The Hereditary Syndromes

  • Nicola Carlomagno
  • Luigi Pelosio
  • Akbar Jamshidi
  • Marius Yabi
  • Francesca Duraturo
  • Paola Izzo
  • Andrea Renda
Part of the Updates in Surgery book series (UPDATESSURG)


Within the ambit of multiple tumors, an important issue is that of already identified hereditary syndromes, a group of anatomical-clinical entities that have been well distinguished and studied for years. Such diseases have a common etiopathogenetic mechanism, mostly represented by a genetic mutation. It is easy to understand how a patient, who has in his or her genetic history a genomic alteration, could develop multiple tumors.


Familial Adenomatous Polyposis Adenomatous Polyposis Coli Lynch Syndrome Adenomatous Polyposis Coli Gene Adenomatous Polyposis Coli Mutation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Renda A, Izzo P, D’Armeinto F et al (2004) Chirurgia oncologica “Dna-guidata”. Archivio e Atti SIC, Pozzi, Rome, 1:141–172Google Scholar
  2. 2.
    Rolandelli RH, Roslin JJ (2003) Colon. In: Sabiston DC (ed) Trattato di chirurgia. Le basi biologiche della moderna pratica chirurgica, prima edizione italiana sulla sedicesima americana. Delfino Editore, Rome, pp 662–696Google Scholar
  3. 3.
    Bertario L, Russo A, Sala P et al (2003) Multiple approach to the exploration of genotypephenotype correlations in familial adenomatous polyposis. J Clin Oncol 21(9): 1698–1707PubMedCrossRefGoogle Scholar
  4. 4.
    Soravia C, Berk T, Madlensky L et al (1998) Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62(6): 1290–1301PubMedCrossRefGoogle Scholar
  5. 5.
    Lal G, Gallinger S (2000) Familial adenomatous polyposis. Semin Surg Oncol 18(4):314–323PubMedCrossRefGoogle Scholar
  6. 6.
    Lynch HT, Smyrk TC, McGinn T et al (1995) Attenuated familial adenomatous polyposis (AFAP): a phenotipically and genotipically distinctive variant of FAP. Cancer 76:2427–2433PubMedCrossRefGoogle Scholar
  7. 7.
    Arvanitis ML, Jagelman DG, Fazio VW et al (1990) Mortality in patients with familial adenomatous polyposis. Dis Col & Rectum 33(8):639–642CrossRefGoogle Scholar
  8. 8.
    Giardiello FM, Brensinger JD, Tersmette AC et al (2000) Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119:1447–1453PubMedCrossRefGoogle Scholar
  9. 9.
    Lynch HT, Krush AJ (1971) Cancer family G revisited: 1895-1970. Cancer 27:1505–1511PubMedCrossRefGoogle Scholar
  10. 10.
    Warthin AS (1913) Heredity with reference to carcinoma. Arch Intern Med 12:546–555Google Scholar
  11. 11.
    Warthin AS (1925) The further study of a cancer family. J Cancer Res 9:279–286Google Scholar
  12. 12.
    Rijcken FE, Mourits MJ, Kleibeuker JH et al (2003) Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 91(1):74–80PubMedCrossRefGoogle Scholar
  13. 13.
    Moslein G (2003) Clinical implications of molecular diagnosis in hereditary nonpolyposis colorectal cancer. Recent Results Cancer Res 162:73–78PubMedGoogle Scholar
  14. 14.
    Moley JF, Wells SA Jr (2003) Ipofisi e surreni. In: Sabiston DC (ed) Trattato di chirurgia. Le basi biologiche della moderna pratica chirurgica, prima edizione italiana sulla sedicesima americana. Delfino Editore, Rome, pp 662–696Google Scholar
  15. 15.
    Lévy-Bohbot N, Merle C, Goudet P et al (2004) Prevalence, characteristics and prognosisof MEN 1-associated glucagonomas, VIPomas,and somatostatinomas Study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol 28:1075–1081PubMedCrossRefGoogle Scholar
  16. 16.
    Calender A, Cadiot G, Mignon M (2001) Néoplasie endocrinienne multiple de type 1: aspects génétiques et cliniques. Gastroenterol Clin Biol 25:B38–B48PubMedGoogle Scholar
  17. 17.
    Chanson P, Cadiot G, Murat A (1997) Management of patients and subjects at risk for multiple endocrine neoplasia type 1: MEN 1. GENEM 1. Groupe d’Etude des Neoplasies Endocriniennes Multiples de type 1. Horm Res 47:211–220PubMedCrossRefGoogle Scholar
  18. 18.
    Marx S, Spiegel AM, Skarulis MC et al (1998) Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 129:484–494PubMedGoogle Scholar
  19. 19.
    Cadiot G, Mignon M, Gresze (2003) Diagnostique des tumeurs endocrines de la région duodéno-pancréatique. Gastroenterol Clin Biol 27:S6–S14PubMedGoogle Scholar
  20. 20.
    Skogseid B, Oberg K, Benson L et al (1987) A standardized meal stimulation test of the endocrine pancreas for early detection of pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: five years experience. J Clin Endocrinol Metab 64:1233–1240PubMedCrossRefGoogle Scholar
  21. 21.
    Triponez F, Dosseh D, Goudet P et al (2006) Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg 243:265–272PubMedCrossRefGoogle Scholar
  22. 22.
    Brandi ML, Gagel RF, Angeli A et al (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671PubMedCrossRefGoogle Scholar
  23. 23.
    Doherty GM, Thompson NW (2003) Multiple endocrine neoplasia type 1: duodenopancreatic tumours. J Intern Med 253:590–598PubMedCrossRefGoogle Scholar
  24. 24.
    Wilkinson S, Teh BT, Davey KR et al (1993) Cause of death in multiple endocrine neoplasia type 1. Arch Surg 128:683–690PubMedGoogle Scholar
  25. 25.
    Dean PG, van Heerden JA, Farley DR et al (2000) Are patients with multiple endocrine neoplasia type I prone to premature death? World J Surg 24:1437–1441PubMedCrossRefGoogle Scholar
  26. 26.
    Ebeling T, Vierimaa O, Kyto S et al (2004) Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations. J Clin Endocrinol Metab 89(7):3392–3396PubMedCrossRefGoogle Scholar
  27. 27.
    Geerdink EAM, Van der Luijtl RB, Lips CJ (2003) Do patients with multiple endocrine neoplasia benefit from periodical screening? Eur J Endocrinol 149:577–582PubMedCrossRefGoogle Scholar
  28. 28.
    Marini F, Falchetti A, Del Monte F et al (2006) Multiple endocrine neoplasia type 2. Orphanet J Rare Dis 1:45PubMedCrossRefGoogle Scholar
  29. 29.
    Farnebo F, Kytola S, Teh BT et al (1999) Alternative genetic pathways in parathyroid tumorigenesis. J Clin Endocrinol Metab 84:3775–3780PubMedCrossRefGoogle Scholar
  30. 30.
    Lips CJ, Landsvater RM, Hoppener JW et al (1994) Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331:828–835PubMedCrossRefGoogle Scholar
  31. 31.
    Robinson MF, Furst EJ, Nunziata V et al (1992) Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2. Henry Ford Hosp Med J 40:249–252PubMedGoogle Scholar
  32. 32.
    Brandi ML, Gagel RF, Angeli A et al (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671PubMedCrossRefGoogle Scholar
  33. 33.
    Papotti M, Botto Micca F et al (1993) Poorly differentiated thyroid carcinomas with primordial cell component. A group of aggressive lesions sharing insular, trabecular, and solid patterns. Am J Surg Pathol 17:291–301PubMedCrossRefGoogle Scholar
  34. 34.
    Carling T (2005) Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin Oncol 17:7–12PubMedCrossRefGoogle Scholar
  35. 35.
    Eng C (1996) The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med 335:943–951PubMedCrossRefGoogle Scholar
  36. 36.
    Dralle H, Gimm O, Simon D et al (1998) Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 22:744–750PubMedCrossRefGoogle Scholar
  37. 37.
    Neumann HP, Bausch B, McWhinney SR et al (2002) Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. “Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466PubMedCrossRefGoogle Scholar
  38. 38.
    Yarden RI, Papa MZ (2006) BRCA1 at the crossroad of multiple cellular pathways: approaches for therapeutic interventions. Mol Cancer Ther 5(6): 1396–1404PubMedCrossRefGoogle Scholar
  39. 39.
    Schmeler KM, Sun CC, Bodurka DC et al (2006) Prophylactic bilateral salpingo-oophorectomy compared with surveillance in women with BRCA mutations. Obstet Gynecol 108:515–520PubMedGoogle Scholar
  40. 40.
    Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689PubMedCrossRefGoogle Scholar
  41. 41.
    Struewing JP, Hartge P, Wacholder S et al (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401–1408PubMedCrossRefGoogle Scholar
  42. 42.
    Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130PubMedCrossRefGoogle Scholar
  43. 43.
    Eisinger F (1998) Recommendations for medical management of hereditary breast and ovarian cancer: The French National Ad Hoc Committee. Ann Oncol 9:939–950PubMedCrossRefGoogle Scholar
  44. 44.
    Robson ME (2002) Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer. Cancer Control 6:457–465Google Scholar
  45. 45.
    Peterson G (1999) Genetic testing for cancer: the surgeon’s critical role. Clinical cancer genetics: 1998 (what’s available to you in your practice). J Am Coll Surg 188(1):89–93PubMedGoogle Scholar
  46. 46.
    Hernegger GS, Moore HG, Guillem JG (2002) Attenuated familial adenomatous polyposis: an evolving and poorly understood entity. Dis Colon Rectum 45:127–136PubMedCrossRefGoogle Scholar
  47. 47.
    Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 348:709–715CrossRefGoogle Scholar
  48. 48.
    Ames BN, Gold LS (1991) Endogenous mutagens and the causes of aging and cancer. Mutat Res 250:3–16PubMedGoogle Scholar
  49. 49.
    Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited variants of MYH associated with somatic G:C fi T:A mutations in colorectal tumors. Nat Genet 30:227–232PubMedCrossRefGoogle Scholar
  50. 50.
    Enholm S, Hienonen T, Suomalainen A et al (2003) Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finish colorectal cancer patients. Am J Pathol 163:827–832PubMedGoogle Scholar
  51. 51.
    Halford SE, Rowan AJ, Lipton L et al (2003) Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Am J Pathol 162:1545–1548PubMedGoogle Scholar
  52. 52.
    Jones S, Emmerson P, Maynard J et al (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C fi T:A mutations. Hum Mol Genet 11:2961–2967PubMedCrossRefGoogle Scholar
  53. 53.
    Sampson JR, Dolwani S, Jones S et al (2003) Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362:39–41PubMedCrossRefGoogle Scholar
  54. 54.
    Sieber OM, Lipton L, Crabtree M et al (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348:791–799PubMedCrossRefGoogle Scholar
  55. 55.
    Venesio T, Molatore S, Cattaneo F et al (2004) High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis. Gastroenterology 126:1681–1685PubMedCrossRefGoogle Scholar
  56. 56.
    Jones S, Lambert S, Williams GT et al (2004) Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Br J Cancer 90:1591–1593PubMedCrossRefGoogle Scholar
  57. 57.
    Leite JS, Isidro G, Martins M et al (2005) Is prophylactic colectomy indicated in patients with MYH-associated polyposis? Colorectal Dis 7:327–331PubMedCrossRefGoogle Scholar
  58. 58.
    Chandrasekharappa SC, Guru SC, Manickam P et al (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407PubMedCrossRefGoogle Scholar
  59. 59.
    Lemmens I, Van de Ven WJ, Kas K et al (1997) Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN 1. Hum Mol Genet 6:1177–1183Google Scholar
  60. 60.
    Schnepp RW, Chen YX, Wang H et al (2006) Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 66(11):5707–5715PubMedCrossRefGoogle Scholar
  61. 61.
    Agarwal SK, Novotny EA, Crabtree JS et al (2003) Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter. Proc Natl Acad Sci USA 100:10770–10775PubMedCrossRefGoogle Scholar
  62. 62.
    Kaji H, Canaff L, Lebrun JJ et al (2001) Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type h signalling. Proc Natl Acad Sci USA 98:3837–3842PubMedCrossRefGoogle Scholar
  63. 63.
    Schnepp RW, Hou Z, Wang H et al (2004) Functional interaction between tumor suppressor menin and activator of S-phase kinase. Cancer Res 64:6791–6796PubMedCrossRefGoogle Scholar
  64. 64.
    Kumagai H, Sato N, Yamada M et al (1999) A novel growth-and cell cycle-regulatedprotein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells. Mol Cell Biol 19:5083–5095PubMedGoogle Scholar
  65. 65.
    Masai H, Matsui E, You Z et al (2000) Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a critical threonine residue of Cdc7 bY Cdks. J Biol Chem 275:42–52CrossRefGoogle Scholar
  66. 66.
    Howe JR, Moley JF, Goodfellow P, Wells SA Jr (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856PubMedCrossRefGoogle Scholar
  67. 67.
    Mulligan LM, Kwok JB, Healey CS et al (1993) Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460PubMedCrossRefGoogle Scholar
  68. 68.
    Da Silva AM, Maciel RM, Da Silva MR et al (2003) A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab 88:5438–5443PubMedCrossRefGoogle Scholar
  69. 69.
    Jing S, Wen D, Yu Y et al (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85:1113–1124PubMedCrossRefGoogle Scholar
  70. 70.
    Santoro M, Melillo RM, Carlomagno F et al (2004) RET: normal and abnormal functions. Endocrinology 145:5448–5451PubMedCrossRefGoogle Scholar
  71. 71.
    Santoro M, Carlomagno F, Melillo RM, Fusco A (2004) Dysfunction of the RET receptor in human cancer. Cell Mol Life Sci 61:2954–2964PubMedCrossRefGoogle Scholar
  72. 72.
    Jain S, Watson MA, DeBenedetti MK et al (2004) Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Res 64:3907–3913PubMedCrossRefGoogle Scholar
  73. 73.
    Thull DL, Vogel VG (2004) Recognition and management of hereditary breast cancer syndromes. Oncologist 9:13–24PubMedCrossRefGoogle Scholar
  74. 74.
    Carlomagno N, Scarano MI, Gargiulo S et al (2001) Familial colonic polyposis: effect of molecular analysis on the diagnostic-therapeutic approach. Ann Ital Chir 72(2):207–214PubMedGoogle Scholar
  75. 75.
    Traboulsi EI, Apostolides J, Giardiello FM et al (1996) Pigmented ocular fundus lesions and APC mutations in familial adenomatous polyposis. Ophthalmic Genet 17(4): 167–174PubMedCrossRefGoogle Scholar
  76. 76.
    Olschwang S, Laurent-Puig P, Thuille B et al (1992) Frequent polymorphism in the 13th exon of the adenomatous polyposis coli gene. Hum Genet 90:161–163PubMedCrossRefGoogle Scholar
  77. 77.
    Nagase H, Miyoshi Y, Horii A et al (1992) Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 52:4055–4057PubMedGoogle Scholar
  78. 78.
    Wu JS, Mc Gannon EA, Church JM (1998) APC genotype, polyp number and surgical options in familial adenomatous polyposis. Ann Surg 227:57–62PubMedCrossRefGoogle Scholar
  79. 79.
    Nordling M, Engwall Y, Wahistrom J et al (1997) Novel mutations in APC gene and clinical features in Swedish patients with polyposis coli. Am Cancer Res 17:4275–4280Google Scholar
  80. 80.
    Caspari R, Friedi W, Mandl M et al (1994) Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet 343:629–632PubMedCrossRefGoogle Scholar
  81. 81.
    Presciuttini S, Varesco L, Sala P et al (1994) Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations. Ann Hum Genet 58:331–342PubMedCrossRefGoogle Scholar
  82. 82.
    Giardiello FM, Krush AJ, Petersen GM et al (1994) Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC gene mutation. Gastroenterology 106(6): 1542–1547PubMedGoogle Scholar
  83. 83.
    Giardiello FM, Brensinger JD, Luce MC et al (1997) Phenotypic expression of disease in families that have mutations in the 5’ region of the adenomatous polyposis coli gene. Ann Intern Med 126(7):514–519PubMedGoogle Scholar
  84. 84.
    Cunningham C, Dunlop MG (1996) Molecular genetic basis of colo-rectal cancer susceptibility. Br J Surg 83:321–329PubMedCrossRefGoogle Scholar
  85. 85.
    Leggett BA, Young IP, Biden K et al (1997) Severe upper gastrointestinal polyposis associated with sparse colonie polyposis in a familial adenomatous polyposis family with an APC mutation at codon 1250. Gut 41:518–521PubMedCrossRefGoogle Scholar
  86. 86.
    Nugent KP, Phillips RK, Hodgson SV et al (1994) Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis. Gut 35:1622–1623PubMedCrossRefGoogle Scholar
  87. 87.
    Spirio L, Otterud B, Stauffer D et al (1992) Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 51(1):92–100PubMedGoogle Scholar
  88. 88.
    Olschwang S, Tiret A, Laurent-Puig P et al (1993) Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell 75(5):959–968PubMedCrossRefGoogle Scholar
  89. 89.
    Caspari R, Olschwang S, Friedl W et al (1995) Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet 4(3):337–340PubMedCrossRefGoogle Scholar
  90. 90.
    Davies DR, Armstrong JG, Thakker N et al (1995) Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 57(5):1151–1158PubMedGoogle Scholar
  91. 91.
    Moisio A-L, Jarvinen H, Peltomaki P (2002) Genetic and clinical characterisation of familial adenomatous polyposis: a population-based study. Gut 50:845–850PubMedCrossRefGoogle Scholar
  92. 92.
    Gebert JF, Dupon C, Kadmon M et al (1999) Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg 229:350–361PubMedCrossRefGoogle Scholar
  93. 93.
    Friedl W, Caspari R, Sengteller M et al (2001) Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 48:515–521PubMedCrossRefGoogle Scholar
  94. 94.
    Matsumoto T, Lida M, Kobori Y et al (2002) Genetic predisposition to clinical manifestations in familial adenomatous polyposis with special reference to duodenal lesions. Am J Gastroenterol 97:180–185PubMedCrossRefGoogle Scholar
  95. 95.
    Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96(4):261–268PubMedCrossRefGoogle Scholar
  96. 96.
    Eccles DM (2004) Hereditary cancer: guidelines in clinical practice. Breast and ovarian cancer genetics Ann Oncol 15(Suppl 4): iv133–iv138Google Scholar

Copyright information

© Springer-Verlag Italia 2009

Authors and Affiliations

  • Nicola Carlomagno
    • 1
  • Luigi Pelosio
    • 1
  • Akbar Jamshidi
    • 1
  • Marius Yabi
    • 1
  • Francesca Duraturo
    • 2
  • Paola Izzo
    • 2
  • Andrea Renda
    • 1
  1. 1.Surgical, Anesthesiology-rianimative and Emergency Sciences DepartmentFederico II UniversityNaplesItaly
  2. 2.Department of Biochemistry and Biomedical TechnologiesFederico II UniversityNaplesItaly

Personalised recommendations