(Circulation. 1998;98:2560-2566.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Identification of a Novel Genetic Locus for Familial Cardiac Myxomas and Carney Complex
From the Cardiology Division, Department of Medicine and Department of Cell Biology and Anatomy, Cornell University Medical College, The New York Hospital, New York, NY (M.C., C.M., C.T.B.); Pacing and Electrophysiology, MeritCare Heart Services, Fargo, ND (A.D.M.); National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, Md (L.S.K., S.E.T., C.A.S.); Center for Arthritis and Rheumatic Diseases, Virginia Beach, Va (A.E.D.); Department of Genetics, Harvard Medical School, Children's Hospital, Boston, Mass (B.K.); Department of Dermatology, Royal Victoria Hospital (A.D.I.) and Department of Medical Genetics, Queen's University (A.H.), Belfast, Northern Ireland, UK; and Department of Pathology, Mayo Clinic, Rochester, Minn (J.A.C.).
Correspondence to Craig T. Basson, MD, PhD, Cardiology Division, Department of Medicine, Cornell University Medical College, The New York Hospital, Starr 4, 525 E 68th St, New York, NY 10021. E-mail ctbasson{at}mail.med.cornell.edu
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Abstract |
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Background—Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown.
Methods and Results—We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex. Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene.
Conclusions—The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.
Key Words: genetics • cardiovascular diseases • growth substances • genes • myxoma
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Introduction |
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Primary intracardiac tumors, such as myxomas, occur in at least 7 of 10 000 individuals1 and are an important clinical problem whose pathogenesis is poorly understood. Cardiac myxomas may occur as isolated findings or as components of heritable multisystem disease. Several inherited syndromes that relate lentiginosis to myxomas have been reported,2 3 and the most commonly associated myxomas are intracardiac, particularly atrial. Multiple acronyms have been proposed for such lentiginosis: atrial myxoma syndromes, including LAMB (Lentigines, Atrial myxomas, Mucocutaneous myxomas, and Blue nevi) syndrome and NAME (Nevi, Atrial myxoma, Myxoid neurofibroma, and Ephelides) syndrome. However, recent nosology3 4 aggregates them under the broader category of Carney complex.
In the autosomal dominant syndrome Carney
complex,3 4 5 6 7 8 affected individuals variably express the
disease phenotype but typically exhibit cutaneous disease
(lentigines, ephelides, and blue nevi) in the setting of intracardiac
myxomas. Cutaneous hyperpigmentation most commonly occurs on the face
and trunk as well as on the lips, sclera, and mucosal surfaces of oral
and genital regions and is present in 
95% of individuals
affected by Carney complex.5 Lentiginosis is present
at birth, intensifies during puberty, and may fade with aging during
adulthood. Associated intracardiac myxomas are often atrial, but
ventricular tumors also occur. Familial syndromic atrial
myxomas are estimated1 to account for 7% of all atrial
myxomas and may be particularly refractory to therapy. Whereas sporadic
atrial myxomas occur most commonly as isolated left atrial lesions in
middle-aged women, familial atrial myxomas6 occur in
individuals of all ages without sex preference and are often bilateral
and/or multicentric. Although sporadic atrial myxomas are usually
highly amenable to curative surgical resection, familial lesions
frequently recur, often at locations distant from the initial site of
surgery.6 8
Extracardiac myxomas4 5 6 occasionally occur in Carney complex. Such extracardiac myxomas are usually mucocutaneous, but less often, myxomas of the breast, testis, adrenal gland, thyroid gland, and brain are seen. Nonmyxomatous tumors such as pituitary adenoma, breast fibroadenoma, and psammomatous melanotic schwannoma are also observed. Cutaneous and neoplastic disease in the Carney complex may be associated with nonneoplastic endocrine abnormalities, most commonly Cushing syndrome secondary to primary pigmented nodular adrenocortical hyperplasia. Pituitary and thyroid dysfunction have also been noted. A variety of hematological, immunological, and rheumatic disorders (eg, anemia, polycythemia, fever, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and Raynaud's phenomenon) have all been associated with atrial myxomas. Such systemic abnormalities have been suggested9 10 11 to be secondary to myxoma secretion of the cytokine interleukin 6 and frequently resolve with tumor resection. Histopathological studies of Carney complex lentigines and cardiac myxomas have not demonstrated features unique to this syndrome to differentiate them from their sporadic counterparts.
The gene defect that produces cardiovascular and
cutaneous disease in Carney complex remains unknown, and no cytogenetic
abnormalities have consistently been associated with the Carney
complex. Because of the known proto-oncogene functions of GTP binding
proteins, DeMarco et al12 hypothesized that defects in
Gs
might explain Carney complex, but they were
unable to identify any such mutations. Telomeric rearrangements in
sporadic atrial myxomas have occasionally been noted13 14 15
to involve chromosomes 2, 12, and 17. Stratakis et al7
used linkage analysis to propose a chromosomal locus in a
6.4-cM interval on chromosome 2p, but we have recently proved that
Carney complex is genetically heterogeneous.16
In this study, we now show that a genetic defect on chromosome 17q
causes Carney complex in at least 4 unrelated families.
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Methods |
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Clinical Status
Informed consent was obtained from all participants in accordance with approval by the respective review boards of participating institutions. All family members were evaluated by a thorough history and physical examination without knowledge of genotype status. If there was any evidence of dermatologic, cardiac, or endocrine disease suggestive of Carney complex, patients were further evaluated by electrocardiography, transthoracic echocardiography, serum chemistry, and hematology.
Genotype Analyses
Peripheral blood was obtained from each family
member, and lymphoblastoid lines were established by transformation
with the Epstein-Barr virus.17 Genomic DNA was isolated
from either cell lines or peripheral
lymphocytes.16 17 Polymorphic short tandem repeats
(also called microsatellites) were amplified by polymerase chain
reaction with published nucleotide primer
sequences,18 analyzed on denaturing
polyacrylamide gels16 17 and visualized by
autoradiography.
Linkage Analyses
Two-point logarithm of the odds (LOD) scores were
calculated with LINKAGE software (version 5.1; Reference 1919 ).
Multipoint LOD scores were calculated with LINKMAP
software.20 The LOD score indicates the statistical
likelihood that 2 genetic loci are linked. A LOD score 3.0 indicates
a significant likelihood of linkage (odds in favor of linkage, 1000:1)
to a novel locus. A LOD score 1.3 (odds in favor of linkage, 20:1) is
sufficient (in Reference 2121 , see Equation 4.10) to establish
significant linkage (P0.05) to a locus identified in other
kindreds with a LOD score 3.0. A LOD score 
-2.0 is generally
accepted as evidence against linkage between loci.16 17 19
Penetrance of Carney complex was set at a level of P=0.95
for all analyses, and the disease gene frequency was set at
0.001. Allele frequencies were taken from published
data,18 22 and all LOD scores reported were confirmed not
to be significantly altered by changes in allele frequencies. The
HOMOG program was used to test for genetic
heterogeneity.21
Statistical Analyses
Incidence of specific Carney complex clinical manifestations
among adults was defined as the percentage of individuals 16 years
old with a given finding. To compare frequencies of Carney complex
manifestations among all 4 families affected by this syndrome,
Kruskall-Wallis nonparametric analysis was
performed with CRUNCH software. To further contrast manifestations
between pairs of families, a 2-tailed Fisher exact
nonparametric test was performed. By use of a Bonferroni
correction for multiple comparisons, a limit was established for
statistical significance at P<0.00083.
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Results |
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Clinical Evaluations
Families YA, YB, YC01, and YC11 (Figure 1
) are unrelated Caucasian kindreds, with
typical clinical findings (Figure 2) of
Carney complex. All affected individuals in these 4 families exhibited
cutaneous manifestations of Carney complex, including mucocutaneous
hyperpigmentation (ie, lentiginosis, ephelides, and/or blue nevi). Most
adults exhibited or had histories of intracardiac myxomas, and some
individuals had experienced as many as 3 recurrences despite
adequate surgical resection.
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Family YA has 16 affected individuals (Table 1). Eleven affected individuals in
family YA were 16 years old, and all but 2 had evidence of current or
previous intracardiac myxomas. Extracardiac myxomas were noted to occur
in the breast and skin. Endocrinologic disorders were noted to involve
the adrenal and thyroid glands in affected individuals in family YA.
Two individuals had primary pigmented nodular adrenocortical disease
with resultant Cushing syndrome requiring adrenalectomy. One individual
has been diagnosed with several thoracic and lumbar spine psammomatous
melanotic schwannomas.
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Clinical features of affected individuals in family YB (Table 1
)
were similar. Five individuals were affected by Carney complex, and
preliminary descriptions of these individuals have previously been
described.23 All were adults, and 4 had been found to have
intracardiac tumors. Three individuals had mucocutaneous myxomas, and
the remaining 2 individuals had lesions on physical examination that
were most consistent with mucocutaneous myxomas, although
biopsy was not available. Two individuals also had histories of
nonmyxomatous tumors (spleen, thyroid). Other than the individual who
had required thyroid resection for malignancy, no other affected
individual in family YB had clinical evidence of endocrinologic
abnormalities. One individual (II-6) was considered to have an
indeterminate diagnosis for initial linkage analyses because
complete clinical data were not available.
Six individuals in family YC01 (previously referred to as
CAR017 ) were affected by Carney complex (Table 1). Two
were affected by intracardiac myxomas, but all had mucocutaneous
myxomas. Four individuals had breast myxoid tumors. Nonmyxomatous tumor
diagnoses included follicular thyroid carcinoma and pituitary adenoma.
All affected individuals in family YC01 had acromegaly and/or primary
pigmented nodular adrenocortical disease.
Clinical features of the 8 affected family members in family YC11
(Table 1) have been described previously.24 In brief, all
individuals were known to exhibit typical lentiginosis. Although the
eldest affected individual (I-1) was deceased and therefore was not
available for further clinical evaluation, all other individuals were
affected by mucocutaneous myxomas, but none had cardiac myxomas. Three
individuals required surgical intervention for pilonidal sinuses. One
individual was affected by a gastric carcinoma, and 2 were diagnosed
with breast fibroadenomas. Elevated prolactin levels were detected in 2
women, although no source for this endocrinopathy has yet been
identified.
Adults (age >16 years) in families YA, YB, YC01, and YC11 who were affected by Carney complex shared many similar clinical features. No significant differences were noted in the incidence of cutaneous abnormalities (lentiginosis/hyperpigmentation), the incidence of all myxomas (cardiac and extracardiac), or the incidence of endocrinopathy. However, by Kruskall-Wallis analysis, statistically significant differences were seen in the frequency of cardiac myxomas among the 4 families (P=0.003). By 2-tailed Fisher exact test, the incidence of cardiac myxomas was significantly lower (P=0.007) in family YC11 (0%) than in family YA (82%) or YB (80%). Similarly, Kruskall-Wallis analysis demonstrated statistically significant differences in the frequencies of extracardiac myxomas among the 4 families (P=0.02), with lowest incidence rate in family YA (45%) compared with families YB (100%), YC01 (100%), and YC11 (88%). Finally, the incidence of nonmyxomatous tumors in affected adults among the 4 families differed significantly (P=0.007). Although the 2-tailed Fisher exact test failed to identify significant differences between all pairs of families analyzed, the nonmyxomatous tumor frequency in family YA (9%) was significantly different from the frequency in family YC01 (100%).
Confirmation of Carney Complex Genetic Heterogeneity
We have previously demonstrated that family YA is not linked to
the proposed Carney complex locus on chromosome 2p.16 In
this investigation, we now show that family YB is also not linked to
the chromosome 2p locus (Table 2),
because LOD scores of greater magnitude than -2.0 were obtained over
the 2p interval. Thus, we are able to confirm genetic
heterogeneity of Carney complex. With similar
analysis of families YC01 and YC11 (Table 2), some LOD scores
were noted to be between -1.0 and 1.0, and thus, neither linkage nor
nonlinkage to chromosome 2 could be definitively established for these
families. Therefore, exploration of other loci to explain Carney
complex in families YA, YB, YC01, and YC11 was warranted.
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Demonstration of a Novel Carney Complex Locus on Chromosome
17q
Highly polymorphic short tandem repeat sequences
dispersed throughout the genome were analyzed for linkage to
the Carney complex disease gene in family YA. Because telomeric
rearrangements had been reported13 15 to occur on the
short arm of chromosome 17 in Carney complex myxomas, our initial
efforts focused on this chromosome. No linkage was demonstrated with
microsatellites on chromosome 17p (not shown), and analysis
with random microsatellites excluded <1% of the human genome.
However, linkage was then detected between microsatellite D17S807 on
the long arm of chromosome 17 and the Carney complex in family YA (LOD
score, 5.9; 
=0). Therefore, several additional polymorphic short
tandem repeats (D17S944, D17S942, D17S795, and D17S789) on 17q2 were
used to analyze family YA further. Linkage was confirmed
between the Carney complex in family YA (Table 3) and these chromosome 17q
polymorphisms; maximal 2-point LOD scores achieved demonstrated
with odds of 
105.9:1 that the gene responsible
for Carney complex is located on chromosome 17q2. Moreover, multipoint
analysis of Carney complex in family YA revealed a maximal
multipoint LOD score at this locus of 6.16 (Figure 3).
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To determine whether the gene responsible for Carney complex in
family YA could also be mutated to produce the various clinical
features found in affected members of families YB, YC01, and YC11,
linkage studies in these families were performed (Table 3). Two-point
LOD scores were calculated between polymorphic loci now established
to be linked to Carney complex in family YA and the disease gene in
families YB, YC01, and YC11. Linkage was observed between these
chromosome 17q loci and the Carney complex disease gene with odds of
101.5:1 in family YB,
101.8:1 in family YC01, and
102.9:1 in family YC11. HOMOG analyses of
data from all 4 families (YA, YB, YC01, and YC11) revealed no evidence
of genetic heterogeneity. Genetic homogeneity was
evident (P<0.001), and the likelihood of linkage of Carney
complex in all 4 families to the D17S789 locus on chromosome 17q2 was
calculated by HOMOG to be 1.259x101.2:1. Thus,
these data demonstrate that the gene defect that causes Carney complex
in families YA, YB, YC01, and YC11 resides on the long arm of
chromosome 17 (Figure 4).
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Genotyping analyses revealed that disease haplotypes of affected individuals are different in each family evaluated. Therefore, families YA, YB, YC01, and YC11 are genetically unrelated, and the Carney complex in these 4 families is not secondary to a common founder effect but rather is the result of independent mutation events.
Data from these haplotype analyses (Table 4) permitted the identification of
recombination events to define the Carney complex locus (CAR) genetic
interval (Figure 4). The genotypes of individual II-3 in family
YB and of individual II-8 in family YC01 suggested that a recombination
event had occurred between locus D17S807 and the Carney complex disease
gene. Analyses also identified recombination between the
D17S785 locus and the disease gene in individual II-4 (family YB),
individual II-7 (family YC01), and individuals II-4 and II-8 (family
YC11). Collectively, these data mapped the gene responsible for Carney
complex to a 17 cM region between D17S807 and D17S785 that is localized
at chromosome 17q2.
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Two known tumor suppressor genes map to chromosome 17q: BRCA1 and
neurofibromin (NF1). However, their known genetic map
location3 22 outside of the interval between D17S807 and
D17S785 excludes them as candidate genes and positions them centromeric
to the CAR locus. Moreover, exclusion of NF1 as a Carney complex
candidate gene is confirmed by linkage analysis performed in
family YA, with a microsatellite (NF1CA) contained within the
neurofibromin gene (LOD score, -2.8 at =0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our analyses demonstrate that a gene defect located on the long arm of chromosome 17 causes autosomal dominant syndrome Carney complex. In 3 of the families studied, this chromosome 17q2 gene defect is associated with intracardiac myxoma formation. Moreover, although Carney complex in these families is associated with different frequencies of cardiac myxoma, extracardiac myxoma, and nonmyxomatous tumor formation, genetic linkage analysis demonstrates that mutations at chromosome 17q2 can produce the range of diverse clinical features observed in Carney complex. We hypothesize that different mutations in the as yet unidentified CAR disease gene may have different pathological consequences and thus may account for the variable phenotypes among families affected by Carney complex. Tissue/organ specificity in other multiple neoplasia syndromes has been shown to relate to the intragenic location of the mutation, eg, mutations25 in the RET proto-oncogene in multiple endocrine neoplasia type II.
In addition to the chromosome 17q locus reported here, Stratakis and colleagues7 proposed that a gene defect at chromosome 2p may cause Carney complex. The possibility of still more Carney complex loci still exists, and the relative contributions of mutations at the 17q2 and the 2p loci remain to be determined. Although analyses of previously reported families7 suggested the existence of the chromosome 2p locus, the limited size of the families available in that study precluded assessment of linkage to chromosome 2p on an individual family basis. Therefore, it is unknown how many of these families actually transmit Carney complex as a result of a chromosome 2p gene defect. It is noteworthy that YC01 was one of the families included in the prior investigation7 of the putative chromosome 2p locus, but yet it is now shown to be affected by Carney complex on the basis of the chromosome 17q2 gene defect. Moreover, LOD scores for each of the 4 families (YA, YB, YC01, and YC11) reported here demonstrate that in each case, Carney complex is clearly secondary to genetic abnormality at the chromosome 17q2 locus. Thus, we conclude that the CAR locus on chromosome 17q2 is a major genetic cause of familial myxomas and the Carney complex.
Positional cloning studies are currently under way to identify the CAR disease gene. Genes encoding for a wide variety of protein classes may cause Carney complex, and some that have been mapped3 22 to chromosome 17q2 include growth hormone, platelet–endothelial cell adhesion molecule I, intercellular adhesion molecule 2, TBX2 transcription factor, and several enzymes for DNA and protein structural modification. Oncogenes and tumor suppressor genes are likely candidates, and several have also been mapped3 22 to chromosome 17. Notably, the genetic mapping studies reported here already exclude from the CAR locus, and therefore as candidate Carney complex disease genes, neurofibromin and BRCA1, the chromosome 17q tumor suppressor genes that cause neurofibromatosis and breast cancer, respectively. Refinement of the CAR locus genetic map will facilitate analysis of other candidate genes, and such refinement is feasible given the presence of recombination events in several individuals between the CAR disease gene and the current short tandem repeats (D17S807 and D17S805) flanking the CAR locus.
Investigation of the Carney complex disease gene on chromosome 17q2 will enhance our diagnosis and management of cardiac and extracardiac myxomas. Moreover, in both heritable and acquired cardiac disorders, such as cardiomyopathy and ischemic heart disease, the inability of the terminally differentiated myocyte to proliferate thwarts definitive therapeutics. Cardiac myxomas are thought to arise from rests of subendocardial primitive mesenchymal cells with the capacity to proliferate and to differentiate into multiple cell types.26 27 28 29 Identification of the Carney complex disease gene will elucidate basic mechanisms that regulate cardiac cell growth and will ultimately suggest modalities to promote cardiac remodeling.
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Acknowledgments |
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Dr Basson was supported by NIH grant HL-03468. We are grateful to family members and their physicians for their participation in this study. We thank Dr Peter Okin for assistance with statistical analyses and acknowledge technical assistance by Mohammed Miri and Barbara McDonough and computing services sponsored by the UK Human Genome Mapping Project Resource Center. We are indebted to Drs Christine Seidman, Jonathan Seidman, and Bruce Lerman for their advice and consultation.
Received June 8, 1998; revision received August 11, 1998; accepted August 21, 1998.
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 I Bossis, A Voutetakis, L Matyakhina, S Pack, M Abu-Asab, I Bourdeau, K J Griffin, N Courcoutsakis, S Stergiopoulos, D Batista, et al. A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus J. Med. Genet., August 1, 2004; 41(8): 596 - 600. [Abstract] [Full Text] [PDF]
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M. Veugelers, M. Bressan, D. A. McDermott, S. Weremowicz, C. C. Morton, C. C. Mabry, J.-F. Lefaivre, A. Zunamon, A. Destree, J.-M. Chaudron, et al. Mutation of Perinatal Myosin Heavy Chain Associated with a Carney Complex Variant N. Engl. J. Med., July 29, 2004; 351(5): 460 - 469. [Abstract] [Full Text] [PDF]
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 I. Bourdeau, A. Lacroix, W. Schurch, P. Caron, T. Antakly, and C. A. Stratakis Primary Pigmented Nodular Adrenocortical Disease: Paradoxical Responses of Cortisol Secretion to Dexamethasone Occur in Vitro and Are Associated with Increased Expression of the Glucocorticoid Receptor J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3931 - 3937. [Abstract] [Full Text] [PDF]
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L Matyakhina, S Pack, L S Kirschner, E Pak, P Mannan, J Jaikumar, S E Taymans, F Sandrini, J A Carney, and C A Stratakis Chromosome 2 (2p16) abnormalities in Carney complex tumours J. Med. Genet., April 1, 2003; 40(4): 268 - 277. [Abstract] [Full Text] [PDF]
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C. A. Koch, K. Pacak, and G. P. Chrousos The Molecular Pathogenesis of Hereditary and Sporadic Adrenocortical and Adrenomedullary Tumors J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5367 - 5384. [Abstract] [Full Text] [PDF]
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 J. Saarela, M. Schoenberg Fejzo, D. Chen, S. Finnila, M. Parkkonen, S. Kuokkanen, E. Sobel, P. J. Tienari, M.-L. Sumelahti, J. Wikstrom, et al. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24 Hum. Mol. Genet., September 15, 2002; 11(19): 2257 - 2267. [Abstract] [Full Text] [PDF]
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C. T. Basson and H. T. Aretz Case 11-2002 - A 27-Year-Old Woman with Two Intracardiac Masses and a History of Endocrinopathy N. Engl. J. Med., April 11, 2002; 346(15): 1152 - 1158. [Full Text] [PDF]
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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]
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 A. Lacroix, N. N'Diaye, J. Tremblay, and P. Hamet Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome Endocr. Rev., February 1, 2001; 22(1): 75 - 110. [Abstract] [Full Text]
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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]
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C. D. Malchoff Carney Complex--Clarity and Complexity J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4010 - 4012. [Full Text]
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C. A. Stratakis, T. Papageorgiou, A. Premkumar, S. Pack, L. S. Kirschner, S. E. Taymans, Z. Zhuang, W. H. Oelkers, and J. A. Carney Ovarian Lesions in Carney Complex: Clinical Genetics and Possible Predisposition to Malignancy J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4359 - 4366. [Abstract] [Full Text]
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S. D. Pack, L. S. Kirschner, E. Pak, Z. Zhuang, J. A. Carney, and C. A. Stratakis Genetic and Histologic Studies of Somatomammotropic Pituitary Tumors in Patients with the "Complex of Spotty Skin Pigmentation, Myxomas, Endocrine Overactivity and Schwannomas" (Carney Complex) J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3860 - 3865. [Abstract] [Full Text]
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P. A. Araoz, S. L. Mulvagh, H. D. Tazelaar, P. R. Julsrud, and J. F. Breen CT and MR Imaging of Benign Primary Cardiac Neoplasms with Echocardiographic Correlation RadioGraphics, September 1, 2000; 20(5): 1303 - 1319. [Abstract] [Full Text] [PDF]
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M. R. Gadelha, K. N. Une, K. Rohde, M. Vaisman, R. D. Kineman, and L. A. Frohman Isolated Familial Somatotropinomas: Establishment of Linkage to Chromosome 11q13.1-11q13.3 and Evidence for a Potential Second Locus at Chromosome 2p16-12 J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 707 - 714. [Abstract] [Full Text]
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 C. Gaissmaier, C. T. Basson, M. Casey, C. Mah, A. D. Merliss, L. S. Kirschner, S. E. Taymans, C. A. Stratakis, A. E. Denio, B. Korf, et al. Carney Complex • Response Circulation, December 21, 1999; 100 (25): e150 - e150. [Full Text] [PDF]
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 C. A. Stratakis, N. Sarlis, L. S. Kirschner, J. A. Carney, J. L. Doppman, L. K. Nieman, G. P. Chrousos, and D. A. Papanicolaou Paradoxical Response to Dexamethasone in the Diagnosis of Primary Pigmented Nodular Adrenocortical Disease Ann Intern Med, October 19, 1999; 131(8): 585 - 591. [Abstract] [Full Text] [PDF]
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S. J. Marx CLINICAL REVIEW 109: Contrasting Paradigms for Hereditary Hyperfunction of Endocrine Cells J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3001 - 3009. [Full Text]
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S. R. Bornstein, C. A. Stratakis, and G. P. Chrousos Adrenocortical Tumors: Recent Advances in Basic Concepts and Clinical Management Ann Intern Med, May 4, 1999; 130(9): 759 - 771. [Abstract] [Full Text] [PDF]
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C. A. Stratakis, J. A. Carney, L. S. Kirschner, H. S. Willenberg, S. Brauer, M. Ehrhart-Bornstein, and S. R. Bornstein Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 1122 - 1128. [Abstract] [Full Text]
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