Original article

Long-term outcome of neonates with suspected

Hirschsprungs disease, but normal rectal biopsy
Daniel Harleva, Oleg Kharenkoa, Jacob Waxmana, Tanya Frankela, Dan Turnera,b and Oren Leddera,b

Background and objectives Hirschsprungs disease (HD) must always be considered in very early-onset constipation.
Although HD has a well-described clinical course, little is known about those neonates in whom HD was excluded. We aimed to
describe the long-term clinical outcomes of neonates with a clinical suspicion of HD that was excluded by rectal suction biopsy.
Methods This is a single-center double-cohort comparative study. Neonates who underwent rectal mucosa biopsy for
suspected HD were age and sex matched with healthy controls. A survey on clinical outcomes, stooling patterns, and other
gastrointestinal (GI)-related conditions was sent to parents. Pathology slides were re-reported by an experienced histopathologist
blinded to the clinical data.
Results A total of 51 neonates were included [25 cases, 26 controls; 41% males, median time of follow-up 4.25 years
(interquartile range 2.76.9)]. Nine (36%) of patients in the case group required prolonged laxative use for constipation during the
rst year of life compared with 0 (0%) controls (P < 0.001). This difference was maintained at the end of follow-up, with 5 (20%)
versus 0 (0%), respectively (P = 0.02). Case neonates were signicantly more likely to be hospitalized or to be diagnosed with a
chronic GI-related condition than the controls (33 vs. 12%, P = 0.01; and 19 vs. 8%, P = 0.04, respectively).
Conclusion Neonatal constipation is associated with long-term GI-related disorders and should be considered clinically
signicant even when the diagnosis of HD is excluded. Neonates with early-onset abnormal stooling patterns should be
monitored with adequate pediatrician or pediatric gastroenterologist follow-up. Eur J Gastroenterol Hepatol 28:917922
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

Introduction these variant HD disorders, ganglion cells are present on

Hirschsprungs disease (HD), also known as congenital
aganglionic megacolon, is a congenital disorder in which
ganglion cells are absent in the colon, causing constipation
and, in severe cases, life-threatening toxic megacolon. The
aganglionosis starts at the anus and progresses proximally
to varying degrees [1]. Several clinical parameters have
been shown to predict the diagnosis of HD, such as failure
to pass meconium within 2448 h and early onset of
constipation, especially if accompanied by vomiting and
abdominal distension [2,3]. Diagnosis may be supported
by a plain abdominal radiography, contrast enema, or
manometry, but a denite diagnosis can only be made by
rectal biopsy showing aganglionosis and hypertrophic
nerve bers [4,5]. A biopsy showing the presence of even
one ganglion excludes the diagnosis of HD.
The spectrum between HD and health has a wide range
of variant HD. However, controversy exists in terms of
the various diagnoses and outcomes in this spectrum. In
European Journal of Gastroenterology & Hepatology 2016, 28:917922
Keywords: chronic constipation, Hirschsprung, infant, rectal biopsy
a
Shaare Zedek Medical Center and bThe Hebrew University of Jerusalem,
Jerusalem, Israel
Correspondence to Oren Ledder, MD, Pediatric Gastroenterology and Nutrition
Unit, Shaare Zedek Medical Center, The Hebrew University; PO Box 3235,
Jerusalem 91031, Israel
Tel: + 972 266 66482; fax: + 972 265 55756; e-mail: orenl@szmc.org.il
Received 28 December 2015 Accepted 1 March 2016
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal's website (www.eurojgh.com).
rectal suction biopsy, but may be atypical in number (e.g.
hyperganglionosis and hypoganglionosis) or in phenotyp-
ing (e.g. immature or small ganglion cells). Described
conditions within the spectrum of variant HD include,
among others, intestinal neuronal dysplasia and neuronal
hypoplasia [6,7].
We aimed to describe the long-term clinical outcomes of
neonates with early constipation and a clinical suspicion of
HD that was excluded by rectal suction biopsy. We further
aimed to compare the clinical outcomes of neonates with
typical and atypical ganglion cells identied on their rectal
biopsy.
Methods
Study design
This is a single-center double-cohort comparative study.
The case group included neonates with very early-onset
constipation who underwent rectal suction biopsy for
suspected HD and in whom the diagnosis of HD was
excluded on the basis of the presence of ganglion cells on
histology. The control group included neonates who were
matched to the observation cohort by sex and gestational
age, who were born on the same day as the cases with the
same gestational age, but were discharged without the
need for rectal biopsy.
Inclusion criteria for the case group were neonates who
were subjected to a rectal suction biopsy at Shaare Zedek
Medical Center between 1996 and 2013 under the age of
3 months for suspected HD and in whom the diagnosis
was excluded. At our center, all rectal biopsies are

0954-691X Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000000636 917

Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

918 European Journal of Gastroenterology & Hepatology
referred and performed by experienced pediatric gastro-
enterologists or pediatric surgeons on the basis of the
clinical presentation and, sometimes, imaging studies. We
excluded neonates who had less than 1 year of follow-up.
Neonates with signs or symptoms suggestive of gastro-
enterological pathology by hospital discharge were exclu-
ded from the control group.
Cases were identied from the hospitals electronic
database by searching ICD-9 coding. Charts of neonates
found by the electronic search were screened for eligibility.
Controls were randomly selected and matched from the
same electronic database. Parents of eligible children were
contacted by a letter asking them to complete a short
questionnaire detailing the occurrence of constipation,
vomiting, abdominal distension, and abdominal pain.
Those who did not respond by mail were followed up by a
phone call with an option to complete the questionnaire
orally or through an emailed electronic questionnaire.
Other relevant clinical data were obtained from the med-
ical chart after obtaining parental consent. The pathology
slides were retrieved and re-reported by a histopathologist
with 22 years of clinical experience, blinded to the clinical
outcome. Histological ndings related to ganglion size,
maturity, and number were described on a standardized
case report form. Immature ganglia were characterized by
small numbers of cells per ganglion with an irregular
distribution.
Outcome measures
The primary outcome was the proportion of patients with
chronic constipation, dened as children requiring laxative
treatment for more than a 1-month period during the rst
year of life. Despite the absence of formal verication of
this outcome measure as accurately reecting neonatal
constipation, in the absence of a better outcome measure,
and within the connes of a retrospective analysis with the
associated risk of recall bias, this easy to remember,
objective endpoint was selected. This sought to minimize
recall bias and is easily validated by an outpatient chart
review. Furthermore, prolonged use of laxatives (longer
than 1 month) was specied because of the relatively
widespread ad hoc use of laxatives for transient con-
stipation of doubtful clinical signicance and prolonged
usage likely representing more clinically signicant con-
stipation. Secondary outcomes were dened as the pro-
portion of children who had chronic constipation during
the rst year of life as dened by the Rome III criteria, and
incidence and severity of other gastrointestinal (GI) dis-
orders including, but not limited to, vomiting, abdominal
pain, and distention. These data were obtained from the
questionnaire utilizing focused questions on stool fre-
quency, stool consistency (Bristol stool scale), straining
with defecation, pain and irritability (WongBaker faces
rating scale), vomiting/reux, the need for assisted stool-
ing, and other features. The secondary outcomes were
considered exploratory in nature because of recall bias.
The last follow-up was characterized as the survey-derived
clinical manifestations at the time of survey completion.
Statistical analysis
Statistical analysis of unpaired data was carried out on
outcomes by frequencies and proportions (with
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
August 2016 Volume 28 Number 8
corresponding 95% condence intervals), means SD, or
medians (interquartile range), as appropriate for the dis-
tribution normality. Continuous data were compared
using Students t-test or the Wilcoxon rank sum test as
appropriate for the distribution normality. Categorical
variables were compared using 2 or Fisher exact tests, as
appropriate. Statistical analyses were carried out using
SPSS for Windows V21.0 (IBM, Armonk, New York,
USA), with P value less than 0.05 considered the sig-
nicance threshold.
Results
A total of 55 neonates were identied in the case group
and 110 neonates were matched in the control group.
Three cases died during infancy and, of the remaining, 25
consented to complete the survey. Amongst the control
group, of the 110 surveys distributed, 26 consented to
participate in the study.
The median duration of follow-up was 4.25 years
(interquartile range 2.76.9; range 1.911.8).There were
no signicant differences between the two groups in
demographics and other background variables (Table 1).
The case group had a signicantly shorter period of
exclusive breastfeeding and a nonsignicant trend toward
shorter partial breastfeeding than the control group
6.7 4.1 versus 4.2 4.8 (P = 0.05) and 11.7 5.2 versus
8.7 8.2 (P = 0.13), respectively.
Outcomes over the rst year
Most of the measured outcomes were signicantly differ-
ent between the study groups during the rst year of life
(Fig. 1). Under the primary analysis, nine (36%) neonates
in the case group required laxatives for more than 1 month
during the rst year of life compared with 0 (0%) in the
control group (P < 0.001). This nding was similarly
reported by the caregivers for stool consistency as well as
vomiting, abdominal distension, abdominal pain, use of
anal stimulants, effort while defecating, and general
irritability.
Long-term outcomes
Outcomes at the last follow-up remained signicantly
higher in the study group than the control group (Fig. 2),
but were signicantly improved compared with outcomes
at 1 year of age. At the last follow-up, constipation (72 vs.
32%, P = 0.02) and vomiting (52 vs. 12%, P = 0.01) were
present in signicantly higher proportions in the case
cohort. There was a trend toward improved rates of
abdominal pain and reduced laxative use (Fig. 3).
A signicantly higher incidence of a subsequent diag-
nosis of a chronic or an otherwise signicant medical or
surgical condition was identied in the study cohort
compared with the control (32 vs. 8%, P = 0.04). These
conditions largely, although not exclusively, involved the
digestive tract, including two patients with cystic brosis
and one with intestinal volvulus, one patient with a limited
bowel resection (unclear clinical details surrounding this
presentation), one patient with Noonan syndrome, one
patient with global developmental delay (not otherwise
specied), and another patient who developed a brain
abscess. There was also a signicantly higher rate of
Outcomes following exclusion of HD Harlev et al. www.eurojgh.com 919

Table 1. Basic characteristics of the entire cohort

Entire cohort (N = 51) [n (%)] Control group (N = 26) [n (%)] Study group (N = 25) [n (%)] P-value

Males 21 (41) 13 (50) 8 (32) 0.19

Agea (years) 5.8 2.9 6.3 3.2 5.2 2.6 0.20
Gestational age (weeks) 36.2 3.9 36.1 3.6 36.2 4.4 0.94
Race 0.81
Ashkenazi 20 (39) 11 (42) 9 (36)
Sephardic 16 (31) 9 (35) 7 (28)
Mixed 13 (25) 6 (23) 7 (28)
Arabic 2 (4) 0 (0) 2 (8)
Family history of GI disorderb 17 (33) 9 (35) 8 (32) 0.84
Exclusive breastfeeding (months) 5.5 4.6 6.7 4.1 4.2 4.8 0.05
Exclusive and partial breastfeeding (months) 10.2 6.9 11.7 5.2 8.7 8.2 0.13
Child sequence in family 3.0 1.1 2.8 1.1 2.6 1.0 0.58
Unrelated diagnosesc 10 (19) 2 (8) 8 (32) 0.04
Hospitalizationd 17 (33) 3 (12) 14 (56) 0.01

Medians [IQR], means SD and proportions (95% CI) are presented as appropriate.
CI, condence interval; GI, gastrointestinal; IQR, interquartile range.
a
At the time of survey completion.
b
According to the parental survey documentation, includes irritable bowel disease, inammatory bowel disease, reux, peptic ulcer disease, chronic constipation, and celiac
disease.
c
Neonates diagnosed with other diseases during the follow-up period.
d
Neonates hospitalized during the follow-up period for any reason.

N = 25
Control N = 26 Case N = 25 80
80 P = 0.02 First year End of follow-up
P < 0.001 70
P < 0.001
P < 0.001
70 60
P < 0.001 P = 0.2
P < 0.001 P = 0.01
60 P < 0.001 50
Percentage

P < 0.001
50 40 P = 0.2
Percentage

30
40 P = 0.001
20
30
10
20 P = 0.051
0
10 Constipation Abdominal pain Laxative use Vomiting

Fig. 3. Long-term outcomes of the case cohort: 1 year versus the end of
0
follow-up.
n

ng

ng

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ts
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ea n al

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lit
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iti

iti
at

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al se
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ita
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neonates who had a hospital admission by the end of

di

In

follow-up in the study group than in the control group: 14

Fig. 1. Clinical manifestations during the rst year of life in controls versus (56%) versus 3 (12%) (P = 0.01). Six of these admissions
suspected Hirschsprungs disease cases. were for GI-related conditions including chronic con-
stipation or the underlying GI surgical condition as
listed above.
To assess the extent to which recall bias may have
affected the results of our study, a subanalysis was carried
out comparing recent cases with longer follow-up cases.
No signicant differences were detected between the
Control N = 26 Case N = 25
groups, suggesting that recall bias did not likely sig-
40
nicantly affect the data accuracy (Supplementary
P = 0.01 Table 2 Supplementary Appendix, Supplemental digital
35 P = 0.01 content 1, http://links.lww.com/EJGH/A93).
30

25 Atypical ganglia
Percentage

P = 0.02
20
To assess the signicance of atypical ganglion cells, the
15
P = 0.35 study cohort was subdivided into 2 groups on the basis of
10 normal histology (six cases) and atypical histology (13
5 cases), including small ganglions (n = 9) and/or immature
ganglions (n = 11) (Figs 47). Seven cases had both small
0
Constipation Abdominal pain Laxative use Vomiting and immature ganglions. Six cases had inadequate biopsy
Fig. 2. Clinical manifestations at the end of follow-up in controls versus preparations, in which ganglion cells were identied, but
suspected Hirschsprungs disease cases. with inadequate specimen to further categorize the

Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

920 European Journal of Gastroenterology & Hepatology
Fig. 4. Normal ganglion cells (arrows) (hematoxylin and eosin).
Fig. 5. Normal ganglion cells (arrows) (calretinin immunohistochemistry).
Fig. 6. Immature ganglion cells (arrows) (hematoxylin and eosin).
phenotype, and were thus excluded from this sub-analysis.
No specimens fullled the classication criteria of either
hyperganglionosis or hypoganglionosis. The small number
of patients in this sub-analysis limited statistical analysis of
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
August 2016 Volume 28 Number 8
Fig. 7. Immature ganglion cells (arrows) (calretinin immunohistochemistry).
ndings; however, no signicant differences were noted
between those with normal and abnormal ganglionic
phenotype in any of the clinical outcomes both by 1 year
and by the end of the follow-up (Supplementary Table 3
Supplementary Appendix, Supplemental digital content 2,
http://links.lww.com/EJGH/A94).
Discussion
Our study showed for the rst time that neonates with
early-onset constipation in whom HD was excluded by
way of a normal rectal biopsy had an increased rate of
constipation throughout early childhood. This suggests
that clinical presentation in the rst few days is predictive
of future long-term stooling behavior even in the
absence of HD.
The prevalence of childhood constipation varies sig-
nicantly between studies, ranging from 1.1 to 28.8%
[813], the vast majority of which are functional in nature.
Less frequent among the causes of constipation are
neurological disorders including HD variants. These
include intestinal neuronal dysplasia [1418], hypo-
ganglionosis [1921], immature ganglion cells, absence of
argyrophil plexus, internal anal sphincter achlasia, smooth
muscle cell abnormalities, perinuclear vacuolation, and
megacystis-microcolon-intestinal hypoperistalsis syndrome
[2226].
The clinical signicance of small and immature gang-
lions remains unclear. In our study, 13 of the rectal
biopsies had atypical ganglion cells; however, none ful-
lled the diagnostic criteria for small and immature
ganglions. Within the limitation of the small numbers
analyzed, we found no difference between the long-term
outcomes of neonates with small or immature ganglion
cells compared with those with normal ganglion cells.
These ndings should be studied further with a larger
cohort to better assess the clinical signicance of these
histological variants.
Our observation cohort had a signicantly higher rate
of diagnosis of a chronic medical condition at the time
of survey. The majority of these neonates (six of eight)
were diagnosed with conditions largely involving the GI
tract including cystic brosis, volvulus, and chronic
Outcomes following exclusion of HD Harlev et al.
constipation. This nding supports the suggestion that
clinical suspicion of a defecation disorder, even in neonates
in whom a rectal suction biopsy excludes HD, leads to a
signicantly higher risk for development of medical mor-
bidity involving the GI system in the future. We also found
a higher proportion of neonates who had been hospitalized
in whom many of these hospitalizations were related to GI
conditions. The additional nding of a higher hospitali-
zation rate in the study group suggests the clinical burden
and relevance of these medical conditions and diagnoses.
These data indicate that the nding of constipation in
neonates, even with normal biopsies, is associated with a
clinical burden that should be recognized.
It is noteworthy that all of the clinical manifestations
assessed at the last follow-up indicated signicant
improvements when compared with the rst year; how-
ever, these were still signicantly higher than the
control group.
In our study group, there was a trend to more females
(although this was not statistically signicant), whereas in
HD, there is a recognized male predominance of 75%
[27]. Considering that the entire studied cohort did not
have HD, this sex distribution, although interesting, is of
unclear signicance.
A further interesting nding in this comparative ana-
lysis is the signicant difference in the age until which the
neonates diet was exclusively breastmilk. The study design
does not allow us to answer whether this is a cause or
effect phenomenon. We may speculate that infants pre-
senting with chronic constipation may be suggested var-
ious maternal dietary changes for suspected neonatal
allergy that can be difcult to maintain or even be sug-
gested on medical or neighborly advice to commence
formula feeds. Alternatively, this nding may suggest
that formula is associated with a higher rate of constipa-
tion as reported previously by Van den Berg et al. [28].
In any case, the retrospective nature of our analysis
cannot elucidate a cause and effect relationship of the
association.
Our study is the rst to report the signicance of early
stooling disorder in predicting longer term defecation
behavior, despite the exclusion of HD, but it is not without
limitations, most notably recall bias. We made signicant
efforts to minimize this bias by selecting easy to remember
outcomes. Our comparative analysis of results on the basis
of length of follow-up conrmed that this potential con-
founder did not affect our results to any signicant level.
We did nd that the rates of constipation and vomiting did
improve from 1 year to the end of follow-up, with a trend
toward improvement in abdominal pain and reduced
laxative use; however, the presence of these features was
still considerably higher than that in the control group.
Unfortunately, our subgroups were too small to enable a
statistical analysis of the different histological abnormal-
ities; thus, this comparison remains merely descriptive in
nature.
We suggest that constipation in neonates should be
considered clinically signicant even when HD is excluded.
This may be important for counseling families and for
planning medical follow-up in GI clinics after hospital
discharge.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.eurojgh.com 921
Acknowledgements
This study has been carried out as part of the DG MD
degree requirements from the Hebrew University
Hadassah Medical School in Jerusalem.
Tali Bdolah-Abram assisted in designing statistical
analysis.
Authors contribution: Drs Harlev and Ledder collected
data, carried out the initial analyses, drafted the initial
manuscript, and approved the nal manuscript as sub-
mitted; Dr Turner conceptualized and designed the study,
critically reviewed the manuscript, and approved the nal
manuscript as submitted; Dr Waxman and Frankel
designed the data-collection instruments, collected data,
critically reviewed the manuscript, and approved the nal
manuscript as submitted; Dr Kharenko retrieved pathol-
ogy slides, re-reported their pathology, and approved the
nal manuscript as submitted.
Conicts of interest
There are no conicts of interest.
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