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Idiopathic hemihypertrophy (IH) is a congenital overgrowth syndrome associated with an increased risk of embryonal cancers in childhood. A related developmental disorder is Beckwith-Wiedemann syndrome (BWS), which increases risk for embryonal cancers, including Wilms tumor. Constitutional epigenetic alterations associated with BWS have been well characterized and include epigenetic alterations of imprinted genes on 11p15. The frequency of hypermethylation of H19 in children with IH and Wilms tumor, 20% (3/15), was significantly lower than the frequency in children with BWS and Wilms tumor, 79% (11/14; P = .0028). These results indicate that children with IH and Wilms tumor have different constitutional epigenotypes from those of children with BWS and Wilms tumor. [ABSTRACT FROM AUTHOR]

Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57KIP2 or loss of imprinting of either of two imprinted gene domains on 11p5: LIT1, which is near p57KIP2, or H19/IGF2. Unlike Prader-Willi and Angelman syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57KIP2, indicating deletion of an element important for the regulation of p57KIP2 expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans. [ABSTRACT FROM AUTHOR]

A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors-that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes. [ABSTRACT FROM AUTHOR]

Studies the association of in vitro fertilization with Beckwith-Wiedemann Syndrome and epigenetic alterations of the H19 and LIT1 genes. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on human genetics.

Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = .002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively ( P = .012 and P = .02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P = .003 ), cancer ( P = .03), and hypoglycemia (P = .05 ). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects. [ABSTRACT FROM AUTHOR]