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Horm Metab Res 2015; 47(07): 497-503
DOI: 10.1055/s-0034-1394371
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

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

F. Bertoin   *
1   Department of Endocrinology, CHU Reims, Hôpital Robert Debré, Reims, France
,
E. Letouzé   *
2   Programme Cartes d’Identité des Tumeurs, Ligue Nationale contre le Cancer, Paris, France
,
P. Grignani
3   Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
,
M. Patey
4   Department of Pathology, CHU Reims, Hôpital Robert Debré, Reims, France
,
S. Rossignol
5   Laboratory of Endocrine Functional Explorations, APHP, Hôpital Armand Trousseau, INSERM UMRS 938 Team 4, Université Pierre et Marie Curie-Paris, Faculté de Médecine, Paris, France
,
R. Libé
6   Department of Endocrinology-Metabolism-Cancer, APHP, Institut Cochin, Université Paris V-René Descartes, Paris, France
,
C. Pasqual
7   Service of Diabetology, Hospital of Troyes, Troyes, France
,
S. Lardière-Deguelte
8   Department of Endocrine Surgery, CHU Reims, Hôpital Robert Debré, Reims, France
,
C. Hoeffel-Fornes
9   Department of Radiology, CHU Reims, Hôpital Robert Debré, Reims, France
,
D. Gaillard
10   Department of Genetics, CHU Reims, Hôpital Robert Debré, Reims, France
,
C. Previderè
3   Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
,
B. Delemer
1   Department of Endocrinology, CHU Reims, Hôpital Robert Debré, Reims, France
,
E. Lalli
11   Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR7275, Sophia Antipolis-Valbonne, France
› Author Affiliations
Further Information

Publication History

received 24 June 2014

accepted 29 September 2014

Publication Date:
03 November 2014 (online)

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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

* These authors contributed equally to this work


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  • 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
    Search in Google Scholar
  • 2 Wiedemann HR. Tumours: An hemihypertrophy associated with Wiedemann-Beckwith syndrome. Eur J Pediatrics 1983; 141: 129
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 5 Cohen MM. Beckwith-Wiedemann syndrome: historical, clinicopathological and etiopathogenetic perspectives. Pediatr Develop Pathol 2005; 8: 287-304
    CrossrefPubMedSearch in Google Scholar
  • 6 Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C 2010; 154: 343-354
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 12 Fleisher AS, Meltzer SJ, James SP. Colon polyps in Beckwith-Wiedemann syndrome: role of imprinted genes. Gastroenterology 2000; 18: 637
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 26 Poh MM, Ballard TN, Wendel JJ. Beckwith-Wiedemann syndrome and juvenile fibroadenoma: a case report. Ann Plastic Surg 2010; 64: 803-806
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Search in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar