Early Human Development: Charlotte Wetherill, Jonathan Sutcliffe
Early Human Development: Charlotte Wetherill, Jonathan Sutcliffe
Early Human Development: Charlotte Wetherill, Jonathan Sutcliffe
a r t i c l e
i n f o
a b s t r a c t
Hirschsprung disease and Anorectal Malformations are congenital disorders presenting in neonates with distal
intestinal obstruction. Hirschsprung disease is associated with a functional distal bowel obstruction resulting
from the abnormal development of the enteric nervous system and ensuing aganglionosis of the distal gut.
Anorectal Malformations comprise a spectrum of anatomical anomalies causing a mechanical bowel obstruction.
Both conditions are frequently associated with congenital abnormalities/syndromes, which require careful assessment and evaluation. Surgical intervention is usually required for both conditions with careful preparation
and meticulous technique. Long-term follow-up allows early identication and treatment of potentially debilitating symptoms, which include faecal incontinence.
2014 Elsevier Ltd. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . .
Hirschsprung disease . . . . . . . . . . . . . .
2.1.
Denition and pathophysiology . . . . . .
2.2.
Aetiology . . . . . . . . . . . . . . . .
2.3.
Genetics . . . . . . . . . . . . . . . .
2.4.
Presentation . . . . . . . . . . . . . .
2.5.
Initial management . . . . . . . . . . .
2.6.
Diagnosis . . . . . . . . . . . . . . . .
2.7.
Denitive management . . . . . . . . .
2.8.
Outcome analysis . . . . . . . . . . . .
2.9.
Research directions . . . . . . . . . . .
2.10.
Key guidelines for Hirschsprung disease .
3.
Anorectal malformations . . . . . . . . . . . .
3.1.
Introduction . . . . . . . . . . . . . .
3.2.
Classication . . . . . . . . . . . . . .
3.3.
Associated abnormalities . . . . . . . . .
3.4.
Presentation and initial management . . .
3.5.
Denitive surgery . . . . . . . . . . . .
3.6.
Outcome analysis . . . . . . . . . . . .
3.7.
Research directions . . . . . . . . . . .
3.8.
Key guidelines for anorectal malformations
Conict of interest statement . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1. Introduction
E-mail addresses: [email protected] (C. Wetherill),
[email protected] (J. Sutcliffe).
1
Tel.: +441133925831; fax: +44 1133925827.
http://dx.doi.org/10.1016/j.earlhumdev.2014.09.016
0378-3782/ 2014 Elsevier Ltd. All rights reserved.
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016
Hirschsprung disease
Meconium ileus/cystic brosis
Meconium plug
Small Left Colon Syndrome (seen in infants of diabetic mothers)
Ileal atresia
Colonic atresia
Missed anorectal malformation
Malrotation with volvulus
Sepsis.
Infants can present later in the neonatal period, or even as older children. A history of constipation from the rst month of life, delayed passage of meconium beyond 24 h, a positive family history of HD or
associated syndromes or failure to thrive with abdominal distension
should alert clinicians to the possibility of HD. Hirschsprung associated
enterocolitis (HAEC) is a particularly important complication. HAEC is
a condition of intestinal inammation, characterised clinically by
fever, abdominal distension, diarrhoea and sepsis [4]. This serious and
potentially fatal complication may be the presenting feature and is
often mistaken for gastroenteritis.
2.3. Genetics
2.5. Initial management
Inheritance patterns in HD are complex and a polygenetic mode of
inheritance exists, with a low sex-dependant penetrance and variable
expressivity [3]. This is manifested clinically by discrepancies between
individuals with known mutations but not expressing the HD phenotype, and the variable length of the affected bowel segment. Several
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016
initiated whilst washouts continue. Once full feeds are established, the
frequency of washouts can be reduced to once a day. The infant is
now in a position to allow further investigations to establish a denitive
diagnosis. Parents are trained to perform the washouts safely and
counselled for signs of enterocolitis.
In some cases, and particularly in long segment HD, decompression
by rectal washout is unsuccessful, and the infant must be reassessed
and potentially taken to theatre for formation of a temporary stoma.
Contrast enema studies retain a role in many centres in the investigation of distal intestinal obstruction. They can usually, but not always,
indicate the position of the Transition Zone in HD. This in turn may be
useful for surgical planning and counselling parents. If a Classic segment
is present, a calibre change is usually seen in the recto-sigmoid region,
with the rectum being less distended than the bowel just above the
Transition zone (see Fig. 1b). Risks of contrast studies include perforation, sepsis and inaccurate identication of Transition zone (long segment disease is frequently missed).
2.6. Diagnosis
The gold standard investigation for the diagnosis of HD is histopathological [5]. Once full decompression has been achieved with washouts,
a suction rectal biopsy can be performed on the ward without a general
anaesthetic. This provides 2 to 3 specimens from above the dentate line.
Aganglionosis is pathognomonic for HD. Supplementary staining techniques using acetyl cholinesterase (AchE) demonstrate hypertrophied
(more than 40 m) nerve cells. Washouts are recommenced 24 h post
biopsy.
Pre-term infants have immature enteric nervous systems and therefore biopsy results can be misleading. Small babies are also more at risk
of perforation and sepsis following rectal biopsy; therefore it is advisable to wait until the infant has reached around 37 weeks corrected gestational age before undertaking a suction rectal biopsy.
2.7. Denitive management
Fig. 1. a. Supine abdominal radiograph on day 1 of life showing multiple loops of bowel
with signicant dilatation and a paucity of air in the pelvis in keeping with distal intestinal
obstruction. b. Single image taken from a series during a contrast enema study, demonstrating spastic, aganglionic distal bowel, with dilated normal bowel proximally, in keeping with classic short segment HD. TZ = Transition Zone
In a stable infant with newly diagnosed HD, the initial aim is to establish a good rectal washout technique that parents can perform at
home. This enables the child to grow until the optimal time for admission for the denitive pull-through procedure. The timing of this varies
between centres, but in general, is undertaken within the rst few
weeks of life.
Denitive surgery for HD takes the form of a pull-through procedure in which the more proximal, ganglionic bowel is brought down
to the anus and anastomosed. Three main procedures exist for HD:
Duhamel, Soave and Swenson procedures. Features common to all
three procedures include the use of histological analysis (usually ontable frozen section) to identify the ganglionic bowel, resection of
Aganglionic and Transition zone bowel and preservation of the anal
continence mechanism.
The Duhamel pull-through is characterised by a retro-rectal dissection through which the ganglionic bowel is delivered and anastomosed
to the posterior rectal wall. A stapling device is then used to create a unied pouch between the pull-through segment and the native rectum.
The native rectum is transected just above this staple line allowing removal of the upper rectum and any aganglionic or Transition zone proximal to this. The residual distal native rectum therefore contributes to
the pouch and since this is aganglionic, constipation is more often
seen after a Duhamel than with other procedures [6].
Soave and Swenson procedures are both now undertaken
transanally with the resection starting at a point just above the dentate
line and extending around the entire circumference of the rectum. The
Soave procedure involves an endorectal dissection, initially a submucosal dissection, deepening to include the muscular layers after a few
centimetres. The purported benets are to remain inside the rectal
wall thereby reducing damage to the sacral plexus. This however is at
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016
the expense of retaining a cuff of aganglionic bowel wall, which has the
potential to cause obstructive features. The Swenson procedure, again
transanal, begins just above the dentate line and is circumferential,
but extends through the rectal wall so ensuring the entire aganglionic
proximal bowel is removed. Whilst the sacral plexus is potentially exposed, proponents of this increasingly popular technique claim that
careful adherence to the wall of the bowel reduces the risk of nerve injury. One nal consideration with these two transanal procedures is the
potential effect on the continence mechanism by undue retraction on
the sphincters during the course of dissection.
Controversy exists with respect to the need for laparoscopy or laparotomy to facilitate a pull-through. For classic segment disease, it is certainly possible for either Soave or Swenson to be performed entirely
transanally without mobilisation from above, although the risk of a
twist in the pull-though is increased.
The ability to biopsy tissue adequately is a further consideration. In
order to fully exclude an inadvertent pull-though of transition zone tissue, a pathologist would ideally receive full thickness biopsies from all 4
quadrants of the circumference of the section of bowel, for on-table frozen section prior to pull-through. Currently many centres use tissue
from only 1 quadrant as a proxy for histological adequacy. Finally, our
understanding of the nature of the Transition zone is incomplete; currently the presence of hypertrophied nerves in the submucosa is used
as a marker for function [7], but it seems likely that this denition will
be further developed.
2.8. Outcome analysis
In order to inform decision-making and resolve current controversies, long-term outcome evaluation is required [8]. One systematic review has used a validated bowel function score to compare young
adults who were operated on for HD as infants with normal controls.
Overall the results show that 47% of HD patients had a normal bowel
function score. Faecal soiling was the most common GI symptom, experienced by 48%, with difculty holding back defecation (40%), constipation (30%) and social problems related to bowel function (29%). 14% of
HD patients experienced frank faecal accidents, compared to 0% of the
control population [9].
These data were derived from a group with great experience in longterm outcome evaluation. As with other congenital conditions welldesigned, long-term studies using validated outcome measures are
required but difcult to obtain for any single centre, for a number of
reasons. Many of the functional outcomes, such as continence, constipation, enterocolitis and sexual function are difcult to quantify. Furthermore, HD is relatively rare and any one centre will have a limited
number of patients. Operative procedures evolve with time, as will
non-operative management. Comparison of outcome with historical patients from the same centre is therefore awed, and comparison between centres is also limited for similar reasons. This must be the
focus of consideration to allow a sound platform for future work.
2.9. Research directions
Pathophysiology does the Transition zone, currently dened histologically correlate precisely with the functional Transition zone? Do
other cell groups have a role in spasticity?
Diagnosis current diagnosis relies on an absence of ganglion cells. A
reliable test using a positive marker would facilitate histopathological
practice.
Treatment can progenitor cells be induced to usefully repopulate
the ENS?
Outcome analysis long-term outcome is even more important to
focus on in rare conditions with subjective symptoms for patients
who may go on to live for several decades, thus spanning individual
clinicians' careers. Knowing which symptoms to address informs the
development of new techniques.
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016
oesphageal, renal, limb). The higher the defect, the more likely that associated abnormalities will be found.
Vertebral abnormalities include sacral hypoplasia, hemivertebrae
and tethered cord. The presence and degree of sacral hypoplasia or spinal cord anomaly correlate with prognosis. Plain radiographs and spinal
cord ultrasound in the neonatal period therefore provide useful information and are recommended. It should be noted that the window for
USS to visualise the spinal cord is limited and this investigation should
be requested within the rst month or so of life.
Cardiac echo is required to evaluate the heart. Structural cardiac
anomalies may be severe and careful coordination of treatment may
be required.
Oesophageal atresia may be excluded with the placement of a nasogastric tube. Occasionally an H-type tracheo-oesophageal stula is
suspected, warranting further investigation.
Renal tract abnormalities may be seen. Whilst a broad range of
anomalies have been described, the passage of at least some urine in
the neonatal period excludes the rare but catastrophic diagnosis of bilateral renal agenesis. Vesico-ureteric reux is common and is the basis for
many centres recommending prophylactic long-term trimethoprim administration. Renal tract USS in the neonatal period with subsequent
MCUG is usually indicated for patients with ARM.
Limb defects include radial aplasia and polydactyly, but may be more
subtle. Recognisable genetic defects, such as TownesBrocks syndrome
are less common but are the focus of ongoing investigation.
Gynaecological abnormalities such as vaginal septae or even vaginal
aplasia are seen in girls with cloacal defects and are increasingly
recognised in association with less severe anomalies [10]. Finally, the association with low anorectal anomalies, particularly rectal stenosis, with
sacral abnormalities and presacral masses (Currarino triad) has been
described [11]. Investigation with MRI for a presacral mass must be considered in patients with rectal stenosis.
Fig. 2. Single image taken from a series during a contrast study of the distal bowel. After
cannulating the mucous stula in a patient with a split descending colostomy for ARM,
contrast lls the bowel and then begins to ll the bladder demonstrating a stula from
the bowel to the bulbar urethra (arrow).
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016
References
[1] Sutcliffe J, Sugarman I, Levitt M. Anorectal anomalies and Hirschsprung disease (including stomas). Surgery - Oxford International Edition 2013;31(12):6318.
[2] Kenny SE, Tam PKH, Garcia-Barcelom M. Hirschsprung3s disease. Seminars in pediatric surgery 2010;19(3):194200.
[3] Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, et al.
Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet
2008;45(1):114.
[4] Frykman PK, Short SS. Hirschsprung-associated enterocolitis: prevention and therapy. Semin Pediatr Surg 2012;21(4):32835.
[5] Lewis NA, Levitt MA, Zallen GS, Zafar MS, Iacono KL, Rossman JE, et al. Diagnosing
Hirschsprung's disease: increasing the odds of a positive rectal biopsy result.
J Pediatr Surg 2003;38(3):4126 [discussion-6].
[6] Chatoorgoon K, Pena A, Lawal TA, Levitt M. The problematic Duhamel pouch in
Hirschsprung's disease: manifestations and treatment. Eur J Pediatr Surg 2011;
21(6):3669.
[7] Kapur RP, Kennedy AJ. Transitional zone pull through: surgical pathology considerations. Semin Pediatr Surg 2012;21(4):291301.
[8] Levitt MA, Dickie B, Pena A. Evaluation and treatment of the patient with
Hirschsprung disease who is not doing well after a pull-through procedure. Semin
Pediatr Surg 2010;19(2):14653.
[9] Rintala RJ, Pakarinen MP. Long-term outcomes of Hirschsprung's disease. Semin
Pediatr Surg 2012;21(4):33643.
[10] Breech L. Gynecologic concerns in patients with anorectal malformations. Semin
Pediatr Surg 2010;19(2):13945.
[11] Hamrick M, Eradi B, Bischoff A, Louden E, Pena A, Levitt M. Rectal atresia and stenosis: unique anorectal malformations. J Pediatr Surg 2012;47(6):12804.
[12] Haider N, Fisher R. Mortality and morbidity associated with late diagnosis of
anorectal malformations in children. Surgeon 2007;5(6):32730.
[13] Pea A, Devries PA. Posterior sagittal anorectoplasty: important technical considerations and new applications. J Pediatr Surg 1982;17(6):796811.
[14] Levitt MA, Pena A. Outcomes from the correction of anorectal malformations. Curr
Opin Pediatr 2005;17(3):394401.
Please cite this article as: Wetherill C, Sutcliffe J, Hirschsprung disease and anorectal malformation, Early Hum Dev (2014), http://dx.doi.org/
10.1016/j.earlhumdev.2014.09.016