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Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort

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Abstract

Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15–20 % of familial isolated pituitary adenomas and 50–80 % of cases with AIP mutation exhibit a somatotropinoma. Herein we report clinical characteristics of a large family where AIP R304X variants have been identified. AIP mutation analysis was performed on a large (n = 52) Turkish family across six generations. Sella MRIs of 30 family members were obtained. Basal pituitary hormone levels were evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family members (25 %) were found to have a heterozygous nonsense germline R304X mutation in the AIP gene. Seven of the 13 mutation carriers (53.8 %) had current or previous history of pituitary adenoma. Of these 7 mutation carriers, all but one had somatotropinoma/somatolactotropinoma (85.7 % of the pituitary adenomas). Of the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis of acromegaly was 32 ± 10.3 years while the mean age of symptom onset was 24.8 ± 9.9 years. Three of the six (50 %) acromegaly cases with AIP mutation within the family presented with a macroadenoma and none presented with gigantism. Biochemical disease control was achieved in 66.6 % (4/6) of the mutation carriers with acromegaly after a mean follow-up period of 18.6 ± 17.6 years. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family.

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References

  1. 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

    Article  CAS  PubMed  Google Scholar 

  2. Fontana E, Gaillard R (2009) Epidemiology of pituitary adenoma: results of the first Swiss study. Rev Med Suisse 5:2172–2174

    CAS  PubMed  Google Scholar 

  3. 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

    Article  Google Scholar 

  4. Holdaway IM, Rajasoorya C (1999) Epidemiology of acromegaly. Pituitary 2:29–41

    Article  CAS  PubMed  Google Scholar 

  5. Beckers A, Daly AF (2007) The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157:371–382

    Article  CAS  PubMed  Google Scholar 

  6. Daly AF, Tichomirowa MA, Beckers A (2009) Genetic, molecular and clinical features of familial isolated pituitary adenomas. Horm Res. doi:10.1159/000192448

    Google Scholar 

  7. Soares BS, Frohman LA (2004) Isolated familial somatotropinoma. Pituitary 7:95–101

    Article  PubMed  Google Scholar 

  8. Iwata T, Yamada S, Mizusawa N, Golam HM, 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

    CAS  Google Scholar 

  9. Toledo RA, Lourenço 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

    Article  CAS  PubMed  Google Scholar 

  10. Daly AF, Tichomirowa MA, Petrossians P, Heliovaara 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. doi:10.1210/jc.2009-2556

    Google Scholar 

  11. 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. doi:10.1126/science.1126100

    PubMed  Google Scholar 

  12. Zatelli MC, Torre ML, Rossi R, Ragonese M, Trimarchi F, Degli Uberti E, Cannavò S (2012) Should aip gene screening be recommended in family members of FIPA patients with R16H variant? Pituitary. doi:10.1007/s11102-012-0409-5

    Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. Georgitsi M, Raitila A, Karhu A, Tuppurainen K, Ma¨kinen 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 JF, Bours V, Salvatori R, Beckers A (2010) The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in children and adolescents with pituitary adenoma. Clin Genet. doi:10.1111/j.1399-0004.2010.01406.x

    PubMed  PubMed Central  Google Scholar 

  16. Beckers A, Aaltonen LA, Daly AF, Karhu A (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 34:239–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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) Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat 31:950–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. Buchbinder S, Bierhaus A, Zorn M, Nawroth PP, Humpert P, Schilling T (2008) Aryl hydrocarbon receptor interacting protein gene (AIP) mutations are rare in patients with hormone secreting or non-secreting pituitary adenomas. Exp Clin Endocrinol Diabetes 116:625–628

    Article  CAS  PubMed  Google Scholar 

  20. Carver LA, Bradfield CA (1997) Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J Biol Chem 272:11452–11456

    Article  CAS  PubMed  Google Scholar 

  21. Meyer BK, Perdew GH (1999) Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry 38:8907–8917

    Article  CAS  PubMed  Google Scholar 

  22. Marlowe JL, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96:1174–1184

    Article  CAS  PubMed  Google Scholar 

  23. Pollenz RS, Dougherty EJ (2005) Redefining the role of the endogenous XAP2 and C-terminal hsp70-interacting protein on the endogenous Ah receptors expressed in mouse and rat cell lines. J Biol Chem 280:33346–33356

    Article  CAS  PubMed  Google Scholar 

  24. Petrulis JR, Perdew GH (2002) The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem Biol Interact 141:25–40

    Article  CAS  PubMed  Google Scholar 

  25. Krawczak M, Ball EV, Cooper DN (1998) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 63:474–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Occhi G, Jaffrain-Rea ML, Trivellin G, Albiger N, Ceccato F, De Menis E, Angelini M, Ferasin S, Beckers A, Mantero F, Scaroni C (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 33:800–805

    Article  CAS  PubMed  Google Scholar 

  27. Chahal HS, Stals K, Unterländer 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

    Article  CAS  PubMed  Google Scholar 

  28. Hai N, Aoki N, Shimatsu A, Mori T, Kosugi S (2000) 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 52:509–518

    Article  CAS  Google Scholar 

  29. Frohman LA, Eguchi K (2004) Familial acromegaly. Growth Horm IGF Res 14(Suppl A):S90–S96

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study was supported by the Research Fund of the University of Istanbul. Istanbul, Turkey, Project No. 16892.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

    Mutlu Niyazoglu, Esra Hatipoglu & Pinar Kadioglu

  2. Department of Genetics, Institute for Experimental Medicine (DETAE), Istanbul University, Istanbul, Turkey

    Muge Sayitoglu & Sinem Firtina

  3. Department of Neurosurgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

    Nurperi Gazioglu

  4. Cerrahpasa Tip Fakultesi, IcHastaliklari Anabilim Dali, Endokrinoloji-Metabolizma ve Diyabet Bilim Dali, 34303 Cerrahpasa, Istanbul, Turkey

    Pinar Kadioglu

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  1. Mutlu Niyazoglu
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Correspondence to Pinar Kadioglu.

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Niyazoglu, M., Sayitoglu, M., Firtina, S. et al. Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort. Pituitary 17, 220–226 (2014). https://doi.org/10.1007/s11102-013-0493-1

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