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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pituitary. Author manuscript; available in PMC 2008 May 5.
Published in final edited form as:
Pituitary. 2004; 7(2): 73–82.
doi:  10.1007/s11102-005-5348-y
PMCID: PMC2366887

Pituitary Pathology in Carney Complex Patients


Carney complex (CNC) is a familial multiple neoplasia syndrome with features overlapping those of McCune-Albright syndrome (MAS) and multiple endocrine neoplasia (MEN) type 1 (MEN 1). Like MAS and MEN 1 patients, patients with CNC develop growth hormone (GH)- producing pituitary tumors. Occasionally, these tumors are also prolactin-producing, but there are no isolated pro-lactinomas or other types of pituitary tumors. In at least some patients with CNC, the pituitary gland is characterized by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only. Hyperplasia most likely precedes the formation of GH-producing adenomas in CNC, as has been suggested in MAS-related somatotropinomas, but has never been seen in MEN 1 patients. In at least one case of a patient with CNC and advanced acromegaly, a GH-producing macroadenoma showed extensive genetic changes at the chromosomal level. So far, half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost. Loss-of-hererozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1α of the cAMP-dependent protein kinase A (PKA) may act as a tumor-suppressor gene in CNC somatomammotrophs. These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients.

Keywords: Carney complex, pituitary tumors, hyperplasia, genetics, PRKAR1A, protein kinase A


The complex of “spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas” or Carney complex (CNC) is a multiple endocrine neoplasia(MEN) and lentiginosis syndrome [14] that is inherited in an autosomal dominant manner [5], and is genetically heterogeneous [68]. Although growth hormone (GH) and prolactin (PRL) secretion are frequently abnormal in affected patients [9,10], clinical acromegaly or significant hyperprolactinemia and GH- or PRL-producing tumors, respectively, have been detected in less than one fifth of them [11,12]. The pattern of biochemical abnormalities of GH and PRL secretion without pituitary tumors that are detectable by common imaging modalities, and infrequent development of clinically significant acromegaly is reminiscent of the situation in McCune- Albright syndrome (MAS) [1316]. Studies of tumors excised from patients with CNC had indicated that their molecular abnormality may be in the molecular pathway that involves the stimulatory α-subunit of the guanine nucleotide-binding protein (Gsα) [17,18], GNAS— the gene responsible for MAS [13]. However, Gsα mutations were not present in an investigation of a series of CNC tumors [18].

Approximately half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene [19,20], which codes for the regulatory subunit type 1α of the cAMP-dependent protein kinase A (PKA) [21]. Loss-of-hererozygosity (LOH) in some tumors from patients with CNC suggested that PRKAR1A, may act as a tumor-suppressor gene in tissues affected by CNC [22,23]. However, PRKAR1A’s role in human oncogenesis is controversial, and studies mainly from cell line-related work have not suggested a tumor-suppressor role [24].

Pituitary Findings in Patients with CNC

Clinical and histopathologic analysis

GH-producing tumors have been identified so far in several CNC patients (Table 1) with clinically diagnosed acromegaly at the National Institutes of Health [25]. The frequency of PRKAR1A mutations in these patients is the same as in the whole group (approximately 50%); clinical details have been described elsewhere [25]. All CNC-related GH-producing tumors stained positive for PRL and occasionally for other hormones (Table 1). Most of the patients who had acromegaly as the primary manifestation of CNC had macroadenomas, as is the case for most acromegalic patients. Multiple macroscopic and microscopic tumors were seen in the pituitary gland of several patients (Fig. 1), including one with a microadenoma (data not shown). In these patients, extra-tumoral pituitary parenchyma showed evidence of GH- and PRL-producing cell hyperplasia.

Fig. 1
Hyperplasia (and tumor tissue) in the pituitary gland from a CNC patient with acromegaly and a GH-producing pituitary adenoma (case 3,Table 2): immuno-stainings with antibodies specific for (A) reticulin; (B) GH; (C) PRL; and (D) LH β-subunit ...
Table 1
Clinical presentation and histology of pituitary adenomas from patients with CNC

Adenohypophyseal hyperplasia, characterized by poorly delineated zones with increased cellularity and an expanded, somewhat irregular reticulin pattern was seen in most pituitary gland tissues excised from CNC patients (Fig. 2). A zone of probable transition from hyperplasia to adenoma, characterized by the gradual disappearance of the reticulin pattern and increasing cellularity, was also documented in these cases.

Fig. 2Fig. 2
Panels A and B are from case 1 (Table 1): (A) Abnormally expanded and irregular reticulin pattern, consistent with adenohypophesial cell hyperplasia (×100); (B) disrupted reticulin pattern in the adenomatous tissue from the same patient (×40). ...

Both hyperplastic areas and adenoma tissue stained for GH and PRL in all patients. PRL-staining was less intense and more limited than GH-staining [25], although in all cases it was the same cellular population that demonstrated immunoreactivity for both GH and PRL at consecutive sections. Staining for α- subunit was also present in most tumors in the same pattern as that of PRL. Occasional staining for TSH (β-subunit) and LH was also present in diffusely and rarely present cells of some adenomas and within foci of normal cells entrapped within the tumors. ACTH and FSH staining, when obtained, could only be seen in foci of normal cells entrapped within the tumors or the hyperplasia.

Electron microscopy studies

We recently described the electron microscopy findings of two GH-producing tumors from patients with CNC (Cases 1 and 2, Table 2) [26]. One additional patient has recently been studied (Case 3, Table 2, Fig. 3).

Fig. 3Fig. 3Fig. 3Fig. 3
Electron microscopy images from the same patient (case 3, Table 2) with GH- and LH-producing tumorlets [A and B] (7,682× and 5,380× respectively). Secretory granules are identified by GH-specific antibody [C] (14,200×) and double ...
Table 2
Clinical and electron microscopy findings of pituitary adenomas from 3 CNC patients

The tumors described by Kurtkaya-Yapicier et al. consisted of large, closely apposed, slightly irregular cells. The nuclei were ovoid or variably irregular and possessed a well to extensively developed nucleolus as well as small quantities of stippled heterochromatin. Rough endoplasmic reticulum was abundant and organized in parallel arrays or well-developed and randomly disposed short profiles. Golgi complexes were conspicuous, occupied a large portion of the cytoplasm and contained spherical or irregular, fused, immature secretory granules. Outside the Golgi zone, secretory granules were scant and measured up to 350 nm in diameter, most ranging between 200–250 nm. Extrusion of secretory granules was occasionally seen. Cell membranes between neighboring cells often showed complex inter-digitation. Cytoplasmic fibrous bodies were not identified. A very few adenoma cells (1%) were densely granulated, possessed well-developed rough endoplasmic reticulum and very prominent Golgi complexes. Their secretory granules measured up to 500 nm in diameter, most ranging between 350–400 nm. Granule extrusion was seen. Based on immunoelectron microscopy (see below), these cells were considered mammosomatotrophs.

In the first tumor [26], many of the tumor cells had lactotrophic characteristics, but secretory granules in their Golgi areas labeled for both PRL and GH. The large secretory granules of the densely granulated cell component were either bi-hormonal or mono-hormonal, labelling either for GH and/or PRL. Thus, the immunore-activities in this case were not necessarily true to the ultrastructural phenotype.

In the second tumor, both nontumoral adenohypophysis and adenoma were seen [26]. The adenoma featured large irregular cells with eccentric, sometimes markedly irregular nuclei of which containing moderately developed nucleoli and small amounts of stippled heterochromatin. Rough endoplasmic reticulum was poorly to moderately developed and Golgi complexes were inconspicuous. Secretory granules were small (less than 250 nm) and sparse in some adenoma cells, numerous and measured up to 450 nm in others. Several tumor cells contained a prominent fibrous body. The non-tumoral adenohypophysis was normal Immunogold labeling for only GH was noted in this tumor [26].

A third tumor has been investigated recently (case 3 in Table 2, Fig. 3). Its features were similar to the above two tumors (Table 2, Fig. 3) but, in addition, LH- and GH-staining was seen in several tumor cells.

Overall, the electron microscopy features of CNC-associated pituitary tumors are not consistent but appear to be highly variable and not very different from those of GH-secreting, sporadic (non-syndromic) pituitary adenomas [26].

Genetic analysis of CNC pituitary tumors

Comparative genomic hybridization (CGH) analysis of 3 CNC-associated microadenomas showed no significant changes over normal DNA [25]. In contrast, analysis of the most aggressive tumor, an invasive macroadenoma, showed multiple changes, including losses of chromosomal regions 6q, 7q, 11p, 11q, and gains of 1pter-p32, 2q35-qter, 9q33-qter, 12q24-qter, 16, 17, 19p, 20p, 20q, 22p, 22q [25]. The greatest contiguous changes were losses of the long arm of chromosome 6 and the entire chromosome 11.

The CNC tumors studied to date from patients with inactivating PRKAR1A mutations have demonstrated LOH for the17q22–24 PRKAR1A locus [19]. There have been no studies of pituitary tissue from patients with CNC that appear to have other genetic defects.


Acromegaly is usually characterized by a slow, progressive course. In CNC this course is even slower and acromegaly is often unmasked by adrenalectomy for primary pigmented nodular adrenocortical disease (PPNAD) [27]. In our prospective evaluation of patients with CNC, we have had the opportunity to observe the “development” of pituitary adenomas, so far in 4 patients. In these cases, biochemical abnormalities of GH and PRL secretion were present in advance of radiological detection of the tumor [9,10]. The incidence of GH-producing pituitary tumors in CNC has been estimated at less than 15% [1,6,11], whereas GH “paradoxical” responses to various stimuli [such as to thyrotropin-releasing hormone (TRH)] or IGF-I elevation, without a detectable tumor,maybe present in up to 80% of affected patients [25]. The finding of probable hyperplasia in pituitary tissue from patients with CNC, who underwent TSS for acromegaly, is consistent with these clinical observations.

The GH-secreting adenoma in all cases where adequate tissue was available for examination appeared to be surrounded by regions with expanded irregular reticulin structure, and GH-, PRL-, and occasionally α- subunit immunoreactive cells. It is noteworthy that in these patients, multiple tumors were also seen both macroscopically and microscopically. PRL staining was not present in all the GH-stained areas; accordingly, PRL levels in the peripheral blood were not markedly elevated in most patients with CNC, in contrast to GH or IGF-I levels in the same patients. Electron microscopy studies showed siginificant differences between the two CNC-related adenomas [26], suggesting that not all GH-producing adenomas are the same and these lesions are potentially pleiomorphic.

The genetic investigation complemented the above findings by suggesting that in its evolution, the largest and most aggressive CNC-associated tumor [25] had accumulated a series of genetic changes; in contrast, the small adenomas had normal CGH results. These findings are in agreement with the hypothesis that pituitary tumors develop from clonal expansion of transformed somatic cells [28,29]. They are also consistent with observations in patients with MAS [1416] and some patients with MEN 1 [30]. CNC and MAS are genetic conditions that share skin pigmentation abnormalities, adrenocortical hyperplasia, thyroid tumors and even myxomas. However, in most tissues, the lesions are histologically and clinically different in the two conditions: skin lentigines and blue nevi versus café-au-lait spots, micronodular and pigmented dysplasia versus adrenocortical macronodular hyperplasia, hormonally silent nodules or cancerversus thyroid hormone hypersecretion, and skin versus intramuscular myxomas [1,6,14,31,32]. Mammosomatotroph hyperplasia may be the only lesion that is in fact common in CNC and MAS [33]. Clinically, too, both share a “pro-acromegalic” state [34], which only rarely leads to the detection of an adenoma [10,1416,34]. Similar, long-standing somatotroph hyperplasia, which only occasionally leads to pituitary adenoma has been seen in several other patients, albeit GHRH-induced [35,36].

The genetic changes required for the formation of an adenoma in the background of benign hyperplasia are not known but appear to be multiple. As other investigators have shown in tumors with Gsα mutations or allelic losses of the MEN 1 locus [37,38], pituitary genetic changes tend to increase in number and significance in parallel with the clinical behavior of the neoplasm [28,29]. Pituitary tumorigenesis in CNC patients may follow the pattern of mutation accumulation that has been suggested for other neoplasms [39,40]. The extensive genetic instability of cells cultured from CNC tumors suggests that secondary “hits” underlie tumor formation in CNC, the first “hit” being the germline PRKAR1A mutation, in at least these patients that have a PRKAR1A defect. This corresponds to Knudson’s hypothesis [41].

Is PRKAR1A Mutated in Other Pituitary Tumors?

We speculated above that the germline CNC mutation causes a predisposition towards other molecular events that are necessary for pituitary tumor formation in CNC patients. Although the evidence suggests that this may be the case in CNC, it is not known whether PRKAR1A can cause sporadic pituitary tumors when mutated at the somatic level. Three recent studies [4244] have demonstrated that PRKAR1A is an unlikely molecular etiology of non-familial pituitary tumors, not unlike the case of menin, the MEN 1 gene [45].


Occasional CNC patients with known PRKAR1A-inactivating mutations have somatomammotroph hyperplasia and/or adenomas. Additional genetic changes at the somatic level are triggered by the hyperplasia, which in turn cause the formation of GH-producing adenomas in some, but not all, patients. Molecular investigation of PRKAR1A’s effects on cellular signalling and the cell cycle, as well as mouse model studies, are expected to shed light on this gene’s role in pituitary tumorigenesis. Although epigenetic modification of its function is not unlikely, somatic PRKAR1A mutations are not frequent in sporadic pituitary tumors.


1. Carney JA, Young WF. Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist. 1992;2:6–21.
2. Stratakis CA. 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. 1998;30:285–290.
3. Carney JA. Carney complex: The complex of myxomas, spotty pigmentation, endocrine veractivity, and schwannomas. Semin Dermatol. 1995;14:90–98. [PubMed]
4. Stratakis CA, Kirschner LS, Carney JA. Carney complex: Diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity & schwannomas [letter] Am J Med Genet. 1998;80:183–185. [PubMed]
5. Carney JA, Hruska LS, Beauchamp GD, Gordon H. Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc. 1986;61:165–172. [PubMed]
6. Stratakis CA, Carney JA, Lin J-P, Papanicolaou DA, Karl M, Kastner DL, et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome: Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest. 1996;97:699–705. [PMC free article] [PubMed]
7. Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation. 1998;98:2560–2566. [PubMed]
8. Stratakis CA, Kirschner LS, Taymans SE, Carney JA, Basson CT. Genetic Heterogeneity in Carney Complex (OMIM 160980): Contributions of loci at chromosomes 2 and 17 in its genetics. Am J Hum Genet. 1999;65 Suppl:A447.
9. Stratakis CA, Kirschner LS, Papanicolaou DA, Sarlis NJ, Raff S, Veldhuis JD, et al. 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. 1998. Jun, pp. P3–P552.
10. Raff SB, Carney JA, Krugman D, Doppman JL, Stratakis CA. Prolactin abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and skin myxomas” (Carney complex) J Pediatr Endocrinol Metab. 2000;13:373–379. [PubMed]
11. Watson JC, Stratakis CA, Bryant-Greenwood PK, Koch CA, Kirschner LS, et al. The neurosurgical implications of Carney complex. J Neurosurg. 2000;92:413–418. [PubMed]
12. Irvine AD, Armstrong DK, Bingham EA, Hadden DR, Nevin NC, Hughes AE. Evidence for a second genetic locus in Carney complex. Br J Dermatol. 1998;139:572–576. [PubMed]
13. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Ffiedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325:1688–1695. [PubMed]
14. Gessl A, Freissmuth M, Czech T, Matula C, Hainfellner JA, Buchfelder M, et al. Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gsα protein. J Clin Endocrinol Metab. 1994;79:1128–1134. [PubMed]
15. Garcia MB, Koppeschaar HIP, Lips CJ, Thijsen JH, Krenning EP. Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: Dynamic endocrine studies and treatment with the somatostatin analogue octreotide. J Endocrinol Invest. 1994;17:59–65. [PubMed]
16. Cuttler L, Jackson JA, Uz-Zafar S, Levitsky LL, Mellinger RC, Frohman LA. Hypersecretion of growth hormone and prolactin in McCune-Albfight syndrome. J Clin Endocrinol Metab. 1989;68:1148–1154. [PubMed]
17. Stratakis CA, Jenkins RB, Pras E, Mitsiadis CS, Raff SB, Stalboerger PG, et al. Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex) J Clin Endocrinol Metab. 1996;81:3607–3614. [PubMed]
18. DeMarco L, Stratakis CA, Boson WL, Yakbovitz O, Carson E, Adrade LM, et al. Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gsα gene. Hum Genet. 1996;98:185–188. [PubMed]
19. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26:89–92. [PubMed]
20. Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum Mol Genet. 2000;9:3037–3046. [PubMed]
21. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: Diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001;86:4041–4046. [PubMed]
22. Stergiopoulos SG, Stratakis CA. Human tumors associated with Carney complex and germline PRKAR1A mutations: A protein kinase A disease! FEBS Lett. 2003;546:59–64. [PubMed]
23. Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J. Molecular analysis of the cyclic AMP—dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney Complex and primary pigmented nodular adreno-cortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: Augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet. 2002;71:1433–1442. [PubMed]
24. Cho-Chung Y. cAMP signaling in cancer genesis and treatment. Cancer Treat Res. 2003;115:123–143. [PubMed]
25. Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA. 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. 2000;85:3860–3865. [PubMed]
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. Pituitary adenoma in Carney complex: An immunohistochemical, ultrastructural, and immunoelectron microscopic study. Ultrastruct Pathol. 2002;26:345–353. [PubMed]
27. Ogo A, Haji M, Natori S, Kanzaki T, Kabayama Y, Osamura RY, et al. Acromegaly with hyperprolactinemia developed after bilateral adrenalectomy in a patient with Cushing’s syndrome due to adrenocortical nodular hyperplasia. Endocr J. 1993;40:17–25. [PubMed]
28. Asa SL, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas. Endocr Rev. 1998;19:798–827. [PubMed]
29. Farrell WE, Clayton RN. Epigenetic change in pituitary tumorigenesis. Endocr Relat Cancer. 2003;10:323–330. [PubMed]
30. Shintani Y, Yoshimoto K, Horie H, Sano T, Kanesaki Y, Hosoi E, et al. 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. 1995;42:331–340. [PubMed]
31. Stratakis CA, Courcoutsakis NA, Abati A, Filie A, Doppman JL, Carney JA, et al. Thyroid gland abnormalities in patients with the “syndrome of spotty skin pigmentation, myxomas, and endocrine overactivity” J Clin Endocrinol Metab. 1997;82:2037–2043. [PubMed]
32. Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, et al. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med. 1999;131:585–591. [PubMed]
33. Kovacs K, Horvath E, Thomer MO, Rogol AD. Mammosomatotroph hyperplasia associated with acromegaly and hyperprolactinemia in a patient with the McCune-Albright syndrome. Virch Arch Pathol Anat. 1984;403:77–86.
34. Feuillan PP, Jones J, Ross JL. Growth hormone hypersecretion in a girl with McCune-Albright syndrome: comparison with controls and response to a dose of long-acting somatostatin analog. J Clin Endocrinol Metab. 1995;80:1357–1360. [PubMed]
35. Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormone-producing tumors: Clinical, biochemical, and morphological manifestations. Endocr Rev. 1988;9:357–373. [PubMed]
36. Ezzat S, Asa SL, Stefaneanu L, Whittom R, Smyth HS, Horvath E, et al. Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing hormone-producing bronchial carcinoid. J Clin Endocrinol Metab. 1994;78:555–560. [PubMed]
37. Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest. 1993;91:2815–2821. [PMC free article] [PubMed]
38. Kytola S, Makinen MJ, Kahkonen M, Teh BT, Leisti J, Salmela P. Comparative genomic hybridization studies in tumours from a patient with multiple endocrine neoplasia type 1. Eur J Endocrinol. 1998;139:202–206. [PubMed]
39. Cho KR, Vogelstein B. Genetic alterations in the adenoma-carcinoma sequence. Cancer. 1992;70:1727–1731. [PubMed]
40. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;4:138–141. [PubMed]
41. Knudson AG. Hereditary cancer: Two hits revisited. J Cancer Res Clin Oncol. 1996;122:135–140. [PubMed]
42. 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. 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. 2002;39:e78. [PMC free article] [PubMed]
43. Kaltsas GA, Kola B, Borboli N, Morris DG, Gueorguiev M, Swords FM, Czirjak S, Kirschner LS, Stratakis CA, Korbonits M, Grossman AB. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Clin Endocrinol (Oxf) 2002;57:443–448. [PubMed]
44. Yamasaki H, Mizusawa N, Nagahiro S, Yamada S, Sano T, Itakura M, Yoshimoto K. GH-secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23–24. Clin Endocrinol (Oxf) 2003;58:464–470. [PubMed]
45. Asa SL, Somers K, Ezzat S. The MEN-1 gene is rarely down-regulated in pituitary adenomas. J Clin Endocrinol Metab. 1998;83:3210–3212. [PubMed]