The Beckwith-Wiedemann syndrome phenotype and the risk of cancer

Schneid, H; Vazquez, M.-P.; Vacher, C.; Gourmelen, M; Cabrol, Sylvie; Bouc, Yves Le

doi:10.1002/(sici)1096-911x(199706)28:6<411::aid-mpo3>3.0.co;2-j

Cited by 49 publications

(16 citation statements)

References 18 publications

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“…While there may be ascertainment bias due to the incomplete identi®ca-tion of all Costello syndrome patients, the frequency of malignant tumors in Costello syndrome could be as high as 17%. This frequency is comparable to the 7± 21% reported in BWS [Schneid et al, 1997;DeBaun and Tucker, 1998]. The high frequency of malignancies in Costello syndrome may warrant tumor screening.…”

Section: Discussionsupporting

confidence: 77%

Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

et al. 2002

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We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7–21% frequency of solid tumors in Beckwith‐Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3–6 months until age 8–10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6–12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome. © 2002 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 77%

Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

et al. 2002

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“…To our knowledge, there is only a single measurement of serum IGF-II in a 30-week-old BWS fetus (Lutton et al 1996) demonstrating a 2.5-to 4-fold increase over the normal concentration range for this particular gestational age (Lassarre et al 1991;Reece et al 1994). Postnatally, however, only three of 27 BWS patients examined (0 to 14 years of age) exhibited serum IGF-II levels exceeding significantly normal levels (Schneid et al 1997). Although it cannot be excluded that the level of IGF-II was abnormally high during gestation, but was somehow downregulated postnatally in the majority of these cases, additional uncertainties exist.…”

Section: Discussionmentioning

confidence: 92%

Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith–Wiedemann and Simpson–Golabi–Behmel syndromes

Eggenschwiler¹,

Ludwig²,

Fisher³

et al. 1997

Genes Dev.

309

212

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In mice, the imprinted Igf2 gene (expressed from the paternal allele), which encodes a growth-promoting factor (IGF-II), is linked closely to the reciprocally imprinted H19 locus on chromosome 7. Also imprinted (expressed from the maternal allele) is the Igf2r gene on chromsome 17 encoding the type 2 IGF receptor that is involved in degradation of excess IGF-II. Double mutant embryos carrying a deletion around the H19 region and also a targeted Igf2r allele, both inherited maternally, have extremely high levels of IGF-II (7-and 11-fold higher than normal in tissues and serum, respectively) as a result of biallelic Igf2 expression (imprint relaxation by deletion of H19-associated sequence) in combination with lack of the IGF2R-mediated IGF-II turnover. This excess of IGF-II causes somatic overgrowth, visceromegaly, placentomegaly, omphalocele, and cardiac and adrenal defects, which are also features of the Beckwith-Wiedemann syndrome (BWS), a genetically complex human disorder associated with chromosomal abnormalities in the 11p15.5 region where the IGF2 gene resides. In addition, the double mutant mouse embryos exhibit skeletal defects and cleft palate, which are manifestations observed frequently in the Simpson-Golabi-Behmel syndrome, another overgrowth disorder overlapping phenotypically, but not genetically, with BWS.

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“…Estimates of the risk of tumor development among patients with BWS vary widely (4 to 21%) (1,18,19). In this series, tumors were diagnosed for 22 of 159 patients (14%), including hepatoblastomas in seven cases, adrenal carcinoma in one, rhabdomyosarcoma in one, and Wilms' tumor in 13 (8% of all patients).…”

Section: Renal Abnormalities Among Patients With Bwsmentioning

confidence: 86%

Renal Abnormalities in Beckwith-Wiedemann Syndrome Are Associated with 11p15.5 Uniparental Disomy

Goldman¹,

Smith²,

Shuman³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Beckwith-Wiedemann syndrome (BWS) is a somatic overgrowth syndrome characterized by a variable incidence of congenital anomalies, including hemihyperplasia and renal malformations. BWS is associated with disruption of genomic imprinting and/or mutations in one or more genes encoded on 11p15.5, including CDKN1C (p57 KIP2 ). It was hypothesized that genotypic and epigenotypic abnormalities of the 11p15.5 region affecting CDKN1C were associated with renal abnormalities. Medical records for 159 individuals with BWS were reviewed. All underwent at least one abdominal ultrasonographic evaluation. Testing for paternal uniparental disomy (UPD) at 11p15.5, CDKN1C mutations, and imprinting defects at KvDMR1 was performed for 96, 32, and 47 patients, respectively. Of the 159 patients, 67 (42%) exhibited renal abnormalities, mainly nephromegaly (25%), collecting system abnormalities (11%), and renal cysts (10.5%). The frequency of renal lesions among patients who were tested for genetic abnormalities did not differ from that among patients who were not tested. Paternal UPD was demonstrated in 22 of 96 cases (23%), CDKN1C mutations in eight of 32 cases (25%), and KvDMR1 imprinting defects in 21 of 47 cases (45%). The 22 UPD-positive patients exhibited a significantly higher incidence of renal abnormalities (P ϭ 0.0026). Surprisingly, the eight patients with CDKN1C mutations exhibited no significant increase in the incidence of renal lesions (P ϭ 0.29). Imprinting defects at KvDMR1, which might downregulate CDKN1C, were also not associated with a significant difference in the incidence of renal disease. Whereas UPD at 11p15.5 in BWS was associated with a higher incidence of renal abnormalities, mutations at CDKN1C and KvDMR1 imprinting defects were not, suggesting that imprinted genes on 11p15.5 other than CDKN1C are critical for renal development.Beckwith-Wiedemann syndrome (BWS) is a congenital disorder characterized by somatic overgrowth, macroglossia, anterior abdominal wall defects, and macrosomia. Additional but variable features include a typical facial appearance, ear lobe creases or pits, facial nevus flammeus, hemihyperplasia, neonatal hypoglycemia, organomegaly, genitourinary abnormalities, and a predisposition to develop embryonal tumors (1,2). Renal abnormalities have been observed in up to 59% (range, 25 to 59%) of patients with BWS (2-4). The most common renal abnormalities are nephromegaly (19 to 59%), simple cysts (13 to 19%), hydronephrosis (12 to 14%), and medullary cysts (5 to 13%). Other, less common findings include nephrocalcinosis (with or without nephrolithiasis) (4%), increased cortical and pyramidal echogenicity (4%), a double collecting system (4%), and caliceal diverticula (1.3%). The molecular mechanisms causing these renal abnormalities are undefined.BWS is associated with disruption of genomic imprinting of one or more genes in the 11p15.5 region. Genomic imprinting is a process that results in parent-of-origin-specific gene expression. Approximately 20% of sporadic BWS cases demonstr...

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The Beckwith-Wiedemann syndrome phenotype and the risk of cancer

Cited by 49 publications

References 18 publications

Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith–Wiedemann and Simpson–Golabi–Behmel syndromes

Renal Abnormalities in Beckwith-Wiedemann Syndrome Are Associated with 11p15.5 Uniparental Disomy

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