Download Cancer Prone Disease Section Beckwith-Wiedemann syndrome Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Cancer Prone Disease Section
Mini Review
Beckwith-Wiedemann syndrome
Marcel Mannens
DNA-diagnostics laboratory, University of Amsterdam, Academic Medical Center Department of Clinical
Genetics PO Box 22700 1100 DE Amsterdam, the Netherlands (MM)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/BeckwithWiedemannID10037.html
DOI: 10.4267/2042/37714
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Clinics
Alias
Exomphalos-macroglossia-gigantism triad
Inheritance
Incidence of 7/105; given the variable expression of the
symptoms, the actual frequency is likely to be higher;
generally there is sporadic occurrence of the syndrome
(85%); inheritance is mostly maternal (imprinting) with
a more severe phenotype after maternal transmission.
Note
Clinically and genetically heterogeneous; three distinct
regions on 11p15 have been associated with BWS
(BWSCR1/2/3); BWSCR2 seems to be particularly
associated with hemihypertrophy.
Phenotype and clinics
Multiple features that occur variably; most prominent is
the EMG triad (exomphalos-macroglossia-gigantism):
apart from the abdominal wall defects and pre- and
postnatal growth abnormalities, earlobe pits or creases,
facial nevus flammeus, hypoglycemia, renal
abnormalities
and
hemihypertrophy
(unilateral
overgrowth) are frequently seen.
Patient with Beckwith-Wiedemann syndrome. The face shows the enlarged tongue (macroglossia), the ear the typical earlobe creases Marcel Mannens.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
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Beckwith-Wiedemann syndrome
Mannens M
Neoplastic risk
Protein
Description: Untranslated.
Expression: Highly expressed in endodermal and
mesodermal embryonic tissues; in adult brain, only in
the pons and globus pallidus; in adult tissues,
expression is primarily confined to skeletal and cardiac
muscle; other tissues are down-regulated postnatal but
re-expressed in tumours that express the gene during
embryogenesis.
Function: Putative tumour suppressor; proposed
regulatory function for IGF2 expression (under debate).
Mutations
Germinal: Hypermethylated in 10-20% of sporadic
BWS cases; familial transmission unclear yet; loss of
imprinting (LOI) can be induced in deletion mouse
models.
Somatic: Hypermethylated in 10-20% of sporadic BWS
cases mostly somatic events due to UPD in mosaic
form; LOI in tumours.
The increased risk for childhood solid tumours is 7.5%
(thousand fold increase); tumours most frequently seen
are nephroblastoma (Wilms tumour), adrenocortical
carcinoma, rhabdomyosarcoma and hepatoblastoma;
clinical risk factors are hemihypertrophy and
nephromegaly; genetic risk factors are uniparental
disomy (UPD) and H19/IGF2 imprinting defects.
Treatment
In general surgical correction of the abdominal wall
defects and macroglossia; monitoring the glycemia
during the first 3 days and early treatment of
hypoglycemia (deleterious for central nervous system)
is of importance to avoid further complications;
frequent screening for tumour development.
Prognosis
Clinical features tend to become less with ageing;
tumour risk decreases strongly after the 4-7th year of
birth.
IGF2 (insulin-like growth factor 2
(somatomedin A))
Cytogenetics
Alias: IGF-II, somatomedin A, Hs.75963
Location: 11p15.5
DNA/RNA
Transcription: 1356 bp mRNA, paternally expressed,
maternal imprint.
Protein
Description: 180 amino acids, 20,14 kDa
(unprocessed).
Expression: IGF2 has the highest levels of expression
in tissues that are affected by prenatal overgrowth in
BWS; the main source of expression is liver;
expression depends on promoter usage; P1 is
exclusively active in adult liver, whereas P3 and P4
exert their action in liver prenatal; P2 is only active in
certain tumour cell lines.
Localisation: Secreted.
Function: Embryonal growth factor, mitogen.
Homology: Belongs to the insulin/IGF/relaxin family.
Mutations
Germinal: Hypomethylated; LOI in sporadic BWS
cases; familial transmission unclear yet; BWS
phenotype can be induced in igf2 overexpressing
mouse models.
Somatic: Hypomethylated, LOI in sporadic BWS cases;
mostly somatic events due to UPD in mosaic form; LOI
in tumours.
Inborn conditions
Paternal duplications of chromosome region 11p15,
maternal translocations involving chromosome region
11p15.3-p15.5.
Cytogenetics of cancer
Apart from chromosome 11 aberrations, multiple
chromosomes are involved in tumour development;
promising prognostic indicators in Wilms tumour might
be chromosome 1p and 16q aberrations; tther molecular
abnormalities associated with an adverse outcome in
Wilms tumour are 22q allele loss or P53 aberrations.
Other findings
Note
In 10-20% of BWS cases, uniparental disomy of
chromosome region 11p15 is seen, mostly in a mosaic
form.
Genes involved and proteins
H19
Alias: D11S813E, D11S878E, ASM, ASM1
Location: 11p15.5
Note
Imprinted, maternally expressed, untranslated mRNA.
DNA/RNA
Description: The human H19 gene is 2.7 kb long and
includes 4 small introns; maternally expressed, paternal
imprint.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
CDKN1C (cyclin-dependent kinase
inhibitor 1C)
Alias: KIP2, P57KIP2, P57, CDKN5
Location: 11p15.5
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Beckwith-Wiedemann syndrome
Mannens M
ZNF215
DNA/RNA
Description: 1511 bp messenger, preferentially
maternally expressed (paternal imprint).
Protein
Description: 316 amino acids; 32,177 kDa, CDK
inhibitory domain, PAPA repeat, conserved C-terminal
domain.
Expression: It is expressed in the heart, brain, lung,
skeletal muscle, kidney, pancreas and testis; high levels
are seen in the placenta, low levels in liver.
Localisation: Nuclear.
Function
Summary: Cyclin-dependent kinase inhibitor 1C is a
tight-binding inhibitor of several G1 cyclin/Cdk
complexes and a negative regulator of cell
proliferation; mutations of CDKN1C are implicated in
sporadic cancers and Beckwith-Wiedemann syndrome
suggesting that it is a tumour suppressor candidate; in
BWS however, no evidence for tumour association was
found.
Homology: p21CIP1 CdK inhibitor gene family.
Mutations
Germinal: Mostly maternal, nucleotide substitutions,
small deletions.
Somatic: CDKN1C mutations are described in tumour
formation; mouse mutation-models reveal part of the
BWS phenotype in particular the abdominal-wall
defects.
Alias: zinc finger protein 215, BAZ2
Location: 11p15.4
DNA/RNA
Description: mRNA of 3480 bp, 9 exons, at least 5
splice variants; exon 9 runs antisense of a second gene:
ZNF214.
Transcription: Imprinted in a tissue specific manner,
the maternal allele being preferentially expressed.
Protein
Description: 517 amino acids, 60,048 kDa; KRABA
domain; similarities to a KRABB domain; SCAN box;
nuclear localisation signal KKKR; 2 x 2 zinc-fingers.
Expression: Widely expressed at low levels; expression
is highest in testis; splice variants of ZNF215 show
tissue specific expression.
Localisation: Nuclear.
Function: Putative transcription factor; ZNF215 was
cloned from a region associated with hemihypertrophy,
cardiac abnormalities, Wilms tumour and minor BWS
features; as such the gene might be responsible for a
distinct phenotype in BWS.
Homology: Belongs to the Krueppel family of C2H2type zinc finger proteins.
Mutations
Germinal: Various amino acids substitutions found in
BWS / hemihypertrophy patients; causal relationship
with phenotype unclear.
Somatic: In tumours no mutations found so far.
KCNQ1OT1 (KCNQ1 overlapping
transcript)
References
Alias: KCNQ1 overlapping transcript 1, LIT1,
KvDMR1, KvLQT1-AS, Long QT intronic transcript 1
Location: 11p15.5
DNA/RNA
Description: Maternally imprinted gene, > 80 kb RNA.
Transcription: Intronic transcript 1, embedded in intron
9 (and 10) of KCNQ1, in opposite orientation;
expressed in most human tissues and from the paternal
allele, the maternal allele being imprinted through a
specific methylation of a CpG island; abnormally
expressed in patients with Beckwith-Wiedemann
syndrome, independently of IGF2 imprinting; no
abnormal imprinting in Wilms tumour.
Protein
Expression: Untranslated.
Function: Unknown; it is postulated that KCNQ1OT1
might influence the expression of nearby imprinted
genes such as CDKN1C or IGF2/H19.
Mutations
Germinal: Aberrant methylation in 50-80% of BWS
patients not always 100% (might be due to UPD in
some cases); inheritance unclear.
Somatic: Unclear; there is no association between
aberrant methylation and tumour development.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
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Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Mannens M. Beckwith-Wiedemann syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(1):62-65.
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