Horm Metab Res 2005; 37(6): 347-354
DOI: 10.1055/s-2005-870135
Review
© Georg Thieme Verlag KG Stuttgart · New York

Clinical and Genetic Features of Familial Pituitary Adenomas

A.  F.  Daly1 , M.-L.  Jaffrain-Rea2 , A.  Beckers1
  • 1Department of Endocrinology, C.H.U. de Liège, Liège, Belgium
  • 2Department of Experimental Medicine, University of l’Aquila, Italy
Further Information

Publication History

Received 24 December 2004

Accepted after revision 30 January 2005

Publication Date:
07 July 2005 (online)

Abstract

Inherited or familial pituitary tumor syndromes such as multiple endocrine neoplasia type 1 and Carney complex provide an important insight into the genetics and molecular pathology of endocrine cancers. Our understanding of these conditions is expanding rapidly due to the identification of the genes and proteins affected and the availability of murine knockout models. The successes achieved to date in understanding multiple endocrine neoplasia type 1 and Carney complex have helped in the identification and study of new inherited pituitary tumor syndromes such as isolated familial somatotropinomas. This review assesses the current status of research into the clinical features, genetics and molecular pathologies of multiple endocrine neoplasia type 1, Carney complex, and isolated familial somatotropinomas, and details ongoing work to delineate familial isolated pituitary adenomas, a potentially new clinical entity.

References

  • 1 Agarwal S K, Lee Burns A, Sukhodolets K E, Kennedy P A, Obungu V H, Hickman A B, Mullendore M E, Whitten I, Skarulis M C, Simonds W F, Mateo C, Crabtree J S, Scacheri P C, Ji Y, Novotny E A, Garrett-Beal L, Ward J M, Libutti S K, Richard Alexander H, Cerrato A, Parisi M J, Santa Anna A S, Oliver B, Chandrasekharappa S C, Collins F S, Spiegel A M, Marx S J. Molecular pathology of the MEN1 gene.  Ann N Y Acad Sci. 19;  1014 189-98
  • 2 Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.  Nature. 1988;  332 85-87
  • 3 Chandrasekharappa S C, Guru S C, Manickam P, Olufemi S E, Collins F S, Emmert-Buck M R, Debelenko L V, Zhuang Z, Lubensky I A, Liotta L A, Crabtree J S, Wang Y, Roe B A, Weisemann J, Boguski M S, Agarwal S K, Kester M B, Kim Y S, Heppner C, Dong Q, Spiegel A M, Burns A L, Marx S J. Positional cloning of the gene for multiple endocrine neoplasia-type 1.  Science. 1997;  276 404-407
  • 4 Online Mendelian Inheritance in Man (OMIM) Entry 131 100 .Multiple Endocrine Neoplasia, Type I; MEN1 Menin. OMIM (TM). Johns Hopkins University, Baltimore, MD. http://www.ncbi.nlm.nih.gov/omim
  • 5 Fromaget M, Vercherat C, Zhang C X, Zablewska B, Gaudray P, Chayvialle J A, Calender A, Cordier-Bussat M. Functional characterization of a promoter region in the human MEN1 tumor suppressor gene.  J Mol Biol. 2003;  333 87-102
  • 6 Sayo Y, Murao K, Imachi H, Cao W M, Sato M, Dobashi H, Wong N C, Ishida T. The multiple endocrine neoplasia type 1 gene product, menin, inhibits insulin production in rat insulinoma cells.  Endocrinology. 2002;  143 2437-2440
  • 7 La P, Schnepp R W, Petersen C D, Silva A C, Hua X. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2.  Endocrinology. 2004;  145 3443-3450
  • 8 Namihira H, Sato M, Murao K, Cao W M, Matsubara S, Imachi H, Niimi M, Dobashi H, Wong N C, Ishida T. The multiple endocrine neoplasia type 1 gene product, menin, inhibits the human prolactin promoter activity.  J Mol Endocrinol. 2002;  29 297-304
  • 9 Wautot V, Vercherat C, Lespinasse J, Chambe B, Lenoir G M, Zhang C X, Porchet N, Cordier M, Beroud C, Calender A. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.  Hum Mutat. 2002;  20 35-47
  • 10 Pannett A AJ, Thakker R V. Multiple endocrine neoplasia type 1.  Endocr Rel Cancer. 1999;  6 449-473
  • 11 Hai N, Aoki N, Shimatsu A, Mori T, Kosugi S. Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1.  Clin Endocrinol (Oxf). 2000;  52 509-518
  • 12 Burgess J R, Nord B, David R, Greenaway T M, Parameswaran V, Larsson C, Shepherd J J, Teh B T. Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN1).  Clin Endocrinol (Oxf). 2000;  53 205-211
  • 13 Poisson A, Zablewska B, Gaudray P. Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1.  Cancer Lett. 2003;  189 1-10
  • 14 Agarwal S K, Novotny E A, Crabtree J S, Weitzman J B, Yaniv M, Burns A L, Chandrasekharappa S C, Collins F S, Spiegel A M, Marx S J. Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter.  PNAS. 2003;  100 10 770-10 775
  • 15 Heppner C, Bilimoria K Y, Agarwal S K, Kester M, Whitty L J, Guru S C, Chandrasekharappa S C, Collins F S, Spiegel A M, Marx S J, Burns A L. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation.  Oncogene. 2001;  20 4917-4925
  • 16 Kaji H, Canaff L, Lebrun J J, Goltzman D, Hendy G N. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling.  Proc Natl Acad Sci USA. 2001;  98 3837-3842
  • 17 Schnepp R W, Hou Z, Wang H, Petersen C, Silva A, Masai H, Hua X. Functional interaction between tumor suppressor menin and activator of S-phase kinase.  Cancer Res. 2004;  64 6791-6796
  • 18 La P, Silva A C, Hou Z, Wang H, Schnepp R W, Yan N, Shi Y, Hua X. Direct binding of DNA by tumor suppressor menin.  J Biol Chem. 2004;  279 49 045-49 054
  • 19 Schnepp R W, Mao H, Sykes S M, Zong W X, Silva A, La P, Hua X. Menin induces apoptosis in murine embryonic fibroblasts.  J Biol Chem. 2004;  279 10 685-10 691
  • 20 Guru S C, Goldsmith P K, Burns A L, Marx S J, Spiegel A M, Collins F S, Chandrasekharappa S C. Menin, the product of the MEN1 gene, is a nuclear protein.  Proc Natl Acad Sci USA. 1998;  95 1630-1634
  • 21 Stewart C, Parente F, Piehl F, Farnebo F, Quincey D, Silins G, Bergman L, Carle G F, Lemmens I, Grimmond S, Xian C Z, Khodei S, Teh B T, Lagercrantz J, Siggers P, Calender A, Van de Vem V, Kas K, Weber G, Hayward N, Gaudray P, Larsson C. Characterization of the mouse Men1 gene and its expression during development.  Oncogene. 1998;  17 2485-2493
  • 22 Crabtree J S, Scacheri P C, Ward J M, Garrett-Beal L, Emmert-Buck M R, Edgemon K A, Lorang D, Libutti S K, Chandrasekharappa S C, Marx S J, Spiegel A M, Collins F S. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.  Proc Natl Acad Sci USA. 2001;  98 1118-1123
  • 23 Bertolino P, Tong W M, Galendo D, Wang Z Q, Zhang C X. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1.  Mol Endocrinol. 2003;  17 1880-1892
  • 24 Bertolino P, Radovanovic I, Casse H, Aguzzi A, Wang Z Q, Zhang C X. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs.  Mech Dev. 2003;  120 549-560
  • 25 Biondi C A, Gartside M G, Waring P, Loffler K A, Stark M S, Magnuson M A, Kay G F, Hayward N K. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues.  Mol Cell Biol. 2004;  24 3125-3131
  • 26 Zhuang Z, Vortmeyer A O, Pack S, Huang S, Pham T A, Wang C, Park W S, Agarwal S K, Debelenko L V, Kester M, Guru S C, Manickam P, Olufemi S E, Yu F, Heppner C, Crabtree J S, Skarulis M C, Venzon D J, Emmert-Buck M R, Spiegel A M, Chandrasekharappa S C, Collins F S, Burns A L, Marx S J, Lubensky I A. et al . Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas.  Cancer Res. 1997;  57 4682-4686
  • 27 Ramsdell J S. Transforming growth factor-alpha and -beta are potent and effective inhibitors of GH4 pituitary tumor cell proliferation.  Endocrinology. 1991;  128 1981-1990
  • 28 Lacerte A, Lee E H, Reynaud R, Canaff L, De Guise C, Devost D, Ali S, Hendy G N, Lebrun J J. Activin inhibits pituitary prolactin expression and cell growth through Smads, Pit-1 and menin.  Mol Endocrinol. 2004;  18 1558-1569
  • 29 Zhuang Z, Ezzat S Z, Vortmeyer A O, Weil R, Oldfield E H, Park W S, Pack S, Huang S, Agarwal S K, Guru S C, Manickam P, Debelenko L V, Kester M B, Olufemi S E, Heppner C, Crabtree J S, Burns A L, Spiegel A M, Marx S J, Chandrasekharappa S C, Collins F S, Emmert-Buck M R, Liotta L A, Asa S L, Lubensky I A. Mutations of the MEN1 tumor suppressor gene in pituitary tumors.  Cancer Res. 1997;  57 5446-5451
  • 30 Poncin J, Stevenaert A, Beckers A. Somatic MEN1 gene mutation does not contribute significantly to sporadic pituitary tumorigenesis.  Eur J Endocrinol. 1999;  140 573-576
  • 31 Wenbin C, Asai A, Teramoto A, Sanno N, Kirino T. Mutations of the MEN1 tumor suppressor gene in sporadic pituitary tumors.  Cancer Lett. 1999;  142 43-47
  • 32 Schmidt M C, Henke R T, Stangl A P, Meyer-Puttlitz B, Stoffel-Wagner B, Schramm J, von Deimling A. Analysis of the MEN1 gene in sporadic pituitary adenomas.  J Pathol . 1999;  188 168-173
  • 33 Fukino K, Kitamura Y, Sanno N, Teramoto A, Emi M. Analysis of the MEN1 gene in sporadic pituitary adenomas from Japanese patients.  Cancer Lett. 1999;  144 85-92
  • 34 Asa S L, Somers K, Ezzat S. The MEN-1 gene is rarely down-regulated in pituitary adenomas.  J Clin Endocrinol Metab. 1998;  83 3210-3212
  • 35 Tanaka C, Kimura T, Yang P, Moritani M, Yamaoka T, Yamada S, Sano T, Yoshimoto K, Itakura M. Analysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of the MEN1 gene in sporadic pituitary adenomas.  J Clin Endocrinol Metab. 1998;  83 2631-2634
  • 36 Tanaka C, Yoshimoto K, Yamada S, Nishioka H, Ii S, Moritani M, Yamaoka T, Itakura M. Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese.  J Clin Endocrinol Metab. 1998;  83 960-965
  • 37 Theodoropoulou M, Cavallari I, Barzon L, D’Agostino D M, Ferro T, Arzberger T, Grubler Y, Schaaf L, Losa M, Fallo F, Climinale V, Stalla G K, Pagotto U. Differential expression of menin in sporadic pituitary adenomas.  Endocr Relat Cancer. 2004;  11 333-344
  • 38 Skogseid B, Eriksson B, Lundqvist G, Lorelius L E, Rastad J, Wide L, Akerstrom G, Oberg K. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds.  J Clin Endocrinol Metab. 1991;  73 281-287
  • 39 Burgess J R, Shepherd J J, Parameswaran V, Hoffman L, Greenaway T M. Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN1): clinical, biochemical, and radiological features of pituitary disease in a large MEN1 kindred.  J Clin Endocrinol Metab. 1996;  81 2642-2646
  • 40 Marx S, Spiegel A M, Skarulis M C, Doppman J L, Collins F S, Liotta L A. Multiple endocrine neoplasia type 1: clinical and genetic topics.  Ann Intern Med. 1998;  129 484-494
  • 41 Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study.  J Clin Endocrinol Metab. 2002;  87 457-465
  • 42 Beckers A, Betea D, Valdes Socin H, Stevenaert A. The treatment of sporadic versus MEN1-related pituitary adenomas.  J Int Med. 2003;  253 599-605
  • 43 Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros J J, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A. Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases.  Hum Mut. 1999;  13 54-60
  • 44 Beckers A, Abs R, Reyniers E, De Boulle K, Stevenaert A, Heller F R, Kloppel G, Meurisse M, Willems P J. Variable regions of chromosome 11 loss in different pathological tissues of a patient with the multiple endocrine neoplasia type I syndrome.  J Clin Endocrinol Metab. 1994;  79 1498-1502
  • 45 Farid N R, Buehler S, Russell N A, Maroun F B, Allerdice P, Smyth H S. Prolactinomas in familial multiple endocrine neoplasia syndrome type I. Relationship to HLA and carcinoid tumors.  Am J Med. 1980;  69 874-880
  • 46 Olufemi S E, Green J S, Manickam P, Guru S C, Agarwal S K, Kester M B, Dong Q, Burns A L, Spiegel A M, Marx S J, Collins F S, Chandrasekharappa S C. Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland.  Hum Mutat. 1998;  11 264-269
  • 47 Hao W, Skarulis M C, Simonds W F, Weinstein L S, Agarwal S K, Mateo C, James-Newton L, Hobbs G R, Gibril F, Jensen R T, Marx S J. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma.  J Clin Endocrinol Metab. 2004;  89 3776-3784
  • 48 Valdes Socin H, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, Stevenaert A, Beckers A. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.  Eur J Endocrinol. 2003;  148 433-442
  • 49 Carney J A, Hruska L S, Beauchamp G D, Gordon H. Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity.  Mayo Clinic Proc. 1985;  61 165-172
  • 50 Stratakis C A. Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes.  J Endocrinol Invest. 2001;  24 370-383
  • 51 Stratakis C A, Kirschner L S, Carney J A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.  J Clin Endocrinol Metab. 2001;  86 4041-4046
  • 52 Casey M, Mah C, Merliss A D, Kirschner L S, Taymans S E, Denio A E, Korf B, Irvine A D, Highes A, Carney J A, Stratakis C A, Basson C T. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.  Circulation. 1998;  98 2560-2566
  • 53 Stratakis C A, Carney J A, Lin J P, Papanicolaou D A, Karl M, Kastner D L, Pras E, Chrousos G P. Carney complex, a familial multiple endocrine neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.  J Clin Invest. 1996;  97 699-705
  • 54 Veugelers M, Wilkes D, Burton K, McDermott D A, Song Y, Goldstein M M, La P erle, Vaughan C J, O’Hagan A, Bennett K R, Meyer B J, Legius E, Karttunen M, Norio R, Kaariainen H, Lavyne M, Neau J P, Richter G, Kirali K, Farnsworth A, Stapleton K, Morelli P, Takanashi Y, Bamforth J S, Eitelberger F, Noszian I, Manfroi W, Powers J, Mochizuki Y, Imai T, Ko G T, Driscoll D A, Goldmuntz E, Edelberg J M, Collins A, Eccles D, Irvine A D, McKnight G S, Basson C T. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.  Proc Natl Acad Sci USA. 2004;  101 14 222-14 227
  • 55 Bossis I, Voutetakis A, Bei T, Sandrini F, Griffin K J, Stratakis C A. Protein kinase A and its role in human neoplasia: the Carney complex paradigm.  Endocr Related Cancer. 2004;  11 265-280
  • 56 Kirschner L S, Sandrini F, Monbo J, Lin J P, Carney J A, Stratakis C A. Genetic heterogeneity and spectrum of mutations of the PPKAR1A gene in patients with the Carney complex.  Hum Mol Genet. 2000;  9 3037-3046
  • 57 Bossis I, Stratakis C A. Minireview: PRKAR1: normal and abnormal functions.  Endocrinology. 2004;  145 5452-5458
  • 58 Kirschner L S, Kusewitt D F, Matyakhina L, Towns W H 2nd, Carney J A, Westphal H, Stratakis C A. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues.  Cancer Res. 2005;  65 4506-4514
  • 59 Griffin K J, Kirschner L S, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S, Weinberg F D, Claflin E, Meoli E, Cho-Chung Y S, Stratakis C A. Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors.  Cancer Res. 2004;  64 8811-8815
  • 60 Griffin K J, Kirschner L S, Matyakhina L, Stergiopoulos S G, Robinson-White A, Lenherr S M, Weinberg F D, Claflin E S, Batista D, Bourdeau I, Voutetakis A, Sandrini F, Meoli E M, Bauer A J, Cho-Chung Y S, Bornstein S R, Carney J A, Stratakis C A. A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours.  J Med Genet. 2004;  41 923-931
  • 61 Kaltsas G A, Kola B, Borboli N, Morris D G, Gueorguiev M, Swords F M, Czirjak S, Kirschner L S, Stratakis C A, Korbonits M, Grossman A B. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and otherpituitary tumours.  Clin Endocrinol (Oxf). 2002;  57 443-448
  • 62 Lania A G, Mantovani G, Ferrero S, Pellegrini C, Bondioni S, Peverelli E, Braidotti P, Locatelli M, Zavanone M L, Ferrante E, Bosari S, Beck-Peccoz P, Spada A. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein.  Cancer Res. 2004;  64 9193-9198
  • 63 Stergiopoulos S G, Stratakis C A. Human tumors associated with Carney complex and germline PPKAR1A mutations: a protein kinase A disease!.  FEBS Letters. 2003;  546 59-64
  • 64 Pack S D, Kirschner L S, Pak E, Zhuang Z, Carney J A, Stratakis C A. Genetic and histological studies of somatomammotropic tumors in patients with the “Complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex).  J Clin Endo Metab. 2000;  85 3860-3865
  • 65 Kurtkaya-Yapicier O, Scheithauer B W, Carney J A, Kovacs K, Horvath E, Stratakis C A, Vidal S, Vella A, Young W F Jr, Atkinson J L, Lloyd R V, Kontogeorgos G. Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural,and immunoelectron microscopic study.  Ultrastruct Pathol. 2002;  26 345-353
  • 66 Lucio-Camelo D C, Une K N, Ferreira R ES, Khoo S K, Nickolov R, Bronstein M D, Vaisman M, Teh B T, Frohman L A, Mendonça B B, Gadelha M R. A meiotic recombination in a new isolated familial somatotropinoma kindred.  Eur J Endocrinol. 2004;  150 643-648
  • 67 Frohman L A, Eguchi K. Familial acromegaly.  Growth Horm IGF Res. 2004;  14 Suppl A S90-96
  • 68 De Menis E, Prezant T R. Isolated familial somatotropinomas: clinical features and analysis of the MEN1 gene.  Pituitary. 2002;  5 11-15
  • 69 Verloes A, Stevenaert A, Teh B T, Petrossians P, Beckers A. Familial acromegaly: case report and review of the literature.  Pituitary. 1999;  1 273-277
  • 70 Ferretti E, Jaffrain-Rea M L, Asteria C, Di Stefano D, Esposito V, Ferrante L, Daniele P, Tiberti C, Gallucci M, Bosman C, Alesse E, Gulino A, Beck-Peccoz P, Tamburrano G. Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features.  Eur J Endocrinol. 2001;  144 227-235
  • 71 Teh B T, Kytölä S, Farnebo F, Bergman L, Wong F K, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Menon J, Khir A, Tan T T, Chan S P, Zaini A, Khalid B AK, Sandelin K, Thompson N, Brandi M L, Warth M, Stock J, Leisti J, Cameron D, Shepherd J J, Öberg K, Nordenskjöld M, Salmela P. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.  J Clin Endocrinol Metab. 1998;  83 2621-2626
  • 72 Berezin M, Karasik A. Familial prolactinoma.  Clin Endocrinol (Oxf). 1995;  42 483-486
  • 73 Gardner D F, Barlascini C O Jr, Downs R W Jr, Sahni K S. Cushing’s disease in two sisters.  Am J Med Sci. 1989;  297 387-389
  • 74 Links T P, Monkelbaan J F, Dullaart R P, Van Haeften T W. Growth hormone-, alpha-subunit and thyrotropin-cosecreting pituitary adenoma in familial setting of pituitary tumor.  Acta Endocrinol. 1993;  129 516-518
  • 75 Chedid A, Hoversland R C, Chefjec G, McCune S A, Jurin R R, Evans E E. Hereditary pituitary prolactinomas: a new rat model.  Acta Endocrinol. 1988;  119 535-542
  • 76 Beckers A. Familial isolated pituitary adenomas.  J Int Med. 2004;  255 698

Prof. A. Beckers M. D., Ph. D.

Department of Endocrinology

C.H.U. de Liège · Domaine Universitaire du Sart Tilman · 4000 Liège · Belgium

Phone: +32 (4) 366 70 84

Fax: +32 (4) 366 72 61

Email: albert.beckers@chu.ulg.ac.be

    >