Beckwith-Wiedemann syndrome

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Beckwith-Wiedemann syndrome

Written	2000-11	Marcel Mannens
		DNA-diagnostics laboratory, University of Amsterdam, Academic Medical Center Department of Clinical Genetics PO Box 22700 1100 DE Amsterdam, the Netherlands

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Identity

Other names Exomphalos-macroglossia-gigantism triad
Atlas_Id 10037

Genes implicated in CDKN1C H19 ICR1 TGM1 IGF2 KCNQ1OT1 NSD1 ZNF215
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

Clinics

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

Neoplastic risk 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

Cytogenetics

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

Gene Name 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

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

Gene Name IGF2 (insulin-like growth factor 2 (somatomedin A))

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

Gene Name CDKN1C (cyclin-dependent kinase inhibitor 1C)

Alias KIP2, P57KIP2, P57, CDKN5

Location 11p15.5

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

Gene Name KCNQ1OT1 (KCNQ1 overlapping transcript)

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

Gene Name ZNF215

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 C2H2-type 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

Bibliography

Disruption of a novel imprinted zinc-finger gene, ZNF215, in Beckwith-Wiedemann syndrome.

Alders M, Ryan A, Hodges M, Bliek J, Feinberg AP, Privitera O, Westerveld A, Little PF, Mannens M

American journal of human genetics. 2000 ; 66 (5) : 1473-1484.

PMID 10762538

Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly.

Beckwith J

Birth Defects. 1969 ; 5 : 188-196.

Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry.

DeBaun MR, Tucker MA

The Journal of pediatrics. 1998 ; 132 (3 Pt 1) : 398-400.

PMID 9544889

Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases.

Elliott M, Bayly R, Cole T, Temple IK, Maher ER

Clinical genetics. 1994 ; 46 (2) : 168-174.

PMID 7820926

Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments.

Hoovers JM, Kalikin LM, Johnson LA, Alders M, Redeker B, Law DJ, Bliek J, Steenman M, Benedict M, Wiegant J, Lengauer C, Taillon-Miller P, Schlessinger D, Edwards MC, Elledge SJ, Ivens A, Westerveld A, Little P, Mannens M, Feinberg AP

Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (26) : 12456-12460.

PMID 8618920

Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting.

Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S, Oshimura M, Feinberg AP

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (9) : 5203-5208.

PMID 10220444

Molecular genetics of Wiedemann-Beckwith syndrome.

Li M, Squire JA, Weksberg R

American journal of medical genetics. 1998 ; 79 (4) : 253-259.

PMID 9781904

The Beckwith-Wiedemann syndrome phenotype and the risk of cancer.

Schneid H, Vazquez MP, Vacher C, Gourmelen M, Cabrol S, Le Bouc Y

Medical and pediatric oncology. 1997 ; 28 (6) : 411-415.

PMID 9143384

Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways.

Steenman M, Westerveld A, Mannens M

Genes, chromosomes & cancer. 2000 ; 28 (1) : 1-13.

PMID 10738297

[FAMILIAL MALFORMATION COMPLEX WITH UMBILICAL HERNIA AND MACROGLOSSIA--A NEW SYNDROME?]

WIEDEMANN HR

Journal de genetique humaine. 1964 ; 13 : 223-232.

PMID 14231762

Citation

This paper should be referenced as such :

Mannens, M

Beckwith-Wiedemann syndrome

Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):62-65.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/BeckwithWiedemannID10037.html

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jlhuret@AtlasGeneticsOncology.org.

Other names	Exomphalos-macroglossia-gigantism triad
Atlas_Id	10037
Genes implicated in	CDKN1C H19 ICR1 TGM1 IGF2 KCNQ1OT1 NSD1 ZNF215
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


Neoplastic risk	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

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

Gene Name	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

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

Gene Name	IGF2 (insulin-like growth factor 2 (somatomedin A))
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

Gene Name	CDKN1C (cyclin-dependent kinase inhibitor 1C)
Alias	KIP2, P57KIP2, P57, CDKN5
Location	11p15.5

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

Gene Name	KCNQ1OT1 (KCNQ1 overlapping transcript)
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

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

Gene Name	ZNF215
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 C2H2-type 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

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed