Kabuki Syndrome and Cancer in Two Patients
Loredana Amoroso,5Roberta Catania,1Monica Pennisi,6Salvatore D’Amico,1and Andrea Di Cataldo1*
1Unit of Pediatric Hematology/Oncology, Department of Pediatrics, University of Catania, Catania, Italy
3Unit of Pediatric Genetic and Immunology, University of Messina, Messina, Italy
4Liver and Multiorgan Transplant Unit, University of Modena and Reggio Emilia, Modena, Italy
5Department of Hematology/Oncology, Gaslini Children’s Hospital, Genova, Italy
6Unit of Radiology, University of Catania, Catania, Italy
Received 10 September 2009; Accepted 29 January 2010
Both hepatoblastoma and neuroblastoma are occasionally asso-
syndrome and trisomy 18. There have been no reports of hep-
atoblastoma in patients with Kabuki syndrome, whereas one
patient with neuroblastoma and this syndrome has been re-
ported. In this paper we present two patients with Kabuki
and an infant, of 6 months affected by neuroblastoma.
? 2010 Wiley-Liss, Inc.
Key words: kabuki syndrome; hepatoblastoma; alpha fetopro-
Kabuki syndrome (KS), known as Kabuki make-up syndrome or
as a rare disorder of unknown cause with characteristic facies,
postnatalgrowth retardation, mental retardation and other anom-
alies [Niikawa et al., 1988]. Most patients have five cardinal
tip and prominent ears; (2) skeletal anomalies, including brachy-
dactyly, and spinal deformity with or without sagittal cleft verte-
in patients with KS features, the absence of molecular abnormalit-
ies is not a reason to exclude the diagnosis when the typical
clinical picture is present [Adam and Hudgins, 2004]. Although
the observation of some parents presenting mild features of the
rence of KS is usually sporadic and its etiology is unknown [Adam
and Hudgins, 2004].
Hepatoblastoma (HB) is the most common pediatric liver
malignancy and constitutes 1% of all pediatric cancers. Cases of
hepatoblastoma associated with Beckwith-Wiedemann syndrome
and other congenital syndromes as familial adenomatous polypo-
sis, Li Fraumeni syndrome, trisomy 18 have been reported, but no
one with Kabuki syndrome [Schnater et al., 2003].
Neuroblastoma (NB), a neoplasm of the sympathetic nervous
system, is the second most common extracranial solid malignancy
NB or associated with neurofibromatosis 1, Hirschsprung disease
observed in a patient with KS [Merks et al., 2005].
We describe two KS patients respectively with the diagnosis of
HB and NB.
Andrea Di Cataldo, M.D., Unit of Pediatric Hematology and Oncology,
Department of Pediatrics, Via Santa Sofia 78, 95123 Catania, Italy.
Published online 00 Month 2010 in Wiley InterScience
How to Cite this Article:
Tumino M, Licciardello M, Sorge G, Cutrupi
MC, Di Benedetto F, Amoroso L, Catania R,
Pennisi M, D’Amico S, Di Cataldo A. 2010.
Kabuki syndrome and cancer in two patients.
Am J Med Genet Part A 9999:1–4.
? 2010 Wiley-Liss, Inc.
A 6-year-old boy was admitted in our Department of Pediatrics
with clinical features suggesting a syndrome. He was born at the
35th week of gestation with a weight of 2,710g and presented with
congenital hypothyroidism. Physical examination revealed broad
and arched eyebrows with sparseness, long palpebral fissures with
eversion of the lateral portion of lower lids, bilateral ptosis, iris
coloboma, ears with prominent lobules, small nose with depressed
tip and short columella, smooth philtrum, oval palate, microceph-
aly, hypotonia and joint laxity, prominent fingertip pads, mild
delay (Fig. 1). These clinical pictures were indicative of KS. No
cardiac abnormalities were found. Abdominal ultrasound was
performed and no renal abnormalities were found, whereas a mass
located in the right lobe of the liver, measuring 6cm as maximum
presence of the mass that showed contrast enhancement. Further-
(n.v. age-matched 3–14ng/ml). Finally, after a liver biopsy a fetal
type HB was diagnosed. No other localizations of disease were
found. The patient, after informed consent was signed, was treated
according to SIOPEL 3 protocol of the International Childhood
administratedwith strict renal monitoring, and obtaining a reduc-
tion of both tumor volume and AFP level. Late effects of treatment
was performed followed by two courses of cisplatin as adjuvant
chemotherapy. The child is in complete remission 2 years after the
end of treatment.
A 6-month-old girl was referred to our center since abdominal
ultrasound and CT showed a large, heterogeneous and lobulated
adrenal mass (Fig. 2) and a nodular hypodense lesion in the right
lobe liver. An increased urinary level of vanillymandelic (45mg/mg
four sites did not show tumor infiltration. Bone scintigraphy was
negative. After informed consent was signed by parents, a radical
surgical resection of the adrenal mass was performed and the
histology exam showedaNBwithfavorablecharacteristics accord-
ing to the International Neuroblastoma Pathology Committee
(INPC) classification [Shimada et al., 1999]. No MYCN oncogene
amplification was found in tumor cells. In conclusion it was a
stage 4s NB according to International Neuroblastoma Staging
System (INSS) classification [Brodeur et al., 1994], with neither
clinical nor biological risk factors, and no other treatment was to
be done. The girl is alive in complete remission 18 months after
The patient, who was born at 33rd week of gestation with a
history of prenatally diagnosed interatrial communication, right
ventricle hyperplasia and pulmonary valve stenosis and congenital
hypothyroidism, presented with many dysmorphic anomalies,
initially suggestive for Noonan syndrome. This was later excluded
by the mutational analysis of PTPN11 gene. Eventually KS-like
of the lateral portion of lower lids, broad arched eyebrows with
lateral sparseness,short columellawithdepressednasal tip, promi-
The array CGH (Agilent Human Genome CGH Microarray, kit
FIG. 1. Facial photograph of Patient 1: long palpebral fissures with
eversion of lateral portion of lower lids, depressed nasal tip,
prominent and cupped ears.
FIG. 2. ComputedtomographyofPatient2:intheleftretroperitoneal
space, near the upper kidney pole, a 3cm of diameter,
heterogeneous adrenal mass with mild enhancement after
injection of contrast medium.
2AMERICAN JOURNAL OF MEDICAL GENETICS PART A
affecting multiple organ system. The diagnosis of KS is clinical
[Adam and Hudgins, 2004], although it has been associated with
various chromosomal alterations, including 1p interstitial dupli-
6q deletion, 12q duplication, t(3p;10p), t(15q;17q) and 20p12.1
microdeletion [Maas et al., 2007]. Since its genetic heterogeneity,
there is no clinically available genetic test to confirm the diagnosis.
Thus, minimal diagnostic criteria have been described: long palpe-
bral fissures with eversion of lateral portion of lower lids, broad
arched eyebrows with lateral sparseness, short columella with
depressed nasal tip, prominent or cupped ears, developmental
delay and mental retardation [Adam and Hudgins, 2004]. In
cardiac malformations, genitourinary anomalies, gastrointestinal
defects, liver disease, endocrinopathies, immunodeficiency, sus-
ceptibility to autoimmune diseases[Kawame et al., 1999].As far as
the correlation with neoplasia is concerned, as further as we know,
only four cases have been described, one each with acute lympho-
blastic leukemia [Scherer et al., 2003], Burkitt lymphoma [Ijichi
et al., 1996], fibromyxoid sarcoma [Shahdadpuri et al., 2008] and
NB [Merks et al., 2005].
In our patients the diagnosis of KS was based on clinical features
belonging to minimal diagnostic criteria. Both presented with the
characteristic facies, growth and developmental delay, congenital
ital heart defect. They were diagnosed as having HB or NB. Both
tumors usuallyoccur sporadically, but familial cases have been de-
[Sanders and Furman, 2003], Beckwith-Wiedemann syndrome [Di
Cataldo et al., 1996], Li Fraumeni syndrome, trisomy 18, glycogen
storage disease type I [Schnater et al., 2003] and recently Noonan
syndrome[Mutesa et al.,2008;Yoshida et al.,2008] and neurofibro-
as Hirschsprung disease, congenital central hypoventilation syn-
drome and Costello syndrome [Gripp, 2005; Raabe et al., 2008].
Congenital anomalies particularly in children aged less than 1 year
have beendescribed [Munzer et al.,2008]. While there have beenno
with KS that developed NB.
Prognosis of patients affected by malignancies in association
with a syndrome is generally not different from sporadic cases, but
administration or surgical resection and, consequently, the
Therelationbetween KSandmalignancies remainsunclear.Itis
known that constitutional molecular defects play a role in onco-
genesis, as shown by the increase incidence of cancers in children
with many molecular defined syndromes. It is difficult to find the
correlation between KS and cancer development as KS remains
Although the number of reported cases about cancer develop-
ment in patients affected by KS remains small, we suggest that
KS in children should be carefully examined for malignancy.
Consequently, a regular clinical and echographic screening
could be proposed for KS patients, in order to detect the tumor
We wish to thank Mr. Giuseppe Auteri for secretarial work and
Ibiscus, Lega per la ricerca ed il trattamento della leucemia e dei
tumori del bambino, for funding.
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export NOTES file keeping the same file name.
9. When complete, attach your NOTES file to a reply e-mail message. Be sure to include your
name, the date, and the title of the journal your article will be printed in.