Journal of Pediatric Surgery (2006) 41, 126 – 131

www.elsevier.com/locate/jpedsurg

New clinical and therapeutic perspectives in Currarino

syndrome (study of 29 cases)
Celia Crétollea, Michel Zérahb, Francis Jaubertc, Sabine Sarnackia, Yann Révillona,
Stanislas Lyonnetd, Claire Nihoul-Fékétéa,*
a
Deparment of Pediatric Surgery, Hôpital Necker-Enfants Malades, 75015 Paris cedex 15, France
b
Deparment of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, 75015 Paris cedex 15, France
c
Deparment of Pathology, Hôpital Necker-Enfants Malades, 75015 Paris cedex 15, France
d
Deparment of Medical Genetics, Hôpital Necker-Enfants Malades, 75015 Paris cedex 15, France

Index words: Abstract

Currarino syndrome; Purpose: The aim of the study was to clearly define the anomalies that compose the Currarino syndrome
Sacrum anomaly; (CS). We highlight the frequency of associated malformations of the spinal cord and the possibility of a
Hindgut anomalies; communication between the presacral tumor and the spinal canal, leading to neurological complications.
Presacral tumor; Methods: We studied 29 patients with CS, including 12 familial cases; histological examination of the
Spinal cord anomalies; presacral tumor was performed, and cytogenetic and molecular biology studies of the HLXB9 locus
Genetic disease were carried out.
Results: All except 2 patients had a sacral malformation; 23 had an anorectal anomaly and 8 had
isolated chronic intestinal pseudo-obstruction. There were 20 presacral tumors, one of which was
malignant. There was a communication between the presacral tumor and the spinal canal in 12 cases,
and tethering of the spinal cord in 17 cases.
Twenty-five patients underwent surgery with a single-stage operation for 7, on both the intestinal and the
presacral malformations, and, when required, the spinal cord anomalies.
Twelve patients harbored a heterozygous point mutation of the coding sequence of HLXB9 gene.
Conclusion: By accurate evaluation of the 4 main features in the CS, the correct surgical management,
including neurosurgery, can be performed in a 1-stage approach.
D 2006 Elsevier Inc. All rights reserved.

Currarino et al [1], in 1981, described a rare congenital
complex syndrome (Currarino syndrome [CS]) character-
ized by a sacral bone defect, a congenital hindgut anomaly,
and a presacral tumor. Neural tube defects are frequently
Presented at the 36th Annual Meeting of the American Pediatric
Surgical Association, Phoenix, AZ, May 29 - June 1, 2005.
* Corresponding author. Tel.: +33 1 44 49 41 52; fax: +33 1 44 49 41 60.
E-mail address: claire.fekete@nck.ap-hop-paris.fr (C. Nihoul-Fékété).
associated malformation [2,3]. Several authors have
reported malignant degeneration of the presacral tumor
even in the pediatric age [4].
A family tendency was noted in some early case reports
of CS with autosomal dominant inheritance [5]. As there is a
broad inter- and intrafamilial phenotypic variability [6-13],
the true incidence of the disorder is unknown.
In 1998, genetic studies suggested that the locus involved
in the normal sacral and anorectal development maps to the

0022-3468/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jpedsurg.2005.10.053
New clinical and therapeutic perspectives in Currarino syndrome (study of 29 cases)
terminal end of human chromosome 7 (7q36) [14].
Recently, mutations of the HLXB9 gene in this locus, known
to be involved in the development of anterior motoneurons
[15-17], were identified as responsible for CS [6,18,19]. The
HLXB9 homeobox gene encodes a 403–amino acid tran-
scription factor called HB9 protein.
1. Patients and methods
Twenty-nine patients from unrelated families, treated
from 1982 to 2004, were included in the study provided
they had 3 major features of the CS. Among these cases,
3 were fetuses from late terminations owing to severe
malformation syndromes. Twelve cases were familial cases
(multiplex) and 17 were sporadic (simplex). Mean follow-
up period was 7.6 years (range, 8 months–25 years). Ages
on the admission ranged from 7 days to 16 years. The
hindgut anomalies were classified as obstructive infundib-
ular anus (anus appears abnormal with a high anocutaneous
junction and an anorectal stenosis), imperforate anus (low or
high), and/or chronic intestinal pseudo-obstruction (CIPO).
The existence of a presacral malformative tumor and/or a
spinal cord malformation was clearly demonstrated by
magnetic resonance imaging (MRI). Histological examina-
tion of the presacral tumor was performed.
A standard karyotype and a fluorescence in situ
hybridization with the 7q36 probe were possible in
24 patients. DNA extracted from blood samples of the
29 index patients was prepared for sequencing analysis of
HLXB9 gene.
Treatment was directed according to the malformation
lesions. Surgery was not necessary for sacral anomalies.
Initially, intestinal malformations were treated separately by
an abdominal approach or proctoplasty or bougienage,
whereas the presacral tumors and neurological anomalies
were treated separately by a sacral approach. Tethered cord
was released because of neurological symptoms, association
with a presacral tumor, and/or loss of motility of the spinal
cord on MRI. Since 1995, patients were treated in a single-
stage perineal approach or posterior sagittal anorectoplasty
(PSARP), which allows correction of intestinal and tumor
malformations. Association with a symptomatic tethered
cord and/or lipoma was corrected by an extended PSARP
posterior to the sacrum (posterior sagittal transsacral and
perineal [PSSP] approach), requiring collaboration with
pediatric neurosurgeons. Postoperative complications were
studied. The development of a presacral tumor or that of
unoperated tethered cord was regularly checked for at
postoperative follow-up.
2. Results
The phenotype features were similar for the 14 male and
15 female patients. A sacral malformation was present in
127
27 patients consisting of a sickle-shaped sacrum in 12, a
sacral agenesis below the S2 vertebra in 12, and a complex
sacral malformation in 3 cases (Table 1).
Twenty-three patients had an anorectal malformation
comprising a low imperforation anal type in 18 cases (with a
typical infundibulum anus in 12 and high imperforation anal
type in 5 cases). Eight patients, including 2 patients without
any anorectal malformation, had CIPO. Twenty had
presacral tumor, 11 of these were familial cases, and the
last one was qualified as bsporadic,Q but the family history
could not be explored.
3. Discussion
First recognized in 1981, the CS is an uncommon genetic
disorder. Most series concern only a few cases [20-27]. In
the 3 main series of the literature, the authors focused on
phenotypic and genetic disorders, but therapeutic manage-
ment was not described [6,18,19]. Lee et al [28] described
surgical treatments and the results in 11 CS cases, but
genetic analysis was not performed. To our knowledge, we
report the most comprehensive series, including phenotypic
analysis, radiological and surgical management, postopera-
tive sequelae, and genetic disorders of patients with CS.
Martuccielo et al [3] reported a similar study involving
6 cases.
This 29-patient series provides evidence of the difference
in expressivity of CS. Twelve of our patients had
typical scimitar sacrum and 15 had sacral agenesis or
a complex malformation. Two patients with a normal
sacrum were nevertheless considered as CS because of the
finding of familial mutation of the HLXB9 gene in one
and the presence of other clinical features of CS in the
other case.
High anorectal malformation was rare (5 cases), and
none of these patients had the HLXB9 mutation, suggesting
that high imperforation anal type may result from a dif-
ferent embryogenesis process. Chronic intestinal pseudo-
obstruction is part of the CS, but no precise defect either in
intrinsic innervation or muscular coats of the hindgut has
been discovered.
Congenital tumor is frequent in CS, but its development
can be delayed, and mean age at diagnosis in our series was
5 years. It is therefore mandatory, when the diagnosis of CS
is made, to perform a spinal cord MRI and to repeat it at
intervals during childhood [29].
Malignancy in CS has been reported in the literature in
2 children (2 years old) and in 4 adults [30-35]: malignant
teratomas in 4 cases, leiomyosarcoma in 1, and neuroendo-
crine tumor in 1. In our series, 1 patient had diagnosis of
tumoral malignancy. This 2-year-old girl was operated twice
for immature teratoma and underwent chemotherapy after
surgery without tumoral relapse. Another patient is also
atypical because of the association of a presacral teratoma
and an N-myc–negative pararenal neuroblastoma with a
 128
Table 1 Results in 29 patients with CS
Patient Multiplex Sacrum Hindgut Histology Medullar Other Management Sequelae
or simplex of the tumor anomalies malformations
1 M HS LIA-Inf A BT/ TC-lipoma-syringomyelia Occipital angioma (1) PA; (2) PSARP None
2 M HS LIA-Inf A AM/+ TC Mqllerian duplication (1) AA; (2) PA Transient CSF
leak
3 M HS LIA and AM and BT/+ Isolated lipoma Mqllerian duplication (1) PA; (2) AA None
CIPO
4 M HS LIA-Inf A BT/+ TC Clinodactyly (1) PA for presacral Neurological
abscess; (2) PSARP bladder
5 M HS CIPO AM/+ TC-syringomyelia None PSSP for presacral Transient CSF
abscess leak
6 M HS LIA-Inf A BT/+ None None PSSP None
and CIPO
7 M Normal Normal BT/ None None AA None
8 M Agenesis below S2 LIA-Inf A AM/+ TC None AA None
vertebra
9 M HS LIA-Inf A AM and BT/+ TC-syringomyelia None PSARP None
10 M Agenesis below S2 LIA-Inf A None TC Mqllerian duplication AA None
vertebra aortic stenosis
11 M Complex malformation LIA and None None Mqllerian duplication Bougienages None
CIPO left kidney agenesis
12 M Agenesis below S2 LIA-Inf A BT/+ TC Neuroblastoma PSSP None
vertebra (N-myc negative)
13 S Agenesis below S2 LIA-Inf A BT/+ TC-syringomyelia Somatotrope deficiency, Bougienages None
vertebra clinodactyly
14 S HS LIA BT/ TC-lipoma None (1) proctoplasty; None
(2) perineal approach

C. Crétolle et al.
15 S Agenesis below S2 HIA AM/ Isolated lipoma Familial obesity (1) AA; (2) PA None
vertebra
16 S HS Normal BT/+ None None (1) AA; (2) PA None
17 S Agenesis below S2 LIA-Inf A BT/ None Somatotrope deficiency (1) PA; (2) AA Fecal and
vertebra urinary
incontinence
 New clinical and therapeutic perspectives in Currarino syndrome (study of 29 cases)
18 S HS LIA and None TC-lipoma-hydromyelia None PSARP None
CIPO
19 S Agenesis below S2 HIA None TC-lipoma-syringomyelia Hypospadias PSARP None
vertebra
20 S Normal LIA-Inf A MT/ None Cloacal (1) AA for presacral Urinary
malformation tumor; (2) PA for incontinence
tumor recurrence
21 S HS LIA-Inf A AM/+ None Mqllerian duplication Bougienages None
and CIPO
22 S Agenesis below S2 HIA None TC-lipoma Squint PSARP None
vertebra
23 S Complex malformation CIPO BT/ TC Arnold-Chiari S anterior (1) AA for (Urinary
pituitary insufficiency enterocystoplasty; incontinence)
(2) PA
24 S Agenesis below S2 Normal None TC-lipoma Developmental and None None
vertebra growth delay–corpus
callosum agenesis–
coloboma
25 S Agenesis below S2 LIA None TC–lipoma–syringo- Developmental delay (1) PA; (2) AA for (Urinary
vertebra diastematomyelia enterocystoplasty incontinence)
26 S HS LIA and CIPO BT/ None Rieger syndrome AA None
27 S Complex malformation Normal Not investigated Not investigated Hemiuterus agenesis– None
corpus callosum
agenesis–ectopic and
hypoplastic right kidney
28 S Agenesis below S2 HIA AM/+ TC-lipoma- Hirsutism– hemiuterus None
vertebra diastematomyelia agenesis
29 S Agenesis below S2 HIA Not investigated Not investigated Not precise None
vertebra
Cases 27 to 29 are fetuses. Rieger syndrome consists of facial dysmorphy, ocular anomalies, growth delay, but no mental retardation. HS indicates hemisacrum; HIA, high imperforation anal type; LIA, low
imperforation anal type; Inf A, infundibulum anus; BT, benign tumor; MT, malignant tumor; AM, anterior meningocele; AA, abdominal approach; PA, posterior approach; CSF, cerebrospinal fluid; +,
communication with spinal canal; , no communication with spinal canal.

129
130
584 del A mutation of the HLXB9 gene (there is no similar
case reported in the literature).
The surgeon must always be alert to the possibility of a
communication between the spinal canal and the tumor that
could lead to severe neurological complications if not
treated correctly. The presence of a tethered cord was also
frequent (17 of the 27 explored patients) [29,36]. Surgery
was already necessary in 9 of the 17 tethered cord cases in
our series, and other 8 cases are regularly investigated for
fear of the onset of neurological symptoms.
As mentioned in the literature [1,3,4,6,13,28], mqllerian
duplications were frequent, and a correlation with malfor-
mation sequences of CS has to be confirmed.
The embryogenesis of the syndrome is much debated.
Currarino et al [1] proposed a model of the bsplit notochord
syndromeQ consequence of persistent abnormal adhesions
between the endoderm and the neural ectoderm, occurring
before the appearance of the notochord; therefore, the
notochord is split and impedes anterior fusion of vertebrae.
According to Gegg et al [9], this process of primary
neurulation fails to explain anomalies of the caudal region.
Instead, the defect would have to be in the caudal eminence,
involving secondary neurulation to unify the triad features.
Errors in migration or development of the caudal eminence
stem cells, supplying progenitors for tissues of all the 3 germ
layers in the caudal region, could result in a disorganized
mass (ie, the teratoma) that is physically attached dorsally to
the spinal conus and ventrally to the anorectal junction.
Surgical management is not required in all intestinal
malformation types. However, the surgical treatment has to
be performed as soon as a presacral tumor is diagnosed.
Surgery is also mandatory in case of infectious complica-
tions or fixed tethered spinal cord. Posterior sagittal
anorectoplasty is a well-established procedure for treating
anorectal stenosis and presacral mass, but in situations where
tethered cord is symptomatic, we propose a PSSP approach
that allows simultaneous treatment of intestinal, tumor, and
neurological anomalies. The possibility of malignant trans-
formation should also be considered, and resection of the
presacral mass together with excision of the coccyx is
mandatory and easier to perform via a PSSP approach.
HLXB9 mutations account for the pathogenesis of most
of the patients with familial CS, but are evident only in part
of sporadic patients [6]. Familial cases of CS are probably
underestimated because information concerning these fam-
ilies is not often available; in the literature, at least 50% of
the patients have family histories that are positive for 1 or
more of the components of the syndrome [9].
The complete Currarino triad, better defined as Currar-
ino syndrome, is rare. This syndrome should be considered
even in the presence of a partial phenotype. The wide
phenotypic variability requires combined pediatric and
neurosurgical assessment.
In those patients with suspicion of CS, a mutational
analysis should also be considered to offer precise genetic
counseling and full workup of family members.
C. Crétolle et al.
Acknowledgments
This work was supported by funding from the Associ-
ation pour la Recherche sur le Cancer and the Fédération des
Maladies Orphelines. We would like to thank Pr R Skaba
(Pediatric Surgery Department, Motol Hospital, Prague,
Czech Republic) and Pr J Tovar (Pediatric Surgery
Department, Insalud Hospital, Lapaz, Madrid, Spain) for
their collaboration in this study.
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131
Discussion
Daniel Teitelbaum, MD (Ann Arbor, MI): I am very
impressed with the review. It was a beautiful paper. I
was quite impressed with the number of pseudo-
obstruction patients that you had, but I did not hear
much about the management of those or the recognition
of these particular patients. How do you deal with those
particular patients?
Claire Fekete, MD (response): Constipation is a severe
problem in Currarino syndrome and is related in the
literature. Washout procedure is required. Sometimes
even surgical shortening of the colon is necessary.
Until now we did not find any myopathy or neuro-
pathy in the colon, but Martucello (from Genoa) has
described anomalies of the innervation of the colon in
Currarino syndrome.
Keith Ashcraft, MD (Mission Hills, KS): That was a very
lovely paper. Thank you. I would like to know more
about the malignancy in this one patient. What was the
cell type? Was it a malignant teratoma, because
malignancies are very, very rare in these patients.
Claire Fekete, MD (response): That was alpha-fetoprotein-
positive malignant teratoma, and in the literature there
are nearly 10 cases of malignant recurrences.
Patricia Donahoe, MD (Boston, MA): This is an instructive
and informative contribution, which illustrates the
importance of genetics in the congenital malformations
that we deal with. I wonder, Dr Fekete, how did you
come upon the 7Q26? Was the HLXB9 just a candidate
gene? Did you find it in a deletion? What do you think is
the genetic etiology in other patients that did not have
this mutation as a cause?
Claire Fekete, MD (response): We wanted to study that
because it is a locus that is involved in the sacral and
motor neuron development and in that locus there is
also a tumor suppressive gene. Next step is to find
downstream genes and we will take into account the
mullerian duplication.