help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stratakis, C. A.
Right arrow Articles by Carney, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stratakis, C. A.
Right arrow Articles by Carney, J. A.
Right arrowPubmed/NCBI databases
*Genetics Home Reference
Medline Plus Health Information
*Ovarian Cancer
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4359-4366
Copyright © 2000 by The Endocrine Society

Original Studies

Ovarian Lesions in Carney Complex: Clinical Genetics and Possible Predisposition to Malignancy

Constantine A. Stratakis, Theocharis Papageorgiou, Ahalya Premkumar, Svetlana Pack, Lawrence S. Kirschner, Susan E. Taymans, Zhengping Zhuang, Wolfgang H. Oelkers and J. Aidan Carney

Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development (C.A.S., T.P., L.S.K., S.E.T.); Department of Diagnostic Radiology, Warren Magnuson Clinical Center (A.P.); and Laboratory of Pathology, National Cancer Institute (S.P., Z.Z.), National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology, Free University of Berlin (W.H.O.), D-12200 Berlin, Germany; and Department of Laboratory Medicine and Pathology, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome (OMIM 160980, http://www.ncbi.nlm.nih.gov/omim) with features overlapping those of other multiple endocrine neoplasias and hamartomatoses, Peutz-Jeghers syndrome (PJS) in particular. Although a number of patients with CNC and ovarian tumors have been described in individual patient reports, it is unclear whether ovarian lesions constitute a component of the syndrome or are coincidental events. We investigated 18 women with CNC [age at first evaluation, 31.3 ± 12.1 yr (mean ± SD)] prospectively for the development of ovarian tumors over a period of 35.7 ± 30.6 months by physical examination and pelvic ultrasonography. They were compared with 11 women (age at first evaluation, 32.9 ± 17 yr) who were enrolled under the same protocol (follow up, 32.3 ± 25.1 months) and served as a control group. In addition, a registry of 178 women from among a total of 309 patients with CNC was searched retrospectively for any having ovarian tumors. Seven available histological specimens were rereviewed. None of the CNC patients had ovarian tumors analogous to those of PJS. Two patients with CNC in the prospective group developed ovarian tumors and were operated upon. One had bilateral oophorectomy for asynchronous serous cystadenomas. The second patient had a unilateral serous cystadenoma. Resected tumor tissue from both patients was tested for genetic abnormalities of the chromosomal regions to which CNC genetic loci have been mapped. Both showed genomic amplification of chromosomal region 2p16. An additional 10 patients had at least 1 sonogram positive for ovarian cysts. Only 1 of the patients in the control group was found to have a persistent, simple ovarian cyst by ultrasonography. The registry of 178 CNC patients included 4 who had undergone surgery for ovarian tumors. The diagnoses included endometrioid adenocarcinoma (1 patient) and metastatic mucinous adenocarcinoma (the primary site was probably ovarian; 1 patient). In addition, 7 of 12 patients (58%) with CNC, who died of other causes, had ovarian lesions at autopsy. In conclusion, although the same stromal tumor, large-cell calcifying Sertoli cell tumor, affects the testes in CNC and PJS, we did not find such tumors in a small population of CNC patients that was studied prospectively or a larger group of CNC patients that was studied retrospectively. The results of our study also suggested that women with CNC commonly develop ovarian cysts and may be at risk for ovarian carcinoma. The chromosome 2p16 CNC locus was involved in ovarian pathology with apparent copy number gain, suggesting that at least molecularly there is some involvement of the CNC gene(s) in these lesions. Although ovarian tumors do not seem to be a major manifestation of CNC, sonography of the ovaries may be part of the initial evaluation for this genetic syndrome in women with CNC; follow-up of any identified lesion is recommended because of the possible risk for malignancy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE COMPLEX OF spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas, or Carney complex (CNC), is a multiple neoplasia and lentiginosis syndrome (1, 2, 3, 4) that is inherited in an autosomal dominant manner (5) and appears to be genetically heterogeneous (6, 7, 8). In addition to the established components of the syndrome (4), patients with CNC may be predisposed to a variety of other tumors, including colonic polyps and carcinoma, and other gastrointestinal thyroid, and breast cancers (6, 9, 10, 11).

This possible predisposition to a variety of benign and malignant tumors that do not fit in the classic definition of a syndrome is not unusual; it occurs in other forms of inherited multiple endocrine neoplasias (MEN) and lentiginoses (2, 12). CNC may be regarded as a type of MEN with manifestations that include primary pigmented nodular adrenocortical disease (13, 14), GH-producing pituitary adenomas (15), testicular tumors (16), and various thyroid lesions (9). The testicular tumors are of three types: large cell calcifying Sertoli cell tumor (LCCSCT) (16), nodular adrenocortical rests, and Leydig cell tumor (1, 4). As a sporadic neoplasm, LCCSCT, a stromal tumor, is among the rarest of testicular lesions (16); however, it occurs frequently in male patients with CNC (1, 16) and occasionally in Peutz-Jeghers syndrome (PJS) (17). PJS and CNC also share other clinical manifestations, although the causative genetic defects appear to be different (18).

In this study we investigated the possibility that female patients with CNC might develop 1) ovarian tumors similar to those occurring in female patients with PJS (19, 20, 21), or 2) tumors analogous to LCCSCT and the Leydig cell neoplasms of male patients with CNC or PJS (1, 16, 17). The clinical investigation consisted of two parts: 1) a prospective study of patients with CNC and a control group enrolled in an ongoing research protocol; these patients underwent semiannual physical and sonographic examination over an average period of 3 yr; 2) a retrospective analysis of reported patients with CNC; only ovarian lesions identified after surgery or at autopsy were included in this analysis. The laboratory investigation included the hybridization of chromosome 2 probes (from the 2p16 CNC locus) on ovarian tumors of CNC patients. The combined data indicate that female patients with CNC may be predisposed to ovarian tumors, but not of the types seen in PJS or analogous to the stromal tumors of the male gonads seen in CNC and PJS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

The institutional review boards of NICHHD, NIH, and the Mayo Clinic approved the contact of families with CNC and the participation of patients and their relatives in the present study after they gave informed consent. All patients in the prospective study were seen by one of the authors (C.A.S.). A complete description of most of the families was previously published (6). Family CAR.110 has been reported previously (22). The medical records, ovarian ultrasonographic, and other radiological studies were reviewed by the investigators. Available tissue specimens were rereviewed by 1 of the authors (J.A.C.). All patients were screened for the clinical manifestations of CNC according to the criteria established by Stratakis et al. (6). Three patients from family CAR.01, 3 patients from family CAR.19, and 1 from each of the CAR.03, CAR.07, CAR.15, CAR.16, CAR.20, CAR.102, and CAR.110 families and 5 other patients without any family history of CNC (sporadic cases), were enrolled in the prospective study (Table 1Go). A total of 15 first degree relatives of patients with sporadic CNC underwent physical examination by 1 of the authors (C.A.S.), and none had stigmata of the disease. Six female relatives of our patients were also enrolled in our protocol as a control group; 5 additional patients without CNC, who were enrolled under the same protocol, were also followed as controls (Table 2Go).


View this table:
[in this window]
[in a new window]
  		Table 1. Prospective evaluation of 18 patients with Carney complex: sonographic and surgical findings

 

View this table:
[in this window]
[in a new window]
  		Table 2. Prospective evaluation by ovarian US of 11 patients that were enrolled in the Carney complex study but were not affected by the syndrome

 
Retrospective analysis of records of patients with CNC was also performed. These included patients reported in the literature (the patient reported in Ref. 23 is one such example) or whose data have been collected from referring physicians by 2 of the authors (C.A.S. and J.A.C.). This worldwide registry consists of 309 patients with CNC, of whom 178 are female. The records of the latter were searched for ovarian lesions, either surgical or recorded at autopsy (Table 3Go).


View this table:
[in this window]
[in a new window]
  		Table 3. Ovarian lesions found retrospectively in patients with CNC

 
Protocol of the prospective study

For the prospective study, each patient underwent physical examination and ultrasonography (US) of the ovary at least annually. If a lesion was present, semiannual evaluation was undertaken. A total of 18 women with CNC [age at first evaluation, 31.3 ± 12.1 yr (mean ± SD)] and 11 control subjects (age at first evaluation, 32.9 ± 17 years) were studied prospectively for the development of ovarian tumors over a period of 35.7 ± 30.6 months (median, 31; range, 5–126 months) and 32.7 + 25.1 months (median, 34; range, 5–70 months), respectively (Tables 1Go and 2Go).

Gray scale and color Doppler transabdominal and transvaginal US of the ovaries was performed, using 3.5- and 5-MHz transducers on Acuson 128xp (Acuson, Mountain View, CA) and Wide Vu (Diasonics, San Francisco, CA) scanners. The uterus and ovaries were measured in three dimensions. Ovarian volumes were calculated, and the ovaries were evaluated for the presence of masses. When present, masses were measured and categorized as simple cysts or complex masses. Color Doppler was also used to evaluate the masses. Resistive and pulsatility indexes of the masses were obtained in 16 ovaries from 11 women.

Statistical analysis of the data was performed using t test, {chi}2 analysis (with Fischer’s correction where indicated). All averages are expressed as the mean ± SD.

Tissue and fluorescent in situ hybridization (FISH) analyses

Paraffin-embedded specimens from the patients who underwent surgery during the prospective study [two ovarian masses from patient 1 (who had asynchronous bilateral masses) and one from patient 2] were processed and stained for histopathological analysis according to standard procedures. Slides from paraffin-embedded tissues from four patients with ovarian cancer and other diagnoses were rereviewed by one of the authors (J.A.C.) for the purposes of this study. In the retrospective study, there was agreement between the original pathologic diagnosis and those obtained in our review.

Tissue for genetic analysis (see below) was obtained at the time of surgery, frozen at -70 C, and stored for later use. FISH was performed following protocols previously described (24, 25). The probes used were bacterial artificial chromosome (BAC) clones that have been mapped to the chromosome 2p16 region (26); control probes from other chromosomes were also used (one from 10q23 is shown in Fig. 4Go.3). BACs were labeled by nick translation; a chromosome 2-specific centromeric {alpha}- satellite probe (Oncor, Gaithersburg, MD) was used for chromosome identification (25, 26). The markers that were tested in FISH experiments and the BAC clones that contained them were: D2S391:b79H12, D2S2378:b1P2, D2S123:b43E19, b400P14 (no polymorphic marker), D2S2352:b112L8, and D2S378:b286c2 (25). After hybridization, chromosomes were counterstained with 4',6'-diamidino-2-phenylindol- dihydrochloride (250 ng/ml, final concentration) in Vectashield (Vector Laboratories, Inc., Burlingame, CA) as an antifading agent. Hybridization signals were analyzed using a Carl Zeiss Axiophot2 fluorescence microscope equipped with the Sensys CCD camera (Photometrics), and fluorescence images were automatically captured and merged using IPLab Spectrum software (Scannalytics, Inc., Fairfax, VA) on a PowerPC 8500/150.



View larger version (75K):
[in this window]
[in a new window]
  		Figure 4. FISH in interphase nuclei from the two tumors excised from patients with CNC (patients 1 and 2, Table 1Go). 1) Mapping of the two clones used in this study to chromosome 2 (2p16) by FISH on a metaphase spread; the green and red signals correspond to BAC 79-H-12 and BAC 43-E-19, which contain markers D2S391 and D2S123, respectively. The D2S123 locus was the marker with the highest logarithm of odds (LOD) score for linkage of chromosome 2 and CNC (see Ref. 6 ). 2) Normal cell from a cell line established from patient 1; the expected four signals (from the pair of chromosomes 2 indicated by the arrows) were found. 3) A cell from the tumor of patient 1 hybridized with a BAC from chromosome 10q23; the expected two signals were found. 4) Interphase nuclei from the tumor of patient 2 hybridized with BAC 400-P-14 (red signal), which lies proximal to 43-E-19 on chromosome 2 (see Ref. 26 ), and an {alpha}-satellite probe specific for chromosome 2 (green signal). Two tumor cells show amplification of the BAC 400-P-14 (red); in these cells, the centromeric {alpha}-satellite probe shows the expected two signals (green). A third cell, located in the lower right of the image, is normal, showing two copies of both probes (a mixture of normal and abnormal cells is often seen in the processing of frozen sections of these tumors). 5) A cell from the tumor of patient 1, hybridized with BACs 79-H-12 and 43-E-19, shows multiple copies of the two clones from the chromosome 2 CNC locus.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patients with CNC evaluated prospectively

Among the 18 female patients with CNC (age at first evaluation, 31.3 ± 12.1 yr) who were studied prospectively for the development of ovarian tumors over an average period of approximately 3 yr (median, 31 months; range, 5–126 months) by physical examination and ultrasound, 12 patients (67%) had at least 1 ultrasound study positive for ovarian cysts (Table 1Go). The lesions enlarged and required surgery in 2 patients (Fig. 1Go). One patient had bilateral oophorectomy for bilateral asynchronous complex cystadenomas. The second had oophorectomy for a unilateral serous cystadenoma; this gradually increased in size over the course of 4 ys (patient 2, Table 1Go and Fig. 1Go). Only 1 patient from the control group of 11 women (age at first evaluation, 32.9 ± 17 yr; median follow-up time, 34 months; range, 5–70 months), including 6 nonaffected relatives of our CNC patients, had a persistent small ovarian cyst that was identified by US (Table 2Go; P = 0.0031).



View larger version (64K):
[in this window]
[in a new window]
  		Figure 1. Progressive changes in the left ovary from patient 2 (Table 1Go) as detected by US over a period of 4 yr. A simple cyst is present (A), which has grown into a complex cyst with think walls (B and C). The same cyst 2 yr later has grown and is divided by thick septae (D). E, Macroscopic appearance of the lesion that was proven to be a serous cystadenoma.

 
There were no differences in either the frequency of ovarian tumors or the number of cysts (or other lesions) found in patients with sporadic forms of the disease vs. those with familial CNC (P > 0.1). Also, there was no difference in the age of appearance of the ovarian lesion between the two groups (P > 0.1).

Retrospective evaluation of a database of patients with CNC

A registry of 309 patients with CNC, which contained 178 females, was searched retrospectively for ovarian neoplasms. Four patients had ovarian tumors that had required operation (Table 3Go, patients 1–4), including unilateral multiple complex cysts in each of 2 patients (no other information was available), endometrioid adenocarcinoma (Fig. 2Go), and mucinous adenocarcinoma (Fig. 3Go; interpreted as metastatic adenocarcinoma) in 1 patient each, respectively. In addition, among 12 patients with CNC who underwent autopsy, ovarian lesions with diagnoses that ranging from benign follicular cysts to teratoma were found in 7 (Table 3Go, patients 5–11).



View larger version (150K):
[in this window]
[in a new window]
  		Figure 2. A, Endometrioid carcinoma of the ovary from a patient with CNC (patient 3, Table 3Go); complex pattern of closely sheeted glandular structures (x40). B, Packed glandular and tubular structures; cells have regular, oval and vesicular nuclei, and a zone of inflammation is present at the bottom right (x100).

 


View larger version (96K):
[in this window]
[in a new window]
  		Figure 3. Metastatic mucinous adenocarcinoma in the ovaries (A and B) of a patient with CNC who had primary pigmented nodular adrenocortical disease (PPNAD; C) and was previously reported in Ref. 23 (patient 4, Table 3Go). The primary site of the carcinoma was most likely one of the ovaries; the patient succumbed to metastatic cancer. Ovarian histology showed cells with variable nuclei (x200; A) arranged in glandular structures in a fibroid stroma (x40; B). Adrenal histology showed the typical multiple nodules of PPNAD set in an otherwise small adrenal gland (x40; C).

 
FISH analysis with 2p16 BAC probes

An interphase FISH analysis of touch preps from the two ovarian tumors (collected from the two patients who were operated upon during the course of the prospective study) was performed using BAC probes from the chromosome 2 CNC critical region (Fig. 4Go.1). All probes displayed a tandem amplification indicating the presence of HSR (homogeneously staining region) on 2p16 (Figs. 4Go.4 and 4.5). The amplicon seems to be extended and included the segment flanked by probes b79H12 and b286C2. Cells that showed a copy number gain were diploid, as shown by the concurrent use of centromeric chromosome {alpha}-satellite probes (Fig. 4Go.4). Probes from other chromosomes applied to CNC ovarian tumors showed normal results (Fig. 4Go.3), whereas the 2p16 probes that showed copy number gain on these tumors showed normal results in normal cells from the same patients (Fig. 4Go.2 and one cell in Fig. 4Go.4).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
CNC is a familial lentiginosis and multiple neoplasia syndrome. Patients with this disorder may exhibit a predisposition to develop a variety of carcinomas, as in another such syndrome, PJS (6). Carcinoma of the ovary has been reported in at least 1 patient with CNC (23); a variety of other ovarian lesions were reported in a retrospective analysis of 51 patients affected with CNC (6). Female patients with PJS are at increased risk of developing ovarian (epithelial and stromal) neoplasms (27) as well as uterine tumors (endometrial and cervical) (20, 21, 27, 28, 29, 30). Male patients with PJS and CNC develop the same testicular stromal cell tumor (LCCSCT) (16, 17). Thus far, however, ovarian sex cord tumors with annular tubules, which occur with PJS (21), have not been reported in CNC.

In the first retrospective review of a large number of patients with CNC (referred to above), although a variety of ovarian lesions were encountered, sex cord tumors were not (6). A number of kindreds and sporadic cases with CNC were then studied by ovarian US in a prospective manner by a NIH clinical protocol. The present study reports the first analysis of these data along with an enhanced retrospective analysis of a worldwide database of CNC patients. From this investigation, several lines of evidence suggest that female patients with CNC develop cysts and tumors of the ovarian surface epithelium, although they do not develop tumors similar to those that occur in women with PJS.

First, 2 of 18 female patients with CNC who were followed by US an average period of approximately 3 yr showed growth of their ovarian tumors and required surgery; the lesions were complex serous cystadenomas. Twelve of the 18 patients (67%) had at least 1 US positive for an ovarian lesion. Only 1 subject in the control group of 11 women (who participated in the same clinical screening protocol) had a simple ovarian cyst (9%). When we recently performed transvaginal US in 46 women receiving tamoxifen for therapy or prevention of breast cancer, who were followed for 2–4 yr by the same protocol of sonography, we found ovarian cysts in no more than 59% of the women (31). In 2 large studies of 2012 and 5479 patients who underwent frequent US, ovarian cysts were found in 22–28% of the various age groups and in 6% of the entire population of the study, respectively (32, 33).

Second, in the retrospective analysis of 178 female patients with CNC, carcinoma of ovarian surface epithelium was identified in two patients, a frequency of 1.12%. Although we have no suitable comparison group, the reported frequency of ovarian cancer among American women is 0.015% (33, 34). The life-time risk for the development of ovarian cancer in industrialized countries is estimated at 1 in 70 women (32) and most of these cancers develop in older women (32, 33, 34, 35). The 2 patients with CNC developed the neoplasm during their fifth decade of life, when this tumor is relatively rare in the general population. In addition, both women were multiparous, had not received hormone treatment, and did not have other known risk factors for ovarian carcinoma (reviewed in Ref. 33). Interestingly, no stromal tumors analogous to those seen in patients with PJS were found in this retrospective analysis.

Third, among 12 patients with CNC who underwent autopsy examination, 7 (58%) had an ovarian lesion. It is noteworthy that this percentage is similar to that found in our prospective sonographic study (67%). There has been no systematic documentation of ovarian cysts in the postmortem examination of normal women, however.

Fourth, the genetic investigation of ovarian tumors from two patients with CNC, employing probes from the chromosome 2 CNC genomic region (26, 36), showed that this locus was involved with copy number gain of 2p16 genomic material. It is unclear at this point whether the genetic change identified is the result of amplification of a gene(s) located on 2p16 or is the result of a tumor-specific chromosomal rearrangement within 2p16. Preliminary data indicate that amplification is the more likely event, although the relevant gene(s) has yet to be cloned (Pack, S., S. E. Taymans, and C. A. Stratakis, unpublished data).

Thus, both clinical and genetic data indicate that surface ovarian epithelium tumor formation in patients with CNC is possibly due to the underlying germline mutation. Tumorigenesis in the ovaries of these patients may follow the pattern of mutation accumulation that has been suggested for other epithelial neoplasms, such as colonic carcinoma (37, 38), as appears to be the case in the thyroid gland of CNC patients (9). In addition, the extensive genetic instability of cells cultured from CNC tumors (39) suggests that secondary "hits" underlie tumor formation in CNC, the first hit being the germline mutation. This corresponds to Knudson’s hypothesis (40), even though there is little evidence to suggest that the 2p16-located gene responsible for CNC has tumor suppression function (39, 41). Indeed, loss of heterozygosity (LOH) of the short arm of chromosome 2 was not found in several genetic studies of ovarian tumors (42, 43, 44). On the other hand, amplification of the same genetic segment, encompassing the chromosome 2 CNC locus (45), was seen in comparative genomic hybridization of ovarian neoplasms (46). This leads us to speculate that the germline CNC mutation causes a predisposition toward other molecular events. These genetic changes may be facilitated by continuing amplification of the chromosome 2 gene(s) and may lead to surface epithelium tumor formation in the ovaries of patients with CNC.

It was surprising that stromal tumors of the ovary (similar to those seen in patients with PJS) had not occurred in women with CNC. In this connection, we have recently found that although CNC and PJS have some clinical similarities, they do not share LOH of the STK11/LKB1 locus (18). As LOH of the PJS gene is commonly present in both PJS-associated and sporadic ovarian tumors, it appears that the mechanism of ovarian tumorigenesis in the two conditions may follow different molecular pathways.

In summary, although we found with sufficient frequency ovarian surface cysts and tumors in women with CNC, we do not think that the results warrant intensive screening of the ovaries in these patients. Nevertheless, ovarian US may be part of the initial evaluation in female patients with CNC; follow-up of any identified lesion is recommended, because of the possible risk for malignancy (47).

Received February 14, 2000.

Revised June 14, 2000.

Accepted July 12, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Carney JA, Young WF. 1992 Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist. 2:6–21.
  2. Stratakis CA. 1998 The familial lentiginosis syndromes are emerging from the obscurity imposed by rarity: new genes and genetic loci for multiple tumors and developmental defects. Horm Metab Res. 30:285–290.[CrossRef]
  3. Carney JA. 1995 Carney complex: the complex of myxomas, spotty pigmentation, endocrine veractivity, and schwannomas. Semin Dermatol. 14:90–98.[Medline]
  4. Stratakis CA, Kirschner LS, Carney JA. 1998 Carney complex: diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas [Letter]. Am J Med Genet. 80:183–185.[CrossRef][Medline]
  5. Carney JA, Hruska LS, Beauchamp GD, Gordon H. 1986 Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc. 61:165–172.[Medline]
  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 Invest. 97:699–705.[Medline]
  7. 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]
  8. Stratakis CA, Kirschner LS, Taymans SE, Carney JA, Basson CT. 1999 Genetic hHeterogeneity in Carney complex (OMIM 160980): contributions of loci at chromosomes 2 and 17 in its genetics. Am J Hum Genet. 65(Suppl):A447.
  9. Stratakis CA, Courcoutsakis N, Abati A, et al. 1997 Thyroid gland abnormalities in patients with the "syndrome of spotty skin pigmentation, myxomas, and endocrine overactivity" (Carney complex). J Clin Endocrinol Metab. 82:2037–2043.[Abstract/Free Full Text]
  10. Courcoutsakis NA, Chow CK, Shawker T, Carney JA, Stratakis CA. 1997 Breast imaging findings in the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas (Carney complex). Radiology. 205:221–227.[Abstract/Free Full Text]
  11. Carney JA, Stratakis CA. 1996 Ductal adenoma of the breast [Letter]. Am J Surg Pathol. 20:1154–1155.[Medline]
  12. Marx SJ. 1998 Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 129:484–494.[Abstract/Free Full Text]
  13. 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]
  14. Stratakis CA, Kirschner LS. 1998 Clinical and genetic analysis of bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm. Metab Res. 30:456–463.
  15. Watson JC, Stratakis CA, Bryant-Greenwood PK, et al. 2000 The neurosurgical implications of Carney complex. J Neurosurg. 92:413–418.[CrossRef][Medline]
  16. Premkumar A, Stratakis CA, Shawker TH, Papanicolaou DA, Chrousos GP. 1997 Testicular ultrasound in Carney complex. J Clin Ultrasound. 25:211–214.[CrossRef][Medline]
  17. Young S, Gooneratne S, Straus Jr FH, Zeller WP, Bulun SE, Rosenthal IM. 1995 Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol. 19:50–58.
  18. Stratakis CA, Kirschner LS, Taymans SE, et al. 1998 Carney complex, Peutz-Jeghers syndrome, Cowden disease and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations but not genetic loci. J Clin Endocrinol Metab. 83:2977–2986.[Abstract/Free Full Text]
  19. Podczaski E, Kaminski PF, Pees RC, Singapuri K, Sorosky JI. 1991 Peutz-Jeghers syndrome with ovarian sex cord tumor with annular tubules and cervical adenoma malignum. Gynecol Oncol. 42:74–78.[CrossRef][Medline]
  20. Nishioka Y, Kobayashi K, Sagae S, et al. 1999 Mutational analysis of STK11 gene in ovarian carcinomas. Jpn J Cancer Res. 90:629–632.[CrossRef][Medline]
  21. Young RH, Welch WR, Dickersin GE, Scully RE. 1982 Ovarian sex stromal tumor with annular tubules; review of 74 cases including 27 with Peutz-Jeghers syndrome and 4 with adenoma malignum of the cervix. Cancer. 50:1384–1402.[CrossRef][Medline]
  22. Nwokoro NA, Korytkowski MT, Rose S, et al. 1997 Spectrum of malignancy and premalignancy in Carney syndrome. Am J Med Genet. 73:369–377.[CrossRef][Medline]
  23. Oelkers W, Bahr V, Hensen J, Pickartz H. 1986 Primary adrenocortical micronodular adenomatosis causing Cushing’s syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells. Acta Endocrinol (Copenh). 113:370–377.[Abstract/Free Full Text]
  24. Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, Gray J. 1988 Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci USA. 85:9138–9142.[Abstract/Free Full Text]
  25. Taymans SE, Pack S, Pak E, Torpy D, Zhuang Z, Stratakis CA. 1998 Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab. 83:1033–1036.[Abstract/Free Full Text]
  26. Taymans SE, Kirschner LS, Giatzakis C, Stratakis CA. 1999 Radiation hybrid mapping of chromosomal region 2p15–p16:integration of expressed and polymorphic sequences maps at the Carney complex (CNC) and Doyne’s honeycomb retinal dystrophy (DHRD) loci. Genomics. 56:344–349.[CrossRef][Medline]
  27. Wang Z-J, Churchman M, Campbell IG, et al. 1999 Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumours. Br J Cancer. 80:70–72.[CrossRef][Medline]
  28. Boardman L, Thibodeau SN, Schaid DJ, et al. 1998 Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 128:896–899.[Abstract/Free Full Text]
  29. Young RH, Scully RE. 1988 Mucinous ovarian tumors associated with mucinous adenocarcinomas of the cervix: clinicopathologic analysis of 16 cases. Int J Gynecol Pathol. 7:99–111.[Medline]
  30. Spigelman AD, Murday V, Phillips RKS. 1989 Cancer and the Peutz-Jeghers syndrome. Gut. 30:1588–1590.[Abstract/Free Full Text]
  31. Premkumar A, Avila N, Dwyer A, et al. 1999 Effects of tamoxifen one the ovaries, evaluation with gray scale and color Doppler ultrasound. J Women Imaging. 1:18–23.
  32. Powles TJ, Jones AL, Ashley SE, et al. 1994 The royal Marsden hospital pilot tamoxifen chemoprevention trial. Breat Cancer Res Treat. 31:73–82.[CrossRef][Medline]
  33. Crayford TJB, Campbell S, Bourne TH, Rawson HJ, Collins WP. 2000 Benign ovarian cysts and ovarian cancer: a cohort study with implications for screening. Lancet. 355:1060–1063.[CrossRef][Medline]
  34. National Cancer Institute. 1991 Surveillance, epidemiology, and end results (SEER): cancer statistics review, 1973–1990. Bethesda: NCI; NIH Publication 93–2789.
  35. Daly M, Obrams GI. 1998 Epidemiology and risk assessment for ovarian cancer Semin Oncol. 25:255–264.[Medline]
  36. Kirschner LS, Taymans SE, Pack S, et al. 1999 Genomic mapping of chromosomal region 2p15–p21 (D2S378–D2S391): integration of Genemap’98 within a framework of yeast and bacterial artificial chromosomes. Genomics. 62:21–33.[CrossRef][Medline]
  37. Cho KR, Vogelstein B. 1992 Genetic alterations in the adenoma-carcinoma sequence. Cancer. 70:1727–1731.[CrossRef][Medline]
  38. Vogelstein B, Kinzler KW. 1993 The multistep nature of cancer. Trends Genet. 4:138–141.
  39. Stratakis CA, Jenkins RB, Pras E, et al. 1996 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. 81:3607–3614.[Abstract]
  40. Knudson AG. 1971 Mutation and cancer statistical study of retinoblastoma. Proc Natl Acad Sci USA. 68:820–823.[Abstract/Free Full Text]
  41. Knudson AG. 1996 Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 122:135–140.[CrossRef][Medline]
  42. Cliby W, Ritland S, Hartmann L, et al. 1993 Allelotype of ovarian cancer. Cancer Res. 53:2393–2398.[Abstract/Free Full Text]
  43. Papp J, Csokay B, Bosze P, Zalay Z, Toth J, Ponder B, Olah E. 1996 Allele loss from large regions of chromosome 17 is common only in certain histological subtypes of ovarian carcinomas. Br J Cancer. 74:1592–1597.[Medline]
  44. Watson RH, Neville PJ, Roy Jr WJ, Hitchcock A, Campbell IG. 1998 Loss of heterozygosity on chromosomes 7p, 7q, 9p and 11q is an early event in ovarian tumorigenesis. Oncogene. 17:207–212.[CrossRef][Medline]
  45. Taymans SE, Kirschner LS, Pack S, Ping Z, Stratakis CA. 1999 YAC-BAC contig of the Carney complex (CNC) critical region on 2p16 and copy number gain of 2p16 in CNC tumors: evidence for a novel oncogene? Am J Hum Genet. 65(Suppl):A326.
  46. Lynch HT, Casey MJ, Lynch J, White TE, Godwin AK. 1998 Genetics and ovarian carcinoma. Semin Oncol. 25:265–280.[Medline]
  47. Bourne TH, Whitehead MI, Campbell S. 1991 Ultrasound screening for familial ovarian cancer. Gynecol Oncol. 43:92–97.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
A. J. Robinson-White, W. W. Leitner, E. Aleem, P. Kaldis, I. Bossis, and C. A. Stratakis
PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes
Cancer Res., November 1, 2006; 66(21): 10603 - 10612.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
A J Bauer and C A Stratakis
The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis
J. Med. Genet., November 1, 2005; 42(11): 801 - 810.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. A. Stratakis, L. S. Kirschner, and J. A. Carney
Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation
J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4041 - 4046.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. S. Kirschner, F. Sandrini, J. Monbo, J.-P. Lin, J. A. Carney, and C. A. Stratakis
Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex
Hum. Mol. Genet., December 1, 2000; 9(20): 3037 - 3046.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. D. Malchoff
Carney Complex--Clarity and Complexity
J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4010 - 4012.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stratakis, C. A.
Right arrow Articles by Carney, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stratakis, C. A.
Right arrow Articles by Carney, J. A.
Right arrowPubmed/NCBI databases
*Genetics Home Reference
Medline Plus Health Information
*Ovarian Cancer

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals