Carney Complex, Type 2


For a general phenotypic description and a discussion of genetic heterogeneity of Carney complex, see CNC1 (160980).


Stratakis et al. (1995, 1996) studied 101 patients from 11 North American kindreds with Carney complex. Skin myxomas, cardiac myxomas, Cushing syndrome, and acromegaly were present in, respectively, 62%, 30%, 31%, and 8% of the patients. They demonstrated linkage to markers on the short arm of chromosome 2 (2p16) with a maximum 2-point lod score of 5.97 at theta = 0.03 for linkage to a (CA)n dinucleotide repeat polymorphism (Leach et al., 1994). Candidate genes in the proximity, including the proopiomelanocortin gene (176830) and the DNA-mismatch repair gene MSH2 (609309), were excluded.

Stratakis et al. (1996) examined 15 tumor and normal tissue specimens from 13 patients with Carney complex. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3 to 22 and 14 loci on chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly overrepresented (p less than 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73, 59, 47, 46, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The authors concluded that tumors and tumor cell lines from patients with Carney complex demonstrate significant genomic, but not microsatellite length, instability. Thus, the Carney complex gene or genes on chromosome 2p16 are different from the MSH2 and MSH6 genes and have a dominant, rather than recessive, tumor function. These genes appear to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

Basson et al. (1997) presented evidence from linkage studies that the Carney complex is genetically heterogeneous. They studied a kindred with 7 affected individuals in 4 generations. All 6 living affected individuals exhibited pleomorphic spotty skin pigmentation typical of the Carney complex. All 4 of the 6 affected individuals who had reached adulthood had had left and/or right atrial myxomas. Three individuals whose atrial myxomas were resected had recurrence at least once, distant from the operative site. Three of them had histories of extracardiac myxomas, 2 in the breast and 1 in the vagina. Endocrine abnormalities were present in 3, 2 showed thyroid dysfunction, and 1 required adrenalectomy for Cushing syndrome. Linkage studies yielded lod scores of less than -2.0 over the 10-cM interval between D2S391 and D2S393, where the Carney complex had previously been mapped by Stratakis et al. (1996).

Basson (1999) pointed out that one of the 'chromosome 2' families of Stratakis et al. (1996) was in fact found to be linked to chromosome 17.

Stratakis (1999) evaluated genetic heterogeneity in Carney complex as follows: whereas there are several families with individual lod scores over 3 that mapped to chromosome 17, there are also several families for which the chromosome 17 locus can definitely be excluded. Most of these families (although not all, perhaps leaving room for a third locus) mapped to 2p16 with an aggregate lod score over 5.

Analysis of chromosome rearrangements in tumors is a useful tool for uncovering genes with a role in tumorigenesis and/or tumor progression. Matyakhina et al. (2003) used comparative genomic hybridization (CGH) to demonstrate a low level 2p amplification in 4 of 8 CNC tumors; 1 tumor showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumors, they completed the genomic mapping of the CNC2 region, and analyzed 46 tumor samples from CNC patients with and without PRKAR1A mutations by FISH using BACs. Consistent cytogenetic changes in the region were detected in 40 (87%) of the samples analyzed. Amplification of the region represented as homogeneously stained regions (HSRs) was found in 24 samples (60%). Three tumors (8%) showed both amplification and deletion of the region in their cells. Thirteen tumors (32%) showed deletion only. Matyakhina et al. (2003) concluded that cytogenetic changes of the 2p16 region that harbors the CNC2 locus are frequently observed in tumors from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumors. Both thyroid and adrenal tumors constitute part of CNC indicating that the responsible gene(s) in the area may indeed be involved in both inherited and sporadic endocrine tumor pathogenesis and/or progression.