A Case of Acrocephalosyndactyly With Low Imperforate Anus
By Tetsuro Kodaka, Yutaka Kanamori, Masahiko Sugiyama, and Kohei Hashizume
Tokyo, Japan
The authors report a case of a female acrocephalosyndactyly
with imperforate anus without fistula, which is rare in girls.
Acrocephalosyndactyly is characterized by premature clo-
sure of the sutures (craniosynostosis) and fusion or webbing
of hands and feet (syndactyly). The most general types of the
syndrome are the Apert syndrome and the Pfeiffer syn-
drome. They usually have some fibroblast growth factor
receptor (FGFR) gene mutations, so that acrocephalosyndac-
tyly is thought to be involved in “FGFR-related craniosynos-
tosis.” To the authors’ knowledge, only 4 cases of anorectal
A CROCEPHALOSYNDACTYLY is defined as a
congenital syndrome characterized by peaking of
the head caused by premature closure of the skull sutures
(craniosynostosis) and fusion or webbing of hands and
feet (syndactyly).1 It is classified from type I to type V.
The most general types are the Apert syndrome (type I)2
and the Pfeiffer syndrome (type V).3 Both of them are
described to be inherited in an autosomal dominant
fashion, but most of the time they are sporadic. We
report on a Japanese girl with acrocephalosyndactyly
without familial history, the case was complicated by
imperforate anus without fistula, which is rare in girls.
To our knowledge, only 4 cases of anorectal anomaly in
acrocephalosyndactyly have been reported in the world.
CASE REPORT
A Japanese girl was born by normal delivery after a 37-week, 6-day
pregnancy. Her birth weight was 3,308 g. At birth, her unusual
appearance (peaking of the head, fusion of second and third fingers in
the bilateral hands and feet) was pointed out, and she was suspected to
have Apert syndrome (Fig 1). She also had an imperforate anus without
perineal fistula. Her rectal pouch localization showed low imperforate
anus without fistula (covered anus complete), which is extremely rare
in girls (Fig 2).4 The second day after birth, her operation (minimal
posterior sagittal anoplasty)5 was performed (Fig 3). The postoperative
course was uneventful, and she is now undergoing follow-up at the
outpatient clinic with neurosurgeons, plastic surgeons, and pediatric
surgeons.
From the Department of Pediatric Surgery, Faculty of Medicine,
University of Tokyo, Tokyo, Japan.
Address reprint requests to Tetsuro Kodaka, Department of Pediat-
ric Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, Japan 113-8655.
© 2004 Elsevier Inc. All rights reserved.
1531-5037/04/3901-0044$30.00/0
doi:10.1016/j.jpedsurg.2003.09.037
32
anomaly in acrocephalosyndactyly have been reported in the
world. The relationship between anorectal anomaly and the
FGFR gene is not clear now, but might be clarified in the
future.
J Pediatr Surg 39:E10. © 2004 Elsevier Inc. All rights re-
served.
INDEX WORDS: Acrocephalosyndactyly, anorectal anomaly,
fibloblast growth factor receptor, gene mutation, craniosyn-
ostosis.
DISCUSSION
Acrocephalosyndactyly has been classified into 5
types (Table 1). The most common types in the entity are
Apert syndrome and Pfeiffer syndrome.
Apert syndrome was named by Apert, a French phy-
sician, in 1906.6 It is characterized by early fusion of
skull sutures (craniosynostosis), midface retrusion (af-
fecting that area of the face from the middle of the eye
socket to the upper jaw) and symmetrical webbed digits
(syndactyly). Most cases are sporadic, but autosomal
dominant inheritance can occur. It is identified to be
derived from the genetic change. The gene is on chro-
mosome 10 called fibroblast growth factor receptor 2
(FGFR2).7 Two of the genetic mutations are especially
responsible for the Apert syndrome. One is Ser252Trp,
associated with cleft palate, the other is Pro253Arg,
associated with syndactyly.8
Pfeiffer syndrome was reported by Pfeiffer in 1964.9
This is characterized by turribracephaly, partial soft tis-
sue syndactyly of the hands and feet but markedly
broadened and shortened thumbs and toes. Similar to
Apert syndrome, most Pfeiffer cases are sporadic, but
some autosomal dominant inheritance has been reported.
It is also derived from FGFR1 or FGFR2 gene muta-
tions.10 Many points of mutation have been reported.
FGFR gene mutations are also pointed out in Crouzon
syndrome,11 Muenke syndrome, Jackson-Weiss syn-
drome, and Beare-Stevenson syndrome. These syn-
dromes are now thought to be composed of 1 syndrome,
FGFR-related craniosynostosis syndrome. We believe
that our case is the Pfeiffer syndrome rather than the
Apert syndrome. But this distinction seems already
worthless, and we should consider these syndromes in-
clusively to be FGFR-related disease.
As for visceral anomalies in acrocephalosyndactyly,
Journal of Pediatric Surgery, Vol 39, No 1 (January), 2004: E10
ACROCEPHALOSYNDACTYLY WITH ARM
Fig 1. The patient at birth. Her head is peaking because of pre-
mature closure of the skull sutures (craniosynostosis).
Fig 2. Invertogram shows that her rectal pouch localization
showed low imperforate anus without fistula (coverd anus com-
plete).
33
Fig 3. Minimal posterior sagittal anoplasty: (1) Midline minimal
incision through posterior musculature, (2) identification of the rectal
pouch and incision into the posterior and inferior wall of the rectum,
(3) mobilization of the rectum.
Cohen12 reported ones in the Apert syndrome. According
to this report, cardiovascular and genitourinary anoma-
lies are found most commonly (10% and 9.6%, respec-
tively). On the other hand, respiratory and gastro-
intestinal anomalies seem to be rare (both 1.5%). In
gastrointestinal anomalies, Cohen12 reported esophageal
atresia, pyloric stenosis, biliary atresia, and anorectal
anomaly. Except for the Apert syndrome, few visceral
anomalies in acrocephalosyndactyly have been reported.
Only 4 cases of acrocephalosyndactyly with anorectal
anomaly have been reported (Table 2).13-16 Our case is so
similar that of Ohashi15 that is thought to be included in
the Pfeiffer syndrome. But that is not to be discussed. It
is important for us to know whether our case has an
FGFR gene mutation; we are sure that it does.
Additionally, 2 anorectal anomalies have been re-
ported to have FGFR gene mutations. One is a case of
Crouson syndrome, which was revealed to have a
W290G mutation in exon IIIa of the FGFR2 gene.17 The
other is a case of Beare-Stevenson Cutis gyrata syn-
drome, which was reported to have FGFR2 mutation
(Tyr375Cys).18 Except for that, some anorectal anoma-
lies have been reported in other “FGFR-related cranio-
synostosis syndromes,” which not have been found to
have FGFR mutations yet but are thought to have.19
Furthermore, it is reported that some novel variant
form of FGFRs have been identified in human gastroin-
testinal epithelium in recent years.20,21 FGFRs also are
reported to be related to Hirschsprung’s disease.22
Table 1. The Classification of Acrocephalosyndactytly
Type I Apert syndrome
Type II Vogt cephalosyndactyly
Type III Saethre-Chotzen syndrome
Type IV Waardenburg syndrome
Type V Pfeiffer syndrome
34
Table 2. Anorectal Anomalies in Acrocephalosyndactyly
1. Blank CE13 (1960): Apert syndrome and ectopic anus
2. Cohen MM14 (1975): Pfeiffer syndrome and ectopic anus
3. Ohashi H15 (1993): Pfeiffer syndrome and imperforate anus
4. Pfeiffer RA16 (1996): Unclassified type and anal stenosis
REFERENCES
1. Escobar V, Bixler D: On the classification of he acrocephalosyn-
dactyly syndrome. Clin Genet 12:169-178, 1977
2. Kaplan LC: Clinical assessment and multispecialty management
of Apert syndrome. Clin Plast Surg 18:217-225, 1991
3. Cohen MM Jr, Keiborg S: Pfeiffer syndrome update, clinical
subtypes, and guidelines for differential diagnosis. Am J Med Genet
45:300-307, 1993
4. Endo M, Hayashi A, Ishihara M, et al: Analysis of 1992 patients
with anorectal malformations over the past two decades in Japan.
J Pediatr Surg 34:435-441, 1999
5. Peña A, Devries PA: Posterior sagittal anorectoplasty: Important
technical consideration and new applications. J Pediatr Surg 17:796-
811, 1982
6. Apert E: De L’acrocephalosindactylie. Bull Soc Med Paris 23:
1310-1330, 1906
7. Wilkie AOM, Slaney SF: Apert syndrome results from localized
mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet
9:165-172, 1995
8. Slaney SF, Oldridge M: Differential effects of FGFR2 mutations
on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet
58:923-932, 1996
9. Pfeiffer RA: Dominant erbliche Akrocephalosyndaktylie. Z
Kinderheik 90:301-320, 1964
10. Schell U, Hehr A: Mutations in FGFR1 and FGFR2 cause
familial and sporadic Pfeiffer syndrome. Hum Mol Genet 4:323-328,
1995
11. Rutland P, Pulleyn LJ: Identical mutations in the FGFR2 cause
both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet 9:173-176,
1995
12. Cohen MM Jr: Visceral anomalies in the Apert syndrome. Am J
Med Genet 45:758-760, 1993
KODAKA ET AL
Therefore, some anorectal anomalies for which ge-
netic analysis is undertaken would have FGFR gene
mutations. The relationship between anorectal anomaly
and FGFR gene is not clear now, but it might be clarified
in the future.
13. Blank CE: Apert’s syndrome (a type of acrocephalosyndactyly-
observations on a British series of thirty-nine cases. Ann Hum Genet
(London) 24:151-164, 1960
14. Cohen MM: An etiologic overview of craniosynostosis syn-
dromes. Birth Defects XI OAS 2:137-189, 1975
15. Ohashi H: Anorectal anomaly in Pfeiffer syndrome. Clin Dys-
morph 2:28-33, 1993
16. Pfeiffer RA: Asymmetrical coronal synostosis, cutaneous syn-
dactyly of the fingers and toes, and jejunal atresia in a male infant.
Am J Med Genet 63:175-176, 1996
17. Park WJ, Meyers GA, Li X, et al: Novel FGFR2 mutations in the
Crouzon and Jack-Weiss syndromes show allelic heterogeneity and
phenotypic variability. Hum Mol Genet 4:1229-1233, 1995
18. Akai T, Iizuka H, Kishibe M, et al: A case of Beare-Stevenson
cutis gyrata syndrome confirmed by mutation analysis of fibroblast
growth factor receptor 2 gene. Pediatr Neurosurg 37:97-99, 2002
19. Flanagan N, Boyadjiev SA, Harper J, et al: Familial craniosyn-
ostosis, anal anomalies, and porokeratpsis: CAP syndrome. J Med
Genet 35:763-766, 1998
20. Murgue B, Tsunelkawa S, Rosenberg I, et al: Identification of a
novel variant form of fibroblast growth factor receptor 3 (FGFR2 IIIb)
in human colonic epithelium. Cancer Res 54:5206-5211, 1994
21. Takaishi S, Sawada M, Morita Y, et al: Identification of a novel
alternative splicing of human FGF receptor 4: solubule-form splice
variant expressed in human gastrointestinal epithelial cells. Biochem
Biophys Res Commun 267:658-662, 1994
22. Yoneda A, Wang Y, O’Brian DS, et al: Cell-adhesion molecules
and fibroblast growth factor signaling in Hirschsprung’s disease. Pedi-
atr Surg Int 17:299-303, 2001