Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Abstract

Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/ or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31, and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at ϭ 0.03 for the marker CA-2 (odds in favor of linkage 10 6 :1). The flanking markers CA7 and D2S378 defined a region of ‫ف‬ 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes

“…Multiple intramuscular myxomas occasionally occur in MAS, a disorder that manifests CALS and may feature acromegaly and Cushing syndrome, the latter arising from adrenal cortical hyperplasia rather than PPNAD, however (2). Finally, there are similarities between the MEN syndromes and Carney complex: Lesions are often bilateral and multifocal; somatotropinomas, lipomas and other benign skin lesions are common to both MEN 1 and the complex; and adrenal pathology is present in both conditions (10,19,42). In addition, the distribution of the facial lesions in MEN 2B and the Carney complex has a curious and remarkable anatomical symmetry: the eyelids, lips, tongue, and ears are affected in both syndromes.…”

“…About 10% of patients with Carney complex have a GH-secreting pituitary adenoma that results in acromegaly (10,19) (Figure 2a). Although most of the known patients with this condition had macroadenomas, a number of recently investigated cases show that abnormal 24-hour GH secretion can precede the development of a pituitary tumor in Carney complex (Stratakis et al manuscript in preparation).…”

“…Information derived from these cases has resulted in a reordering of the frequency of occurrence of the components of Carney complex, with spotty skin pigmentation currently the most frequent component (10). In addition, three new components of the syndrome have been identified: psammomatous melanotic schwannoma, epithelioid blue nevus, and ductal adenoma of the breast (26, 37-39).…”

“…It is evident that the syndrome shares components (lentiginosis, Cushing syndrome, acromegaly, thyroid and gonadal tumors) (10,19), a transmission pattern (autosomal dominant inheritance with possible parent of origin effects) (41), and a pattern of organ involvement (bilateral and multifocal involvement in the case of paired organs) with other syndromes (42). Among these, two that feature spotty skin pigmentation, the Peutz-Jeghers and LEOPARD syndromes, have components in common with Carney complex.…”

“…genetic defect or defects remain elusive. Recently, the genetic loci for the "syndrome of spotty skin pigmentation, myxomas and endocrine overactivity" or Carney complex and PJS were identified (10,11). Another familial lentiginosis, Ruvalcaba-Myhre-Smith or Bannayan-Zonana syndrome was recently found to be caused by mutations in the PTEN gene (12).…”