Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study
Daly, Adrian; Tichomirowa, Maria A.; Petrossians, Patricket al.
2010 • In Journal of Clinical Endocrinology and Metabolism, 95 (11)
[en] Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively.
<br />Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas.
<br />Design: This study was an international, multicenter, retrospective case collection/database analysis.
<br />Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments.
<br />Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls.
<br />Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy.
<br />Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Daly, Adrian ; Université de Liège - ULiège > Département des sciences cliniques > Endocrinologie
Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study
Publication date :
2010
Journal title :
Journal of Clinical Endocrinology and Metabolism
ISSN :
0021-972X
eISSN :
1945-7197
Publisher :
Endocrine Society, Chevy Chase, United States - Maryland
Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A 2006 High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91:4769-4775
Fernandez A, Karavitaki N, Wass JA 2010 Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72:377-382
Asa SL, Ezzat S 2009 The pathogenesis of pituitary tumors. Annu Rev Pathol 4:97-126
Melmed S 2003 Mechanisms for pituitary tumorigenesis: the plastic pituitary. J Clin Invest 112:1603-1618
Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B, Stratakis CA, Hedley-Whyte ET, Klibanski A 2008 Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically non-functioning pituitary adenomas. J Clin Endocrinol Metab 93:4119-4125
Boikos SA, Stratakis CA 2006 Carney complex: pathology and molecular genetics. Neuroendocrinology 83:189-199
Marx SJ 2005 Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 5:367-375
Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Höfler H, Fend F, Graw J, Atkinson MJ 2006 Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci USA 103:15558-15563 (Pubitemid 44625631)
Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Ciccarelli E, Brue T, Ferolla P, Emy P, Colao A, De Menis E, Lecomte P, Penfornis F, Delemer B, Bertherat J, Wémeau JL, De Herder W, Archambeaud F, Stevenaert A, Calender A, Murat A, Cavagnini F, Beckers A 2006 Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 91:3316-3323
Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gündogdu S, De Menis E, Mäkinen MJ, Launonen V, Karhu A, Aaltonen LA 2006 Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312:1228-1230
Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA, Murat A, Emy P, Gimenez-Roqueplo AP, Tamburrano G, Raverot G, Barlier A, De Herder W, Penfornis A, Ciccarelli E, Estour B, Lecomte P, Gatta B, Chabre O, Sabaté MI, Bertagna X, Garcia Basavilbaso N, Stalldecker G, Colao A, Ferolla P, Wémeau JL, Caron P, Sadoul JL, Oneto A, Archambeaud F, Calender A, Sinilnikova O, Montañana CF, Cavagnini F, Hana V, Solano A, Delettieres D, Luccio-Camelo DC, Basso A, Rohmer V, Brue T, Bours V, Teh BT, Beckers A 2007 Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 92:1891-1896 (Pubitemid 46997206)
Georgitsi M, Raitila A, Karhu A, Tuppurainen K, Mäkinen MJ, Vierimaa O, Paschke R, Saeger W, van der Luijt RB, Sane T, Robledo M, De Menis E, Weil RJ, Wasik A, Zielinski G, Lucewicz O, Lubinski J, Launonen V, Vahteristo P, Aaltonen LA 2007 Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc Natl Acad Sci USA 104:4101-4105
Barlier A, Vanbellinghen JF, Daly AF, Silvy M, Jaffrain-Rea ML, Trouillas J, Tamagno G, Cazabat L, Bours V, Brue T, Enjalbert A, Beckers A 2007 Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab 92:1952-1955
Iwata T, Yamada S, Mizusawa N, Golam H, Sano T, Yoshimoto K 2007 The aryl hydrocarbon receptor-interacting protein gene is rarely mutated in sporadic GH-secreting adenomas. Clin Endocrinol (Oxf) 66:499-502
Yu R, Bonert V, Saporta I, Raffel LJ, Melmed S 2006 Aryl hydrocarbon receptor interacting protein variants in sporadic pituitary adenomas. J Clin Endocrinol Metab 91:5126-5129 (Pubitemid 44917362)
Toledo RA, Lourenco Jr DM, Liberman B, Cunha-Neto MB, Cavalcanti MG, Moyses CB, Toledo SP, Dahia PL 2007 Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma. J Clin Endocrinol Metab 92:1934-1937
Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S, Chahal HS, Igreja SC, Jordan S, Rowe J, Stolbrink M, Christian HC, Wray J, Bishop-Bailey D, Berney DM, Wass JA, Popovic V, Ribeiro-Oliveira Jr A, Gadelha MR, Monson JP, Akker SA, Davis JR, Clayton RN, Yoshimoto K, Iwata T, Matsuno A, Eguchi K, Musat M, Flanagan D, Peters G, Bolger GB, Chapple JP, Frohman LA, Grossman AB, Korbonits M 2008 The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab 93:2390-2401
Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari M, Verma S, Daly AF, Raygada M, Keil MF, Papademetriou J, Drori-Herishanu L, Horvath A, Tsang KM, Nesterova M, Franklin S, Vanbellinghen J-F, Bours V, Salvatori R, Beckers A 23 February 2010 The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in children and adolescents with pituitary adenoma. Clin Genet 10.1111/j.1399-0004.2010.01406.x
Cazabat L, Guillaud-Bataille M, Bertherat J, Raffin-Sanson ML 2009 Mutations of the gene for the aryl hydrocarbon receptor-interacting protein in pituitary adenomas. Horm Res 71:132-141
Georgitsi M, Heliövaara E, Paschke R, Kumar AV, Tischkowitz M, Vierimaa O, Salmela P, Sane T, De Menis E, Cannavò S, Gündogdu S, Lucassen A, Izatt L, Aylwin S, Bano G, Hodgson S, Koch CA, Karhu A, Aaltonen LA 2008 Large genomic deletions in AIP in pituitary adenoma predisposition. J Clin Endocrinol Metab 93:4146-4151
Nwosu BU, Lee MM 2008 Evaluation of short and tall stature in children. Am Fam Physician 78:597-604
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2002 2000 CDC Growth charts for the United States: methods and development. Vital Health Stat 11 1-190 (http://www.cdc.gov/ nchs/data/series/sr-11/sr11-246.pdf)
World Health Organization Multicentre Growth Reference Study Group. 2009 WHO child growth standards: growth velocity based on weight, length and head circumference: methods and development. Geneva: World Health Organization (http://www.who.int/childgrowth/standards/velocity/tr3-velocity-report.pdf)
Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, Del Monte P, Bernasconi D, Loli P, Faustini-Fustini M, Borretta G, Terzolo M, Losa M, Morabito A, Spada A, Beck-Peccoz P, Lania AG 2006 Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. Eur J Endocrinol 155:823-829
Buchfelder M, Schlaffer S 2009 Surgical treatment of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23:677-692
Theodoropoulou M, Tichomirowa MA, Sievers C, Yassouridis A, Arzberger T, Hougrand O, Deprez M, Daly AF, Petrossians P, Pagotto U, Beckers A, Stalla GK 2009 Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly. Int J Cancer 125:2122-2126
Petrossians P, Borges-Martins L, Espinoza C, Daly A, Betea D, Valdes-Socin H, Stevenaert A, Chanson P, Beckers A 2005 Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur J Endocrinol 152:61-66
Karavitaki N, Turner HE, Adams CB, Cudlip S, Byrne JV, Fazal-Sanderson V, Rowlers S, Trainer PJ, Wass JA 2008 Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide. Clin Endocrinol (Oxf) 68:970-975
Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B 2005 Pegvisomant therapy in pituitary gigantism: successful treatment in a 12- year-old girl. Eur J Endocrinol 153:195-201 (Pubitemid 41167475)
Müssig K, Gallwitz B, Honegger J, Strasburger CJ, Bidlingmaier M, Machicao F, Bornemann A, Ranke MB, Häring HU, Petersenn S 2007 Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp Clin Endocrinol Diabetes 115:198-202
Goldenberg N, Racine MS, Thomas P, Degnan B, Chandler W, Barkan A 2008 Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J Clin Endocrinol Metab 93:2953-2956
Schoof E, Dörr HG, Kiess W, Lüdecke DK, Freitag E, Zindel V, Rascher W, Dötsch J 2004 Five-year follow-up of a 13-year-old boy with a pituitary adenoma Rausing gigantism - effect of octreotide therapy. Horm Res 61:184-189
Colao A 2009 Pituitary tumours: the prolactinoma. Best Pract Res Clin Endocrinol Metab 23:575-596
Ciccarelli A, Daly AF, Beckers A 2005 The epidemiology of prolactinomas. Pituitary 8:3-6
Vergès B, Boureille F, Goudet P, Murat A, Beckers A, Sassolas G, Cougard P, Chambe B, Montvernay C, Calender A 2002 Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab 87:457-465
Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, René-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA 2009 Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 94:2085-2091
Jennings JE, Georgitsi M, Holdaway I, Daly AF, Tichomirowa M, Beckers A, Aaltonen LA, Karhu A, Cameron FJ 2009 Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene. Eur J Endocrinol 161:799-804
Occhi G, Jaffrain-Rea ML, Trivellin G, Albiger N, Ceccato F, De Menis E, Angelini M, Ferasin S, Beckers A, Mantero F, Scaroni C 30 March 2010 The R304X mutation of the aryl hydrocarbon receptor interacting protein gene in familial isolated pituitary adenomas: mutational hot-spot or founder effect? J Endocrinol Invest 10.3275/6956
Naves LA, Daly AF, Vanbellinghen JF, Casulari LA, Spilioti C, Magalhães AV, Azevedo MF, Giacomini LA, Nascimento PP, Nunes RO, Rosa JW, Jaffrain-Rea ML, Bours V, Beckers A 2007 Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene. Eur J Endocrinol 157:383-391
Wang ZJ, Churchman M, Avizienyte E, McKeown C, Davies S, Evans DG, Ferguson A, Ellis I, Xu WH, Yan ZY, Aaltonen LA, Tomlinson IP 1999 Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients. J Med Genet 36:365-368
Lin BC, Nguyen LP, Walisser JA, Bradfield CA 2008 A hypomorphic allele of aryl hydrocarbon receptor-associated protein-9 produces a phenocopy of the AHR-null mouse. Mol Pharmacol 74:1367-1371
Lin BC, Sullivan R, Lee Y, Moran S, Glover E, Bradfield CA 2007 Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality. J Biol Chem 282:35924-35932 (Pubitemid 350277155)
Heliövaara E, Raitila A, Launonen V, Paetau A, Arola J, Lehtonen H, Sane T, Weil RJ, Vierimaa O, Salmela P, Tuppurainen K, Mäkinen M, Aaltonen LA, Karhu A 2009 The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas. Am J Pathol 175:2501-2507
Vargiolu M, Fusco D, Kurelac I, Dirnberger D, Baumeister R, Morra I, Melcarne A, Rimondini R, Romeo G, Bonora E 2009 The tyrosine kinase receptor RET interacts in vivo with aryl hydrocarbon receptor-interacting protein to alter surviving availability. J Clin Endocrinol Metab 94:2571-2578
Jaffrain-Rea ML, Angelini M, Gargano D, Tichomirowa MA, Daly AF, Vanbellinghen JF, D'Innocenzo E, Barlier A, Giangaspero F, Esposito V, Ventura L, Arcella A, Theodoropoulou M, Naves LA, Fajardo C, Zacharieva S, Rohmer V, Brue T, Gulino A, Cantore G, Alesse E, Beckers A 2009 Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 16:1029-1043
Beckers A, Daly AF 2007 The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157:371-382 (Pubitemid 350018439)