Beckwith–Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management.
Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed.
SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism.
SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $94.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229–249.
Romanelli V, Nevado J, Fraga M, et al. Constitutional mosaic genome-wide uniparental disomy due to diploidisation: an unusual cancer-predisposing mechanism. J Med Genet. 2011;48:212–216.
Gartler SM, Waxman SH, Giblett E. An XX/XY human hermaphrodite resulting from double fertilization. Proc Natl Acad Sci USA 1962;48:332–335.
Malan V, Vekemans M, Turleau C. Chimera and other fertilization errors. Clin Genet. 2006;70:363–373.
Inbar-Feigenberg M, Choufani S, Cytrynbaum C, et al. Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: diagnostic and management issues. Am J Med Genet A. 2013;161A:13–20.
Kalish JM, Conlin LK, Bhatti TR, et al. Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. Am J Med Genet A. 2013;161A:1929–1939.
Repnikova E, Roberts J, Kats A, et al. Biparental/androgenetic mosaicism in a male with features of overgrowth and placental mesenchymal dysplasia. Clin Genet. 2018;94:564–568.
Conlin LK, Thiel BD, Bonnemann CG, et al. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet. 2010;19:1263–1275.
Robinson WP, Lauzon JL, Innes AM, Lim K, Arsovska S, McFadden DE. Origin and outcome of pregnancies affected by androgenetic/biparental chimerism. Hum Reprod. 2007;22:1114–1122.
Kaiser-Rogers KA, McFadden DE, Livasy CA, et al. Androgenetic/biparental mosaicism causes placental mesenchymal dysplasia. J Med Genet. 2006;43:187–192.
Ohtsuka Y, Higashimoto K, Sasaki K, et al. Autosomal recessive cystinuria caused by genome-wide paternal uniparental isodisomy in a patient with Beckwith–Wiedemann syndrome. Clin Genet. 2015;88:261–266.
Wilson M, Peters G, Bennetts B, et al. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am J Med Genet A. 2008;146A:137–148.
Gogiel M, Begemann M, Spengler S, et al. Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith–Wiedemann syndrome and ovarian steroid cell tumour. Eur J Hum Genet. 2013;21:788–791.
Bertoin F, Letouzé E, Grignani P, et al. Genome-wide paternal uniparental disomy as a cause of Beckwith–Wiedemann syndrome associated with recurrent virilizing adrenocortical tumors. Horm Metab Res. 2015;47:497–503.
Borgulová I, Soldatova I, Putzová M, et al. Genome-wide uniparental diploidy of all paternal chromosomes in an 11-year-old girl with deafness and without malignancy. J Hum Genet. 2018;63:803–810.
Kapur RP, Cole B, Zhang M, Lin J, Fligner CL. Placental mesenchymal dysplasia and fetal renal-hepatic-pancreatic dysplasia: androgenetic-biparental mosaicism and pathogenesis of an autosomal recessive disorder. Pediatr Dev Pathol. 2013;16:191–200.
Cools M, Drop SLS, Wolffenbuttel KP, Oosterhuis JW, Looijenga LHJ. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev. 2006;27:468–484.
Farrugia MK, Sebire NJ, Achermann JC, Eisawi A, Duffy PG, Mushtaq I. Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies. J Pediatr Urol. 2013;9:139–144.
Lee PA, Nordenström A, Houk CP, et al. Global disorders of sex development update since 2006: perceptions, approach and care. Horm Res Paediatr. 2016;85:158–180.
Sugawara N, Kimura Y, Araki Y. Successful second delivery outcome using refrozen thawed testicular sperm from an infertile male true hermaphrodite with a 46, XX/46, XY karyotype: case report. Hum Cell. 2012;25:96–99.
Carson JC, Hoffner L, Conlin L, et al. Diploid/triploid mixoploidy: a consequence of asymmetric zygotic segregation of parental genomes. Am J Med Genet A. 2018;176:2720–2732.
Fancsovits P, Tóthné ZG, Murber A, Takács FZ, Papp Z, Urbancsek J. Correlation between first polar body morphology and further embryo development. Acta Biol Hung. 2006;57:331–338.
We thank the patients and their families for sharing their stories. J.M.K. is supported by the National Institutes of Health (K08 CA193915), Alex’s Lemonade Stand Foundation, St. Baldrick’s Foundation, and the University of Pennsylvania Orphan Disease Center.
The authors declare no conflicts of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.