Clinical Dysmorphic Syndromes with Tumorigenesis

Česká verzia

Authors: D. Ilenčíková; M. Čižmárová; A. Krajčiová; S. Požgayová; A. Rybárová; L. Kovács
Authors place of work: II. detská klinika, LF UK a DFNsP Bratislava, Slovenská republika
Published in the journal: Klin Onkol 2012; 25(Supplementum): 39-48

Summary

Genetic alterations cause predisposition to malignancy by increased cancer risk related to constitutional mutations in growth-regulating or DNA repair genes. Some pediatric malignancies are associated with dysmorphic features in several body areas. Through physical examination, we recognise characteristic signs of genetic dysmorphic disorders, such as somatic overgrowth, undergrowth, macrocephaly, microcephaly and dysmorphic changes of the face, eyes, mouth and lips, heart, gastrointestinal tract, urinary tract, genitalia and skeleton. Recognition of a cancer-associated dysmorphic syndrome allows intensive cancer screening and genetic counseling. Therefore, it is recommended that every child with cancer should be examined by a clinical geneticist. Molecular diagnostics of germinal mutations may very effectively detect families at high risk of malignancy and help provide primary prevention. This work presents clinical syndromes with genetic backround and cancer screening recommendations for 18 syndromes with increased cancer risk.

Key words:
genetic dysmorphic syndromes – RAS-MAPK signaling pathway – malignance in childhood

Molecular diagnostics of Rasopathies was supported by The League against Cancer of the sR.

The authors declare they have no potential conflicts of interest concerning drugs, pruducts, or services used in the study.

The Editorial board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
24. 4. 2012

Accepted:
25. 6. 2012

Zdroje

1. Merks JH, Caron HN, Hennekam RC. High incidence of malformation syndrome in a series of 1,073 children with cancer. Am J Med Genet A 2005; 34A(2): 132– 143.

2. Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet 2005; 137C(1): 53– 71.

3. Martin RA, Grange DK, Zehnbauer B et al. LIT1 and H19 methylation defect in isolated hemihyperplasia. Am J Med Genet A 2005; 134A(2): 129– 131.

4. Niemitz EL, Feinberg AP, Brandenburg SA et al. Children with idiopathic hemihypertrophy and Beckwith- Wiedemann syndrome have different constitutional epigenotypes associated with Wilms tumor. Am J Hum Genet 2005; 77(5): 887– 891.

5. Weng EY, Moeschler JB, Graham JM Jr. Logitudinal observations on 15 children with Wiedemann‑Beckwith syndrome. Am J Med Genet 1995; 56(4): 366– 373.

6. Pettenati MJ, Haines JL, Higgins RR et al. Wiedemann‑Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of literature. Hum Genet 1986; 74(2): 143– 154.

7. Slavotinek A, Gaunt L, Donnai D. Paternally inherited duplications of 11p15.5 and Beckwith- Wiedemann syndrome. J Med Genet 1997; 34(10): 819– 826.

8. Weksberk R, Shumann C, Smith AC. Beckwith- Wiedermann syndrome. Am J Med Genet C 2005; 137C(1): 12– 23.

9. Rump P, Zeegers MP, van Essen AJ. Tumor risk in Beckwith- Wiedemann syndrome: a review and meta‑anlysis. Am J Med Genet A 2005; 136(1): 95– 104.

10. Bliek J, Glicquel C, Gaston V et al. Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith- Wiedemann syndrome (BWS). J Pediatr 2004; 145(6): 796– 799.

11. Choyke PL, Siegel MJ, Craft AW et al. Screening for Wilms tumor in children with Beckwith- Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 1999; 32(3): 196– 200.

12. Evermann DB, Shuman C, Dzolganovski B et al. Serum alpha- fetoprotein levels in Beckwith- Wiedemann syndrome. J Pediatr 2000; 137(1): 123– 127.

13. Cohen MM Jr, Neri G, Weksberg R. Overgrowth Syndromes. New York: Oxford University Press 2002: 75– 110.

14. Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA 2001; 285(17): 2240– 2243.

15. Zhou XP, Marsh DJ, Hampel H et al. Germline and germline mosaic PTEN mutations associated with a Proteus‑like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet 2000; 9(5): 765– 768.

16. Cohen MM Jr, Gorlin RJ. Noonan‑like/ multiple giant cell lesion syndrome. Am J Hum Genet 1991; 40(2): 159– 166.

17. Tatton- Brown K, Douglas J, Coleman K et al. Genotype- phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 2005; 77(2): 193– 204.

18. Hersh JH, Cole TR, Bloom AS et al. Risk of malignancy in Sotos syndrome. J Pediatr 1992; 120(4 Pt 1): 572– 574.

19. Golabi M, Rosen L. A new X‑linked mental retardation- overgrowth syndrome. Am J Med Genet 1984; 17(1): 345– 358.

20. Pilia G, Hughes- Benzie RM, MacKenzie A et al. Mutations in GPC3, a glypican gene, cause the Simpson- Golabi- Behmel overgrowth syndrome. Nat Genet 1996; 12(3): 241– 247.

21. Li M, Shuman C, Fei Y et al. GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson- Golabi- Behmel syndrome. Am J Med Genet 2001; 102(2): 161– 168.

22. Ruvalcaba RH, Myhre S, Smith DW. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet 1980; 18(6): 413– 416.

23. Marsh DJ, Dahia PL, Zheng Z et al. Germline mutations in PTEN are present in Bannayan- Zonana syndrome. Nat Genet 1997; 16(4): 33– 34.

24. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program 2007; 1: 29– 39.

25. Kutler DI, Singh B, Satagopan J et al. A 20‑year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003; 101(4): 1249– 1256.

26. Taniguchi T, D’Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood 2006; 107(11): 4223– 4233.

27. Krutílková V, Eckschlager T. Přehled syndromů spojených s rizikem nádorů dĕtského vĕku. Klin Onkol 2009; 22 (Suppl): 45– 49.

28. Ball LG, Xiao W. Molecular basis of ataxia telangiectasia and related diseases. Acta Pharmacol Sin 2005; 26(8): 897– 907.

29. Seemanová E, Mišovicová N, Schindler D. Louis- Barové syndrom (ataxia teleangiectasia) v konsanguinní rodině. Čes Slov Pediat 2006; 61(11): 666– 668.

30. Callén E, Samper E, Ramírez MJ et al. Breaks and telomeres and TRF2- independent end fusions in Fanconi anemia. Hum Mol Genet 2002; 11(4): 439– 444.

31. Amor- Guéret M. Bloom syndrome, genomic instability and cancer: the SOS‑like hypothesis. Cancer Lett 2006; 236(1): 1– 12.

32. Gorlin RJ, Goltz RW. Multiple nevoid basal- cell epithelioma, jaw cysts and bifid rib: a syndrome. N Engl J Med 1960; 262: 908– 912.

33. Reis A, Küster W, Linss G et al. Localisation of gene for for naevoid basal- cell carcinoma syndrome. Lancet 1992; 339(8793): 617.

34. Hahn H, Gillies S, Negus K et al. Mutation of the human homolog of drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85(6): 841– 851.

35. Stone DM, Phillips H, Noll M et al. The tumour- suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996; 384(6605): 129– 134.

36. Cowan R, Hoban P, Kelsey A et al. The gene for the naevoid basal cell carcinoma syndrome acts as tumour- suppressor gene in medulloblastoma. Br J Cancer 1997; 76(2): 141– 145.

37. Featherstone T, Taylor AM, Harnden DG. Studies on the radiosensitivity of cells from patients with basal cell naevus syndrome. Am J Hum Genet 1983; 35(1): 58– 66.

38. Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities A possible mental retardation syndrome. Am J Dis Child 1963; 105: 588– 608.

39. Hennekam RC. Rubistein‑Taybi syndrome. Eur J Hum Genet 2006; 14(9): 981– 985.

40. Lacombe D, Saure R, Taine L et al. Confirmation of assigment of a locus for Rubistein‑Taybi syndrome gene to 16p13.3. Am J Med Genet 1992; 44(1): 126– 128.

41. Petrij F, Giles RH, Dauwerse HG et al. Rubistein‑Taybi syndrome caused by mutations in the transcriptional co‑activator CBP. Nature 1995; 376(6538): 348– 351.

42. Bartsch O, Schmidt S, Richter M et al. DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubistein‑Taybi syndrome (RSTS) and in another patient with incomplete RSTS. Hum Genet 2005; 117(5): 485– 493.

43. Miller RW, Rubinstein JH. Tumors in Rubistein‑Taybi syndrome. Am J Med Genet 1995; 56(1): 112– 115.

44. Kitao S, Shimamoto A, Goto M et al. Mutations in RECQL4 cause a subset of cases of Rothmund- Thomson syndrome. Nat Genet 1999; 22(1): 82– 84.

45. Cumin I, Cohen JY, David A et al. Rothmund- Thomson syndrome complicated by osteosacroma. Med Pediatr Oncol 1996; 26(6): 414– 416.

46. Piquero‑Casals J, Okubo AY, Nico MM. Rothmund- Thomson syndrome in three siblings and development of cutaneous squamous cell carcinoma. Pediatr Dermatol 2002; 19(4): 312– 316.

47. Wang LL, Levy ML, Lewis RA et al. Clinical manifestations in cohort of 41 Rothmund- Thomson syndrome patients. Am J Med Genet 2001; 102(1): 11– 17.

48. Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol 2010; 1(1): 2– 26.

49. Wittinghofer A. Signal transduction via Ras. Biol Chem 1998; 379(8– 9): 933– 937.

50. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011; 25(1): 161– 179.

51. Noonan JA, Ehmke DA. Associated non cardiac malformations in children with congenital hearth disease. J Pediatr 1963; 63: 468– 470.

52. Tartaglia M, Kalidas K, Shaw A et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype- phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70(6): 1555– 1563.

53. Graham JM Jr, Kramer N, Bejjani BA et al. Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome. Am J Med Genet A 2009; 149A(10): 2122– 2128.

54. Lepri F, De Luca A, Stella L et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype- phenotype correlations. Hum Mutat 2011; 32(7): 760– 762.

55. Pandit B, Sarkozy A, Pennacchio LA et al. Gain‑of- function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007; 39(8): 1007– 1012.

56. Schubbert S, Zenker M, Rowe SL et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006; 38(3): 331– 336.

57. Koudova M, Seemanova E, Zenker M. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur J Med Genet 2009; 52(5): 337– 340.

58. Martinelli S, De Luca A, Stellacci E et al. Heterozygous germline mutations in the CBL tumor- suppressor gene cause a Noonan syndrome‑like phenotype. Am J Hum Genet 2010; 87(2): 250– 257.

59. Cirstea IC, Kutsche K, Dvorsky R et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 2010; 42(1): 27– 29.

60. Kratz CP, Rapisuwon S, Reed H et al. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet 2011; 157(2): 83– 89.

61. Jongmans MC, van der Burgt I, Hoogerbrugge PM et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet 2011; 19(8): 870– 874.

62. Niihori T, Aoki Y, Narumi Y et al. Germline KRAS and BRAF mutations in cardio- facio- cutaneous syndrome. Nat Genet 2006; 38(3): 294– 296.

63. van Den Berg H, Hennekam RC. Acute lymphobastic leukaemia in a patient with cardiofaciocutaneous syndrome. J Med Genet 1999; 36(10): 799– 800.

64. Lin AE, Alexander ME, Colan SD et al. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/ MAPK pathway syndrome. Am J Med Genet A 2011; 155A(3): 486– 507.

65. Gripp KW. Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 2005; 137C(1): 72– 77.

66. Allanson JE, Hall JG, van Allen MI. Noona phenotype associated with neurofibromatosis. Am J Med Genet 1985; 21(3): 457– 462.

67. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda Md, USA, July 13– 15, 1987. Neurofibromatosis 1988; 1(3): 172– 178.

68. Opitz JM, Weaver DD. The neurofibromatosis- Noonan syndrome. Am J Med Genet 1985; 21(3): 477– 490.

69. Hüffmeier U, Zenker M, Hoyer J et al. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A 2006; 140(24): 2749– 2756.

70. Romano JA, Pierpont ME, Roberts AN et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010; 126(4): 746– 759.

71. Maertens O, Brems H, Vandesompele J et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 2006; 27(10): 1030– 1040.

72. Li W, Cui Y, Kushner SA et al. The HMG- CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15(21): 1961– 1967.