Review article

Hirschsprung disease, associated syndromes, and

genetics: a review
Jeanne Amiel, Stanislas Lyonnet
Abstract
Hirschsprung disease (HSCR, aganglionic
megacolon) is the main genetic cause of
functional intestinal obstruction with an
incidence of 1/5000 live births. This devel-
opmental disorder is a neurocristopathy
and is characterised by the absence of the
enteric ganglia along a variable length of
the intestine. In the last decades, the
development of surgical approaches has
dramatically decreased mortality and
morbidity, which has allowed the emer-
gence of familial cases. HSCR appeared to
be a multifactorial malformation with
low, sex dependent penetrance and vari-
able expression according to the length of
the aganglionic segment, suggesting the
involvement of one or more gene(s) with
low penetrance. So far, eight genes have
been found to be involved in HSCR. This
frequent congenital malformation now
stands as a model for genetic disorders
with complex patterns of inheritance.
(J Med Genet 2001;38:729739)
Keywords: Hirschsprung disease; aganglionic megaco-
lon; genetics
Harald Hirschsprung rst described in 1888
two unrelated boys who died from chronic
severe constipation with abdominal distension
resulting in congenital megacolon.
1
The ab-
sence of intramural ganglion cells of the
myenteric and submucosal plexuses (Auer-
bachs and Meissners plexuses, respectively)
downstream from the dilated part of the colon
was considered to be the cause of the disease in
the 1940s.
2
This allowed simple and reliable
diagnostic conrmation from rectal suction
biopsies using histochemical staining for ace-
tylcholinesterase (AchE).
3
In 1948, Swenson
and Bill developed a surgical procedure
4
and
the survival of patients uncovered familial
transmission of HSCR.
5
In 1973, Bolande
6
proposed the term neurocristopathy for syn-
dromes or tumours involving neural crest (NC)
cells. HSCR resulting from an anomaly of the
enteric nervous system (ENS) of NC origin is
therefore regarded as a neurocristopathy.
6 7
HSCR occurs as an isolated trait in 70% of
patients, is associated with a chromosomal
abnormality in 12% of cases, and with
additional congenital anomalies in 18% of
cases.
813
In the latter group of patients, some
monogenic syndromes can be recognised.
Isolated HSCR appears to be a multifactorial
malformation with low, sex dependent pen-
etrance, variable expression according to the
length of the aganglionic segment, and suggest-
ing the involvement of one or more gene(s)
with low penetrance.
5 14
These parameters
must be taken into account for accurate evalu-
ation of the recurrence risk in relatives.
Segregation analyses suggested an oligogenic
mode of inheritance in isolated HSCR.
14
With
a relative risk as high as 200, HSCR is an
excellent model for the approach to common
multifactorial diseases. So far, genetic hetero-
geneity in HSCR has been shown with eight
specic genes involved. The major susceptibil-
ity gene is RET, which is also involved in mul-
tiple endocrine neoplasia type 2 (MEN 2). The
identication of modier genes is currently
under way. The aim of this paper is to review
the clinical data on syndromic HSCR and the
molecular ndings over the last 10 years.
Denition and classication
HSCR is a congenital malformation of the
hindgut characterised by the absence of
parasympathetic intrinsic ganglion cells in the
submucosal and myenteric plexuses.
2
It is
regarded as the consequence of the premature
arrest of the craniocaudal migration of vagal
neural crest cells in the hindgut between the
fth and twelfth week of gestation to form the
enteric nervous system (ENS) and is therefore
regarded as a neurocristopathy.
6 15
While the
internal anal sphincter is the constant inferior
limit, patients can be classied as short
segment HSCR (S-HSCR, 80%of cases) when
the aganglionic segment does not extend
beyond the upper sigmoid, and long segment
HSCR (L-HSCR, 20% of cases) when agan-
glionosis extends proximal to the sigmoid. Four
HSCR variants have been reported: (1) total
colonic aganglionosis (TCA, 3-8% of cases),
16
(2) total intestinal HSCR when the whole
bowel is involved,
16
(3) ultra short segment
HSCR involving the distal rectum below the
pelvic oor and the anus,
17
and (4) suspended
HSCR, a controversial condition, where a por-
tion of the colon is aganglionic above a normal
distal segment.
J Med Genet 2001;38:729739 729
Dpartement de
Gntique, Unit
INSERM U-393,
Hpital
Necker-Enfants
Malades, 149 rue de
Svres, 75743 Paris
Cedex 15, France
J Amiel
S Lyonnet
Correspondence to:
Dr Lyonnet,
[email protected]
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Clinical features and diagnosis
In most cases, the diagnosis of HSCR is made
in the newborn period
13
owing to intestinal
obstruction with the following features: (1)
failure to pass meconium within the rst 48
hours of life, (2) abdominal distension that is
relieved by rectal stimulation or enemas, (3)
vomiting, and (4) neonatal enterocolitis. Some
patients are diagnosed later in infancy or in
adulthood with severe constipation, chronic
abdominal distension, vomiting, and failure to
thrive.
18
Finally, although a rare presentation,
unexplained perforation of the caecum or
appendix should make the diagnosis be consid-
ered.
On abdominal x ray, a distended small bowel
and proximal colon with an empty rectum are
common ndings. The classical image is a
dilated proximal colon with the aganglionic
cone narrowing towards the distal gut. On
barium enema a small rectum with uncoordi-
nated contractions is seen. The transition zone
represents the site where the narrow agangli-
onic bowel joins the dilated ganglionic bowel.
On a plain x ray taken later, delayed barium
evacuation is observed. Anorectal manometry
shows absence of relaxation of the internal
sphincter in response to rectal distension.
19
The
reliability of this test becomes excellent from
day 12 after birth when the normal rectoenteric
reex is present.
20
Suction rectal biopsy con-
rms the diagnosis in most cases,
21
but a full
thickness rectal biopsy is needed for diagnosis
of HSCR. Furthermore, extramucosal serial
biopsies will be required at laparotomy to
dene the proximal limit of the aganglionic
segment.
DiVerential diagnosis
Other causes of intestinal obstruction should
be considered when abdominal distension and
failure to pass meconium occur in a newborn
infant, namely: (1) meconium ileus resulting
from cystic brosis, (2) intestinal malforma-
tions such as lower ileal and colonic atresia,
isolated or occasionally associated with HSCR,
intestinal malrotation, or duplication, (3) ENS
anomalies grouped together as chronic intesti-
nal pseudo-obstruction syndromes, and (4)
functional intestinal obstruction resulting from
maternal infection, maternal intoxication, or
congenital hypothyroidism.
Treatment and prognosis
The treatment of HSCR is surgical. After care-
ful preoperative management, the principle is
to place the normal bowel at the anus and to
release the tonic contraction of the internal
anal sphincter. Since the initial protocol of
Swenson described in 1948,
4
a series of opera-
tive approaches have been developed, such as
the Soave and Duhamel procedures.
22 23
A one
stage procedure is possible when diagnosis is
made early, before colonic dilatation. Other-
wise, a primary colostomy is required. Fistula
or stenosis of the anastomosis and enterocolitis
are the main short term complications.
24
Long
term complications include chronic constipa-
tion (10-15%) and soiling.
25 26
Laparoscopic
techniques have recently been proposed in
HSCR surgery.
27
Mortality is under 6% since
the 1980s and may be related to short term
complications or caused by the associated mal-
formations.
25
However, the treatment of chil-
dren with TCA is still hazardous.
28 29
Epidemiology
The incidence of HSCR is estimated at 1/5000
live births.
5
However, the incidence varies
signicantly among ethnic groups (1.5, 2.1,
and 2.8 per 10 000 live births in Caucasians,
African-Americans, and Asians, respectively).
13
S-HSCR is far more frequent than L-HSCR
(80% and 20%, respectively).
8 10
There is a sex
bias with a preponderance of aVected males
and a sex ratio of 4/1.
14
Interestingly, the
male:female ratio is signicantly higher for
S-HSCR than for L-HSCR (table 1).
13 14
HSCR occurs as an isolated trait in 70% of
cases. A chromosomal abnormality is associ-
ated with it in 12% of cases, trisomy 21 being
by far the most frequent (>90%). Associated
congenital anomalies are found in 18% of
HSCR patients. The ones occurring at a
frequency above that expected by chance
include gastrointestinal malformation, cleft
palate, polydactyly, cardiac septal defects, and
craniofacial anomalies.
11 12
The higher rate of
associated anomalies in familial cases than in
isolated cases (39% versus 21%) strongly
suggests syndromes with Mendelian inherit-
ance.
12
Assessment of all HSCR patients
should include a careful evaluation for recog-
nisable syndromes by a trained dysmorpholo-
gist.
Chromosomal anomalies
A large number of chromosomal anomalies
have been described in HSCR patients. Free
trisomy 21 (Down syndrome) is by far the most
frequent, involving 2-10% of ascertained
HSCR cases.
5 913
In these cases, both the
unbalanced sex ratio (5.5-10.5 male:female)
and the predominance of S-HSCR are even
greater than in isolated HSCR. Overexpression
of genes on chromosome 21 predisposing to
HSCR has been hypothesised and a suscepti-
bility gene mapping to 21q22 postulated in a
Mennonite kindred.
30
However, these data
were not conrmed in other populations. Hith-
erto, mutations in genes predisposing to
HSCR, namely RET, EDNRB, and GDNF,
respectively, have been found in only three
patients with Down syndrome and HSCR.
31 32
Some chromosomal interstitial deletions
reported in combination with HSCR have been
important for the identication of HSCR
predisposing genes, namely (1) 10q11.2 inter-
stitial deletion observed in a few patients with
Table 1 Epidemiology and recurrence risk gures in HSCR
14
L-HSCR S-HSCR
% probands 19 81
Sex ratio (male:female) 1.75 5.5
Genetic model Dominant Multigenic or recessive
Penetrance (%) (male:female) 52:40 17:4
Recurrence risk to sibs* (%)
Male proband 17/13 5/1
Female proband 33/9 5/3
*Recurrence risk are given for male/female sibs respectively.
730 Amiel, Lyonnet
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L-HSCR or TCA,
33 34
leading to the mapping
and identication of the rst gene for HSCR
(RET); (2) 13q22.1-32.1 interstitial deletion in
patients with S-HSCR encompassing a second
gene (EDNRB)
3537
; (3) 2q22-23 interstitial
deletion syndrome in patients with HSCR
(table 2),
3840
leading to the identication of the
SIP1 gene (SMAD interacting protein 1).
41
Rarer chromosomal anomalies reported in
combination with HSCR are summarised in
table 2. DiGeorge syndrome, mosaic trisomy 8,
XXY chromosomal constitution, partial dupli-
cation of chromosome 2q, tetrasomy 9p, and
20p deletion each have been observed once
with HSCR.
Syndromes and associated anomalies
Both the recognition of known entities and the
delineation of novel ones including HSCR as a
feature are of importance for disease prognosis,
accurate genetic counselling, and search for
candidate genes. Syndromes associated with
HSCR can be classied as: (1) pleiotropic neu-
rocristopathies, (2) syndromes with HSCR as a
mandatory feature, (3) occasional association
with recognisable syndromes, and (4) miscella-
neous observations (table 3).
NEUROCRISTOPATHIES
The NC is a transient and multipotent embry-
onic structure that gives rise to neuronal,
endocrine and paraendocrine, craniofacial,
conotruncal heart, and pigmentary tissues.
7
Neurocristopathies encompass tumours, mal-
formations, and single or multifocal abnor-
malities of tissues mentioned above in various
combinations. MEN 2, conotruncal heart
defects, congenital central hypoventilation, and
Table 2 Recurrent chromosomal anomalies with HSCR as a feature
Chromosome Key features Number of reports Gene References
Tri 21 Down syndrome, S-HSCR, 5.5 to 10.5 male:female sex ratio 2 to 10% of HSCR cases ? 5, 913
Del 10q11 Mental retardation, L-HSCR 2 cases RET 33, 34
Del 13q22 Mental retardation, growth retardation, dysmorphic features, S-HSCR 7 cases EDNRB 3537
Del 2q22-q23 Postnatal growth retardation and microcephaly, mental retardation, epilepsy, dysmorphic
features, HSCR*
3 cases SIP1 3841
Del 17q21 4 cases ?
Dup 17q21-q23 MCA/MR 4 cases ?
Tri 22pter-q11 Cat eye syndrome ?
*Both S-HSCR and L-HSCR have been observed. Several patients presenting the same pattern of congenital malformations and normal chromosomes have been
reported.
39
Table 3 Syndromes associated with HSCR (reprinted and adapted from Scriver CM et al, eds. The metabolic and molecular bases of inherited diseases
8th ed. Chap 251. New York: McGraw-Hill: 6231-55.)
Syndromes MIM Key features References
Neurocristopathy syndromes
WS4 (Shah-Waardenburg) 277580 Pigmentary anomalies (white forelock, iris hypoplasia, patchy hypopigmentation), deafness 5357
Yemenite deaf-blind-hypopigmentation 601706 Hearing loss, eye anomalies (microcornea, coloboma, nystagmus), pigmentary anomalies 60
BADS 227010 Hearing loss, hypopigmentation of the skin and retina 61
Piebaldism 172800 Patchy hypopigmentation of the skin 62, 63
Haddad 209880 Congenital central hypoventilation 70, 71
MEN2A 171400 Medullary thyroid carcinoma, phaeochromocytoma, hyperplasia of the parathyroid 4350
Riley-Day 223900 Autonomic nervous system anomalies
HSCR mandatory
Goldberg-Shprintzen 235730 Cleft palate, hypotonia, microcephaly, mental retardation, dysmorphic facial features 79
235740 Polydactyly, unilateral renal agenesis, hypertelorism, deafness 82
HSCR with limbs anomalies 235750 Postaxial polydactyly, ventricular septal defect 83
235760 Hypoplasia of distal phalanges and nails, dysmorphic features 84
604211 Preaxial polydactyly, heart defect, laryngeal anomalies 85
306980 Brachydactyly type D 86
BRESHEK Brain abnormalities, Retardation, Ectodermal dysplasia, Skeletal malformation, Hirschsprung
disease, Ear/eye anomalies, Kidney dysplasia
87
Mesomelic dysplasia, Werner type Mesomelia, polydactyly 170
HSCR occasionally associated
Bardet-Biedl and/or 209900 Pigmentary retinopathy, obesity, hypogenitalism, mild mental retardation, postaxial polydactyly 91, 92
KauVman-McKusick 236700 Hydrometrocolpos, postaxial polydactyly, congenital heart defect 89
Smith-Lemli-Opitz 270400 Growth retardation, microcephaly, mental retardation, hypospadias, 23 toes syndactyly,
dysmorphic features
96
Cartilage-hair hypoplasia 250250 Short limb dwarsm, metaphyseal dysplasia, immunodeciency 97
HSCR rarely associated
Fukuyama congenital muscular dystrophy 253800 Muscular dystrophy, polymicrogyria, hydrocephalus, MR, seizures 99, 100
Clayton-Smith 258840 Dysmorphic features, hypoplastic toes and nails, ichthyosis. 101
Kaplan 304100 Agenesis of corpus callosum, adducted thumbs, ptosis, muscle weakness 102
Okamoto 308840 Hydrocephalus, cleft palate, corpus callosum agenesis 103
Miscellaneous associations
Pallister-Hall (CAVE) 140510
Fryns 229850
Aarskog 100050
Jeune asphyxiating thoracic dystrophy 208500
Frontonasal dysplasia 136760
Osteopetrosis
Goldenhar 164210
Lesch-Nyhan 308000
Rubinstein-Taybi 180849
Toriello-Carey 217980
SEMDJL 271640
Hirschsprung disease, associated syndromes, and genetics 731
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Waardenburg syndrome illustrate each of these
categories and can be associated with HSCR.
Multiple endocrine neoplasia type 2 (MEN 2).
The MEN 2 syndromes include three types of
cancer predisposition with an autosomal domi-
nant mode of inheritance: familial medullary
thyroid carcinoma (FMTC), MEN type 2A,
(MEN 2A) and type 2B (MEN 2B). MEN 2A
is dened by an age related predisposition to
medullary thyroid carcinoma (MTC, 70% by
the age of 70 years), phaeochromocytoma
(50% of cases), and hyperplasia of the parathy-
roid glands (15-35%). In addition to MTCand
phaeochromocytoma, subjects with MEN 2B
present with oral neuromas, marfanoid habi-
tus, and hyperganglionosis of the hindgut.
42
Germline missense mutations of the RET gene
have been identied in MEN 2A, MEN 2B,
and FMTC. Both FMTC and MEN 2A can be
associated with HSCR in some families.
4350
Interestingly, these families present a germline
RET mutation of the MEN 2A or FMTC type
(see below).
4450
This raises the question of
whether all subjects with HSCR, regardless of a
non-contributory family history, should be
screened for RET exon 10 and 11 mutations to
rule out cancer predisposition (3/160 cases in
our series, C609W, C611R, and C620R RET
gene mutations).
Waardenburg syndromes (WS) and related
pigmentary anomalies
WS, an autosomal dominant condition, is by
far the most frequent condition combining
pigmentary anomalies and sensorineural deaf-
ness (1/50 000 live births and 2-5% of all con-
genital deafness), resulting from the absence of
melanocytes of the skin and the stria vascularis
of the cochlea.
51
WS is clinically and genetically
heterogeneous (MIM 193500, MIM 148820,
MIM 193510).
52
The combination of HSCR
with WS denes the WS4 type (Shah-
Waardenburg syndrome, MIM 277580), a
genetically heterogeneous condition. Indeed,
homozygous mutations of the endothelin
pathway
5356
and heterozygous SOX10 muta-
tions have been identied in WS4 patients (see
below).
57
Patients carrying a SOX10 mutation
may also present with CNS involvement
including seizures, ataxia, and demyelinating
peripheral and central neuropathies.
58 59
Pigment related syndromes that may include
HSCR include: (1) Yemenite deaf-blind hypo-
pigmentation syndrome (MIM 601706). A
SOX10 mutation has been reported in one of
these families
60
; (2) Black locks-Albinism-
Deafness Syndrome (BADS, MIM 227010)
with TCA-HSCR reported in one case
61
; (3)
aganglionic megacolon associated with familial
piebaldism (MIM 172800)
62 63
; (4) HSCR and
profound congenital deafness but with no other
WS features has also been reported.
64
Congenital central hypoventilation syndrome
(CCHS, MIM 209880)
Initially termed Ondines curse, CCHS is a
rare, life threatening condition characterised by
abnormal ventilatory response to hypoxia and
hypercapnia owing to failure of autonomic res-
piratory control.
65
CCHS patients often
present symptoms resulting from a broader
dysfunction of the autonomic nervous system
and neural crest cell derived tumours have also
been observed.
6568
CCHS may be a polygenic
disorder with a major locus being involved.
69
Recurrence risk in sibs is estimated as 5% with
few multicase families reported.
65
Haddad syn-
drome (MIM 209880) is dened by the
combination of CCHS with HSCR and repre-
sents 14-20% of CCHS patients.
70 71
In these
cases, L-HSCR (including TCA) is by far the
most frequent, and the sex ratio is equal,
contrary to what is observed in isolated
HSCR.
71
Mutations of the RET and the
endothelin signalling pathways have been iden-
tied in rare CCHS patients: a RET mutation
inherited from a healthy parent in two patients
with Haddad syndrome,
72 73
a GDNF mutation
inherited from a healthy mother in a CCHS
patient,
72
and an EDN3 mutation in a CCHS
patient.
74
Other neurocristopathies
Familial dysautonomia syndrome (FDS, Riley-
Day syndrome, MIM 223900) has been
reported once in association with HSCR.
Although it could have arisen by chance alone,
it is interesting to note that the FDS gene
(IKBKAP) maps to 9q31 where a susceptibility
locus for HSCR has been identied (see
below). Other occasional associations reported
so far include cleft lip with or without cleft pal-
ate, neural crest derived tumours (neuroblas-
toma, ganglioneuroblastoma),
75 76
neural tube
defects (myelomeningocele),
77
and neuro-
bromatosis type 1.
78
The signicance of these
associations is not yet established.
SYNDROMES WITH HSCR AS A MANDATORY
FEATURE
Goldberg-Shprintzen syndrome (MIM 235730)
This rare, probably autosomal recessive, multi-
ple congenital anomalies-mental retardation
syndrome combines HSCR, cleft palate, hypo-
tonia, microcephaly and mental retardation
with or without facial dysmorphic features
(hypertelorism, prominent nose, synophrys,
sparse hair).
79
The observation of both ven-
tricular dilatation and irregular density of white
matter on brain imaging may suggest a neuro-
nal migration defect. Several reports with vari-
able association of microcephaly, iris colo-
boma, cleft palate, and mental retardation may
be variants of this syndrome.
80 81
In our
opinion, patients with a SIP1 gene mutation
have a diVerent condition.
HSCR with limb anomalies
A series of rare syndromes with HSCR and
distal limb anomalies (polydactyly or hypopla-
sia) have been reported. These are: (1) HSCR
with polydactyly, unilateral renal agenesis,
hypertelorism, and congenital deafness (MIM
235740)
82
; (2) HSCR, postaxial polydactyly,
and ventricular septal defects (MIM235750)
83
;
(3) HSCR, hypoplasia of the distal phalanges
and nails, and mild dysmorphic features (MIM
732 Amiel, Lyonnet
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235760)
84
; (4) HSCR with preaxial polydac-
tyly, heart defect, and laryngeal anomalies
(MIM 604211)
85
; (5) HSCR with brachydac-
tyly type D (MIM 306980)
86
; (6) HSCR with
brachydactyly, macrocephaly, and vertebral
anomalies
87
; (7) BRESHEKsyndrome,
88
and (8)
mesomelic dysplasia, Werner type.
170
OCCASIONAL ASSOCIATION IN RECOGNISABLE
SYNDROMES
The occasional association of HSCRwith three
syndromes or groups of syndromes of auto-
somal recessive mode of inheritance may be of
interest for the identication of susceptibility
genes in HSCR.
McKusick-KauVman syndrome (MKKS, MIM
236700) and Bardet-Biedl syndrome (BBS,
MIM 209900)
MKKS is a rare condition characterised by
hydrometrocolpos, postaxial polydactyly, and
congenital heart defect. HSCR is found in 10%
of cases.
89
The MKKS disease causing gene on
20p12, encoding a chaperonin protein, has
recently been identied.
90
BBS is characterised by progressive pigmen-
tary retinopathy, obesity, hypogenitalism, renal
involvement (including cysts, renal cortical
loss, or reduced ability to concentrate urine),
mild mental retardation, and postaxial poly-
dactyly of the hands and feet. BBS is
genetically heterogeneous with at least ve loci
involved, mapped to chromosome arms 2q, 3p,
11q, 15q, and 16q. HSCR has been reported in
several BBS cases.
91 92
Recently, mutations in
the MKKS gene were identied in some BBS
patients conrming clinical overlap at the
molecular level.
93
Smith-Lemli-Opitz syndrome (SLO, MIM
270400)
SLO is characterised by pre- and postnatal
growth retardation and microcephaly, severe
mental retardation, facial dysmorphic features,
hypospadias, and syndactyly between toes 2
and 3. SLO results from cholesterol metabolic
impairment with mutation of the 7-dehydro-
cholesterol reductase gene (DHCR7, chromo-
some 11q12-q13).
94 95
HSCR is observed in a
signicant number of severe SLO patients.
96
Cartilage-hair hypoplasia syndrome (CHH,
MIM 250250)
This skeletal dysplasia, rst described in the
Old Order Amish community, combines meta-
physeal dysplasia with short limb dwarsm,
ne, sparse, and blond hair, transient macro-
cytic anaemia, and immunodeciency. HSCR
is associated with it in approximately 10% of
the cases.
97
The gene (RMRP) has been
mapped to chromosome 9p13.
98
Interestingly,
HSCR has been reported in the Holmgren-
Connor syndrome (MIM 211120), which may
be allelic to CHH.
MISCELLANEOUS OBSERVATIONS
For rare disorders, whether an association with
HSCR observed once is meaningful or oc-
curred by chance alone is not possible to
decide. These conditions are summarised in
table 3 and can be classied as follows: (1) syn-
dromes with muscular dystrophy,
99 100
(2)
syndromes with dermatological ndings,
101
and
(3) syndromes with central nervous system
anomalies.
102 103
Other rare associations include
the nding of HSCR with Fryns syndrome,
Aarskog syndrome, Jeune asphyxiating thoracic
dystrophy, frontonasal dysplasia, osteopetrosis,
Goldenhar syndrome, Lesch-Nyhan syn-
drome, Rubinstein-Taybi syndrome, Toriello-
Carey syndrome, Pallister-Hall syndrome,
spondyloepimetaphyseal dysplasia with joint
laxity (SEMDJL, MIM 271640), persistent
mullerian duct syndromes, and asplenia with
cardiovascular anomaly.
Isolated anomalies
A wide spectrum of additional isolated anoma-
lies have been described among HSCR cases
with an incidence varying from 5% to 30%
according to series.
8 9 11 104107
No constant
pattern is observed and these anomalies
include distal limb, sensorineural, skin, central
nervous system, genital, kidney, and cardiac
malformations. However, cardiac defects,
mostly atrio- or ventriculoseptal defects, are
found with an incidence of 5% of cases of
HSCR, excluding patients with trisomy 21.
Renal dysplasia or agenesis was found in 4.4%
in a series of 160 HSCR cases and may still be
underestimated (personal data). This is of
interest since homozygous knockout mice for
genes involved in the Ret signalling pathway
present with renal agenesis/dysplasia in addi-
tion to megacolon (see below).
108
Genital
anomalies including hypospadias are reported
in up to 2-3% of HSCR patients. Gastro-
intestinal malformations such as Meckel
diverticulum, pyloric stenosis, single umbilical
artery, inguinal hernia, or small bowel atresia
are also found.
109111
Finally, facial dysmorphic
features seem to be extremely frequent when
looked for. These data highlight the import-
ance of a careful assessment by a clinician
trained in dysmorphology for all newborns
diagnosed with HSCR. Skeletal x ray and car-
diac and urogenital echographic survey should
be systematically performed. The observation
of one additional anomaly to HSCR should
prompt chromosomal studies.
Molecular genetics
Segregation studies in non-syndromic HSCR
have shown that the recurrence risk in sibs
varies from 1% to 33% depending on the gen-
der and the length of the aganglionic segment
in the proband and the gender of the sib (table
1).
5 14
Consequently, HSCR has been assumed
to be a sex modied multifactorial disorder, the
eVect of genes playing a major role as
compared to environmental factors (relative
risk of 200).
So far, eight genes are known to be involved
in HSCR in humans, namely the proto-
oncogene RET (RET), glial cell line derived
neurotrophic factor (GDNF), neurturin
(NTN), endothelin B receptor (EDNRB),
endothelin 3 (EDN3), endothelin converting
enzyme 1 (ECE1), SOX10, and SIP1 genes
(table 4).
Hirschsprung disease, associated syndromes, and genetics 733
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THE RET SIGNALLING PATHWAY
The rst susceptibility locus was mapped to
10q11.2 in multigenerational families segregat-
ing HSCR as an incompletely penetrant auto-
somal dominant trait.
112 113
This region had
been targeted because of the observation of an
interstitial deletion of chromosome 10q11.2 in
patients with TCA and mental retardation.
33
The proto-oncogene RET, identied as disease
causing in MEN 2
114 115
and mapping in
10q11.2, was regarded as a good candidate gene
owing to the concurrence of MEN 2A and
HSCR in some families and the expression in
neural crest derived cells. Consequently, RET
gene mutations were identied in HSCR
patients.
116 117
RET is a 1114 amino acid trans-
membrane receptor with a cadherin-like extra-
cellular domain, a cysteine rich region, and an
intracellular tyrosine kinase domain.
118
Expres-
sion and penetrance of a RET mutation is vari-
able and sex dependent within HSCR families.
In large series, the estimated penetrance is 72%
in males and 51% in females.
119
Over 80 muta-
tions have been identied including large dele-
tions encompassing the RET gene, microdele-
tions and insertions, nonsense, missense and
splicing mutations.
119121
There is no mutational
hot spot at variance with MEN 2A, where
mutations occur in a cluster of six cysteines
(exon 10, residues 609, 611, 618, 620; exon 11,
residues 630,634),
44 114 115
and MEN 2B where
the mutation is almost unique (M918T, exon
16, tyrosine kinase domain).
122124
In vitro, MEN
2 mutations have been shown to be activating
mutations leading to constitutive dimerisation
of the receptor and to transformation,
125
while
haploinsuYciency is the most likely mechanism
for HSCR mutations.
126128
Biochemical studies
showed variable consequences of some HSCR
mutations (misfolding, failure to transport the
protein to the cell surface, abolished biological
activity).
127 128
However, a simple activating ver-
sus inactivating model of gene action is not suf-
cient to explain the concurrence of HSCR and
MEN 2A in patients with a MEN 2A RET gene
mutation.
Despite extensive mutation screening, a RET
mutation is identied in only 50% of familial
and 15-20% of sporadic HSCR cases.
119
However, most families with fewexceptions are
compatible with linkage at the RET locus.
129
Recent studies of known polymorphisms
within the RET gene in a series of sporadic
HSCR patients showed a signicantly diVerent
distribution as compared to controls. Several
polymorphic haplotypes could be associated
with predisposition to HSCR.
130 131
Epigenetic
factors could also be involved.
GDNF, known as a major survival factor for
many types of neurones, was shown to be the
RET ligand by both phenotypic similarities
between Ret -/- and Gdnf -/- knockout mice
132134
and Xenopus embryo bioassays.
135
GDNF is a
TGF-B related 211 residue protein, proteolyti-
cally cleaved to a 134 residue mature protein
that homodimerises. To activate RET, GDNF
needs the presence of a novel glycosylphos-
phatidylinositol (GPI) linked coreceptor
GFRA1.
136 137
Four related GPI linked corecep-
tors, GFRA1-4,
138
and four related soluble
growth factors ligands of RET have been iden-
tied, namely GDNF, NTN,
139
persephin
(PSPN),
140
and artemin.
141
Specic combina-
tions of these proteins are necessary for devel-
opment and maintenance of both central and
peripheral neurones and all can signal through
RET. GDNF mutations have been identied in
only six HSCR patients to date, and can be
regarded as a rare cause of HSCR
(<5%).
31 142 143
Moreover, GDNF mutations
may not be suYcient to lead to HSCR since
four out of six patients have additional
contributory factors, such as RET mutations or
trisomy 21.
31 142
Similarly, a NTN mutation has
been identied in one family, in conjunction
with a RET mutation.
144
Finally, although
Gfra1 homozygous knockout mice are pheno-
typically very similar to Ret and Gdnf -/- mice,
no GFRA1 mutations have been identied in
HSCR patients.
145148
THE ENDOTHELIN SIGNALLING PATHWAY
The endothelin pathway was rst studied for its
vasoconstrictive eVect and putative role in
hypertension. EDNRB and EDNRA are G
protein coupled heptahelical proteins that
transduce signals through the endothelins
(EDN1, 2, 3).
149 150
Table 4 Genes involved in HSCR in humans and known mouse models of megacolon
Gene
Human Mouse
Map location
Mode of
inheritance
Phenotype in
mutants
Frequence of mutation
in heterozygotes Refs Natural mutant Knock-out Refs
RET 10q11.2 AD HSCR 50% familial cases 119 L 108
15% sporadic cases Renal agenesis
GDNF 5p13 AD HSCR 5 cases 31, 142, 143 L 132134
Renal agenesis
NTN 19p13 AD HSCR 1 case 144
SOX10 22q13 AD WS4 57, 59, 165 Dom (AD) L 164
Coat spotting
EDNRB 13q22 AR/AD WS4/HSCR 5% 53, 157160 s
l
(AR) S 154
Coat spotting
EDN3 20q13 AR/AD WS4/HSCR <5% 156 ls (AR) S 155
Coat spotting
ECE1 1p36 AD HSCR 1 case 162 S 161
CF and cardiac
defect
Coat spotting
CF defects
SIP1 2q22 Spo HSCR, MR, facial
dysmorphism
6 cases 38, 39, 41
AD: autosomal dominant, AR: autosomal recessive, Spo: sporadic, s
l
: Piebald lethal, ls: lethal spotting, S: short segment megacolon, L: long segment megacolon, CF:
craniofacial, MR: mental retardation.
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A susceptibility locus for HSCR in 13q22
was suggested for three main reasons: (1) a sig-
nicant lod score at 13q22 in a large inbred
Old Order Mennonite community with multi-
ple cases of HSCR,
30 151 152
(2) de novo intersti-
tial deletion of 13q22 in several patients with
HSCR,
36 37 153
and (3) synteny between the
murine locus for piebald-lethal (s
l
), a model of
aganglionosis, and 13q22 in humans. The
critical role of the endothelin pathway in
HSCR was shown by the nding that piebald-
lethal was allelic to the Ednrb knockout mouse
and harboured an Ednrb mutation (table 4).
154
Subsequently, an EDNRB missense mutation
was identied in the Mennonite kindred
(W276C).
53
However, the W276C mutation
was neither necessary (aVected wild type
homozygotes) nor suYcient (unaVected mu-
tant homozygotes) to cause HSCR, and
penetrance was sex dependent (greater in
males than in females).
53
piebald-lethal was con-
sidered a mouse model for WS4 in humans and
some of the aVected Mennonite subjects had
pigmentary anomalies and sensorineural deaf-
ness in addition to HSCR.
30 151
This prompted
a screen of the EDNRB gene in WS4 and
homozygous mutations in a fraction of WS4
families were found.
54
At the same time, an
Edn3 mutation was identied in the lethal spot-
ting (ls) natural mouse model for WS4
155
and
EDN3 homozygous mutations were identied
in WS4 in humans (table 4).
55 56
Both EDNRB and EDN3 were screened in
large series of isolated HSCR patients. While
EDN3 mutations were seldom found,
156
EDNRB mutations were identied in approxi-
mately 5% of the patients.
157160
It is worth
mentioning that the penetrance of EDN3 and
EDNRB heterozygous mutations is incomplete
in those HSCR patients, de novo mutations
have not hitherto been observed, and that
S-HSCR is largely predominant. Interstitial
13q22 deletions encompassing the EDNRB
gene in HSCR patients make haploinsuY-
ciency the most likely mechanism for HSCR
(table 2). Although EDNRB binds all three
endothelins, the similarity of phenotype of the
Ednrb knockout mice to that of the Edn3
knockout mice suggests that EDNRBs major
ligand is EDN3 in neural crest derived cells.
Preproendothelins are proteolytically
cleaved by two related membrane bound met-
alloproteases to give rise to the mature 21 resi-
due endothelin. Ece1 processes only Edn1 and
Edn3. Ece1 knockout mice show craniofacial
defects and cardiac abnormalities in addition
to colonic aganglionosis.
161
A heterozygous
ECE1 mutation has been identied in a patient
combining HSCR and craniofacial and cardiac
defects (R742C).
162
SOX10
The last de novo mouse model for WS4 in
human is dominant megalon (Dom), homo-
zygous Dom mutation being embryonic le-
thal.
163
The Dom gene is Sox10, a member of
the SRY (sex determining factor)-like, high
mobility group (HMG) DNA binding pro-
teins.
164
Subsequently, heterozygous SOX10
mutations have been identied in familial and
isolated patients with WS4 (including de novo
mutation).
57 59 165
At least some mutations
disrupt the DNAbinding domain and may lead
to a loss of function allele, so that again
haploinsuYciency is the most likely mech-
anism for HSCR. Others disrupt the transacti-
vation domain and may result in a dominant
negative eVect. These latest mutations were
identied in patients presenting neurological
impairment in addition to HSCR and pigmen-
tary anomalies.
59
Penetrance appears to be
high, although sibs sharing a mutation and dis-
cordant for HSCR have been described in one
family.
165
Therefore, SOX10 is unlikely to be a
major gene in isolated HSCR.
INTERACTION BETWEEN PATHWAYS
Ret and Ednrb signalling pathways were
considered biochemically independent. How-
ever, G protein coupled receptors and receptor
tyrosine kinases could be engaged in crosstalk.
Moreover, an HSCR patient heterozygous for
weak hypomorphic mutations in both RET and
EDNRB has recently been reported.
166
Each
mutation was inherited from a healthy parent.
Sox10 is involved in cell lineage determina-
tion and is capable of transactivating MITF
synergistically with PAX3.
167
Similarly, Ednrb
transcripts are either absent or drastically
reduced in Dom-/- and +/- mice, respectively.
168
Therefore, the reduced expression of Ednrb in
the dom mouse could arise either from a direct
eVect of Sox10 or from an indirect eVect on a
subset of NC cells of common faith.
Taken all together, several general comments
can be made. RET is the major gene in HSCR
with a heterozygous mutation found in 50% of
familial cases and 15-20% of isolated cases.
RET mutation penetrance is incomplete and
sex dependent. Genotype-phenotype correla-
tion is poor. HSCR is genetically heterogene-
ous and results from mutations in distinct
pathways. Some patients with mutations in more
than one HSCR susceptibility gene are known
(RET + GDNF, RET + NTN, RET + EDNRB).
Multigenic inheritance of Hirschsprung
disease
As mentioned above, RET plays a key role in
non-syndromic HSCR genesis and multiple
genes may be required to modulate clinical
expression. On the other hand, genetic hetero-
geneity, where mutation in one of several genes
is suYcient for phenotypic expression of
HSCR, has been reported (RET, EDNRB,
EDN3, ECE1, SIP1). However, the observation
of non-random association between HSCR,
RET, and chromosome 21q22 in the Menon-
nite population where HSCR imperfectly
segregates with an EDNRB mutation favours
multigenic inheritance resulting from the
cumulative eVects of multiple mutations.
According to the segregation analysis where an
autosomal dominant model in L-HSCR and a
multifactorial model in S-HSCR were more
likely, two approaches have been chosen to test
these hypotheses in L-HSCR and S-HSCR
independently.
Hirschsprung disease, associated syndromes, and genetics 735
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LINKAGE ANALYSIS IN 12 HSCR FAMILIES WITH
THREE OR MORE AFFECTED SUBJECTS IN TWO OR
MORE GENERATIONS
129
L-HSCR is largely predominant in these fami-
lies. All but one family showed linkage to the
RET locus. Mutational analysis identied a
nonsense or missense mutation at a highly
conserved residue in six families, a splice
mutation in two families, and no coding
sequence variation in three families. Linkage to
a novel locus in 9q31 was identied only in
families with no or hypomorphic RET gene
mutation. Therefore, a severe RET mutation
may lead to phenotypic expression by haploin-
suYciency, while hypomorphic RET mutations
would require the action of other mutations.
A SIB PAIR ANALYSIS IN 49 FAMILIES WITH S-HSCR
PROBANDS
169
This study shows that only three loci on chro-
mosomes 3p21, 10q11, and 19q12 are both
necessary and suYcient to explain the inci-
dence and sib recurrence risk in HSCR. A
multiplicative risk across loci with most af-
fected subjects being heterozygotes at all three
loci seems the best genetic model. Interest-
ingly, marker analysis showed a signicant par-
ent of origin eVect at the RET locus, 78% of
shared RET alleles being maternally derived,
which could explain the sex diVerence in
HSCR expression. Finally, linkage to 9q31 was
conrmed in the sib pairs with no or hypomor-
phic RET mutation.
Genetic counselling
HSCR is a sex modied, multifactorial,
congenital malformation with an overall recur-
rence risk in sibs of the proband of 4% (relative
risk=200). In isolated HSCR, adequate relative
risk gures will be provided by taking into
account the sex and length of the aganglionic
segment in the proband and the gender of the
sib (1-33%). According to the Carter paradox,
the highest recurrence risk is for a male sib of a
female proband with L-HSCR (table 1).
Because of poor genotype-phenotype correla-
tion so far, the benet of mutation screening
for HSCR patients appears low except for sys-
tematic testing of exon 10 and 11 of the RET
gene owing to cancer predisposition of MEN
2A mutations. This, unfortunately, is not yet
routine practice.
Many HSCR cases are associated with other
congenital anomalies. In these cases, the long
term prognosis is highly dependent on the
severity of the associated anomalies. Several
known syndromes have straight Mendelian
inheritance. This emphasises the importance of
careful assessment by a clinician trained in
syndromology of all newborns diagnosed with
HSCR.
We thank the HSCR patients and their families and the French
Hirschsprung Disease Association (AFMA) for their coopera-
tion and active participation over 10 years. We sincerely
acknowledge colleagues from all over the world for providing us
with samples as well as all the students and collaborators of our
research group on Hirschsprung disease. Some data in the
present review have been reprinted and adapted from Scriver
CR, et al, ed. The metabolic and molecular bases of inherited
diseases. 8th ed. Chap 251. New York: McGraw-Hill:6231-55.
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Hirschsprung disease, associated syndromes, and genetics 739
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2001 38: 729-739 J Med Genet

Jeanne Amiel and Stanislas Lyonnet

and genetics: a review

Hirschsprung disease, associated syndromes,
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