Carney Complex—Clarity and Complexity

Carl D. Malchoff

University of Connecticut Health Center Surgical Research Center Farmington, Connecticut 06030-1110

Address correspondence and requests for reprints to: Carl D. Malchoff, M.D., University of Connecticut Health Center, Surgical Research Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1110.


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 Introduction
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Genetic investigations of familial tumor syndromes continue to uncover new and critical information concerning tumorigenic mechanisms. Conversely, the identification of these tumorigenic mechanisms ultimately elucidates the full clinical spectrum of a disorder by affording a diagnostic gold standard and by generating novel hypotheses concerning phenotypic expression. Subsequently, the tumorigenic mechanisms may apply to other familial syndromes or to sporadic disorders. These synergies are apparent in recent investigations of the Carney complex (CNC). The diversity and complexity of the clinical spectrum of CNC continues to evolve. There is genetic heterogeneity, and the type I CNC (CNC1) susceptibility gene has been identified. We eagerly await a more accurate description of the CNC1 phenotype, a determination of the role of the CNC1 gene in sporadic forms of CNC type neoplasms, and identification of the CNC2 susceptibility gene.

CNC refers to the familial association of myxomas, spotty pigmentation, and endocrine overactivity. In 1985, J. Aidan Carney and colleagues (1) carefully described many of the clinical characteristics of this disorder based on his analysis of 40 patients. Their findings included cardiac myxomas, skin lesions (both myxomas and pigmented lesions), primary pigmented nodular adrenocortical disease (PPNAD), which causes ACTH-independent Cushing’s syndrome, myxoid fibroadenomas of the breast, growth hormone-secreting pituitary tumors, and both Sertoli cell and Leydig cell (steroid-type) testicular tumors. Inheritance is autosomal dominant with incomplete penetrance. This rare familial tumor syndrome often presents to the endocrinologist because the clinical features include Cushing’s syndrome, acromegaly, and male precocious puberty.

Multiple hypotheses were entertained to explain CNC and its diverse manifestations. These included adrenal stimulating antibodies (2) and activating mutations of the {alpha}-subunit of Gs, as occurs in the McCune-Albright syndrome (3). Interestingly, these hypotheses were not as disparate as one might think. Because PPNAD is a relatively frequent component of this disorder, these hypotheses all proposed that the inherited susceptibility gene would activate the signal transduction pathway that mediates adrenal cortisol production. Components of this pathway (Fig. 1Go) include ACTH, the type 2 melanocortin receptor that binds ACTH, the G protein complex that transduces the ACTH binding message into adenylyl cyclase activation, phosphodiesterases that degrade intracellular cAMP, cAMP-dependent protein kinase (PKA) and its regulatory subunits, and further downstream events. Indeed, clinical syndromes caused by activation of these signal transduction pathways have been described (4, 5). However, there are multiple components to this pathway, there could be unsuspected components, and the CNC susceptibility gene need not be a component of this pathway. Therefore, powerful and complementary genetic methodologies were chosen to provide additional information.



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Figure 1. CNC1 tumorigenesis involves activation of a seven transmembrane domain receptor signaling pathway. The mechanism of CNC1 tumorigenesis involves activation of a seven transmembrane domain receptor (7TMDR) signaling pathway downstream from the cAMP-dependent protein kinase (PKA). The PKA type I-{alpha} regulatory subunit (PPKAR1A) normally inhibits protein phosphorylation by PKA, and this inhibition is released when cAMP binds to PPKAR1A. In the presence of cAMP, PPKAR1A dissociates from PKA, leaving active PKA to promote downstream signaling. Depending on the tissue downstream signaling, effects may include changes in metabolism, ion transport, hormone production, and gene transcription. In CNC1 neoplasms, PPKAR1A is absent or diminished. One defective allele was inherited, and the normal allele may be inactivated by deletion. In the absence of PPKAR1A, PKA signaling is hypersensitive to normal activation. This process gives that cell a selective growth advantage, other growth-promoting events may occur, and a neoplasm becomes apparent clinically. In the adrenal cortex, pituitary, and testicular Leydig cells, the neoplasms are associated with excess production of cortisol, GH, and testosterone, respectively. Activation of the 7TMDR signal transduction pathway proximal to PKA affects hormone production and may initiate tumorigenesis in other clinical disorders. In the McCune-Albright syndrome, the signal transduction pathway is activated by mutations of the {alpha}-subunit of Gs, a member of the G protein complex (5 ). In other tissue-specific clinical disorders, activating mutations of the 7TMDR affect hormone production and may initiate tumorigenesis. Clinical syndromes have been reported that are associated with activating mutations of the LH receptor, TSH receptor, and calcium sensing receptor (4 ).

 
It seemed likely that genetic linkage techniques would facilitate the identification of the CNC susceptibility gene, as they have with many other familial tumor syndromes. Only a limited number of genes in that linkage region potentially modulate cortisol, testosterone, and GH production. However, the availability of adequate clinical resources limits the application of these genetic techniques. Drs. C. A. Stratakis, J. A. Carney, and C. T. Basson all recognized the importance of clinical studies. They carefully evaluated family members to more clearly define the CNC clinical characteristics, and they distinguished affected from unaffected family members. This was the necessary groundwork that became the foundation for the genetic linkage analysis. In this day and age of powerful genetic techniques and near complete sequencing of the entire human genome, the rate-limiting step in finding the CNC gene(s) was old-fashioned clinical evaluation.

The careful clinical evaluations continue to clarify the CNC phenotype. In a 1996 publication, Stratakis et al. (6) evaluated 101 persons from 11 families with CNC. About half of those evaluated were determined to have CNC by the presence of two or more clinical features of this disorder. The most common findings were those of skin pigmentation, which occurred in 96% of affected subjects. Other features included cardiac myxomas (36%), skin myxomas (63%), breast myxomas (22% of all affected subjects divided as 37% in women and 4% in men), PPNAD (32%), acromegaly (8%), Sertoli cell testicular tumors (10%), and thyroid tumors (10%). Subsequently, these investigators have aggressively evaluated affected individuals for tumors in specific organs. In this issue of the JCEM, they combine the North American experience with a European experience provided by Dr. W. H. Oelkers and report a prospective and retrospective analysis of CNC ovarian neoplasms (7). They noted that pigmented skin lesions are a clinical overlap of CNC with Peutz-Jeghers syndrome (PJS) and looked for other evidence of clinical overlap. Because both testicular and ovarian tumors are a component of PJS, they postulated that ovarian neoplasms might be a component of CNC. In addition, they argue that a familial tumor syndrome with an increased incidence of testicular neoplasms may have an increased incidence of ovarian neoplasms (7). Although Dr. Carney’s 1985 CNC description noted only two ovarian lesions, they reasoned that a more aggressive evaluation would uncover more lesions. Eighteen women with CNC (median age, 33 yr) were evaluated prospectively with ultrasound examination over a mean period of 34 months, and 178 women with CNC from a large international registry were evaluated retrospectively. Interestingly, there were no stromal tumors of the ovaries as seen in PJS. Of the 18 women evaluated prospectively, 12 developed ovarian cysts as compared with 1 of 11 in the control group (P = 0.003). Of the affected women, two had progression of cysts and underwent ovariectomy for serous cystadenomas. The retrospective analysis identified only four women with ovarian neoplasms requiring surgery, and one was felt to be metastatic adenocarcinoma. Two ovarian lesions removed in the prospective study demonstrated a copy gain in the chromosomal region of 2p16, which may represent gene amplification. Other studies of affected subjects have more clearly defined the thyroid lesions and the paradoxical response of cortisol production to dexamethasone administration (8, 9).

Careful clinical evaluation greatly facilitated the genetic linkage analysis. Genetic heterogeneity was observed, and the protein kinase A type I-{alpha} regulatory subunit gene (PPKAR1A) was identified as a CNC susceptibility gene. Linkage analysis identified two CNC genetic loci: a 6.4-cM region at 2p16 (6) and a 17-cM region at 17q23-24 (10). A number of CNC candidate genes were excluded by these analyses. The proopiomelanocortin gene was excluded because its chromosomal location on chromosome 2 is telomeric to the CNC locus. There were two known tumor suppressor genes on the long arm of chromosome 17: BRCA1 and NF1, tumor suppressor genes for familial breast carcinoma and for neurofibromatosis type I, respectively. However, these are excluded because their chromosomal locations are centromeric to the CNC locus. In affected subjects tumor-specific loss of heterozygosity (LOH) was found within the 17q linkage region in eight different neoplasms including adrenal lesions, myxomas, GH-secreting pituitary tumors, a follicular thyroid carcinoma, and a testicular tumor (11). Tumor-specific LOH suggests that this CNC susceptibility gene is a tumor suppressor gene. Furthermore, the common region of LOH markedly restricted the chromosomal location of this tumor suppressor gene. The PPKAR1A gene is contained within this chromosomal region. The PKA holoenzyme (Fig. 1Go) is an inactive tetramer consisting of two regulatory and two catalytic subunits. When the regulatory subunits bind cAMP, they dissociate from the catalytic subunits. The free catalytic subunits phosphorylate serine and threonine residues of proteins critical to the activation of downstream processes. In addition to PPKAR1A, the RI-{alpha} regulatory subunit, there are three other PKA regulatory subunits: RI-ß, RII-{alpha}, and RII-ß. Each has a different pattern of tissue expression. Because the PPKAR1A normally inhibits downstream signaling by PKA, it was considered a likely candidate for the CNC tumor suppressor gene. Loss of activity of this regulatory subunit might activate PKA and subsequent downstream signaling. The end points could include hormone production (cortisol, GH, and testosterone) and tumorigenesis. Two groups publishing in September 2000 provide evidence that PPKAR1A is a CNC susceptibility gene. Mutations with a high likelihood of inactivating the PPKAR1A protein were identified in a total of nine CNC families, and in a single sporadic subject with CNC (11, 12). Furthermore, the cAMP-dependent PKA activity in CNC steroid-producing neoplasms increased to a greater degree following cAMP stimulation than the PKA activity from similar sporadic neoplasms (11). Interestingly, the basal kinase activity was equal in CNC and control neoplasms, suggesting that other regulatory proteins can substitute for PPKAR1A. A diminished amount of apparently normal PPKAR1A was found by Western analysis in one myxoma, suggesting that deletion is not a necessary requirement for myxoma formation (12). In summary, the PPKAR1A gene mutations cause CNC in some families, and this disorder is now referred to as CNC1. The gene on chromosome 2p that is mutated in CNC2 remains unknown, for now.

With clarification of the CNC1 susceptibility gene, there is now a molecular gold standard for the diagnosis of CNC1. This will facilitate a clearer clinical description of CNC1 and rapid determination of the role of acquired PPKAR1A mutations in the development of sporadic CNC type neoplasms. The different endocrine abnormalities may have different frequencies in CNC1 as compared with CNC2. We already know that PPNAD and GH-producing pituitary tumors can occur in CNC1, because these tumors demonstrated LOH at the PPKAR1A chromosomal locus and the individuals carrying these tumors had mutations of this gene (11). It is possible, and even likely, that phenotypic diversity exists within a given syndrome as occurs in other familial tumor syndromes, such as the multiple endocrine neoplasia type 2 syndromes. No doubt these same authors will soon let us know if acquired PPKAR1A mutations occur commonly in sporadic cardiac myxomas, spotty skin lesions, GH-producing pituitary adenomas, testicular tumors, and cortisol producing adrenal adenomas.

Other intriguing questions may not be answered as quickly. Will identification of the CNC1 susceptibility gene facilitate the identification of the CNC2 susceptibility gene? Will there be more than one susceptibility gene or phenotype for CNC2? Can identification of the CNC1 gene help us to predict the clinical phenotype other disorders caused by abnormalities of the same signal transduction pathways? It is attractive to speculate that another PKA regulatory subunit causes CNC2. However, a quick review of available databases suggests that this is not the case. The CNC2 gene is on chromosome 2p, whereas the genes for the other known regulatory subunits—RI-ß, RII-{alpha}, and RII-ß—are on chromosomes 7p, 3p, and 7q, respectively. In addition, tumor-specific LOH has not been a consistent feature of CNC2 (7), as might be expected if a regulatory subunit abnormality were the cause of this disorder. Therefore, it seems unlikely other known PKA regulatory subunits are the CNC2 susceptibility gene. Because tumor specific gene amplification may occur in CNC2, it is attractive to postulate that a PKA catalytic subunit is the CNC2 gene. However, the {alpha}, ß, and {gamma} catalytic PKA subunits have chromosomal locations at 19p, 1p, and 9q, respectively. Therefore, they cannot cause CNC2, which has been mapped to chromosome 2p. Identification of the CNC2 susceptibility gene may prove difficult. However, it is likely to be worth the effort, because new information concerning tumorigenic mechanisms in man is likely to be uncovered.

In summary, careful clinical evaluation has been combined with genetic techniques to uncover new and critical information concerning tumorigenic mechanisms in CNC. Conversely, the identification PPKAR1A as the CNC1 susceptibility gene will rapidly elucidate the full clinical spectrum of CNC1 by affording a diagnostic gold standard and generating novel hypotheses concerning phenotypic expression. Subsequently, the lessons learned from investigations into CNC1 may be applicable to other familial syndromes or to sporadic neoplasms of the type found in CNC1.

Received September 19, 2000.

Accepted September 19, 2000.


    References
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 Introduction
 References
 

  1. Carney JA, Gordon H, Carpenenter PC, Shenoy BV, Go VLW. 1985 The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine. 64:270–283.[Medline]
  2. Wulffraat NM, Drexhage HA, Wiersinga WM, van der Gaag RD, Jeucken P, Mol JA. 1988 Immunoglobulins of patients with Cushing’s syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis. J Clin Endocrinol Metab. 66:301–307.[Abstract]
  3. DeMarco L, Stratakis CA, Boson WL, et al. 1996 Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gsa gene. Hum Genet. 98:185–188.[CrossRef][Medline]
  4. Shenker A. 1995 G protein-coupled receptor structure and function: the impact of disease-causing mutations. Balliere’s Clin Endocrinol Metab. 9:427–451.[Medline]
  5. Weinstein L, Shenker A, Gejman P, Merino M, Friedman E, Spiegel A. 1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 325:1688–1695.[Abstract]
  6. Stratakis CA, Carney JA, Lin J-P, et al. 1996 Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Endocrinol Metab. 97:699–705.
  7. Stratakis CA, Papageorgiou T, Premkumar A, et al. 2000 Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J Clin Endocrinol Metab. 85:4359–4366.[Abstract/Free Full Text]
  8. Stratakis CA, Courcoutsakis NA, Abati A, et al. 1997 Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex). J Clin Endocrinol Metab. 82:2037–2043.[Abstract/Free Full Text]
  9. Stratakis CA, Sarlis NJ, Kirschner LS, et al. 1999 Paradoxical response to dexamethasone assists with the diagnosis of primary pigmented nodular adrenocortical disease (PPNAD). Ann Intern Med. 131:585–591.[Abstract/Free Full Text]
  10. Casey M, Mah C, Merliss AD, et al. 1998 Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation. 98:2560–2566.[Abstract/Free Full Text]
  11. Kirschner LS, Carney JA, Pack SD, et al. 2000 Mutations of the gene encoding the protein kinase A type I-{alpha} regulatory subunit in patients with the Carney complex. Nat Genet. 26:89–92.[CrossRef][Medline]
  12. Casey M, Vaughan CJ, He J, et al. 2000 Mutations in the protein kinase A R1{alpha} regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest. 106:R31–R38.




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