This document discusses two rare cases of distal rectal skip-segment Hirschsprung disease (SS-HSCR) and reviews previous literature on SS-HSCR. In SS-HSCR, an aganglionic segment of bowel is interrupted by a focal area of ganglionated bowel. The two cases reported involved very small focal areas of ganglion cells in the distal rectum. In one case, this led to an initial false-negative diagnosis by suction rectal biopsy. The document highlights that distal rectal skip segments can occur and confuse diagnosis, and recommends obtaining multiple rectal biopsies and paying attention to discordant findings to avoid missed or delayed diagnosis when skip segments are present.

1. Distal Rectal Skip-Segment Hirschsprung
Disease and the Potential for False-
Negative Diagnosis
ALEXANDER COE,1
JEFFREY R. AVANSINO,2
AND RAJ P. KAPUR
3*
1
University of Nevada School of Medicine, Reno, NV, USA
2
Department of Surgery, University of Washington and Seattle Children’s Hospital, Seattle, WA, USA
3
Department of Pathology, University of Washington and Seattle Children’s Hospital, Seattle, WA, USA
Received August 7, 2015; accepted September 12, 2015; published online September 15, 2015.
ABSTRACT
In skip-segment Hirschsprung disease (SS-HSCR), an
aganglionic segment of bowel, which extends proximally
from the distal rectum, is interrupted by a ganglionated
“skip segment.” Skip segments are usually located far
proximal to the rectum where they do not interfere with
initial diagnosis, although the possibility of distal SS-
HSCR should be considered during interpretation of
intraoperative biopsies or patients with atypical post-
operative courses. We report 2 cases of SS-HSCR with
skip areas in the distal rectum, 1 of which led to a false-
negative diagnosis by suction rectal biopsy. These 2 cases
of SS-HSCR, along with others in the literature, highlight
the point that ganglionic skip segments can confuse
clinicians and lead to inadequate bowel resection,
diagnostic delay, or a false-negative diagnosis. The
pathogenesis of SS-HSCR is discussed in light of recent
discoveries regarding transmesenteric migration of vagal
neural crest cells and the role of sacral neural crest cells in
hindgut neurodevelopment.
Key words: aganglionosis, calretinin, Hirschsprung
disease, skip area, skip segment, zonal
INTRODUCTION
Timely diagnosis of Hirschsprung disease (HSCR) typi-
cally relies on suction rectal biopsy. Aganglionosis,
a complete absence of ganglion cells in an adequate
sample of distal rectal submucosa, is the primary di-
agnostic feature of HSCR; identification of ganglion cells
usually excludes the diagnosis. Overabundance of enlarged
submucosal nerves, an abnormal pattern of acetylcholin-
esterase-positive mucosal nerves, and the absence of
calretinin-immunoreactive mucosal nerves are additional
helpful diagnostic features. The reliability of suction rectal
biopsy is predicated on the assumption that aganglionosis
in HSCR invariably involves the distal rectum and
a variable length of contiguous proximal bowel.
Skip-segment HSCR (SS-HSCR) is a rare variant of
HSCR in which a focal area of ganglionated bowel is
flanked by aganglionosis proximally and distally [1–21].
This phenotype is different from zonal aganglionosis,
a focal area of aganglionosis between ganglionated bowel
proximally and distally [15,17,22,23]. In the latter, the
distal rectum contains ganglion cells, whereas in SS-
HSCR, the distal aganglionic segment extends through the
distal rectum, as in conventional HSCR. Skip-segment
HSCR is often regarded as a form of total colonic
aganglionosis because the proximal aganglionic segment
frequently encompasses the appendix and/or distal ileum
6 some length of contiguous cecum and colon, and the
distal aganglionic segment encompasses the entire rectum
6 more proximal contiguous bowel. Awareness of skip
lesions is important because standard removal of the distal
aganglionic segment and failure to resect aganglionic
bowel proximal to the skip segment may lead to persistent
dysmotility.
We report 2 children with HSCR, whose otherwise
completely aganglionic rectosigmoid segments were each
interrupted by a small focus of distal rectal ganglion cells.
A review of the literature indicates that these are the 1st
reported examples of distal rectal skip segments. For 1 of
the 2 patients, inadvertent suction rectal biopsy of the
ganglionic skip segment led to initial erroneous exclusion
of HSCR. The diagnostic challenge posed by a rectal skip
segment is discussed, along with likely explanations for
the pathogenesis of SS-HSCR based on recently pub-
lished experimental results.
CASE REPORTS
Case 1
A term male was evaluated at another institution shortly
after birth because of delayed passage of meconium and
abdominal distention. Suction rectal biopsies performed*Corresponding author, e-mail: raj.kapur@seattlechildrens.org
Pediatric and Developmental Pathology 19, 123–131, 2016
DOI:10.2350/15-08-1686-OA.1
ª 2016 Society for Pediatric Pathology

2. at 2 days of life included 2 biopsies that demonstrated the
presence of ganglion cells and 1 biopsy that did not. All of
the biopsies were received in the same container and with
no indication as to their sites of origin relative to the dentate
line. The 2 biopsies with ganglion cells each had intact
calretinin-immunoreactive mucosal innervation (Fig. 1),
whereas the biopsy that lacked ganglion cells had no
calretinin-immunoreactive mucosal nerves (not shown).
Although all 3 biopsies were noted to have “larger
abnormal nerve bundles” (Fig. 1), HSCR was excluded
based on the presence of ganglion cells and calretinin-
positive mucosal innervation. The patient continued to
have constipation and distension. At 4 months of age,
repeat suction biopsies were performed at our institution
with samples taken 1, 2, and 3 cm superior to the dentate
line rectum. Each biopsy showed diagnostic features of
HSCR, including no identifiable ganglion cells, hypertro-
phic nerves, and absent calretinin-immunoreactive muco-
sal innervation. A 16-cm Soave pull-through was
performed several days later. The resected bowel showed
aganglionosis of the distal 10 cm, apart from a small partial
circumferential patch of submucosal ganglion cells in the
amuscular sleeve (Fig. 2). The ganglionic focus (up to 3
submucosal ganglion cells in a single hematoxylin and
eosin [H&E]-stained section) was located ,3 cm from the
distal resection margin (Fig. 2D–F). Abundant hypertro-
phic submucosal nerves with Glut1-immunoreactive peri-
neuria were present in this focus (Fig. 2B and Supplemental
Fig. 1; http://dx.doi.org/10.2350/15-08-1686-OA.S1). Cal-
retinin-immunoreactive mucosal innervation was present
in the overlying mucosa (Fig. 2G), but absent from the
mucosa proximal or distal to this focus.
Case 2
A 5-year-old male with a history of abdominal distension
and bilious emesis at birth had suction rectal biopsies
of 3 sites at 6 days of life to exclude HSCR. Specific
locations of the biopsies were not specified. Each biopsy
had adequate submucosa and diagnostic features of HSCR
including no ganglion cells, nerve hypertrophy, and
absent calretinin-immunoreactive mucosal innervation.
The patient’s family was instructed to do rectal irrigations
for 4 weeks. At 1 month the baby had a Soave pull-
through with an 11-cm resection of rectosigmoid colon.
The resected bowel showed aganglionosis of the distal
8.5 cm, excluding a single microscopic patch of intact
myenteric and submucosal ganglion cells 4 cm from the
distal margin (Fig. 3). A single longitudinal H&E-stained
section through this focus contained 3 intact ganglia, 2
submucosal and 1 myenteric (Fig. 3B,C), with calretinin-
immunoreactive nerves in the overlying mucosa (Fig. 3D)
and enlarged Glut1-immunoreactive nerves in the sub-
mucosa (Fig. 3A and Supplemental Fig. 1). This focus
spanned a rostral-caudal distance of less than 3 mm and
was flanked by aganglionic bowel proximally and distally.
It circumferential extent could not be determined because
only a longitudinal section from this site was obtained.
DISCUSSION
Skip-segment HSCR denotes an interstitial segment of
ganglionic bowel within the otherwise aganglionic distal
colon characteristic of HSCR. Since the 1st reported case
in 1954 by Keefer and Mokrohisky [8], SS-HSCR has
been regarded as exceptionally rare. Including the 2
patients reported here, 27 cases have now been reported in
the English literature and skip segments may be more
prevalent than commonly believed, particularly because
small skip areas (eg, isolated appendiceal) may not have
clinical consequences. Published examples of SS-HSCR
can be subdivided into 3 groups, which may be patho-
genetically distinct (Fig. 4). The largest subset (20
patients; group 1 in Fig. 4) might be considered a variant
of total colonic aganglionosis because both the proximal
(appendix and/or distal ileum) and distal (rectum) ends
of the large intestine lack ganglion cells. A single skip
segment is present between the aganglionic segments
in this group. The location and length of the skip seg-
ment is variable, but it never reaches the distal rectum
and it extends beyond the sigmoid colon in only
1 patient [18].
The 2nd group (Fig. 4) includes 5 patients with
proximal aganglionic segments confined to the large
intestine and not extending into the cecum, appendix, or
small intestine. The 5 patients, including the 2 reported
here, all have relatively short skip segments located distal
to the splenic flexure. Within this group our 2 patients
appear to have the shortest and most distal skip segments,
and the only ones situated in the distal rectum.
The 2 remaining patients (group 3) do not fit cleanly
into either of the other groups. One has small and large
intestinal aganglionosis, which was interrupted by
a ganglionic segment in the small intestine, 45 cm from
the ligament of Treitz [13]. The other has features of both
other groups, including 2 skip segments, 1 bordered
proximally by a aganglionic distal ileum and the other
flanked by aganglionic segments in the left colon and
rectum [18].
The various anatomical forms of SS-HSCR pose
specific challenges to diagnosis and management of HSCR
and invite pathogenetic explanations based on contempo-
rary experimental models of enteric neurodevelopment. In
each of the previously reported 25 cases, the skip segment
was 1st recognized intraoperatively or postoperatively and
the initial diagnosis of HSCR by rectal biopsy was not
affected because the rectum was entirely aganglionic.
In contrast, our 2 patients are remarkable because their
ganglionic skip segments were restricted to small zones
in the distal rectum. Patient 1, and possibly patient 2,
involved only a portion of the circumference of the bowel
wall. In this distal location, a ganglionic skip segment is
readily accessible to rectal biopsy, including via suction
biopsy, and if sampled could lead to erroneous exclusion of
HSCR, as apparently occurred in patient 1. The small skip
segments of both patients lacked 2 important diagnostic
features of HSCR, absent ganglion cells and absent
124 A. COE ET AL.

3. Figure 1. Suction biopsy findings of patient 1. A,B. In 2 of 3 suction biopsies, submucosal ganglion cells (arrows in A and B)
were present with a background of large nerves (arrowheads). C. Calretinin-immunoreactive neurites (arrows) were present
in the overlying mucosa. Scale bars: A, 100 mm; B and C, 50 mm.
DISTAL RECTAL SKIP SEGMENT 125

4. Figure 2. Pull-through resection pathology from patient 1. A. Grossly, the 16-cm-long specimen showed proximal dilatation
and distal narrowing consistent with a 10-cm aganglionic segment. The transition point between full-thickness bowel wall
and the distal submucosal/mucosal sleeve of the Soave pull-through is indicated by an arrow. The approximate locations of
the sections represented in B–G are indicated by arrowheads. B,C. Full-circumference sections from almost the entire
narrowed segment were devoid of ganglion cells, contained enlarged submucosal and myenteric nerves (arrows in B), and
lacked calretinin immunoreactive mucosal innervation (C). D–F. A tiny portion of the bowel circumference, in a section
taken ,3 cm from the distal resection margin, contained rare submucosal ganglion cells (arrow in D, higher magnification
of same in E, another section from same tissue block in F). G. Calretinin-immunoreactive neurites were present in the
overlying mucosa. Scale bars: A, 200 mm; B–G, 50 mm.
126 A. COE ET AL.

5. calretinin-immunoreactive mucosal innervation. As no
frozen tissue from the skip segment was available to
perform acetylcholinesterase histochemistry, it is unclear
whether this method would also have yielded negative or
ambiguous results. Large submucosal nerves were present
in both skip segments and the misleading biopsies with
ganglion cells from patient 1. In retrospect, nerve
hypertrophy should have raised concern; however, most
pathologists are justifiably reluctant to diagnose HSCR in
the face of a rectal biopsy with ganglion cells.
Pathologists and surgeons need to be aware that distal
rectal skip segments occur, albeit rarely, in some patients
with HSCR. Accurate diagnosis of HSCR in such patients
is probably more likely if the following practices are
employed routinely:
1. Obtain multiple rectal biopsies, particularly when
limited to suction biopsies. Skip segments provide yet
another sound rationale for routine biopsy of multiple
rectal sites (eg, 1, 2, and 3 cm) above the dentate line
to increase the likelihood of sampling aganglionic
bowel with classic histological features.
2. Pay attention to discordant biopsy finding and/or
nonclassic histopathological features. If ganglion cells
are present in 1 biopsy, other features in that biopsy
(eg, hypertrophic nerves, abnormal ancillary staining
results) or aganglionosis of other biopsies may be
clues to a skip segment. One of 3 suction biopsies from
our patient 1 was aganglionic and had other features of
HSCR. In retrospect, these features were effectively
dismissed by the outside pathologist, who probably
Figure 3. Histological features of the skip segment of patient 2. A–C. A longitudinal section of the distal rectum, 4 cm from
the distal margin, contained focus of ganglion cells flanked by aganglionic bowel. Many large nerves were present in
(arrows) and around the skip segment. Submucosal (C and boxed area on right in A) and myenteric ganglion (B and boxed
area on left in A) cells were present in this small skip segment. D. Calretinin immunoreactive neurites were present in the
overlying mucosa. Scale bars: A, 200 mm; B–D, 50 mm.
DISTAL RECTAL SKIP SEGMENT 127

6. reasoned that HSCR was excluded by finding ganglion
cells in the other 2 biopsies, and believed the amount
of submucosa in the aganglionic biopsy was sub-
optimal or inadequate. Discordant rectal biopsy
findings can also occur in very-short-segment HSCR,
because biopsies above or close to the proximal extent
of the aganglionic segment can share features with
normal bowel [24]. When ganglion cells are present,
attention to the presence of submucosal nerve
hypertrophy is very important, as it may indicate the
biopsy is just superior to a very short aganglionic
segment or in a distal rectal skip segment.
Figure 4. Diagrammatic representation of skip-segment Hirschsprung disease cases described in the English literature
(reference numbers provided to left of each diagram). The 27 reported cases can be subdivided into group 1 (ileocecal +
rectal aganglionosis), group 2 (ganglionic ileum and right colon with distal skip segments), and group 3 (other). See text for
details. Arrows indicate tiny distal rectal skip segments patients (pt) 1 and 2 from the current study.
Figure 5. Contemporary models of gut colonization by enteric neural crest cells (black dots) based primarily on murine and
avian experimental models. A. Traditional model based on progressive rostral-to-caudal colonization by vagal enteric
neural crest cells (vENCCs) confined to the bowel wall. B. Modification of traditional model to highlight (X) proven cecal
and hypothesized rectal sites of differential expression or function of genes known to be mutated in some patients with
Hirschsprung disease. C. Transient migration of vENCCs in mesentery along the border of the proximal large intestine
before entering the colon and backfilling the cecum. D. Direct transmesenteric migration of vENCCs from midgut to
hindgut. E. Colonization of the hindgut by sacral-derived enteric neural crest cells (sENCCs) with secondary convergence of
the vagal and sacral crest–derived populations in more proximal colon. Some migration of sENCCs from their point of entry
into the hindgut to populate the distal rectum is hypothesized (? in E), but has not been demonstrated explicitly in
murine models.
128 A. COE ET AL.

7. 3. Maintain a low threshold for rebiopsy when clinical
and/or pathological findings are ambiguous. Skip-
segment HSCR is one of several reasons for
potentially misleading biopsy results. Technical
issues related to adequate sample size and location
and very-short-segment HSCR also contribute to
infrequent, but understandable, diagnostic dilemmas.
In such instances, rebiopsy may be indicated and
consideration should be given to alternative biopsy
strategies (eg, strip or full-thickness biopsy under
direct visualization, suction biopsies from numerous
sites and quadrants) designed to exclude very-short-
segment disease, skip areas, and obtain adequate
tissue. Similarly, if a patient’s clinical picture
continues to strongly suggest HSCR, the original
pathology materials should be reviewed and rebiopsy
should be considered.
The pathogenesis of SS-HSCR remains unclear;
however, several interesting hypotheses can be advanced
in light of experimental data from various animal models.
It is now clear that multiple genetic factors play
a significant role in the pathogenesis of HSCR [25,26].
Alterations in expression or function of the tyrosine
kinase receptor, RET, are especially important. In
summarizing data collected by their own group and
others, Chakravarti and colleagues concluded that “HSCR
can be caused by the segregation of multiple common and
rare variants in at least 23 genes and 15 chromosomal
loci, but a RET loss-of-function allele appears to be
necessary for disease expression” [26]. RET and most
other genes implicated to date encode products that
regulate the behaviors of enteric neural crest cells, which
colonize the embryonic gut and give rise to ganglion cells
and glia [27]. For example, RET and its ligand, glial cell
line–derived neurotrophic factor (GDNF), promote pro-
liferation, survival, and directional migration of crest cells
and are required for rostrocaudal colonization of the gut
by vagal enteric neural crest cells (vENCCs), which give
rise to most of the neurons along the entire length of the
gastrointestinal tract [28].
The distribution of ganglion cells in SS-HSCR is
difficult to reconcile with original descriptions of enteric
neurodevelopment based solely on intramural rostrocau-
dal colonization of the gut by a population of vENCCs
[29–31] (Fig. 5A). One possibility is discontinuous
differentiation of neural crest cells into ganglion cells,
possibly caused by local microenvironmental alterations
not conducive to differentiation (Fig. 5B). If regionally
impaired neuronal differentiation is involved, the distal
ileal/cecal and rectal portions of the large intestine seem
to be particularly vulnerable, because these areas are most
consistently affected in SS-HSCR (group 1 in Fig. 4). The
notion that cecal factors that influence vENCC behavior
differ from factors in other parts of the intestinal tract has
some experimental support. Especially high levels of
GDNF [28] and endothelin 3 (edn-3), a peptide that
suppresses neuronal differentiation, are expressed in the
cecum during neural crest cell colonization of this portion
of the gut [32]. In addition, the edn-3 receptor, endothelin
B receptor (ednrB) is differentially activated in vENCCs,
specifically in the cecum, by the transcription factor
Sox10 [33], and mutations in genes that encode the
human homologues of all 3 of these proteins (edn-3,
ednrB, and Sox10) cause syndromic forms of HSCR.
However, regional expression of these same factors has
not been described in the rectum, and it is difficult to
correlate spatial patterns of specific genes with the wide
range of proximal and distal aganglionosis observed in
SS-HSCR.
Kapur and colleagues [7] advanced another model to
explain SS-HSCR based on extramural migration of
vENCCs as they move from the small intestine to the
colon (Fig. 5C). In normal mice, the vanguard of vENCCs
exits the bowel wall at the ileocecal junction, migrates
along the mesenteric border of the proximal colon,
bypasses the cecum, and reenters the colon to disseminate
rostrally and caudally towards both ends of the large
intestine [34,35]. This transient phase, during which
a skip segment is naturally present in the vENCC
distribution, is exaggerated and prolonged in the lethal
spotted HSCR mouse model, but eventually the proximal
aganglionic region is completely colonized [34]. Kapur
and colleagues speculated that failure to “backfill” the
cecum creates a skip segment in some HSCR patients [7].
Recent studies by Nishiyama and colleagues suggest
that transmesenteric migration of vagal neural crest cells
is more extensive than recognized previously and allows
ganglion cell precursors to bypass relatively large
portions of the distal small intestine and proximal colon.
In day 11 murine embryos, the midgut and hindgut are
juxtaposed in a hairpin formation [36]. Nishiyama and
colleagues demonstrated that vENCCs move directly
across the mesentery between the small and large
intestine in response to GDNF-mediated long-range
chemoattraction (Fig. 4D). A shortcut is thereby created,
which allows for a group of vENCCs to break away from
the intramural rostrocaudal migration, exit the gut,
traverse through the mesentery, and enter the hindgut at
a more distal location far ahead of the intramural vENCCs’
wave front. These observations indicate that a colonic
skip segment is a transient phase in the normal
distribution of vagal crest cells in the developing gut,
persistence of which could lead to SS-HSCR. Given the
role that RET/GDNF signals appear to play in the
transmesenteric migration, HSCR-associated genetic de-
fects that reduce RET/GDNF signaling may result in an
insufficient population of transmesenteric vENCCs and/or
inadequate expansion of this population in the hindgut to
back colonize the proximal large intestine in SS-HSCR
patients.
A final theory for the pathogenesis of SS-HSCR
involves the existence of sacral-derived enteric neural crest
cells (sENCCs) (Fig. 4E). In mice and aves, sENCCs enter
the distal hindgut along extrinsic nerves from pelvic
ganglia, travel caudal to rostral, and give rise to a minor
DISTAL RECTAL SKIP SEGMENT 129

8. subset of ganglion cells in the large intestine, and
experimental ablation of vagal crest does not prohibit
hindgut colonization or neural differentiation of sENCCs in
avian embryos [37–40]. Wang and colleagues [39] described
how the sENCCs begin to enter the distal hindgut in day
13.5 murine embryos, prior to arrival of vENCCs, leaving
a transient uncolonized gap between the 2 crest cell
populations. Perpetuation or exaggeration of this gap could
account for the proximal aganglionic zone in SS-HSCR.
However, models based on sENCC colonization are not
straightforward. The normal embryonic distributions of
vENCCs and sENCCs do not predict the most common
pattern of SS-HSCR—ileocecal and distal rectal aganglio-
nosis. Furthermore, given the relatively short distances
traveled by sENCCs as opposed to vENCCs, one might
expect a skip segment composed of some intact hindgut
neurons derived from sENCCs in most patients with
HSCR, even long-segment HSCR. Instead, the complete
lack of distal hindgut ganglion cells observed in most
patients with HSCR presumably indicates that the same
pathogenetic mechanisms that impair colonization of the
entire intestinal tract by vENCCs also negate distal hindgut
colonization or neuronal differentiation by sENCC.
At present, any of the 4 proposed pathogenetic models
could explain the distribution of ganglion cells in SS-
HSCR. These models are not mutually exclusive, and it is
possible that the skip segments arise in different patients for
different reasons. The skip segments in our 2 patients were
located much more distally than any of those described
previously and their proximal aganglionic segments did not
extend to the cecum/appendix as predicted by simple
extension of the transmesenteric models. Given this
distribution, we favor a sENCC origin for ganglion cells
in the skip segments of our cases, but suspect that other
mechanisms underlie the more common pattern of SS-
HSCR with ileocecal and rectal aganglionosis.
In summary, the phenotypic spectrum of SS-HSCR
has been expanded to include relatively small skip
segments located within the distal rectum. Knowledge
gained from experimental studies of enteric neurodeve-
lopment provides insight into possible mechanisms by
which this HSCR phenotype may arise. Inadvertent
biopsy of a distal skip segment can cause confusion and
delay accurate diagnosis. Careful interpretation of the
diagnostic imaging, tissue samples, and overall clinical
presentation, with a low threshold for rebiopsy when
indicated, are paramount in the proper treatment of
individuals with this unusual form of HSCR.
REFERENCES
1. Anderson KD, Chandra R. Segmental aganglionosis of the appendix.
J Pediatr Surg 1986;21:852–854.
2. Burjonrappa S, Rankin L. “Hop the skip” with extended segment
intestinal biopsy in Hirschsprung’s disease. Int J Surg Case Rep
2012;3:186–189.
3. Castle S, Suliman A, Shayan K, Kling K, Bickler S, Losasso B.
Total colonic aganglionosis with skip lesions: report of a rare case
and management. J Pediatr Surg 2012;47:581–584.
4. de Chadarevian JP, Slim M, Akel S. Double zonal aganglionosis in
long segment Hirschsprung’s disease with a “skip area” in
transverse colon. J Pediatr Surg 1982;17:195–197.
5. Doi T, O’Donnell AM, McDermott M, Puri P. Skip segment
Hirschsprung’s disease: a rare phenomenon. Pediatr Surg Int
2011;27:787–789.
6. Erten EE, Cavusoglu YH, Arda N, et al. A rare case of multiple skip
segment Hirschsprung’s disease in the ileum and colon. Pediatr Surg
Int 2014;30:349–351.
7. Kapur RP, deSa DJ, Luquette M, Jaffe R. Hypothesis: pathogenesis
of skip areas in long-segment Hirschsprung’s disease. Pediatr Pathol
Lab Med 1995;15:23–37.
8. Keefer GP, Mokrohisky JF. Congenital megacolon (Hirschsprung’s
disease). Radiology 1954;63:157–175.
9. Martin LW, Buchino JJ, LeCoultre C, Ballard ET, Neblett WW.
Hirschsprung’s disease with skip area (segmental aganglionosis). J
Pediatr Surg 1979;14:686–687.
10. Moore SW, Sidler D, Schubert PA. Segmental aganglionosis (zonal
aganglionosis or “skip” lesions) in Hirschsprungs disease: a report of 2
unusual cases. Pediatr Surg Int 2013;29:495–500.
11. O’Donnell AM, Puri P. Skip segment Hirschsprung’s disease:
a systematic review. Pediatr Surg Int 2010;26:1065–1069.
12. Raghunath BV, Shankar G, Babu MN, et al. Skip segment
Hirschsprung’s disease: a case report and novel management
technique. Pediatr Surg Int 2014;30:119–122.
13. Skelly BL, Ervine E, Bisharat M, Gannon C, Dick AC. Small bowel
skip segment Hirschsprung’s disease presenting with perforated
Meckel’s diverticulum. Pediatr Surg Int 2012;28:645–648.
14. Taguchi T, Tanaka K, Ikeda K, Hata A. Double zonal aganglionosis
with a skipped oligoganglionic ascending colon. Z Kinderchir
1983;38:312–315.
15. Yunis E, Sieber WK, Akers DR. Does zonal aganglionosis really
exist? Report of a rare variety of Hirschsprung’s disease and review
of the literature. Pediatr Pathol 1983;1:33–49.
16. Yang HY, Liu QL, Wang JX, Xu HF. Clinical study of multiple
zonal aganglionosis in long segment Hirschsprung’s disease [in
Chinese]. Zhonghua Yi Xue Za Zhi 2005;85:2772–2774.
17. MacIver AG, Whitehead R. Zonal colonic aganglionosis, a variant
of Hirschsprung’s disease. Arch Dis Child 1972;47:233–237.
18. Seldenrijk CA, van dHHJ, Kluck P, Tibboel D, Moorman VK,
Meijer CJ. Zonal aganglionosis. An enzyme and immunohisto-
chemical study of two cases. Rev Soc Bras Med Trop 1986;19:167–
169.
19. Ziad F, Katchy KC, Al Ramadan S, Alexander S, Kumar S.
Clinicopathological features in 102 cases of Hirschsprung disease.
Ann Saudi Med 2006;26:200–204.
20. Oshio T. Imperforate anus, malrotation, and Hirschsprung’s disease
with double zonal aganglionosis: an extremely rare combination. J
Pediatr Surg 2008;43:222–226.
21. Dalla Valle A. Contributo alla conoscenza della forma famigliare
del megacolon congenito. Pediatria 1920;32:569.
22. Sprinz A, Cohen A, Heaton L. Hirschsprung’s disease with skip
area. Ann Surg 1961;146:143–145.
23. Balanescu RN, Balanescu L, Moga AA, Dragan GC, Djendov FB.
Segmental aganglionosis in Hirschsprung’s disease in newborns—
a case report. Rom J Morphol Embryol 2015;56:533–536.
24. Kapur RP. Calretinin-immunoreactive mucosal innervation in very
short-segment Hirschsprung disease: a potentially misleading
observation. Pediatr Dev Pathol 2014;17:28–35.
25. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung
disease, associated syndromes and genetics: a review. J Med Genet
2008;45:1–14.
26. Kapoor A, Jiang Q, Chatterjee S, et al. Population variation in total
genetic risk of Hirschsprung disease from common RET, SEMA3
and NRG1 susceptibility polymorphisms. Hum Mol Genet
2015;24:2997–3003.
27. Lake JI, Heuckeroth RO. Enteric nervous system development:
migration, differentiation, and disease. Am J Physiol Gastrointest
Liver Physiol 2013;305:G1–G24.
130 A. COE ET AL.

9. 28. Natarajan D, Marcos-Gutierrez C, Pachnis V, de Graaff E.
Requirement of signalling by receptor tyrosine kinase RET for the
directed migration of enteric nervous system progenitor cells during
mammalian embryogenesis. Development 2002;129:5151–5160.
29. Yntema CL, Hammond WS. The origin of intrinsic ganglia of trunk
viscera from vagal neural crest in the chick embryo. J Comp Neurol
1954;101:515–542.
30. Kapur RP, Yost C, Palmiter RD. A transgenic model for studying
development of the enteric nervous system in normal and
aganglionic mice. Development 1992;116:167–175.
31. Fu M, Tam PK, Sham MH, Lui VC. Embryonic development of the
ganglion plexuses and the concentric layer structure of human gut:
a topographical study. Anat Embryol (Berl) 2004;208:33–41.
32. Leibl MA, Ota T, Woodward MN, et al. Expression of endothelin 3
by mesenchymal cells of embryonic mouse caecum. Gut
1999;44:246–252.
33. Zhu L, Lee H-O, Jordan CS, Cantrell VA, Southard-Smith EM, Shin
MK. Spatiotemporal regulation of endothelin receptor-B by SOX10
in neural crest-derived enteric neuron precursors. Nat Genet
2004;36:732–737.
34. Coventry S, Yost C, Palmiter RD, Kapur RP. Migration of ganglion
cell precursors in the ileoceca of normal and lethal spotted embryos,
a murine model for Hirschsprung disease. Lab Invest 1994;71:
82–93.
35. Druckenbrod NR, Epstein ML. The pattern of neural crest advance
in the cecum and colon. Dev Biol 2005;287:125–133.
36. Nishiyama C, Uesaka T, Manabe T, et al. Trans-mesenteric neural
crest cells are the principal source of the colonic enteric nervous
system. Nat Neurosci 2012;15:1211–1218.
37. Burns AJ, Champeval D, Le Douarin NM. Sacral neural crest cells
colonise aganglionic hindgut in vivo but fail to compensate for lack
of enteric ganglia. Dev Biol 2000;219:30–43.
38. Erickson CA, Goins TL. Sacral neural crest cell migration to the gut
is dependent upon the migratory environment and not cell-
autonomous migratory properties. Dev Biol 2000;219:79–97.
39. Wang X, Chan AK, Sham MH, Burns AJ, Chan WY. Analysis of
the sacral neural crest cell contribution to the hindgut enteric
nervous system in the mouse embryo. Gastroenterology
2011;141:992–1002.
40. Kapur RP. Colonization of the hindgut by sacral crest-derived
enteric neural precursors: support for an evolutionarily conserved
model. Dev Biol 2000;227:146–155.
DISTAL RECTAL SKIP SEGMENT 131