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Low-level parental mosaicism in an apparent de novo case of Peutz–Jeghers syndrome

  • G. I. Butel-Simoes
  • A. D. Spigelman
  • R. J. Scott
  • R. E. Vilain
Original Article

Abstract

We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz–Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.

Keywords

Peutz–Jeghers syndrome (PJS) STK11 Mosaic Gonadal Somatic De novo 

References

  1. 1.
    Peutz JL (1921) On a very remarkable case of familial polyposis of the mucous membranes of the intestinal tract and nasopharynx accompanied by peculiar pigmentation of the skin and mucous membranes. Ned Tijdschr Geneeskd 10:134–146Google Scholar
  2. 2.
    Jeghers H, McKusick VA, Katz KH (1949) Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med 241(26):993–1005 & 1031–1036Google Scholar
  3. 3.
    Spigelman AD, Murday V, Phillips RK (1989) Cancer and the Peutz-Jeghers syndrome. Gut 30(11):1588–1590CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, Keller JJ, Westerman AM, Scott RJ, Lim W, Trimbath JD, Giardello FM, Gruber SB, Offerhaus GJA, de Rooji FWM, Paul Wilson JH, Hansmann A, Möslein G, Royer-Pokora B, Vogel T, Philips RKS, Spigelman AD, Houlston RS (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12(10):3209–3215CrossRefPubMedGoogle Scholar
  5. 5.
    van Lier MGF, Wagner A, Mathus-Vliegen EMH, Kuipers EJ, Steyerberg EW, van Leerdam ME (2010) High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105(6):1258–1264CrossRefPubMedGoogle Scholar
  6. 6.
    Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ, Seldin MF, Nations L, Lynch PM, Fidder HH, Friedman E, Frazier ML (2004) Genotype–phenotype correlations in Peutz–Jeghers syndrome. J Med Genet 41(5):327–333CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Launonen V (2005) Mutations in the human LKB1/STK11 gene. Hum Mutat 36(4):291–297CrossRefGoogle Scholar
  8. 8.
    Olschwang S, Markie D, Seal S, Neale K, Phillips R, Cottrell S, Ellis I, Hodgson S, Zauber P, Spigelman A, Iwama T, Loff S, McKeown C, Marchese C, Sampson J, Davies S, Talbot I, Wyke J, Thomas G, Bodmer W, Hemminki A, Avizienyte E, de la Chapelle A, Aaltonen L, Stratton M, Houlston R, Tomlinson I (1998) Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J Med Genet 35:42–44CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Müller O, Back W, Zimmer M (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18(1):38–43CrossRefPubMedGoogle Scholar
  10. 10.
    Hearle N, Lucassen A, Wang R, Lim W, Ross F, Wheeler R, Moore I, Shipley J, Houlston R (2004) Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases. Genes Chromosomes Cancer 41:163–169CrossRefPubMedGoogle Scholar
  11. 11.
    Alessi DR, Sakamoto K, Bayascas JR (2006) LKB1-dependent signaling pathways. Annu Rev Biochem 75(1):137–163CrossRefPubMedGoogle Scholar
  12. 12.
    Aretz S, Stienen D, Uhlhaas S, Loff S, Back W, Pagenstecher C, McLeod DR, Graham GE, Mangold E, Santer R, Propping P, Friedl W (2005) High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26(6):513–519CrossRefPubMedGoogle Scholar
  13. 13.
    Papp J, Kovacs ME, Solyom S, Kasler M, Børresen-Dale A, Olah E (2010) High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers syndrome patients. BMC Med Genet 11:169CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, Bertario L, Blanco I, Bülow S, Burn J, Capella G, Colas C, Friedl W, Møller P, Hes FJ, Järvinen H, Mecklin JP, Nagengast FM, Parc Y, Phillips RK, Hyer W, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen JT, Clark SK, Hodgson SV (2010) Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 59(7):975–986CrossRefPubMedGoogle Scholar
  15. 15.
    McGarrity TJ, Kulin HE, Zaino RJ (2000) Peutz-Jeghers syndrome. Am J Gastroenterol 95(3):596–603CrossRefPubMedGoogle Scholar
  16. 16.
    Utsunomiya J, Gocho H, Miyanaga T, Hamaguchi E, Kashimure A (1975) Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J 136(2):71–82PubMedGoogle Scholar
  17. 17.
    Lim W, Hearle N, Shah B, Murday V, Hodgson SV, Lucassen A, Eccles D, Talbot I, Neale K, Lim AG, O’Donohue J, Donaldson A, Macdonald RC, Young ID, Robinson MH, Lee PW, Stoodley BJ, Tomlinson I, Alderson D, Holbrook AG, Vyas S, Swarbrick ET, Lewis AA, Phillips RK, Houlston RS (2003) Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89(2):308–313CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Scott RJ, Crooks R, Meldrum CJ, Thomas L, Smith CJ, Mowat D, McPhilips M, Spigelman AD (2002) Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients. Clin Genet 63(4):282–287CrossRefGoogle Scholar
  19. 19.
    McKay V, Cairns D, Gokhale D, Mountford R, Greenhalgh L (2016) First report of somatic mosaicism for mutations in STK11 in four patients with Peutz-Jeghers syndrome’. Fam Cancer 15(1):57–61CrossRefPubMedGoogle Scholar
  20. 20.
    den Dunnen JT, Dalgleish R, Maglott D, Hart R, Greenblatt MS, McGowan-Jordan J, Roix AF, Smith T, Atonarakis SE, Taschner PE (2016) HGVS recommendations for the description of sequence variants—2016 update. Hum Mutat 37:564–569CrossRefGoogle Scholar
  21. 21.
    Sgambati MT, Stolle C, Choyke PK, Walther MM, Zbar B, Linehan M, Glenn GM (2000) Mosaicism in von Hippel–Lindau disease: Lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 66:84–91CrossRefPubMedGoogle Scholar
  22. 22.
    Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S (2007) Mosaicism in von Hippel-Lindau disease: an event important to recognise. J Cell Mol Med 11(6):1408–1415CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schwab AL, Tuohy TM, Condie M, Neklason DW, Burt RW (2008) Gonadal mosaicism and familial adenomatous polyposis. Fam Cancer 7(2):173–178CrossRefPubMedGoogle Scholar
  24. 24.
    Delon I, Taylor A, Molenda A, Drummond J, Oakhill K, Girling A, Liu H, Whittaker J, Treacy R, Tishckowitz M (2013) A germline mosaic BRCA1 exon deletion in a woman with bilateral basal-like breast cancer. Clin Genet 84(3):297–299CrossRefPubMedGoogle Scholar
  25. 25.
    Rushlow D, Piovesan B, Zhang K, Prigoda-Lee NM, Marchong MN, Clark RD, Gallie BL (2009) Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat 30(5):842–851CrossRefPubMedGoogle Scholar
  26. 26.
    Zlotogora J (1998) Germline mosaicism. Hum Genet 102(4):381–386CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • G. I. Butel-Simoes
    • 1
  • A. D. Spigelman
    • 2
    • 3
  • R. J. Scott
    • 4
  • R. E. Vilain
    • 5
  1. 1.Monash HealthMonash Medical CentreClaytonAustralia
  2. 2.Hunter Family Cancer ServiceNewcastleAustralia
  3. 3.St Vincent’s Hospital Clinical SchoolUNSWSydneyAustralia
  4. 4.Discipline of Medical GeneticsThe University of NewcastleNewcastleAustralia
  5. 5.Division of Anatomical Pathology, NSW Health Pathology (North)John Hunter HospitalNew LambtonAustralia

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