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Pituitary

, 9:203 | Cite as

Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities

  • Sosipatros A. Boikos
  • Constantine A. StratakisEmail author
Article

Abstract

First described in the mid 80’s, Carney Complex (CNC) is a rare, dominantly heritable disorder with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; they present with elevated growth hormone (GH) levels and mild hyperprolactinemia. However, most patients with CNC have mild hypersomatomammotropinemia starting in adolescence; this is similar to the situation in MAS patients: in both disorders, pituitary hyperplasia appears to precede tumor development. Familial pituitary tumor syndromes such as CNC provide an important insight into the genetics and molecular pathology of pituitary and other endocrine tumors. Our understanding of these conditions is expanding rapidly due to the identification of the causative genes and the availability of murine disease models. The present report reviews the clinical findings related to pituitary tumor development among patients with CNC and provides an update on murine models of the complex.

Keywords

Carney complex Multiple endocrine neoplasias Pituitary tumors Growth hormone Prolactin Acromegaly PRKAR1A Cyclic AMP 

References

  1. 1.
    Carney JA, Young WF (1992) Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist 2:6–21Google Scholar
  2. 2.
    Stratakis CA (1998) The familial lentiginosis syndromes are emerging from the obscurity imposed by rarity: new genes and genetic loci for multiple tumors and developmental defects. Horm Metabol Research 30:285–290CrossRefGoogle Scholar
  3. 3.
    Carney JA (1995) Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol 14:90–98PubMedCrossRefGoogle Scholar
  4. 4.
    Stratakis CA, Kirschner LS, Carney JA (1998) Carney complex: Diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity & schwannomas [letter]. Am J Med Genet 80:183–185PubMedCrossRefGoogle Scholar
  5. 5.
    Carney JA, Hruska LS, Beauchamp GD, Gordon H (1986) Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc 61:165–172PubMedGoogle Scholar
  6. 6.
    Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA (2000) Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26:89–92PubMedCrossRefGoogle Scholar
  7. 7.
    Stratakis CA, Kirschner LS, Carney JA (1996) Carney complex, a familial multiple neoplasia and lentiginoses syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 97:699–705PubMedCrossRefGoogle Scholar
  8. 8.
    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM (1991) Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 12:325:1688–95Google Scholar
  9. 9.
    Gessl A, Freissmuth M, Czech T, Matula C, Hainfellner JA, Buchfelder M, Vierhapper H (1994) Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein. J Clin Endocrinol Metab 79:1128–1134PubMedCrossRefGoogle Scholar
  10. 10.
    Garcia MB, Koppeschaar HP, Lips CJ, Thijssen JH, Krenning EP (1994) Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: dynamic endocrine studies and treatment with the somatostatin analogue octreotide. J Endocrinol Invest 17:59–65PubMedGoogle Scholar
  11. 11.
    Cuttler L, Jackson JA, Saeed uz-Zafar M, Levitsky LL, Mellinger RC, Frohman LA (1989) Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. J Clin Endocrinol Metab 68:1148–1154PubMedGoogle Scholar
  12. 12.
    Stratakis CA, Kirschner LS, Papanicolaou DA, Sarlis NJ, Raff S, Veldhuis JD et al (1998) Familial acromegaly beyond MEN-1: Genetic and clinical studies in non-GHRH dependent somatomammotroph hyperplasia in patients with Carney complex or an inherited chromosome 11 inversion. 80th Annual Meeting of the Endocrine Society, New Orleans, LA, p 3–552Google Scholar
  13. 13.
    Raff SB, Carney JA, Krugman D, Doppman JL, Stratakis CA (2000) Prolactin abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and skin myxomas” (Carney complex). J Pediatr Endocrinol Metab 13:373–379PubMedGoogle Scholar
  14. 14.
    Watson JC, Stratakis CA, Bryant-Greenwood PK, Koch CA, Kirschner LS et al (2000) The neurosurgical implications of Carney complex. J Neurosurg 92:413–418PubMedCrossRefGoogle Scholar
  15. 15.
    Irvine AD, Armstrong DK, Bingham EA, Hadden DR, Nevin NC, Hughes AE (1998) Evidence for a second genetic locus in Carney complex. Br J Dermatol 139:572–576PubMedCrossRefGoogle Scholar
  16. 16.
    Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA (2000) Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J Clin Endocrinol Metab 85:3860–3865PubMedCrossRefGoogle Scholar
  17. 17.
    Sotirios G. Stergiopoulos, Mones S. Abu-Asab, Maria Tsokos, Constantine A (2004) Stratakis pituitary pathology in carney complex patients. Pituitary 7:73–82CrossRefGoogle Scholar
  18. 18.
    Stratakis CA (2006) Cortisol and growth hormone: clinical implications of a complex, dynamic relationship. Pediatr Endocrinol Rev Suppl 2:333–338Google Scholar
  19. 19.
    Asa SL, Ezzat S (1998) The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev 19:798–827PubMedCrossRefGoogle Scholar
  20. 20.
    Warrell WE, Clayton RN (1998) Molecular genetics of pituitary tumors. Trends Endocrinol Metab 9:20–26CrossRefGoogle Scholar
  21. 21.
    Cuttler L, Jackson JA, Uz-Zafar S, Levitsky LL, Mellinger RC, Frohman LA (1989) Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. J Clin Endocrinol Metabol 68:1148–1154CrossRefGoogle Scholar
  22. 22.
    Gessl A, Freissmuth M, Czech T, Matula C, Hainfellner JA, Buchfelder M, Vierhapper H (1994) Growth hormone prolactin thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein. J Clin Endocrinol Metab 79:1128–1134PubMedCrossRefGoogle Scholar
  23. 23.
    Garcia MB, Koppeschaar HIP, Lips CJ, Thijsen JH, Krenning EP (1994) Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: dynamic endocrine studies and treatment with the somatostatin analogue octreotide. J Endocrinol Invest 17:59–65PubMedGoogle Scholar
  24. 24.
    Shintani Y, Yoshimoto K, Hori H et al (1995) Two different pituitary adenomas in a patient with multiple endocrine neoplasia type 1 associated with growth hormone-releasing hormone-producing pancreatic tumor: clinical and genetic features. Endocr J 42:331–340PubMedGoogle Scholar
  25. 25.
    Growth Hormone Research Society: Pituitary Society 2004 (2004) Biochemical assessment and long-term monitoring in patients with acromegaly: statement from a joint consensus conference of the Growth Hormone Research Society and the Pituitary Society. J Clin Endocrinol Metab 89:3099–3102Google Scholar
  26. 26.
    Kurtkaya-Yapicier O, Scheithauer BW, Carney JA, Kovacs K, Horvath E, Stratakis CA, Vidal S, Vella A, Young WF Jr, Atkinson JL, Lloyd RV, Kontogeorgos G (2002) Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study. Ultrastruct Pathol 26:345–353PubMedCrossRefGoogle Scholar
  27. 27.
    Melmed S, Casanueva FF, Cavagnini F, Chanson P, Frohman L, Grossman A, Ho K, Kleinberg D, Lamberts S, Laws E, Lombardi G, Vance ML, Werder KV, Wass J, Giustina A (2002) Acromegaly Treatment Consensus Workshop Participants 2002 Guidelines for acromegaly management. J Clin Endocrinol Metab 87:4054–4058PubMedCrossRefGoogle Scholar
  28. 28.
    Bossis I, Voutetakis A, Matyakhina L, Pack S, Abu-Asab M, Bourdeau I, Griffin KJ, Courcoutsakis N, Stergiopoulos S, Batista D, Tsokos M, Stratakis CA (2004) A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus. J Med Genet 41:596–600PubMedCrossRefGoogle Scholar
  29. 29.
    Horvath A, Boikos S, Weinberg F, Meoli E, Batista D, Stergiopoulos S, Bei T, Matyakhina L, Bossis I, Stratakis CA (2005) PRKAR1A mutations: Analysis of the largest database to date, identification of microdeletions and other novel disease-causing alterations, and functional characterization of expressed mutants. Presented in the Annual Meeting of American Congress of Human Genetics, Salt LakeGoogle Scholar
  30. 30.
    Pack SD, Qin L-X, Pak E, Wang Y, Ault DO, Mannan P, Jaikumar S, Stratakis CA, Oldfield EH, Zhuang Z, Weil RJ (2005) Common genetic changes in hereditary and sporadic pituitary adenomas detected by comparative genomic hybridization genes. Chromosomes & Cancer 43:72–82CrossRefGoogle Scholar
  31. 31.
    Kaltsas GA, Kola B, Borboli N, Morris DG, Gueorguiev M, Swords FM, Czirják S, Kirschner LS, Stratakis CA, Korbonits M, Grossman AB (2002) Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol 57:443CrossRefGoogle Scholar
  32. 32.
    Yamasaki H, Mizusawa N, Nagahiro S, Yamada S, Sano T, Itakura M, Yoshimoto K (2003) GH-secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23–24. Clin Endocrinol (Oxf) 58:464–470CrossRefGoogle Scholar
  33. 33.
    Sandrini F, Kirschner LS, Bei T, Farmakidis C, Yasufuku-Takano J, Takano K, Prezant TR, Marx SJ, Farrell WE, Clayton RN, Groussin L, Bertherat J, Stratakis CA (2002) PRKAR1A, one of the Carney complex genes, and its locus (17q22–24) are rarely altered in pituitary tumours outside the Carney complex. J Med Genet 39(12):e78PubMedCrossRefGoogle Scholar
  34. 34.
    Lania AG, Mantovani G, Ferrero S, Pellegrini C, Bondioni S, Perevelli E, Braidotti P, Locatelli M, Zavanone ML, Ferrante E, Bosari S, Beck-Peccoz P, Spada A (2004) Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res 64:9193–9198PubMedCrossRefGoogle Scholar
  35. 35.
    Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S, Weinberg FD, Claflin E, Meoli E, Cho-Chung YS, Stratakis CA (2004) Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res 64(24):8811–8815PubMedCrossRefGoogle Scholar
  36. 36.
    Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos SG, Robinson-White A, Lenherr SM, Weinberg FD, Claflin ES, Batista D, Bourdeau I, Voutetakis A, Sandrini F, Meoli EM, Bauer AJ, Cho-Chung YS, Bornstein SR, Carney JA, Stratakis CA (2004) A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. J Med Genet 41(12):923–931PubMedCrossRefGoogle Scholar
  37. 37.
    Kirschner LS, Kusewitt DF, Matyakhina L, Towns WH 2nd, Carney JA, Westphal H, Stratakis CA (2005) A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 65(11):4506–4514PubMedCrossRefGoogle Scholar
  38. 38.
    Veugelers M, Wilkes D, Burton K, McDermott DA, Song Y, Goldstein MM, La Perle K, Vaughan CJ, O’Hagan A, Bennett KR, Meyer BJ, Legius E, Karttunen M, Norio R, Kaariainen H, Lavyne M, Neau JP, Richter G, Kirali K, Farnsworth A, Stapleton K, Morelli P, Takanashi Y, Bamforth JS, Eitelberger F, Noszian I, Manfroi W, Powers J, Mochizuki Y, Imai T, Ko GT, Driscoll DA, Goldmuntz E, Edelberg JM, Collins A, Eccles D, Irvine AD, McKnight GS, Basson CT (2004) Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci USA 101(39):14222–14227PubMedCrossRefGoogle Scholar
  39. 39.
    Batista D, Stergiopoulos SG, Griffin KJ, Weinberg F, Stratakis CA (2004) Protein Kinase A activity in the pituitary gland of mice expressing the prkar1a antisense construct. Endocrine Society meeting. New OrleansGoogle Scholar
  40. 40.
    Batista DL, Weinberg F, Stergiopoulos SG, Meoli E, Griffin K, Stratakis CA (2005) Behavior Modifications in mice expressing RI alpha Protein Kinase A subunit mutant. Endocrine Society, San Diego CAGoogle Scholar
  41. 41.
    Pecori Giraldi F, Mizobuchi M, Horowitz ZD, Downs TR, Aleppo G, Kier A, Wagner T, Yun JS, Kopchick JJ, Frohman LA (1994) Development of neuroepithelial tumors of the adrenal medulla in transgenic mice expressing a mouse hypothalamic growth hormone-releasing hormone promoter-simian virus-40T-antigen fusion gene. Endocrinology 134(3):1219–1224PubMedCrossRefGoogle Scholar
  42. 42.
    Batista DL, Weinberg F, Voutetakis A, Bossis I, Kirschner K, Kineman RD, Stratakis CA (2005) Pituitary pathology in transgenic mice expressing the MThGHRH transgene in the prkar1a+/-background. Endocrine Society, San Diego CAGoogle Scholar
  43. 43.
    Batista DL, Weinberg F, Voutetakis A, Bossis I, Kirschner L, Kineman RD, Stratakis CA (2005) Pituitary pathology in transgenic mice expressing the MThGHRH-transgene in the prkar1a+/- background. Pituitary Society Meeting, San Diego, CAGoogle Scholar
  44. 44.
    Batista DL, Weinberg F, Meoli E, Stergiopoulos S, Boikos S, Voutetakis A, Bossis I, Kineman RD, Stratakis CA (2006) Pituitary pathology in MT-GHRH/Prkar1a+/-mice. Presented in the Annual Endocrinology Meeting, BostonGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Sosipatros A. Boikos
    • 1
  • Constantine A. Stratakis
    • 1
    Email author
  1. 1.Section on Endocrinology & Genetics (SEGEN), Developmental Endocrinology Branch (DEB)National Institute of Child Health and Human Development (NICHD), National Institutes of HealthBethesda

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