Genome-Wide Paternal Uniparental Disomy as a Cause of Beckwith-Wiedemann Syndrome Associated with Recurrent Virilizing Adrenocortical Tumors

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by fetal macrosomia, macroglossia, and abdominal wall defects. BWS patients are at risk to develop Wilms tumor, neuroblastoma, hepatoblastoma, and adrenal tumors. A young woman with BWS features, but with inconclusive genetic evidence for the disease, came to clinical observation for signs of virilization at the age of 16 years. An adrenocortical tumor was diagnosed and surgically resected. The tumor underwent 2 local relapses that were also surgically treated. The patient was also operated to remove a breast fibroadenoma. SNP arrays were used to analyze chromosome abnormalities in normal and tumor samples from the patient and her parents. The patient presented genome-wide mosaic paternal uniparental disomy (patUPD) both in the adrenocortical and the breast tumors, with different degrees of loss of heterozygosity (LOH). The more recent relapses of the adrenocortical tumor showed a loss of part of chromosome 17p that was absent in the first tumor. Analysis of a skin biopsy sample also showed mosaic patUPD with partial LOH, while no LOH was detected in leukocyte DNA. This case shows that virilizing adrenocortical tumors may be a clinical feature of patients with BWS. The SNP array technology is useful to diagnose genome-wide patUPD mosaicism in BWS patients with an inconclusive molecular diagnosis and underlines the tumorigenic potential of the absence of the maternal genome combined with an excess of the paternal genome.

Key words

genetic tumor syndromes - adrenal tumors - mosaicism - SNP arrays

• References

• 1 Beckwith JB. Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia: Another syndrome?. Los Angeles: Abstract, Western Society for Pediatric Research; 1963
• 2 Wiedemann HR. Tumours: An hemihypertrophy associated with Wiedemann-Beckwith syndrome. Eur J Pediatrics 1983; 141: 129
• 3 Rump P, Zeegers MPA, van Essen AJ. Tumour risk in Beckwith-Wiedemann syndrome: A review and meta-analysis. Am J Med Genet A 2005; 136: 95-104
• 4 Brioude F, Lacoste A, Netchine I, Vazquez MP, Auber F, Audry G, Gauthier-Villars M, Brugieres L, Gicquel C, Le Bouc Y, Rossignol S. Beckwith-Wiedemann syndrome: growth pattern and tumour risk according to molecular mechanism and guidelines for tumour surveillance. Horm Res Paediatrics 2013; 80: 457-465
• 5 Cohen MM. Beckwith-Wiedemann syndrome: historical, clinicopathological and etiopathogenetic perspectives. Pediatr Develop Pathol 2005; 8: 287-304
• 6 Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C 2010; 154: 343-354
• 7 Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, Louvel A, Luton JP, Le Bouc Y. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumours: study on a series of 82 tumours. J Clin Endocrinol Metab 1997; 82: 2559-2565
• 8 McCauley RG, Beckwith JB, Elias ER, Faerber EN, Prewitt LH, Berdon WE. Benign hemorrhagic adrenocortical macrocysts in Beckwith-Wiedemann syndrome. Am J Roentgenology 1991; 157: 549-552
• 9 Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 2003; 12: R61-R68
• 10 Aleck KA, Hadro TA. Dominant inheritance of Wiedemann-Beckwith syndrome: further evidence for transmission of “unstable premutation” through carrier women. Am J Med Genet 1989; 33: 155-160
• 11 Clouston WM, Cannell GC, Fryar BG, Searle JW, Martin NI, Mortimer RH. Virilizing adrenal adenoma in an adult with the Beckwith-Wiedemann syndrome: paradoxical response to dexamethasone. Clin Endocrinol 1989; 31: 467-473
• 12 Fleisher AS, Meltzer SJ, James SP. Colon polyps in Beckwith-Wiedemann syndrome: role of imprinted genes. Gastroenterology 2000; 18: 637
• 13 Houtenbos I, Ossenkoppele GJ. Acute myeloid leukemia in a 23-year-old patient with Beckwith-Wiedemann syndrome. Cancer Genet Cytogenet 2002; 136: 90-91
• 14 Bémurat L, Gosse P, Ballanger P, Tauzin-Fin P, Barat P, Lacombe D, Lemétayer P, Clémenty J. Successful laparoscopic operation of bilateral pheochromocytoma in a patient with Beckwith-Wiedemann syndrome. J Hum Hypertens 2002; 16: 281-284
• 15 Romanelli V, Nevado J, Fraga M, Trujillo AM, Mori MÁ, Fernández L, Pérez de Nanclares G, Martínez-Glez V, Pita G, Meneses H, Gracia R, García-Miñaur S, García de Miguel P, Lecumberri B, Rodríguez JI, González Neira A, Monk D, Lapunzina P. Constitutional mosaic genome-wide uniparental disomy due to diploidisation: an unusual cancer-predisposing mechanism. J Med Genet 2011; 48: 212-216
• 16 Gogiel M, Begemann M, Sengler S, Soellner L, Goretzlenher U, Eggermann T, Strobl-Wildemann G. 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
• 17 Kalish JM, Conlin LK, Bhatti TR, Dubbs HA, Harris MC, Izumi K, Mostoufi-Moab S, Mulchandani S, Saitta S, States LJ, Swarr DT, Wilkens AB, Zackai EH, Zelley K, Bartolomei MS, Nichols KE, Palladino AA, Spinner NB, Deardorff MA. Clinical features of three girls with mosaic genome-wide paternal uniparental disomy. Am J Med Genet A 2013; 161: 1929-1939
• 18 Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H, Audry G, Vazquez MP, Gicquel C. Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet 2001; 9: 409-418
• 19 Peiffer DA, Le JM, Steemers FJ, Chang W, Jenniges T, Garcia F, Haden K, Li J, Shaw CA, Belmont J, Cheung SW, Shen RM, Barker DL, Gunderson KL. High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res 2006; 16: 1136-1148
• 20 Staaf J, Vallon-Christersson J, Lindgren D, Juliusson G, Rosenquist R, Höglund M, Borg A, Ringnér M. Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios. BMC Bioinformatics 2008; 9: 409
• 21 Letouzé E, Rosati R, Komechen H, Doghman M, Marisa L, Flück C, de Krijger RR, van Noesel MM, Mas JC, Pianovski MA, Zambetti GP, Figueiredo BC, Lalli E. SNP array profiling of childhood adrenocortical tumours reveals distinct pathways of tumourigenesis and highlights candidate driver genes. J Clin Endocrinol Metab 2012; 97: E1284-E1293
• 22 Popova T, Manié E, Stoppa-Lyonnet D, Rigaill G, Barillot E, Stern MH. Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays. Genome Biol 2009; 10: R128
• 23 Staaf J, Lindgren D, Vallon-Christersson J, Isaksson A, Göransson H, Juliusson G, Rosenquist R, Höglund M, Borg A, Ringnér M. Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays. Genome Biol 2008; 9: R136
• 24 Inbar-Feigenberg M, Choufani S, Cytrynbaum C, Chen YA, Steele L, Shuman C, Ray PN, Weksberg R. Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: Diagnostic and management issues. Am J Med Genet A 2013; 161: 13-20
• 25 Raine PA, Noblett HR, Houghton-Allen BW, Campbell PE. Breast fibroadenoma and cardiac anomaly associated with EMG (Beckwith-Wiedemann) syndrome. J Pediatrics 1979; 94: 633-634
• 26 Poh MM, Ballard TN, Wendel JJ. Beckwith-Wiedemann syndrome and juvenile fibroadenoma: a case report. Ann Plastic Surg 2010; 64: 803-806
• 27 Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin JF, Luton JP, Le Bouc Y. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumours. Cancer Res 2001; 61: 6762-6767
• 28 Barreau O, de Reynies A, Wilmot-Roussel H, Guillaud-Bataille M, Auzan C, René-Corail F, Tissier F, Dousset B, Bertagna X, Bertherat J, Clauser E, Assié G. Clinical and pathophysiological implications of chromosomal alterations in adrenocortical tumours: an integrated genomic approach. J Clin Endocrinol Metab 2012; 97: E301-E311
• 29 Kaltsas GA, Mukherjee JJ, Kola B, Isidori AM, Hanson JA, Dacie JE, Reznek R, Monson JP, Grossman AB. Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women?. Clin Endocrinol 2003; 59: 34-43
• 30 Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, Taylor K, Boots LR. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004; 89: 453-462
• 31 Carmina E, Rosato F, Jannì A, Rizzo M, Longo RA. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 2006; 91: 2-6
• 32 Keren B, Chantot-Bastaraud S, Brioude F, Mach C, Fonteneau E, Azzi S, Depienne C, Brice A, Netchine I, Le Bouc Y, Siffroi JP, Rossignol S. SNP arrays in Beckwith-Wiedemann syndrome: an improved diagnostic strategy. Eur J Med Genet 2013; 56: 546-550
• 33 Ting JC, Roberson ED, Miller ND, Lysholm-Bernacchi A, Stephan DA, Capone GT, Ruczinski I, Thomas GH, Pevsner J. Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio. Hum Mutat 2007; 28: 1225-1235
• 34 Schroeder C, Sturm M, Dufke A, Mau-Holzmann U, Eggermann T, Poths S, Riess O, Bonin M. UPDtool: a tool for detection of iso- and heterodisomy in parent-child trios using SNP microarrays. Bioinformatics 2013; 29: 1562-1564