Carney Syndrome 

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD   more...
 
Updated: Apr 17, 2012
 

Background

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome. Historically, the complex involved the association of the following conditions: (1) primary pigmented nodular adrenocortical disease (PPNAD), a pituitary-independent, primary adrenal form of hypercortisolism; (2) lentigines, ephelides, and blue nevi of the skin and mucosae; and (3) a variety of nonendocrine and endocrine tumors. The latter include myxomas of the skin, heart, breast, and other sites; psammomatous melanotic schwannoma; growth hormone–producing pituitary adenoma; testicular Sertoli-cell tumor; and, possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenoma of the breast and acromegaly due to somatomammotroph hyperplasia and adenoma not dependent on growth hormone–releasing hormone.

Although the existence of the complex as an unrecognized inherited syndrome was first suggested in 1985, combinations of several components of the syndrome and their familial occurrence were reported earlier.[1] The Carney complex gene 1 was later identified as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. An inactivating heterozygous germ-line mutation of PRKAR1A has been documented in about two thirds of individuals with Carney complex.

The pathologic findings of multiple, small, pigmented adrenocortical nodules and internodular cortical atrophy were described as early as 1949 in the adrenal glands of children and young adults with Cushing syndrome. In 1980, Atherton and colleagues[2] described a patient with a vast number of macular pigmented lesions on the skin, which involved the lips; myxoid neurofibroma; and domed blue nevi. Echocardiograms revealed dense echoes arising from the space between the mitral leaflets; these findings were consistent with the histologic features of a myxoma. Atherton suggested the term nevi, atrial myxoma, myxoid neurofibromas, and ephelides (NAME) syndrome.

Rhodes and colleagues[3] then described a similar condition for which the term lentigines, atrial myxomas, and blue nevi (LAMB) syndrome was suggested.

Carney[4] conducted a review of cases in 40 patients with cardiac myxomas. He found that many of these patients also had multiple pigmented lesions (lentigines and several types of nevi), which affected the lips, as well as PPNAD, which presented as Cushing syndrome. Some of these patients also presented with testicular tumors, fibroadenomas, and pituitary adenomas. He concluded that these rare conditions were unlikely to occur together by chance and that they represented a unique syndrome. Endocrine overactivity is also part of this syndrome.[5] In fact, corticotropin hormone–independent Cushing syndrome due to primary pigmented nodular adrenocortical disease is an important syndrome characteristic.

Also see Carney Complex.

See the image below.

A pedunculated flesh-colored cutaneous myxoma thatA pedunculated flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.
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Pathophysiology

The Carney myxoma-endocrine complex is believed to exist in at least 2 genetically distinct forms: One form can be mapped to chromosome 17, and the other, to chromosome 2. The chromosome 17 form, designated Carney complex type I, is due to mutations in the PRKAR1A gene. Further research is needed to delineate the exact genetic mutations in Carney complex type II.

Carney complex genes are associated with genomic instability as cell lines established from Carney complex tumors accumulate chromosomal changes, including telomeric associations (tas) and dicentric chromosomes. Myxomas in Carney complex show a high rate of apoptosis, in concordance with the cytogenetic abnormalities in these tumors. Both primary pigmented nodular adrenocortical disease (PPNAD) (a primary bilateral adrenal disorder leading to Cushing syndrome) and myxomatous tumors from patients with Carney complex stain positive for synaptophysin, a neuroendocrine (NE) marker, and the lesions have NE properties on electron microscopy.

An inherited disposition to cardiac myxoma development is seen in these Carney complex patients.[6] They have a mutation in the PRKAR1A gene, which encodes the regulatory R1alpha subunit of protein kinase A—a significant component of the cyclic adenosine monophosphate (cAMP) signaling pathway. Genetically engineered mutant Prkar1a mouse models also show a tendency to develop tumors.

PPNAD, a rare cause of corticotropin-independent Cushing syndrome, may be part of Carney complex. A small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly PPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.[7] PPNAD and pituitary adenoma in a boy with sporadic Carney complex was found to be due to a novel, de novo paternal PRKAR1A mutation (R96X).[8] A patient with Carney complex caused by the newly identified nonsense mutation p.Y21X was described.[9] Another was observed due to novel frameshift mutation, c.597del C (p.Phe200LeufsX6) in PRKAR1A.[10] Since family members with the same mutation can show distinct phenotypes, Carney complex may be viewed as a multifactorial disorder comprising various genetic and environmental factors.

Although most tumors in Carney complex are benign, 1 patient in a large Azorean family was first seen with an adrenocortical cancer.[11, 12] In this family, the disorder was caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A.

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Epidemiology

Frequency

United States

Cardiac myxomas are the most common primary cardiac tumor in the general population and occur with a frequency of 7 cases per 10,000 individuals. Myxomas occurring as part of Carney complex account for 7% of all cardiac myxomas.

International

More than 150 patients have been identified as having Carney syndrome since its recognition as a complex in 1985. Cases in persons with only limited involvement may not be reported. The syndrome is distributed worldwide.

Mortality/Morbidity

  • Cardiac myxomas account for a mortality rate of 25% in patients with this syndrome.
  • Cardiac myxomas are a silent killer, causing major disability with its embolic capacity and even sudden death.
  • The psammomatous melanotic schwannomas are typically benign; however, as many as 10% of cases can metastasize.

Race

Most patients who are affected with Carney complex are white, although the disease has been described in blacks.

Sex

In Carney complex, males and females are affected equally.

Age

The mean patient age at diagnosis of Carney complex is 10-20 years.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Santiago A Centurion, MD  Staff Physician, Department of Dermatology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey

Santiago A Centurion, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, and Sigma Xi

Disclosure: Nothing to disclose.

Manuel A Cruz, MA  Adjunct Assistant Professor, Department of Pathology, UMDNJ-New Jersey Medical School

Manuel A Cruz, MA is a member of the following medical societies: Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

R Stan Taylor, MD  The JB Howell Professor in Melanoma Education and Detection, Departments of Dermatology and Plastic Surgery, Director, Skin Surgery and Oncology Clinic, University of Texas Southwestern Medical Center

R Stan Taylor, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, Christian Medical & Dental Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Christen M Mowad, MD  Associate Professor, Department of Dermatology, Geisinger Medical Center

Christen M Mowad, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Glen H Crawford, MD  Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD  Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Ali Haider, MD, and Walter HC Burgdorf, MD, to the development and writing of this article.

References

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A pedunculated flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.
Polypoid neoplasm of fibrillary collagen and uniform stellate cells within abundant connective tissue mucin. Note telangiectasia and ramification of tumor as strands through a myxoid dermis (hematoxylin-eosin). Courtesy of Dermatology, NYU School of Medicine; photography by Anca Croitoru, MD, and Scott Sanders, MD.
 
 
 
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