Kabuki syndrome and cancer in two patients
ABSTRACT Both hepatoblastoma and neuroblastoma are occasionally associated with congenital syndromes such as Beckwith–Wiedemann syndrome and trisomy 18. There have been no reports of hepatoblastoma in patients with Kabuki syndrome, whereas one patient with neuroblastoma and this syndrome has been reported. In this paper we present two patients with Kabuki syndrome and a neoplasm: a child of 6 years with hepatoblastoma and an infant, of 6 months affected by neuroblastoma. © 2010 Wiley-Liss, Inc.
- SourceAvailable from: David Geneviève[show abstract] [hide abstract]
ABSTRACT: Kabuki syndrome (KS) is a rare, clinically recognisable, congenital mental retardation syndrome. The aetiology of KS remains unknown. Four carefully selected patients with KS were screened for chromosomal imbalances using array comparative genomic hybridisation at 1 Mb resolution. In one patient, a 250 kb de novo microdeletion at 20p12.1 was detected, deleting exon 5 of C20orf133. The function of this gene is unknown. In situ hybridisation with the mouse orthologue of C20orf133 showed expression mainly in brain, but also in kidney, eye, inner ear, ganglia of the peripheral nervous system and lung. The de novo nature of the deletion, the expression data and the fact that C20orf133 carries a macro domain, suggesting a role for the gene in chromatin biology, make the gene a likely candidate to cause the phenotype in this patient with KS. Both the finding of different of chromosomal rearrangements in patients with KS features and the absence of C20orf133 mutations in 19 additional patients with KS suggest that KS is genetically heterogeneous.Journal of Medical Genetics 10/2007; 44(9):562-9. · 5.70 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: PHOX2B is a homeodomain-containing protein that is involved in the development of the peripheral nervous system and is the major disease gene for the rare congenital breathing disorder congenital central hypoventilation syndrome (CCHS). Germline PHOX2B alterations were also recently discovered in neuroblastoma cases with CCHS and/or Hirschsprung disease, but a comprehensive survey for mutational frequency and functional consequence has not been performed. We therefore studied a large panel of hereditary neuroblastomas to understand the frequency and functional effects of PHOX2B mutations. Three of 47 individuals with presumed genetic predisposition to neuroblastoma showed a germline PHOX2B mutation (6.4%). Mutations were also discovered in 2 of 30 human neuroblastoma-derived cell lines, but none of 86 primary tumors from patients with sporadically occurring neuroblastoma. The vast majority of primary tumors showed abundant PHOX2B mRNA expression relative to the remainder of the transcriptome. Consistent with its role as an important neurodevelopmental gene, forced overexpression of wild-type PHOX2B in neuroblastoma cell lines suppressed cell proliferation and synergized with all-trans retinoic acid to promote differentiation. Patient-derived mutant PHOX2B constructs retained the ability to suppress cellular proliferation, but were not able to promote differentiation or activate expression of a known PHOX2B target gene in vitro. These findings show that PHOX2B alterations are a rare cause of hereditary neuroblastoma, but disruption of this neurodevelopmental pathway can interfere with transcription-dependent terminal differentiation. These data also suggest that the genetics of neuroblastoma initiation are complex, and highlight genes involved in normal noradrenergic development as candidate predisposition genes.Oncogene 02/2008; 27(4):469-76. · 7.36 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: BACKGROUND As part of the international cooperative effort to develop a complete set of International Neuroblastoma Risk Groups, the International Neuroblastoma Pathology Committee (INPC) initiated activities in 1994 to devise a morphologic classification of neuroblastic tumors (NTs; neuroblastoma, ganglioneuroblastoma, and ganglioneuroma).METHODS Six member pathologists (H.S., I.M.A., L.P.D., J.H., V.V.J., and B.R.) discussed and defined morphologically based classifications (Shimada classification; risk group and modified risk group proposed by Joshi et al.) on the basis of a review of 227 cases, using various pathologic characteristics of the NTs. The classification-grading system was evaluated for prognostic significance and biologic relevance.RESULTSThe INPC has adopted a prognostic system modeled on one proposed by Shimada et al. It is an age-linked classification dependent on the differentiation grade of the neuroblasts, their cellular turnover index, and the presence or absence of Schwannian stromal development. Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor). Specific features, such as the mitosis-karyorrhexis index, the mitotic rate, and calcification, were also included to allow the prognostic significance of the classification to be tested. Recommendations are made regarding the surgical materials to use for an optimal pathobiologic assessment and the practical handling of samples.CONCLUSIONS The current article covers the essentials and important points regarding the histopathologic evaluation of NTs. Using the morphologic criteria described herein, the INPC is proposing the International Neuroblastoma Pathology Classification. It is reported in a companion article in this issue (Cancer 1999;86:363–71). Cancer 1999;86:349–63. © 1999 American Cancer Society.Cancer 07/1999; 86(2):349 - 363. · 5.20 Impact Factor
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.
Adam MP, Hudgins L. 2004. Kabuki syndrome: A review. Clin Genet
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the international criteria for neuroblastoma diagnosis, staging, and
response to treatment. J Clin Oncol 12:1991–1993.
Di Cataldo A, Haupt R, Fabietti P, Schilir? o G. 1996. Is intensive follow-up
for early detection of tumors effective in children with Beckwith-Wie-
demann syndrome? Clin Genet 50:372–374.
Gripp KW. 2005. Tumor predisposition in Costello syndrome. Am J Med
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Ijichi O, Kawakami K, Matsuda Y, Ikarimoto N, Miyata K, Takamatsu H,
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4AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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Softproofing for advanced Adobe Acrobat Users - NOTES tool
NOTE: ACROBAT READER FROM THE INTERNET DOES NOT CONTAIN THE NOTES TOOL USED IN THIS PROCEDURE.
Acrobat annotation tools can be very useful for indicating changes to the PDF proof of your article.
By using Acrobat annotation tools, a full digital pathway can be maintained for your page proofs.
The NOTES annotation tool can be used with either Adobe Acrobat 4.0, 5.0 or 6.0. Other
annotation tools are also available in Acrobat 4.0, but this instruction sheet will concentrate
on how to use the NOTES tool. Acrobat Reader, the free Internet download software from Adobe,
DOES NOT contain the NOTES tool. In order to softproof using the NOTES tool you must have
the full software suite Adobe Acrobat 4.0, 5.0 or 6.0 installed on your computer.
Steps for Softproofing using Adobe Acrobat NOTES tool:
1. Open the PDF page proof of your article using either Adobe Acrobat 4.0, 5.0 or 6.0. Proof
your article on-screen or print a copy for markup of changes.
2. Go to File/Preferences/Annotations (in Acrobat 4.0) or Document/Add a Comment (in Acrobat
6.0 and enter your name into the “default user” or “author” field. Also, set the font size at 9 or 10
3. When you have decided on the corrections to your article, select the NOTES tool from the
Acrobat toolbox and click in the margin next to the text to be changed.
4. Enter your corrections into the NOTES text box window. Be sure to clearly indicate where the
correction is to be placed and what text it will effect. If necessary to avoid confusion, you can
use your TEXT SELECTION tool to copy the text to be corrected and paste it into the NOTES
text box window. At this point, you can type the corrections directly into the NOTES text
box window. DO NOT correct the text by typing directly on the PDF page.
5. Go through your entire article using the NOTES tool as described in Step 4.
6. When you have completed the corrections to your article, go to File/Export/Annotations (in
Acrobat 4.0) or Document/Add a Comment (in Acrobat 6.0).
7. When closing your article PDF be sure NOT to save changes to original file.
8. To make changes to a NOTES file you have exported, simply re-open the original PDF
proof file, go to File/Import/Notes and import the NOTES file you saved. Make changes and re-
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.