Beckwith-Wiedemann syndrome

Exomphalos-macroglossia-gigantism triad

incidence of 7\/10^{5; 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}

130650

D001506

116 Beckwith-Wiedemann syndrome

C0004903

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

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

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

clinical features tend to become less with ageing; tumour risk decreases strongly after the 4-7th year of birth

paternal duplications of chromosome region 11p15, maternal translocations involving chromosome region 11p15.3-p15.5

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

in 10-20% of BWS cases, uniparental disomy of chromosome region 11p15 is seen, mostly in a mosaic form

D11S813E, D11S878E, ASM, ASM1

imprinted, maternally expressed, untranslated mRNA

the human H19 gene is 2.7 kb long and includes 4 small introns; maternally expressed, paternal imprint

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

putative tumour suppressor; proposed regulatory function for IGF2 expression (under debate)

hypermethylated in 10-20% of sporadic BWS cases; familial transmission unclear yet; loss of imprinting (LOI) can be induced in deletion mouse models

hypermethylated in 10-20% of sporadic BWS cases mostly somatic events due to UPD in mosaic form; LOI in tumours

IGF-II, somatomedin A, Hs.75963

1356 bp mRNA, paternally expressed, maternal imprint

180 amino acids, 20,14 kDa (unprocessed)

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

secreted

embryonal growth factor, mitogen

belongs to the insulin\/IGF\/relaxin family

hypomethylated; LOI in sporadic BWS cases; familial transmission unclear yet; BWS phenotype can be induced in igf2 overexpressing mouse models

hypomethylated, LOI in sporadic BWS cases; mostly somatic events due to UPD in mosaic form; LOI in tumours

KIP2, P57KIP2, P57, CDKN5

1511 bp messenger, preferentially maternally expressed (paternal imprint)

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

nuclear

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

p21CIP1 CdK inhibitor gene family

mostly maternal, nucleotide substitutions, small deletions

CDKN1C mutations are described in tumour formation; mouse mutation-models reveal part of the BWS phenotype in particular the abdominal-wall defects

KCNQ1 overlapping transcript 1, LIT1, KvDMR1, KvLQT1-AS, Long QT intronic transcript 1

maternally imprinted gene, > 80 kb RNA

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

untranslated

unknown; it is postulated that KCNQ1OT1 might influence the expression of nearby imprinted genes such as CDKN1C or IGF2\/H19

aberrant methylation in 50-80% of BWS patients not always 100% (might be due to UPD in some cases); inheritance unclear

unclear; there is no association between aberrant methylation and tumour development

zinc finger protein 215, BAZ2

mRNA of 3480 bp, 9 exons, at least 5 splice variants; exon 9 runs antisense of a second gene: ZNF214

imprinted in a tissue specific manner, the maternal allele being preferentially expressed

517 amino acids, 60,048 kDa; KRABA domain; similarities to a KRABB domain; SCAN box; nuclear localisation signal KKKR; 2 x 2 zinc-fingers

widely expressed at low levels; expression is highest in testis; splice variants of ZNF215 show tissue specific expression

nuclear

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

belongs to the Krueppel family of C2H2-type zinc finger proteins

various amino acids substitutions found in BWS \/ hemihypertrophy patients; causal relationship with phenotype unclear

in tumours no mutations found so far