Kabuki Syndrome and Anorectal Malformations: Implications for Diagnosis and Treatment

Abstract

Kabuki syndrome (KS) is a rare genetic condition characterized by a distinctive facies, intellectual disability, growth delay, and a variety of skeletal, visceral, and other anomalies, including anorectal malformations (ARMs). We present two cases of female patients with KS, diagnosed and successfully managed at our institution, one with a perineal fistula and one with a rectovestibular fistula. Our report, along with a literature review, shows that the syndrome is usually associated with "low" anomalies, with a potential for a good prognosis. Management of the anorectal anomaly in patients with KS is not essentially different from that in other nonsyndromic patients, taking into account the frequent association of the syndrome with serious congenital heart disease, which might affect the decision-making and timing of the stages of anorectal reconstruction. The frequent occurrence of learning and feeding difficulties makes establishment of toilet training and bowel management rather more challenging, requiring the expertise of a multidisciplinary team. The finding of ARMs in female patients with other characteristics of KS, although inconstant, could support the clinical suspicion for the syndrome until genetic confirmation is available, and should alert the physician for the potential of severe cardiac defects.

Full text

Kabuki Syndrome and Anorectal Malformations :
Implications for Diagnosis and Treatment
Sotirios Siminas
1
Colin Tennant Baillie
2
Richard Turnock
2
1
Depar tment of Paediatric Surger y and Urology, Manchester
Children's Hospital, Manchester, United Kingdom
2
Paediatric Surgery Department, Alder Hey Children's Hospital,
Liverpool, United Kingdom
Eur J Pediatr Surg Rep 2015;3:54–58.
Address for correspondence Sotirios Siminas, MD, PhD, FEBPS,
Depar tment of Paediatric Surgery and Urology, Manchester Children's
Hospital, O xford Road, Manchester M13 9WL, United Kingdom
(e-mail: siminas1@gmail.com).
Introduction
Kabuki syndrome (KS) is a rare genetic condition characterized
by clinical variability and genetic heterogeneity, whose molec-
ular basis was only recently identified.
1
Niikawa and Kuroki in
1981 first described the constellation of a distinctive facies,
intellectual disability, growth delay, and a variety of skeletal,
visceral, and other malformations.
2
The syndrome derives its
name from the resemblance of the patient's facies to the
makeup of the actors of the Japanese dance-drama theater
Kabuki. Although literature review as well as our own experi-
ence, shows that the syndrome is most frequently related with
anorectal anomalies of favorable prognosis, the association
with major congenital heart defects and other anomalies,
makes short- and long-term management challenging. We
present two cases of patients with KS treated in our institution
with emphasis on the anorectal aspects of the syndrome.
Case 1
The patient was referred to us at the 22nd day of life and was
noted to have a perineal fistula and groove and an anal index
of less than 0.35. She was born prematurely at 32 weeks of
gestation and was also diagnosed with pulmonary ar tery
stenosis and multiple other congenital anomalies (
►Table 1).
KS was clinically suspected initially by the characteristic
facies and the constellation of other a nomalies and eventually
confirmed, when the tests became available by demonstrat-
ing the introduction of a premature stop mutation in the
MLL2 gene (MLL2/KMT2D MIM# 602113). Her stenotic anus
Keywords
► Kabuki syndrome
► anorectal
malformations
► chromosomal
abnormalities
Abstract
Kabuki syndrome (K S) is a rare genetic condition charac terized by a distinctive facies,
intellectual disabilit y, grow th delay, and a variet y of skeletal, visceral, and other
anomalies, including anorec tal malformations (ARMs). We present t wo cases of female
patients with K S, diagnosed and successfully managed at our institution, one with a
perineal fistula and one with a rec tovestibular fistula. Our report, along with a literature
review, shows that the syndrome is usually associated with “low ” anomalies, with a
potential for a good prognosis. Management of the anorec tal a nomaly in patients with
KS is not essentially different f rom that in other nonsyndromic patients, taking into
account t he frequen t association of the syndrome with se rious congenital hear t disease,
which might affect the decision-making and timing of the stages of anorectal
reconstruction. The frequent occurrence of learning and feeding difficulties makes
establishment of toilet training and bowel management rather more challenging,
requiring the exper tise of a multidisciplinary team. The finding of ARMs in female
patients with other charac teristics of KS, although in constant, could support the clinical
suspicion for the syndrome until genetic confirmation is available, and should alert the
physician for the potential of severe cardiac defects.
received
November 10, 2014
accepted af ter revision
February 2, 2015
published online
May 28, 2015
DOI http://dx.doi.org/
10.1055/s-0035-1547529.
ISSN 2194-7619.
© 2015 Georg Thieme Verlag KG
Stuttgart · New York
Case Report
THIEME
54

was initially treated with dilatat ions (starting from a Hegar
no. 9) that allowed for b owel decompression and was started
on stool softeners (lactulose) from the 1st month of life, while
being followed regularly in the anorectal clinic. Spinal ultra-
sound early in neonatal li fe revealed no structural abnormal-
ities of the caudal spine. Af ter dilatations reached a caliber of a
Hegar no. 12 at the age of 1 year, they were di scontinued. At
the age of 1.5 years and after undergoing cardiac surgery, we
performed anal sphincter mapping un der anesthetic which
showed that although the posi tion of the fistula-anus, based
on the anal index was rather anterior, approximately three
quadrants of the fistula were passing through the external
sphinc ter. An on-table contrast enema showed absence of
megarectum, and a decision was made to manage the ano-
rectal anomaly conservatively, given the lack of retentive
symptoms. She has been regularly followed up, and at the
last clinic vi sit (4-years-old) she was doing very well, being
entirely toilet trained and requiring regular use of small doses
of oral and rectal laxatives.
Case 2
The patient was first seen by us at the age of 4 months due to
an imperforate an us with a rec tovestibular fistula. She was
born as one of the twins at 35 weeks of gestation and was soon
diagnosed with a large atrioventricular septal defect and
patent ductus arteriosus which caused in tractable heart
failure for which she eventually required cardiac surgery.
She was al so found to have other multiple congenital anoma-
lies (
►Table 1). Spinal ultrasound early in neonatal life
revealed no structural abnormalities of the caudal spine. As
per the institutional practice from the referring center, sh e
was initially managed with rectal washouts through the
fistula, in view of a primary definite repair after stabilization
of the cardiac condition. Following the cardiac surgery, she
underwent a posterior sagittal anorectoplasty with covering
sigmoidostomy at the age of 9 months. Following the genetic
review, the constellation of her anomalies was attributed to
KS, mainly based on the characteristic facies associated with
the syndrome and was later confirmed after genetic testi ng
demonstrating anomalies in the MLL2 gene. After dilating her
anus to a Hegar no. 13, the colostomy was closed and the
patient was followed up in the anorectal clinic for bowel
management. At the time of the last follow-up (3.5 years of
age), she had a good functional result with frequent bowel
motions and occasional only use of laxatives, having s tarted
toilet training.
Discussion
The two cases highlighted he re, as well as a literature
review
2–7
(►Table 2) show that wh en K S is associated with
anorectal malformations (AR Ms), the af fected patients are
females and the ARM type is either a rectovesti bular or a
rectoperineal fistula, both considered to have a good func-
tional prognosis. As some of the reviewed articles were
published before the Krickenbeck consensus, the terms
used to desc ribe the anomalies vary, and some of the older
cases were described as anterior stenotic anus.
KS is a rare disease, with estimates of prevalence ranging
from 1 to 32,000 for Japanese children and 1 to 86,000 for
Australian and New Zealand children.
1
In 2010, mutations in
Table 1 Constellation of anomalies in the repor ted patients
Pat ient 1 Patient 2
Face Kabuki facies (ear malformations, epicanthus)
Diversion squint in right eye
Facies, natal teeth
Musculoskeletal Congenital hip dysplasia: Surgery
Bilateral polydact yly of feet
Congenital hip dysplasia
Cranium Trigonocephaly: Surger y Plagiocephaly
Cognitive Mild learning difficulties Learning dif ficulties
Anorectal Anterior anus and perineal groove Anovestibular fistula decompressing through fistula
though—dilatations—washouts
Surgery Sphincter mapping—dilatations—table-
contrast enema: No megarectum
PSARP þ colostomy and colostomy closure (8 wks)
Urogenital Bilateral duplex kidney—vesicoureteral reflux
Cardiac Pulmonary stenosis and patent duc tus arteriosus
Surgery at the age of 1 y
Fallot tetralogy—double outlet right ventricle—surgery
Other GI Feeding dif ficulties
Gastroesophageal reflux
Spinal US: N ormal
Others Prematurit y 32/40 w Twin, premature, 35/40 w
Hypotonia
Management Dilatations
Laxatives
Preoperative and postoperative dilatations
Laxatives
European Jour nal of Pediatr ic Surger y Report s Vol. 3 No. 1/ 2015
Anorectal Malformations in Kabuki Syndrome Simi n as et a l . 55

the gene KMT2D (MLL2 )wereidentified as the major genetic
cause for the dise ase in 56 to 75% of the patients affec ted.
8
Other mutations have also been identified in the gene KDM6A
(UTX),
9
but almost 30% of the patients with the syndrome
have no recognizable genetic anomaly identified.
1
The main-
stay of diagno sis is the typical facial gestal t wit h long palpe-
bral fissures, eversion of the lower eyelid, arched eyebrows,
short columella, thin upper lip, slanted downward mouth
corners, and sometimes prognathism. Other maxillofacial
anomalies include cleft lip and palate (12–50%), dentition
anomalies (53–100%), and craniosynostosis. Failure to thrive
due to feeding difficulties has been docum ented in 65 to 74%
of the patients, with short stature in approximately 58%.
Learning difficulties are rather the rule than the exception,
with more than 90% of the patien ts having some form of
impairment. Other anomalies include a variety of skeletal
malformations (more than 80%, vertebral anomalies or scoli -
osis, brachydactyly, or clinodactyly), ocular anomalies (38–
61%), endocrine disorders (early brea st development the
most common), cardiac defects (40–50%, most common atrial
septal defect– ventr icular septal defect), urogenital anomalies
in 30 to 40% (hydronephrosis and ectopia), hearing loss, and
susceptibility to middle ear infections. Characteristic features
are also the presence of persistent fetal finger pa ds (up to 92%)
and abnormalities of the dermatoglyphic pattern. The syn-
drome has also been associated with a variety of autoimmune
disorders a nd malignancy (medulloblastoma, non-Hodgkin
lymphoma), and a susceptibility to respiratory infections is
well documented.
1,2,6
The association with ARMs is estimat-
ed to be around 7%.
3
The management of the anorectal
anomaly in patien ts with KS is not essentially different
from that in other nonsyndromic patients, but one must
take into account the frequent association of the syndrome
with serious congenital heart disease, which might af fect the
decision-making and timing of the stages in anorectal recon-
struction. A major cardiac defec t might warrant surgical
treatment before definite anorectal reconstruction, and in
these instances, dilatations of the perineal fistula or a decom-
pressing colostomy might prove useful. The frequent occur-
rence of learning and feed ing difficulties make the
establishment of toilet training and bowel management
rather mo re challenging. The importance of a mult idisciplin-
ary team in the management of these complex patients
cannot be overemphasized. The fact though that these anom-
alies are usually in the mild end of the ARM spectrum offer a
good anorectal funct ional prognosis, as was the case for ou r
two patients.
The association of spe cific syndromes with specific types
of ARMs is well documented, as in the case of trisomy 21
linked with anomalies wi thout fistula,
10
or Currarino syn-
drome presenting with a perineal fistula or f unnel anus,
10,11
while other syndromes or chromosomal anomalies do not
Table 2 Repor ted cases with Kabuki syndrome in the literature
S. no. Author (Y) Type of ARM Surger y Other anomalies
1 Matsumura et al (1992)
3
Vestibular fistula Anal transposition
a
Cleft palate, A SD, webbed neck, renal
anomalies, long great toes
2 Matsumura et al (1992)
3
Vestibular fistula Anal transposition
a
Cleft palate, VSD, aortic an eurysm,
horse -shoe kidney, bifi d renal pelv is,
pigmented r etina, abnormal E EG
3 Matsumura et al (1992)
3
Vestibular fistula “Cut-back” procedure
b
Autism, retardation in bone age
4 Matsumura et al (1992)
3
Vestibular fistula Anal transposition
b
Renal agenesis, hip dysplasia, retarda-
tion in bone age, VSD
5 Philip et al (1992)
4
Vestibular fistula PSARP N/A
6 Kokitsu-Nakata et al (1999)
5
Vestibular fistula Bowel management Facies, g rowth retardation, cleft palate,
ectopic right kidney, finger anomalies
7 Kawame et al (1999)
6
Perineal fistula PSARP N/A
8 Abdel-Salam et al (2008)
7
Vestibular fistula PSARP Diaphragmatic defect, co ngenital
heart d efects, c lef t palate, lower lip
pits, hypopigmentation, seizures,
hyperlaxity of j oints and premature
breast development
9 Present study Perineal fistula Bowel management Fa cies, hip dysplasia, trigonocephaly,
finger anomalies, pulmonar y arter y
stenosis, learning dif ficulties
10 Present study Vestibular fistula PSARP Facies, hip dysplasia, plagiocephaly,
Fallot tetralogy, dup lex k idneys, hypo-
tonia, learning dif ficulties
Abbreviation: PSARP, posterior sagittal anorectoplasty.
Note: All patients studied are females.
a
Procedure listed as described by reporting authors, although terms do not reflect current nomenclature. Most li kely term: anterior sagittal approach.
b
Procedure listed as described by reporting authors, although terms do not reflect current nomenclature. Most likely term: perineal operation—anoplasty.
European Journa l of Pediatric Surger y Reports Vol. 3 No. 1/2015
Anorectal Malformations in Kabuki Syndrome Siminas et a l.56

follow a set pattern. Due to the rarity of the disease and the
rather infrequent association with ARMs, it is uncertain
whether KS follows such a pattern, although all reported
cases represent ARM at the mild end of the spectrum, which
could be associated with good prognosis, provided there are
no other risk factors of a poor outcome (dysraphic anomalies,
severe developmental delay). The etiopathogenesis of this
association, and of the occurrence in females in the reported
cases, is yet unclear due to the limited knowledge regarding
the gene transcription regulated by the KMT2D complex
duri ng embryogenesis.
In conclusion, our data, along with data from the literature,
show that the finding of ARMs in female patients with other
characteristics of K S, although inconstant, could support the
clinical suspicion for the syn drome until genet ic confirmation
is available, although pediatric surgeons should be aware of
the high probability of serious cardiac defects.
Con flict of Interest
None.
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