Developing Effective Screening Strategies in Multiple Endocrine Neoplasia Type 1 (MEN 1) on the Basis of Clinical and Sequencing Data of German Patients with MEN 1

Abstract

Background: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting.

Objective: To optimize screening and to analyze possible differences in sporadic versus familial cases.

Methods: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families).

Results: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus.

Conclusion: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Key words

Multiple endocrine neoplasia type 1 - German MEN 1 Register - MEN 1 phenotype/genotype - endocrine tumors - screening

References

• 1 Agarwal S, Kester MB, Debelenko LV, Heppner C, Emmeret-Buck MR, Skarulis MC, Doppmann JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type1 and related states.  Human molecular genetics. 1997;  6 1169-1175
• 2 Bassett JH, Forbes SH, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV. Characterization of mutations in patients with multiple endocrine neoplasa type 1.  American journal of human genetics. 1998;  6 232-244
• 3 Bordi C, Falchetti A, Azzoni C, D’Adda T, Canavese G, Guariglia A, Santini D, Tomassetti P, Brandi ML. Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type 1.  The American journal of surgical pathology. 1998;  21 1075-1082
• 4 Brandi M, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Cheri RG, Libroia A, Lips CJM, Gaetano L, Mannelli M, Pacini F, Ponder PAJ, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. Guidlines for Diagnosis and Therapy of MEN Type 1 and Type 2.  The Journal of clinical endocrinology and metabolism. 2001;  86 5658-5671
• 5 Burgess J, Greenaway TM, Shepherd JJ. Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1.  Journal of Internal Medicine. 1998;  243 465-470
• 6 Calender A, Giraud S, Cougard P, Chanson P, Lenoir G, Murat A, Hamon P, Proye C. Multiple endocrine neoplasia type 1 in France: clinical and genetic studies.  Journal of Internal Medicine. 1995;  238 263-268
• 7 Calender A. Genetic testing in multiple endocrine neoplasia and related syndromes.  Forum (Genova). 1998;  8 146-159
• 8 Cardinal JW, Bergman L, Hayward N, Sweet A, Warner J, Marks L, Learoyd D, Dwight T, Robinson B, Epstein M, Smith M, The BT, Cameron DP, Prins JB. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing.  Journal of Medical Genetics. 2005;  42 69-74
• 9 Chandrasekharappa S, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Lee Burns A, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia type 1.  Science. 1997;  276 404-407
• 10 Chanson P, Cadiot G, Murat A. Management of patients and subjects at risk for multiple endocrine neoplasia type 1: MEN1 GENEM 1. Groupe d’Etudes des Neoplasies Endocriniennes Multiples de type 1.  Hormone research. 1997;  47 211-220
• 11 Chico A, Gallart L, Martin-Campos JM, Catasus L. Genetic, clinical, and biochemical analysis of unrelated Spanish families with multiple endocrine neoplasia type 1.  Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2000;  6 13-19
• 12 Chigot J, Bendib S, Turpin G, Benlian P. Characteristic pathological associations in multiple endocrine neoplasia type 1.  Presse medicale. 1996;  21 ((25)) 1229-1233
• 13 Choi J, MacHugh RB. A reduction factor in goodness-of-it and indepence tests for clustered and weighted observations.  Biometrics. 1989;  45 979-996
• 14 Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Cicarelli E, Brue T, Ferolla P, Emy P, Colao A, De Menis E, Lecompte P, Penfornis F, Delemer B, Bertherat J, Wémau JL, De Herder W, Archambeaud F, Stevenaert A, Calender A, Murat A, Cavagnini F, Beckers A. Clinical Characterization of Familial Isolated Pituitary Adenomas.  J Clin Endocrin Metab. 2006;  , [published ahaed of print].
• 15 Darling T, Skarulis MC, Steinberg SM. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.  Archives of dermatology. 1997;  133 853-857
• 16 Dean PG, Heerden JA van, Farley DR, Thompson GB, Grant CS, Harmsen WS, Ilstrup DM. Are patients with multiple endocrine neoplasia type 1 prone to premature death?.  World journal of surgery. 2000;  24 1437-1441
• 17 Debelenko L, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, Emmert-Buck MR. Identification of MEN 1 gene mutations in sporadic, carcinoid tumors of lung.  Human molecular genetics. 1997;  6 2285-2290
• 18 Doherty G, Olson JA, Frisella MM, Lairmore TC, Wells SA Jr, Norton JA. Lethality of multiple endocrine neoplasia type 1.  World journal of surgery. 1998;  22 581-586
• 19 Doppmann J. Tumor localization in multiple endocrine neoplasia type 1. 487-488. In Marx SJ, moderator. Multiple endocrine neoplasia type 1: Clinical and genetic topics.  Annals of internal medicine. 1998;  129 484-494
• 20 Ellard S, Hattersley AT, Brewert CM, Vaidya B. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostik molecular genetic testing.  Clinical Endocrinology. 2005;  62 169-175
• 21 Evans C, Brown MR, Parks JS, Oyesiku NM. Screening for MEN1 tumor suppressor gene mutations in sporadic pituitary tumors.  Journal of endocrinological investigation. 2000;  23 304-309
• 22 Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamurrano G, Avenia N, Daddi G, Puma F, Ribacchi R, Santeusanio F, Angeletti G, Brandi ML. Thymic neuroendocrine carcinoma (Carcinoid) in multiple endocrine neoplasia type 1 syndrome: the italian series.  The Journal of Clinical Endocrinology & Metabolism. 2004;  90 ((5)) 2603-2609
• 23 Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, Ito K, Shingu K, Kobayashi S, Amano J, Fukushima Y. Novel V184E MEN1 germline mutation in a japanese kindred with familial hyperparathyroidism.  American Journal of medical genetics. 1998;  80 221-222
• 24 Fukino K. Analysis of the MEN 1 gene in sporadic pituitary adenomas from Japanese patients.  Cancer letters. 1999;  144 85-92
• 25 Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Calender A. Germ-line mutation analysis of the multiple endocrine neoplasia type 1 and related disorders.  American journal of human genetics. 1998;  63 455-467
• 26 Guru S, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC. Menin, the product of the MEN1 gene, is a nuclear protein.  Proceedings of the National Academy of Sciences of the United States of America. 1998;  17 ((95)) 1630-1634
• 27 Hellman P, Hennings J, Akerstrom G, Skogseid B. Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1.  Br J Surg. 2005;  92 ((12)) 1508-1512
• 28 Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppmann JL, Alexander RH, Kim YS, Saggar SK, Lubensky IA, Zhuang Z, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ. Somatic mutation of the MEN 1 gene in parathyroid tumors.  Nature genetics. 1997;  16 375-378
• 29 Jäger AC, Lennart FH, Hansen Th, Andersen PH, Brixen K, Reldt-Rasmussen U, Kroustrup JP, Mollerup ChL, Rehfeld JF, Blichert-Tof M, Nielsen FC. Characteristics of the Danish families with multiple endocrine neoplasia type 1.  Molecular and Cellular Endocrinology. 2006;  249 ((1-2)) 123-132
• 30 Johnston L, Chew SL, Lowe D, Reznek R, Monson JP, Savage MO. Investigating familial endocrine neoplasia syndromes in children.  Hormone research. 2001;  55 31-35
• 31 Kann PH. Endoskopische Bildgebung bei neuroendokrinen Pankreastumoren. Eine kritische Bestandsaufnahme.  Medizinische Klinik. 2006;  101 546-551
• 32 Karges W, Schaaf L, Dralle H, Boehm BO. Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1).  Experimental and Clinical Endocrinology & Diabetes. 2000;  108 334-340
• 33 Kassem MZX, Brask S, Eriksen EF, Mosekilde L, Kruse TA. Familial isolated primary hyperparathyroidism.  Clinical endocrinology. 1994;  41 415-420
• 34 Langer P, Wild A, Hall A, Celik I, Rothmund M, Bartsch DK. Prevalence of multiple endocrine neoplasia type 1 in young patients with apparently sporadic primary hyperparathyroidism or pancreaticoduodenal endocrine tumors.  The British journal of surgery. 2003;  90 1599-1603
• 35 Langer P, Cupisti, Bartsch DK, Nies C, Goretzki PE, Rothmund M, Roher HD. Adrenal involvement in mutiple endocrine neoplasia type 1.  World journal of surgery. 2002;  26 891-896
• 36 Lemmens I, Ven WJ Van de, Kas K, Zhang ZX, Geraud S, Wautot V, Buisson N, De Witte K, Salndre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Witt MJ, Lips CJ, Hoeppner JW, Khodaei S, Grant AL, Weber G, Kyolta S, Teh BT, Farnebo F, Thakker RV. Identification of the multiple endocrine neoplasia type 1 gene. The European Consortium on MEN1.  Human Molecular Genetics. 1997;  6 1177-1183
• 37 Majewski JWSD. The MEN1 syndrome an all-or-none phenomenon.  Surgery. 1979;  86 475-484
• 38 Marx SJ, Vinik AJ, Santen RJ. Multiple endocrine neoplasia type 1: assessment of laboratory tests to screen for the gene in large kindred.  Medicine. 1986;  65 226-241
• 39 Marx SJ, Agarwal SK, Heppner C, Kim YS, Kester MB, Goldsmith PK, Skarulis MC, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree JS, Collins FS, Chandrasekharappa SC. The gene for multiple endocrine neoplasia type 1: recent findings.  Bone. 1999;  1
• 40 Marx S, Spiegel AM, Skarulis MC, Doppmann JL, Collins FS, Liotta LA. Endocrine neoplasia type 1: clinical and genetic topics.  Annals of internal medicine. 1998;  129 484-494
• 41 Mayr B, Apenberg S, Rothamel T, Mühlen A von zur, Brabant G. Menin mutations in patients with multiple endocrine neoplasia type 1.  European journal of endocrinology/European Federation of Endocrine Societies. 1997;  137 684-687
• 42 MacKeeby JL, Li X, Zhuang Z, Vortmayer AO, Huang S, Pirner M, Skarulis MC, James-Newton L, Marx SJ, Lubensky IA. Multiple leiomyomas of oesophagus, lung and uterus in multiple endocrine neoplasia type 1.  The American journal of pathology. 2001;  159 1121-1127
• 43 Miedlich S, Lohmann T, Schneyer U, Lamesch P, Paschke R. Familial isolated primary hyperparathyroidism-a multiple endocrine neoplasia type 1 variant?.  European journal of endocrinology/European Federation of Endocrine Societies. 2001;  145 155-160
• 44 Murat A, Heymann MF, Bernat S, Dupas B, Delajartre AY, Calender A, Despins P, Michaud JL, Giraud S, Le Bodic MF, Charbonnel B. Thymic and bronchial neuroendocrine tumors in multiple neoplasia type 1.  Presse medicale. 1997;  8 ((26)) 1616-1621
• 45 Mutch MG, Dilley WG, Sanjurjo F, DeBenedetti MK, Doherty GM, Wells SA Jr, Goodfellow PJ, Lairmore TC. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.  Human mutation. 1999;  13
• 46 Ohye H, Sato M, Matsubara S, Miyauchi A, Imachi H, Murao K, Takahara J. Germline mutation of the multiple endocrine neoplasia type 1 gene in a family with primary hyperparathyroidism.  Endocrine journal. 1998;  45 719-723
• 47 Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB, Dong Q, Burns AL, Spiegel AM, Marx SJ, Collins FS, Chandrasekharappa SC. Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1 Burin) in four kindreds from Newfoundland.  Human mutation. 1998;  11 264-269
• 48 Poncin J, Stevenaert A, Beckers A. MEN1 gene mutation does not contribute to sporadic pituitary tumor genesis.  European journal of endocrinology/European Federation of Endocrine Societies. 1999;  140 573-576
• 49 Royall RM. Model robust confidence intervals using maximum likehood estimators.  International Statistical Review. 1986;  54 221-226
• 50 Samaan NA, Quais S, Ordonez NG, Choksi UA, Sellin RV, Hickey RC. Multiple endocrine neoplasia type 1: clinical, laboratory findings, and management in five families.  Cancer. 1989;  64 741-752
• 51 Sato M, Kihara M, Nishitani A, Murao K, Kobayashi S, Miyauch A, Takahara J. Large and asymptomatic pancreatic islet cell tumor in a patient with muliple endocrine neoplasia type 1.  Endocrine. 2000;  13 263-266
• 52 Skogseid B, Erikson B, Lundqvist G, Lorelius LE, Rastad J, Wide L, Akerstrom G, Oberg K. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds.  The Journal of clinical endocrinology and metabolism. 1991;  73 281-287
• 53 Skogseid B, Rastad J, Oberg K. Multiple endocrine neoplasia type 1: clinical features and screening.  Endocrinology and metabolism clinics of North America. 1994;  23 1-18
• 54 Stock JL, Warth MR, Teh BT, Coderre JA, Overdorf JH, Baumann G, Hintz RL, Hartmann ML, Seizinger BR, Larsson C, Aronin N. A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors not linked to the MEN1 locus at chromosome region 11q13.  The Journal of clinical endocrinology and metabolism. 1997;  82 486-492
• 55 Tanaka C, Yoshimoto K, Yamada S, Nishioka H, Li S, Moritani M, Yamaoka T, Itakura M. Absence of germline mutations of the multiple endocrine neoplasia type 1 gene in familial pituitary adenoma in contrast to MEN1 in Japanese.  The Journal of clinical endocrinology and metabolism. 1998;  82 960-965
• 56 Teh BT, MacArdle J, Parameswaran V, David R, Larsson C, Shepherd J. Sporadic prmary hyperparathyroidism in the settings of multiple endocrine neoplasia type 1.  Archives of surgery. 1996;  131 1230-1232
• 57 Teh BT. Clinopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1.  Medicine. 1997;  76 21-29
• 58 Teh BT, Zedenius J, Kyolta S, Skogseid B, Trotter J, Choplin H, Twigg S, Farnebo F, Giraud S, Cameron D, Robinson B, Calender A, Larsson C, Salmela P. Thymic carcinoids in multiple endocrine neoplasia type 1.  Journal of Internal Medicine. 1998;  243 501-504
• 59 Teh BT, Kytola S, Farnebo F, Bergmann L, Wong FK, Weber G, Hayward NK, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stweward C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Salmela P, Larsson C. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly, and familial isolated hyperparathyroidism.  The Journal of clinical endocrinology and metabolism. 1998;  83 2621-2626
• 60 Thomas-Marques L, Murat A, Delemer B, Penfornis A, Cardot-Bauters C, Baudin E, Niccoli-Sire P, Levoir D, Choplin HB, Chabre O, Jovenin N, Cadiot G. Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1.  Am J Gastroenterol. 2006;  101 ((2)) 266-273
• 61 Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O’Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV. Clinical studies of multiple endocrine neoplasia type 1.  The Quarterly journal of medicine. 1996;  89 653-669
• 62 Vasen HFA, Lamers CBHW, Lips CJM. Screening for the multiple endocrine neoplasia type 1. A study of 11 kindreds in the Netherlands.  Archives of internal medicine. 1989;  149 2717-2722
• 63 Verges B, Bourreille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chame B, Montvernay C, Calender A. Pituitary disease in men type 1 (MEN1): data from France- Belgium-MEN1 multicenter study.  The Journal of clinical endocrinology and metabolism. 2002;  87 457-465
• 64 Villablanca A, Wassif WS, Smith T, Hoog A, Vierimaa O, Kassem M, Dwight T, Forsberg L, Du Q, Learoyd D, Jones K, Stranks S, Juhlin C, Teh BT, Carling T, Robinson B, Larsson C. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism.  European journal of endocrinology/European Federation of Endocrine Societies. 2002;  147 313-322
• 65 Wermer P. Genetic aspects of adenomatosis of endocrine glands.  The American journal of medicine. 1954;  16 363-371
• 66 Wilkinson S. Cause of Death in Multiple Endocrine Neoplasia Type 1.  Archives of surgery. 1993;  128 683-690

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