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      Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith–Wiedemann syndrome as a sporadic adrenocortical tumor

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          Abstract

          Beckwith–Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith–Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith–Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith–Wiedemann syndrome presentation.

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          Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome.

          C Haire, Molly Maher, A Luharia … (2005)
          Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (P<0.0001) and exomphalos was associated with an IC2 defect or CDKN1C mutation but not UPD or IC1 defect (P<0.0001). When comparing birth weight centile, IC1 defect cases were significantly heavier than the patients with CDKN1C mutations or IC2 defect (P=0.018). The risk of neoplasia was significantly higher in UPD and IC1 defect cases than in IC2 defect and CDKN1C mutation cases. Kaplan-Meier analysis revealed a risk of neoplasia for all patients of 9% at age 5 years, but 24% in the UPD subgroup. The risk of Wilms' tumour in the IC2 defect subgroup appears to be minimal and intensive screening for Wilms' tumour appears not to be indicated. In UPD patients, UPD extending to WT1 was associated with renal neoplasia (P=0.054). These findings demonstrate that BWS represents a spectrum of disorders. Identification of the molecular subtype allows more accurate prognostic predictions and enhances the management and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.
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            Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature.

            J. Haines, C. Palmer, Rebecca Wappner … (1986)
            The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia. Twenty-two cases of WBS were examined clinically and cytogenetically, and compared to 226 previously reported cases. Aspects of the clinical evaluations are discussed. All individuals examined were chromosomally normal with no evidence of 11p abnormality as has been reported recently. The relevance of a possible relationship between clinical findings, chromosome abnormalities, and genes present on 11p is discussed. Transmission of this condition is most consistent with autosomal dominant inheritance with incomplete penetrance.
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              Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases.

              Margaret Elliott, Rosemary Bayly, Trevor Cole … (1994)
              Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. To define the range and frequency of complications in BWS, we have studied a cohort of 76 affected patients (two previously reported). The most frequent complications were macroglossia (97%), abdominal wall defect (80%) and birth weight or postnatal growth > 90th centile (88%). Other common features were ear creases/pits (76%), facial naevus flammeus (62%), nephromegaly (59%) and hypoglycaemia (63%). Rarer complications included hemihypertrophy (24%), moderate/severe developmental delay (4%), congenital heart defects (6.5%), polydactyly (4%), neoplasia (4%) and cleft palate (2.5%). Pre-term labour occurred in 53% and polyhydramnios in 33% of BWS pregnancies. The six deaths all occurred in babies born pre-term, three of whom had major congenital abnormalities. Five patients (6.5%) from four kindreds had an unequivocal family history of BWS, but 15 of 68 apparently sporadic cases had a relative with possible BWS (minor features only). Incomplete penetrance may lead to familial BWS being underdiagnosed.
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                Author and article information

                Contributors
                Dorra H'mida Ben-Brahim
                Journal
                Journal ID (nlm-ta): Appl Transl Genom
                Journal ID (iso-abbrev): Appl Transl Genom
                Title: Applied & Translational Genomics
                Publisher: Elsevier
                ISSN (Electronic): 2212-0661
                Publication date PMC-release: 15 October 2014
                Publication date Collection: March 2015
                Publication date (Electronic): 15 October 2014
                Volume: 4
                Pages: 1-3
                Affiliations
                [a ]Department of Cytogenetics and Reproductive Biology, Farhat Hached University Hospital, Sousse, Tunisia
                [b ]Department of Pediatrics, Fattouma Bourguiba University Hospital, Monastir, Tunisia
                [c ]Department of Pathology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
                Author notes
                [* ]Corresponding author. Tel.: + 216 98 436 094; fax: + 216 73 102 595. dorrahmida@ 123456yahoo.fr
                Article
                Publisher ID: S2212-0661(14)00040-4
                DOI: 10.1016/j.atg.2014.10.001
                PMC ID: 4745355
                PubMed ID: 26937341
                SO-VID: 833c4236-1c7f-4fde-9df0-fef740d2d859
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Date received : 24 August 2014
                Date revision received : 30 September 2014
                Date accepted : 2 October 2014
                Categories
                Subject: Article

                Keywords: beckwith–wiedemann syndrome,adrenocortical tumor,hereditary,kcnq1ot1
                Data availability:
                Keywords: beckwith–wiedemann syndrome, adrenocortical tumor, hereditary, kcnq1ot1

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