura T, et al. Clinico-
pathologic relationships of hypoganglionosis.
J Pediatr Surg 2001;36:898–900.
45. Navarro J, Sonsino E, Boige N, et al. Visceral
neuropathies responsible for chronic intestinal
pseudo-obstruction syndrome in pediatric prac-
tice: analysis of 26 cases. J Pediatr Gastroenterol
Nutr 1990;11(2):221–8.
46. Ikeda K, Goto S, Nagasaki A, et al. Hypogenesis of
intestinal ganglion cells: a rare cause of intestinal
obstruction simulating aganglionosis. Z Kinderchir
1988;43(1):54–5.
47. Camilleri M, Carbone LD, Schuffler MD. Familial
enteric neuropathy with pseudoobstruction. Dig
Dis Sci 1991;36(8):1168–71.
48. Noffsinger A, Fenoglio-Preiser C, Maru D, et alIn:
Gastrointestinal disease, vol. Fascicle 5. Washing-
ton, DC: American Registry of Pathology; 2007.
49. Fadda B, Maier WA, Meier-Ruge W, et al. [Neuronal
intestinal dysplasia. Critical 10-years’ analysis of
clinical and biopsy diagnosis]. Z Kinderchir 1983;
38(5):305–11 [in German].
50. Takahashi-Fujigasaki J. Neuronal intranuclear
hyaline inclusion disease. Neuropathology 2003;
23(4):351–9.
51. Schuffler MD, Bird TD, Sumi M, et al. A familial
neuronal disease presenting as intestinal pseu-
doobstruction. Gastroenterology 1978;75(5):
889–98.
52. Barnett JL, McDonnell WM, Appelman HD, et al.
Familial visceral neuropathy with neuronal intranu-
clear inclusions: diagnosis by rectal biopsy.
Gastroenterology 1992;102:684–91.
53. Goutieres F, Mikol J, Aicardi J. Neuronal intranu-
clear inclusion disease in a child: diagnosis by
rectal biopsy. Ann Neurol 1990;27(1):103–6.
54. Pountney DL, Huang Y, Burns RJ, et al. SUMO-1
marks the nuclear inclusions in familial neuronal in-
tranuclear inclusion disease. Exp Neurol 2003;
184(1):436–46.
55. Takahashi-Fujigasaki J, Arai K, Funata N, et al.
SUMOylation substrates in neuronal intranuclear
inclusion disease. Neuropathol Appl Neurobiol
2006;32(1):92–100.
56. Takahashi J, Fukuda T, Tanaka J, et al. Neuronal in-
tranuclear hyaline inclusion disease with
polyglutamine-immunoreactive inclusions. Acta
Neuropathol 2000;99(5):589–94.
738 Kapur
57. McFadden K, Hamilton RL, Insalaco SJ, et al.
Neuronal intranuclear inclusion disease without
polyglutamine inclusions in a child. J Neuropathol
Exp Neurol 2005;64(6):545–52.
58. De Giorgio R, Guerrini S, Barbara G, et al. Inflam-
matory neuropathies of the enteric nervous system.
Gastroenterology 2004;126(7):1872–83.
59. Smith VV, Gregson N, Foggensteiner L, et al.
Acquired intestinal aganglionosis and circulating
autoantibodies without neoplasia or other neural
involvement. Gastroenterology 1997;112:1366–72.
60. Schobinger-Clement S, Gerber HA, Stallmach T.
Autoaggressive inflammation of the myenteric
plexus resulting in intestinal pseudoobstruction.
Am J Surg Pathol 1999;23(5):602–6.
61. Chinn JS, Schuffler MD. Paraneoplastic visceral
neuropathy as a cause of severe gastrointestinal
motor dysfunction. Gastroenterology 1988;95(5):
1279–86.
62. da Silveira AB, Lemos EM, Adad SJ, et al. Megaco-
lon in Chagas disease: a study of inflammatory
cells, enteric nerves, and glial cells. Hum Pathol
2007;38(8):1256–64.
63. Horoupian DS, Kim Y. Encephalomyeloneuropathy
with ganglionitis of the myenteric plexuses in the
absence of cancer. Ann Neurol 1982;11(6):628–32.
64. Smith VV, Schappi MG, Bisset WM, et al. Lymphocytic
leiomyositis and myenteric ganglionitis are intrinsic
features of cystic fibrosis: studies in distal intestinal
obstruction syndrome and meconium ileus.
J Pediatr Gastroenterol Nutr 2009;49(1):42–51.
65. Geboes K, Collins S. Structural abnormalities of the
nervous system in Crohn’s disease and ulcerative
colitis. Neurogastroenterol Motil 1998;10(3):
189–202.
66. Schappi MG, Smith VV, Milla PJ, et al. Eosinophilic
myenteric ganglionitis is associated with functional
intestinal obstruction. Gut 2003;52(5):752–5.
67. Losanoff JE, Kjossev KT, Katrov ET. Eosinophilic
enterocolitis and visceral neuropathy with chronic
intestinal pseudo-obstruction. J Clin Gastroenterol
1999;28(4):368–71.
68. DeSchryver-Kecskemeti K, Clouse RE. Perineural
and intraneural inflammatory infiltrates in the intes-
tines of patients with systemic connective-tissue
disease. Arch Pathol Lab Med 1989;113(4):394–8.
69. Lowichik A, Weinberg AG. Eosinophilic infiltration
of the enteric neural plexuses in Hirschsprung’s
disease. Pediatr Pathol Lab Med 1997;17:885–91.
70. Gohil A, Croffie JM, Fitzgerald JF, et al. Reversible
intestinal pseudo-obstruction associated with
neural crest tumors. J Pediatr Gastroenterol Nutr
2001;33:86–8.
71. Malik M, Connors R, Schwarz KB, et al. Hormone-
producing ganglioneuroblastoma simulating intes-
tinal pseudoobstruction. J Pediatr 1990;116(3):
406–8.
72. Krishnamurthy S, Schuffler MD. Pathology of neuro-
muscular disorders of the small intestine and colon.
Gastroenterology 1987;93:610–39.
73. Gargiulo A, Auricchio R, Barone MV, et al. Filamin A
is mutated in X-linked chronic idiopathic intestinal
pseudo-obstruction with central nervous system
involvement. Am J Hum Genet 2007;80(4):751–8.
74. Clayton-Smith J, Walters S, Hobson E, et al. Xq28
duplication presenting with intestinal and bladder
dysfunction and a distinctive facial appearance.
Eur J Hum Genet 2009;17(4):434–43.
75. Lindberg G, Tornblom H, Iwarzon M, et al. Full-
thickness biopsy findings in chronic intestinal
pseudo-obstruction and enteric dysmotility. Gut
2009;58(8):1084–90.
76. Dyer NH, Dawson AM, Smith BF, et al. Obstruction
of bowel due to lesion in the myenteric plexus. Br
Med J 1969;1(5645):686–9.
77. Shilkin KB, Gracey M, Joske RA. Idiopathic intes-
tinal pseudo-obstruction. Report of a case with
neuropathological studies. Aust Paediatr J 1978;
14(2):102–6.
78. Murr MM, Sarr MG, Camilleri M. The surgeon’s role in
the treatment of chronic intestinal pseudoobstruction.
Am J Gastroenterol 1995;90(12):2147–51.
79. d’Amore ES, Manivel JC, Pettinato G, et al. Intes-
tinal ganglioneuromatosis: mucosal and transmural
types. A clinicopathologic and immunohistochem-
ical study of six cases. Hum Pathol 1991;22(3):
276–86.
80. Carney JA, Go VL, Sizemore GW, et al. Alimentary-
tract ganglioneuromatosis. A major component of
the syndrome of multiple endocrine neoplasia,
type 2b. N Engl J Med 1976;295(23):1287–91.
81. Chambonniere ML, Porcheron J, Scoazec JY, et al.
[Intestinal ganglioneuromatosis diagnosed in adult
patients]. Gastroenterol Clin Biol 2003;27(2):
219–24 [in French].
82. Ortonne JP, Lambert R, Daudet J, et al. Involve-
ment of the digestive tract in Cowden’s disease.
Int J Dermatol 1980;19(10):570–6.
83. Shulman DI, McClenathan DT, Harmel RP, et al.
Ganglioneuromatosis involving the small intestine
and pancreas of a child and causing hypersecre-
tion of vasoactive intestinal polypeptide. J Pediatr
Gastroenterol Nutr 1996;22(2):212–8.
84. O’Riordain DS, O’Brien T, Crotty TB, et al. Multiple
endocrine neoplasia type 2B: more than an endo-
crine disorder. Surgery 1995;118:936–42.
85. Shekitka KM, Sobin LH. Ganglioneuromas of the
gastrointestinal tract. Relation to von Recklinghau-
sen disease and other multiple tumor syndromes.
Am J Surg Pathol 1994;18:250–7.
86. Kanter AS, Hyman NH, Li SC. Ganglioneuromatous
polyposis: a premalignant condition. Report of
a case and review of the literature. Dis Colon
Rectum 2001;44(4):591–3.

87. Hochberg FH, Dasilva AB, Galdabini J, et al.
Gastrointestinal involvement in von Recklinghau-
sen’s neurofibromatosis. Neurology 1974;24(12):
1144–51.
88. Feinstat T, Tesluk H, Schuffler MD, et al. Megacolon
and neurofibromatosis: a neuronal intestinal
dysplasia. Gastroenterology 1984;86:1573–9.
89. Bolande RP, Towler WF. A possible relationship of
neuroblastoma to Von Recklinghausen’s disease.
Cancer 1970;26(1):162–75.
90. Dahl EV, Waugh JM, Dahlin DC. Gastrointestinal
ganglioneuromas. Am J Pathol 1957;33:953–65.
91. Ritter SA. Neuroblastoma of the intestine. Am
J Pathol 1925;1:519–26.
92. Meier-Ruge W. Ueber ein Erkarakungsbild des
Kolons mit Hirschsprung Symptomatik. Verh Dtsch
Ges Pathol 1971;55:506–11 [in German].
93. Borchard F, Meier-Ruge W, Wiebecke B, et al.
Innervationsstorungen des Dickdarms—Klassifika-
tion und Diagnostik. Pathologe 1991;12:171–4 [in
German].
94. Kapur RP. Neuronal dysplasia: a controversial
pathological correlate of intestinal pseudo-obstruc-
tion. Am J Med Genet A 2003;122A:287–93.
95. Meier-Ruge WA, Bruder E, Kapur RP. Intestinal
neuronal dysplasia type B: one giant ganglion is
not good enough. Pediatr Dev Pathol 2006;9(6):
444–52.
96. Estevao-Costa J, Fragoso AC, Campos M, et al. An
approach to minimize postoperative enterocolitis in
Hirschsprung’s disease. J Pediatr Surg 2006;
41(10):1704–7.
97. Meier-Ruge W. Epidemiology of congenital innerva-
tion defects of the distal colon. Virchows Arch A
Pathol Anat Histopathol 1992;420:171–7.
98. Meyrat BJ, Lesbros Y, Laurini RN. Assessment of
the colon innervation with serial biopsies above
the aganglionic zone before the pull-through
procedure in Hirschsprung’s disease. Pediatr
Surg Int 2001;17(2-3):129–35.
99. Schulten D, Holschneider AM, Meier-Ruge W. Prox-
imal segment histology of resected bowel in Hirsch-
sprung’s disease predicts postoperative bowel
function. Eur J Pediatr Surg 2000;10(6):378–81.
100. Ure BM, Holschneider AM, Meier-Ruge WA.
Neuronal intestinal malformations: a retro- and
prospective study on 203 patients. Eur J Pediatr
Surg 1994;4:279–86.
101. Moore SW, Laing D, Kaschula ROC, et al.
A histological grading system for the evaluation of
co-existing NID with Hirschsprung’s disease. Eur
J Pediatr Surg 1994;4:293–7.
102. Kobayashi H, Hirakawa H, Surana R, et al. Intes-
tinal neuronal dysplasia is a possible cause of
persistent bowel symptoms after pull-through oper-
ation for Hirschsprung disease. J Pediatr Surg
1995;30:253–9.
Intestinal Motor Disorders in Children 739
103. Berry CL. Intestinal neuronal dysplasia: does it
exist or has it been invented? Virchows Arch
A Pathol Anat Histopathol 1993;422:183–4.
104. Csury L, Pena A. Intestinal neuronal dysplasia:
myth or reality? Literature review. Pediatr Surg Int
1995;10:441–6.
105. Lake BD. Intestinal neuronal dysplasia. Why does it
only occur in parts of Europe? Virchows Arch 1995;
426:537–9.
106. Sacher P, Briner J, Hanimann B. Is neuronal intes-
tinal dysplasia (NID) a primary disease or
a secondary phenomenon. Eur J Pediatr Surg
1993;3:228–30.
107. Hanimann B, Inderbitzin D, Briner J, et al. Clinical
relevance of Hirschsprung-associated neuronal
intestinal dysplasia (HANID). J Pediatr Surg 1992;
27(3):344–8.
108. Coerdt W, Michel JS, Rippin G, et al. Quantitative
morphometric analysis of the submucous plexus
in age-related control groups. Virchows Arch
2004;444(3):239–46.
109. Meier-Ruge WA, Ammann K, Bruder E, et al. Up-
dated results on intestinal neuronal dysplasia
(IND B). Eur J Pediatr Surg 2004;14(6):384–91.
110. Schmittenbecher PP, Gluck M, Wiebecke B, et al.
Clinical long-term follow-up results in intestinal
neuronal dysplasia (IND). Eur J Pediatr Surg
2000;10:17–22.
111. Schmittenbecher PP, Sacher P, Cholewa D, et al.
Hirschsprung’s disease and intestinal neuronal
dysplasia - a frequent association with implications
for the postoperative course. Pediatr Surg Int 1999;
15:553–8.
112. Banani SA, Forootan HR, Kumar PV. Intestinal
neuronal dysplasia as a cause of surgical failure in
Hirschsprung’s disease: a new modality for surgical
management. J Pediatr Surg 1996;31:572–4.
113. Meyrat BJ, Laurini RN. Plasticity of the enteric
nervous system in patients with intestinal neuronal
dysplasia associated with Hirschsprung’s disease:
a report of three patients. Pediatr Surg Int 2003;
19(11):715–20.
114. Smith VV, Milla PJ. Histological phenotypes of
enteric smooth muscle disease causing functional
intestinal obstruction in childhood. Histopathology
1997;31:112–22.
115. Kapur RP, Correa H. Architectural malformation of the
muscularis propria as a cause for intestinal pseudo-
obstruction: two cases and a review of the literature.
Pediatr Dev Pathol 2009;12(2):156–64.
116. Hart AL, Kamm MA, Palmer JG, et al. An extra-
ordinary cause of megacolon. Lancet 1997;
350(9071):110.
117. Leong MY, Verey F, Newbury-Ecob R, et al. Super-
numerary intestinal muscle coat in a patient with
Hirschsprung disease/Mowat-Wilson syndrome.
Pediatr Dev Pathol 2010. [Epub ahead of print].
740 Kapur
118. Leon SH, Schuffler MD, Kettler M, et al. Chronic
intestinal pseudoobstruction as a complication of
Duchenne’s muscular dystrophy. Gastroenterology
1986;90(2):455–9.
119. Bensen ES, Jaffe KM, Tarr PI. Acute gastric dilata-
tion in Duchenne muscular dystrophy: a case
report and review of the literature. Arch Phys Med
Rehabil 1996;77(5):512–4.
120. Schuffler MD, Beegle RG. Progressive systemic
sclerosis of the gastrointestinal tract and hereditary
hollow visceral myopathy: two distinguishable
disorders of intestinal smooth muscle. Gastroenter-
ology 1979;77:664–71.
121. Smith JA, Hauser SC, Madara JL. Hollow visceral
myopathy. Am J Surg Pathol 1982;6:269–75.
122. Schuffler MD, Pope CE. Studies of idiopathic intes-
tinal pseudoobstruction. II. Hereditary hollow
visceral myopathy: family studies. Gastroenter-
ology 1977;73:339–44.
123. Mitros FA, Schuffler MD, Teja K, et al. Pathologic
features of familial visceral myopathy. Hum Pathol
1982;13:825–33.
124. Faulk DL, Anuras S, Gardner GD, et al. A familial
visceral myopathy. Ann Intern Med 1978;89:600–6.
125. Martin JE, Benson M, Swash M, et al. Myofibro-
blasts in hollow visceral myopathy: the origin of
gastrointestinal fibrosis. Gut 1993;34:999–1001.
126. Mungan Z, Akyuz F, Bugra Z, et al. Familial visceral
myopathy with pseudo-obstruction, megaduode-
num, Barrett’s esophagus, and cardiac abnormali-
ties. Am J Gastroenterol 2003;98(11):2556–60.
127. Cheng W, Lui VC, Chen QM, et al. Enteric nervous
system, interstitial cells of cajal, and smooth
muscle vacuolization in segmental dilatation of
jejunum. J Pediatr Surg 2001;36(6):930–5.
128. Fitzgibbons PL, Chandrasoma PT. Familial visceral
myopathy. Evidence of diffuse involvement of intes-
tinal smooth muscle. Am J Surg Pathol 1987;
11(11):846–54.
129. Isaacson C, Wainwright HC, Hamilton DG, et al.
Hollow visceral myopathy in black South Africans.
S Afr Med J 1985;67:1015–7.
130. Moore SW, Schneider JW, Kaschula RD. Non-
familial visceral myopathy: clinical and pathologic
features of degenerative leiomyopathy. Pediatr
Surg Int 2002;18(1):6–12.
131. Goulet O, Jobert-Giraud A, Michel J-C, et al.
Chronic intestinal pseudo-obstruction syndrome
in pediatric patients. Eur J Pediatr Surg 1999;9:
83–90.
132. Oton E, Moreira V, Redondo C, et al. Chronic intes-
tinal pseudo-obstruction due to lymphocytic leio-
myositis: is there a place for immunomodulatory
therapy? Gut 2005;54(9):1343–4.
133. Nezelof C, Vivien E, Bigel P, et al. [Idiopathic myositis
of the small intestine. An unusual cause of chronic
intestinal pseudo-obstruction in children]. Arch Fr
Pediatr 1985;42(10):823–8 [in French].
134. Ginies JL, Francois H, Joseph MG, et al. A curable
cause of chronic idiopathic intestinal pseudo-
obstruction in children: idiopathic myositis of the
small intestine. J Pediatr Gastroenterol Nutr 1996;
23(4):426–9.
135. McDonald GB, Schuffler MD, Kadin ME, et al.
Intestinal pseudoobstruction caused by diffuse
lymphoid infiltration of the small intestine. Gastro-
enterology 1985;89(4):882–9.
136. Wiesner W, Kocher T, Heim M, et al. CT findings in
eosinophilic enterocolitis with predominantly seros-
al and muscular bowel wall infiltration. JBR-BTR
2002;85(1):4–6.
137. Amiot A, Tchikviladze M, Joly F, et al. Frequency of
mitochondrial defects in patients with chronic intes-
tinal pseudo-obstruction. Gastroenterology 2009;
137(1):101–9.
138. Blondon H, Polivka M, Joly F, et al. Digestive
smooth muscle mitochondrial myopathy in patients
with mitochondrial-neuro-gastro-intestinal ence-
phalomyopathy (MNGIE). Gastroenterol Clin Biol
2005;29(8-9):773–8.
139. Perez-Atayde AR, Fox V, Teitelbaum JE, et al. Mito-
chondrial neurogastrointestinal encephalomyop-
athy. Am J Surg Pathol 1998;22:1141–7.
140. Simon LT, Horoupian DS, Dorfman LJ, et al. Poly-
neuropathy, ophthalmoplegia, leukoencephalop-
athy, and intestinal pseudo-obstruction: POLIP
syndrome. Ann Neurol 1990;28(3):349–60.
141. Giordano C, Sebastiani M, Plazzi G, et al. Mito-
chondrial neurogastrointestinal encephalomyop-
athy: evidence of mitochondrial DNA depletion in
the small intestine. Gastroenterology 2006;130(3):
893–901.
142. Hirano M, Silvestri G, Blake DM, et al. Mitochon-
drial neurogastrointestinal encephalomyopathy
(MNGIE): clinical, biochemical, and genetic
features of an autosomal recessive mitochondrial
disorder. Neurology 1994;44(4):721–7.
143. Ionasescu V, Thompson SH, Ionasescu R, et al.
Inherited ophthalmoplegia with intestinal
pseudo-obstruction. J Neurol Sci 1983;59(2):
215–28.
144. Wedel T, Tafazzoli K, Sollner S, et al. Mitochondrial
myopathy (complex I deficiency) associated with
chronic intestinal pseudo-obstruction. Eur J Pediatr
Surg 2003;13(3):201–5.
145. Hirano M, Marti R, Casali C, et al. Allogeneic stem
cell transplantation corrects biochemical derange-
ments in MNGIE. Neurology 2006;67(8):1458–60.
146. Hutson JM, Catto-Smith T, Gibb S, et al. Chronic
constipation: no longer stuck! Characterization of
colonic dysmotility as a new disorder in children.
J Pediatr Surg 2004;39(6):795–9.

147. Knowles CH, Martin JE. Slow transit constipation:
a model of human gut dysmotility. Review of
possible aetiologies. Neurogastroenterol Motil
2000;12(2):181–96.
148. Shin YM, Southwell BR, Stanton MP, et al. Signs and
symptoms of slow-transit constipation versus func-
tional retention. J Pediatr Surg 2002;37(12):1762–5.
149. Bassotti G, Villanacci V, Maurer CA, et al. The role
of glial cells and apoptosis of enteric neurones in
the neuropathology of intractable slow transit con-
stipation. Gut 2006;55(1):41–6.
150. Wedel T, Roblick UJ, Ott V, et al. Oligoneuronal hypo-
ganglionosis in patients with idiopathic slow-transit
constipation. Dis Colon Rectum 2002;45(1):54–62.
151. Kohler M, Pease PW, Upadhyay V. Megacystis-mi-
crocolon-intestinal hypoperistalsis syndrome
Intestinal Motor Disorders in Children 741
(MMIHS) in siblings: case report and review of
the literature. Eur J Pediatr Surg 2004;14(5):362–7.
152. Richardson CE, Morgan JM, Jasani B, et al. Megacys-
tis-microcolon-intestinal hypoperistalsis syndrome
and the absence of the a3 nicotinic acetylcholine
receptor subunit. Gastroenterology 2001;121:350–7.
153. Puri P, Lake BD, Gorman F, et al. Megacystis-mi-
crocolon-hypoperistalsis syndrome: a visceral
myopathy. J Pediatr Surg 1983;18:64–9.
154. Szigeti R, Chumpitazi BP, Finegold MJ, et al.
Absent smooth muscle actin immunoreactivity of
the small bowel muscularis propria circular layer
in association with chromsome 15q11 deletion in
megacystis-microcolon-intestinal hypoperistalsis
syndrome. Pediatr Dev Pathol 2009. [Epub ahead
of print].