Contributed by Jiangzhou Wang, MD, PhD. and Mohamed A. Virji, MD, PhD.FINAL DIAGNOSIS
CARNEY'S SYNDROME WITH RECURRENT THYROID FOLLICULAR CARCINOMA OF THE THYROID
CHROMOSOME 2p16
CONTRIBUTER'S NOTE
In the early 70's and 80's, there were isolated case reports suggested the association of lentiginosis with cardiac and cutaneous myxomas, and endocrine overactivity (1,2,3). In 1985, Carney and colleagues studied cases at Mayo clinic and reviewed previous reported cases , and presented evidence for the existence of a distinct syndrome consisting of of spotty cutaneous pigmentation, myxomas of heart and elswhere, and endocrine disorders (4). Total of 40 patients were included in this study, 16 males and 24 females, each of whom had two or more of the following lesions: cardiac myxomas in 29 (72%); cutaneous myxoma, single or multiple, in 18 (45%); mammary myxoid fibroadenoma, single or multiple, in 12 females (30%); spotty mucocutaneous pigmentation, including lentigines and blue nevi, in 26 (65%); primary pigmented nodular adrenocortical disease in 18 (45%); testicular tumors, in 9 of 16 male patients (56%) and pitutary growth hormone-secreting tumor in 4 (10%). The possibility that this complex might be inheritable was suggested by the relative young age of the patients, and tendency of the lesions to be multicentric and bilateral when paired organs were involved. Autosomal dominant inheritance of the complex is supported by identification of affected first- and second-degree relatives, and observation of male to male, male to female and female to male transmission patterns (5,6).
Carney's syndrome is considered unique autosomal dominantly transmitted multisystem tumorous disorder characterized by myxomas (heart, skin, and breast), spotty skin pigmentation (lentigines and blue nevi), endocrine tumors (adrenal, testicular, thyroid, and pituitary), and peripheral nerve tumors (schwannomas). Approximately 150 affected patients are known worldwide. The most prevalent clinical manifestation is spotty skin pigmentation, while skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 60, 30, 31 and 8 percent of the patients, respectively (7). The most serious components of the syndrome are cardiac myxomas. In Carney's original paper, twelve of 40 patients died, and nine of 12 died of cardiac myxomas. The molecular basis for the development of myxomas and Carney complex tumors is unclear. Stratakis et al performed linkage analysis on 101 patients from 11 North American kindreds with Carney's syndrome using highly polymorphic microsatellite markers, and the 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 theta =0.03. These markers defined a region of approximately 6.4 cM, which has exhibited cytogenetic aberrations in atrial myxomas with the complex characterized by microsatellite instability (8).
Carney's syndrome has some similarities with, but also major differences from the familial multiple endocrine neoplasia (MEN) syndromes MEN-I, MEN-IIA and MEN-IIB. It shares Cushing syndrome with MENs, but in Carney's syndromethis this is uniquely caused by primary pigmented nodular adrenocortical disease, a pituitary-independent, primary adrenal form of hypercortisolism. It also shares with MENs acromegaly due to a growth hormone-producing pituitary adenoma. This tumor is much more common in MEN-I, but is relatively infrequent in the Carney syndrome (9). The chromosome loci of and/or the genetic defects leading to MEN-I and MEN-IIA and-IIB have been mapped to chromosome 10 and 11 respectively, while Carney's syndrome has shownlinkage to the short arm of chromosome 2. Future studies will focus on identification of the guilty gene and disease-causing mutation(s).
The patient described here shows typical features of Carney's syndrome, which include history of multiple myxomas of heart, breast and vulva, history of pigmented nodular adrenal disease, and multiple nevi involving her lips and oral mucosal membrane. From the family history, her mother (cushingoid, nevi of lips and eyes, died at 62) and her son (nevi, testicular tumor, and thyroid nodule) also appears to be affected, which is consistent with autosomal dominant inheritance. The major medical problems of the patient are recurrent thyroid follicular carcinoma, and recently discovered lung nodules and ovarian mass. Surgical removal of lung nodules and ovarian mass has been suggested. The patient's daughter (congenital adrenal hyperplasia), her sister (tumor of the ovary, large hands and feet, alive), a brother (colon cancer and pituitary tumor, died at 50), and second brother (thyroidectomy, soft tissue tumor, alive) have not been diagnosed to have Carney's syndrome, and their disease status can be clarified with genetic linkage analysis by determining whether they share the same disease associated polymorphic chromosomal markers.
REFERENCES
Contributed by Jiangzhou Wang, MD, PhD. and Mohamed A. Virji, MD, PhD.
