Abstract
Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20 % of the families with FIPA harbor inactivating mutation in aryl hydrocarbon receptor-interacting protein gene (AIP) associated with loss of heterozygosity of the same genetic locus (11q13) in the tumor. Rarely different types of extra-pituitary tumors have been described in the setting of AIP mutation-positive FIPA. We present the case of a patient who was diagnosed with acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and treated by transsphenoidal surgery. At the age of 43 years she was diagnosed with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic studies demonstrated loss of the normal allele (by sequencing and microsatellite analysis) in DNA from the pituitary adenoma but not from the meningioma, suggesting a selective involvement of AIP mutation in the pathogenesis of the pituitary adenoma, and a casual association with the meningioma. Further investigations are required to define the exact role of AIP in non-pituitary tumorigenesis.
References
Melmed S (2009) Acromegaly pathogenesis and treatment. J Clin Invest 119:3189–3202
Chahal HS, Chapple JP, Frohman LA, Grossman AB, Korbonits M (2010) Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends Endocrinol Metab 21:419–427
Guaraldi F, Salvatori R (2011) Familial isolated pituitary adenomas: from genetics to therapy. Clin Transl Sci 4:55–62
Soares BS, Frohman LA (2002) Isolated familial somatotropinoma. Pituitary 7:95–101
Benlian P, Giraud S, Lahlou N, Roger M, Blin C, Holler C, Lenoir G, Sallandre J, Calender A, Turpin G (1995) Familial acromegaly: a specific clinical entity- further evidence from the genetic study of a three-generation family. Eur J Endocrinol 133:451–456
Yamada S, Yoshimoto K, Sano T, Takada K, Itakura M, Usui M, Teramoto A (1997) Inactivation of the tumor suppressor gene on 11q13 in brothers with familial acrogigantism without multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 82:239–242
Gadelha MR, Prezant TR, Une KN, Glick RP, Moskal SF II, Vaisman M, Melmed S, Kineman RD, Frohman LA (1999) Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J Clin Endocrinol Metab 84:249–256
Gadelha MR, Une KN, Rohde K, Vaisman M, Kineman RD, Frohman LA (2000) Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab 85:707–714
Luccio-Camelo DC, Une KN, Ferreira RE, Nickolov R, Bronstein MD, Vaisman M, Teh BT, Frohman LA, Mendonça BB, Gadelha MR (2004) A meiotic recombination in a new isolated familial somatotropinoma kindred. Eur J Endocrinol 150:643–648
Soares BS, Eguchi K, Frohman LA (2005) Tumor deletion mapping on chromosome 11q13 in eight families with isolated familial somatotropinoma and in 15 sporadic somatotropinomas. J Clin Endocrinol Metab 90:6580–6587
Daly AF, Tichomirowa MA, Petrossians P, Heliövaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De Menis E, Montañana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabaté MI, Villa C, Popelier M, Salvatori R, Jennings J, Longás AF, Labarta Aizpún JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De Herder W, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an International Collaborative Study. J Clin Endocrinol Metab 95:E373–E383
Gadelha MR, Kineman RD, Frohman LA (1999) Familial somatotropinomas: clinical and genetic aspects. Endocrinologist 9:277–285
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 A Jr, 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
Renehan AG, Brennan BM (2002) Acromegaly, growth hormone and cancer risk. Best Pract Res Clin Endocrinol Metab 22:639–657
Clayton PE, Banerjee I, Murray PG, Renehan AG (2007) Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7:11–24
Baris D, Gridley G, Ron E, Weiderpass E, Mellemkjaer L, Ekbom A, Olsen JH, Baron JA, Fraumeni JF Jr (2002) Acromegaly and cancer risk: a cohort study in Sweden and Denmark. Cancer Causes Control 13:395–400
Kauppinen-Makelin R, Sane T, Valimaki MJ, Markkanen H, Niskanen L, Ebeling T, Jaatinen P, Juonala M (2010) Finnish Acromegaly Study Group, Pukkala, E’: increased cancer incidence in acromegaly—a nationwide survey. Clin Endocrinol 72:278–279
Orme SM, McNally RJ, Cartwright RA, Belchetz PE (1998) Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734
Glick RP, Lichtor T, Unterman TG (1997) Insulin-like growth factors in central nervous system tumors. J Neurooncol 35:315–325
Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE (2000) The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 21:215–244
CazabaTL Libe R, Perlemoine K, René-Corail F, Burnichon N, Gimenez-Roqueplo AP, Dupasquier-Fediaevsky L, Bertagna X, Clauser E, Chanson P, Bertherat J, Raffin-Sanson ML (2007) Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol 157:1–8
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
Toledo RA, Mendonca BB, Fragoso MC, Soares IC, Almeida MQ, Moraes MB, Lourenço DM Jr, Alves VA, Bronstein MD, Toledo SP (2010) Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis. Clinics (Sao Paulo) 65:407–415
Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S, Grossman AB, Korbonits M (2010) International FIPA Consortium: characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat 31:950–960
Tahir A, Chahal HS, Korbonits M (2010) Molecular genetics of the AIP gene in familial pituitary tumorigenesis. Prog Brain Res 182:229–253
Abs R, Parizel PM, Willems PJ, Van de Kelft E, Verlooy J, Mahler C, Verhelst J, Van Marck E, Martin JJ (1993) The association of meningioma and pituitary adenoma: report of seven cases and review of the literature. Eur Neurol 33:416–422
Chahal HS, Stals K, Unterlander M, Balding DJ, Thomas MG, Kumar AV, Besser GM, Atkinson AB, Morrison PJ, Howlett TA, Levy MJ, Orme SM, Akker SA, Abel RL, Grossman AB, Burger J, Ellard S, Korbonits M (2011) AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med 364:43–50
Gullu BE, Celik O, Gazioglu N, Kadioglu P (2010) Thyroid cancer is the most common cancer associated with acromegaly. Pituitary 13:242–248
Correa LL, Lima GA, Paiva HB, Silva CM, Cavallieri SA, Miranda LC, Gadelha MR (2009) Prostate cancer and acromegaly. Arq Bras Endocrinol Metabol 53:963–968
Bunick EM, Mills LC, Rose LI (1978) Association of acromegaly and meningiomas. JAMA 240:1267–1268
Cannavo S, Curto L, Fazio R, Paterniti S, Blandino A, Marafioti T, Trimarchi F (1993) Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: a case report and review of the literature. J Endocrinol Invest 16:703–708
Curto L, Squadrito S, Almoto B, Longo M, Granata F, Salpietro F, Torre ML, Marini F, Trimarchi F, Cannavo S (2007) MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case. Pituitary 10:299–305
De Menis E, Tulipano G, Villa S, Billeci D, Bonfanti C, Pollara P, Pauletto P, Giustina A (2003) Development of a meningioma in a patient with acromegaly during octreotide treatment: are there any causal relationship? J Endocrinol Invest 26:359–363
Drake WM, Grossman AB, Hutson RK (2005) Effect of treatment with pegvisomant on meningioma growth in vivo. Eur J Endocrinol 152:161–162
Fernandez A, Karavitaki N, Ansorge O, Fazal-Sanderson V, Wass JA (2008) Acromegaly and anaplastic astrocytoma: coincidence or pathophysiological relation? Pituitary. 11:325–330
Furtado SV, Venkatesh PK, Ghosal N, Hegde AS (2010) Coexisting intracranial tumors with pituitary adenomas: genetic association or coincidence? J Cancer Res Ther 6:221–223
Gori G, Nucci U (1965) Association of frontal ependymoma and hypophyseal adenoma. Minerva Neurochir 9:211–213
Gorman P, Hewer RL (1985) Stroke due to atrial myxoma in a young woman with co-existing acoustic neuroma and pituitary adenoma. J Neurol Neurosurg Psychiatry 48:718–719
Honegger J, Buchfelder M, Schrell U, Adams EF, Fahlbusch R (1989) The coexistence of pituitary adenomas and meningiomas: three case reports and a review of the literature. Br J Neurosurg 3:59–69
Irsy G, Goth M, Slovik F, Bálint K, Szabolcs I, Pásztor E, Szilágyi G (1985) Growth hormone producing pituitary adenoma and meningioma. Zentralbl Neurochir 46:337–343
Koutourousiou M, Seretis A, Kontogeorgos G (2009) Intra-sellar schwannoma co-existing with GH-secreting pituitary adenoma. Acta Neurochir (Wien) 151:1693–1697
Mathuriya SN, Vasishta RK, Dash RJ, Kak VK (2000) Pituitary adenoma and parasagittal meningioma: an unusual association. Neurol India 48:72–74
Yarman S, Minareci O (2004) Value of petrosal sinus sampling: coexisting acromegaly, empty sella and meningioma. Neuroradiology 46:1027–1030
Lee Y, Liu J, Patel S, Lai A, Farooqi H, Seligson D, Dong J, Liau L, Becker D, Mischel P, Shams S, Nelson S (2010) Genomic landscape of meningiomas. Brain Pathol 20:751–762
Collins VP (2004) Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry 75(Suppl 2):ii2–ii11
Friend KE (2001) Cancer and the potential place for growth hormone receptor antagonist therapy. Growth Horm IGF Res 11(Suppl A):S121–S123
Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ (2002) Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr Rev 23:623–646
Szymas J, Schluens K, Liebert W, Petersen I (2002) Genomic instability in pituitary adenomas. Pituitary 5:211–219
Trivellin G, Korbonits M (2011) AIP and its interacting partners. J Endocrinol 210:137–155
Chang YF, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76:51–74
Ozfirat Z, Korbonits M (2010) AIP gene and familial isolated pituitary adenomas. Mol Cell Endocrinol 326:71–79
Toledo RA, Lourenco DM Jr, 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
Tichomirowa MA, Barlier A, Daly AF, Jaffrain-Rea ML, Ronchi C, Yaneva M, Urban JD, Petrossians P, Elenkova A, Tabarin A, Desailloud R, Maiter D, Schürmeyer T, Cozzi R, Theodoropoulou M, Sievers C, Bernabeu I, Naves LA, Chabre O, Montañana CF, Hana V, Halaby G, Delemer B, Aizpún JI, Sonnet E, Longás AF, Hagelstein MT, Caron P, Stalla GK, Bours V, Zacharieva S, Spada A, Brue T, Beckers A (2011) High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol 165:509–515
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guaraldi, F., Corazzini, V., Gallia, G.L. et al. Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor. Pituitary 15 (Suppl 1), 61–67 (2012). https://doi.org/10.1007/s11102-012-0391-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11102-012-0391-y