Carney complex (CNC)

Note	A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and other tumors.
Inheritance	A genetically heterogeneous autosomal dominant disorder with high penetrance for CNC1 (penetrance for CNC1 due to PRKARIA defects is close to 100%); this estimate of penetrance does not apply to kindreds with CNC2 because the CNC2 gene (s) is still unknown. Most of the cases of CNC (70%) are familial.

Clinics

Phenotype and clinics	Developmental disorder. In some cases the disease is diagnosed at birth. Onset of the disease occurs commonly at a young age and the median age at detection is 20 years. Spotty skin pigmentation lesions, such as lentigines (small, brown to black, non or slightly elevated, round or irregular) and blue nevi (large, blue to black, domed lesion) observed primarily in the face, eyelids, ears, and borders of the lips are the most common clinical manifestation of CNC (77%). Lentigines tend to fade with the age, usually after the fourth decade of life. Myxomas are frequent lesions in CNC patients; heart myxomas (53%) occur multicentrically, and in any, or all, cardiac chambers; skin myxomas (33%) are detected in the eyelid, the external ear canal, the nipple, the oropharynx, the female genital tract and the female pelvis. Breast myxomas are often bilateral and present in more than 70% of adult women with CNC. Psammomatous melanotic shwannomas , very rare tumors (10%), may occur anywhere in the peripheral nervous system, but most frequently in the gastrointestinal tract and paraspinal symphatetic chain. Breast ductal adenomas, unusual mammary tumors akin to intraductal papillomas have been detected in 3% of CNC cases. Endocrine lesions in CNC include testicular neoplasms (33%), primary pigmented nodule adrenocortical disease (PPNAD) (26%), growth hormone (GH) and prolactin-producing pituitary tumors (14%) and thyroid cancer (5%).
Neoplastic risk	Skin lesions are benign. Heart, skin and breast myxomas are benign lesions. Psammomatous melanotic shwannoma may be malignant and metastasizes aggressively to lungs, brain and other organs Breast ductal adenomas are benign but malignancy was detected in one case Testicular tumors are almost always benign; metastasis has been reported only in one older patient. PPNAD in CNC is always benign. Growth hormone and prolactin-producing pituitary tumors are benign lesions. Thyroid neoplasms may also become malignant.
Treatment	Annual studies: echocardiogram (note that in pediatric patients it should be done during the first 6 months of life and annually thereafter), measurement of urinary free cortisol and serum IGF-1 levels, thyroid ultrasonography, testicular ultrasonography for male and transabdominal pelvic ultrasonography for females; surgery when necessary. Additional clinical and imaging studies may be necessary for the detection of PPNAD and GH-producing pituitary adenoma.
Prognosis	According to the severity of the disease in a given patient, and to the quality of a regular follow up, life span is decreased in patients with CNC. 57% of the deaths are due to heart related causes; others due to the postoperative complications or evolution of the maligant process; a presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease.

Genes involved and Proteins

 

Gene Name	PRKARIA
Location	17q23-24
Note	Mutations in PRKARIA are found in about 46 % of cases of CNC syndrome; there is genetic heterogeneity, and unknown gene(s) on 2p16 is probably also responsible for the disease.

DNA/RNA
Description	10 exons

Protein
Description	48 kDa; contains two tandem cAMP-binding domains at the C-terminus and the dimerization domain at the N-terminus that serves also as a docking site for A Kinase Anchoring Proteins (AKAPs).
Expression	Ubiquitously expressed, in particular in brain, endocrine tissues, adipose tissue and bone.
Function	The function of PRKAR1A is to bind cAMP and regulate the function of the catalytic subunits of the protein kinase A (PKA) holoenzyme. Two regulatory subunits bind two catalytic subunits forming an inactive PKA tetramer. Activation of PKA occurs when 2 cAMP molecules bind to each regulatory subunit eliciting a reversible conformational change that releases active catalytic subunits. Four different regulatory subunits and three catalytic subunits of PKA have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. It may act as a tumor-suppressor in CNC and other tumors.

Mutations
Germinal	Most mutations are null alleles; they are dispersed through the coding region of the gene, involving every exon except 4A, 9 and 10.
Somatic	Many of CNC tumors show loss of heterozygosity.

 

Gene Name	CNC2
Location	2p16

DNA/RNA
Description	Unknown

Protein
Function	Unknown

Mutations
Somatic	Many of CNC tumors show amplification or deletion of the 2p16 region.

External links

Orphanet

Carney complex

Bibliography

Lentiginosis and left atrial myxoma.

Rees JR, Ross FG, Keen G

British heart journal. 1973 ; 35 (8) : 874-876.

PMID 4729862

A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome.

Atherton DJ, Pitcher DW, Wells RS, MacDonald DM

The British journal of dermatology. 1980 ; 103 (4) : 421-429.

PMID 7437308

Large-cell calcifying Sertoli cell tumor of the testis.

Proppe KH, Scully RE

American journal of clinical pathology. 1980 ; 74 (5) : 607-619.

PMID 7446466

Familial Cushing's syndrome with primary adrenocortical microadenomatosis (primary adrenocortical nodular dysplasia).

Schweizer-Cagianut M, Froesch ER, Hedinger C

Acta endocrinologica. 1980 ; 94 (4) : 529-535.

PMID 6254301

Primary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas. A peculiar familial disease.

Schweizer-Cagianut M, Salomon F, Hedinger CE

Virchows Archiv. A, Pathological anatomy and histology. 1982 ; 397 (2) : 183-192.

PMID 7179736

The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: a five-year review.

Carney JA

Medicine. 1983 ; 62 (3) : 159-169.

PMID 6843355

Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the LAMB syndrome.

Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR

Journal of the American Academy of Dermatology. 1984 ; 10 (1) : 72-82.

PMID 6693605

Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome.

Shenoy BV, Carpenter PC, Carney JA

The American journal of surgical pathology. 1984 ; 8 (5) : 335-344.

PMID 6329005

The complex of myxomas, spotty pigmentation, and endocrine overactivity.

Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL

Medicine. 1985 ; 64 (4) : 270-283.

PMID 4010501

Carney's complex.

Bain J

Mayo Clinic proceedings. Mayo Clinic. 1986 ; 61 (6) : page 508.

PMID 3713260

Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity.

Carney JA, Headington JT, Su WP

Archives of dermatology. 1986 ; 122 (7) : 790-798.

PMID 3729510

Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity.

Carney JA, Hruska LS, Beauchamp GD, Gordon H

Mayo Clinic proceedings. Mayo Clinic. 1986 ; 61 (3) : 165-172.

PMID 3945116

A familial syndrome of cardiac myxomas, myxoid neurofibromata, cutaneous pigmented lesions, and endocrine abnormalities.

Wilsher ML, Roche AH, Neutze JM, Synek BJ, Holdaway IM, Nicholson GI

Australian and New Zealand journal of medicine. 1986 ; 16 (3) : 393-396.

PMID 3465316

Ocular pigmented spots and eyelid myxomas.

Kennedy RH, Waller RR, Carney JA

American journal of ophthalmology. 1987 ; 104 (5) : 533-538.

PMID 3674187

Syndrome myxoma: a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasms.

Vidaillet HJ Jr, Seward JB, Fyke FE 3rd, Su WP, Tajik AJ

British heart journal. 1987 ; 57 (3) : 247-255.

PMID 3566983

Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.

Cuttler L, Jackson JA, Saeed uz-Zafar M, Levitsky LL, Mellinger RC, Frohman LA

The Journal of clinical endocrinology and metabolism. 1989 ; 68 (6) : 1148-1154.

PMID 2498385

Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later.

Young WF Jr, Carney JA, Musa BU, Wulffraat NM, Lens JW, Drexhage HA

The New England journal of medicine. 1989 ; 321 (24) : 1659-1664.

PMID 2586567

Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity).

Koopman RJ, Happle R

Human genetics. 1991 ; 86 (3) : 300-304.

PMID 1997386

Multiple lentigines, myxoid tumours and endocrine overactivity; four cases of Carney's complex.

Handley J, Carson D, Sloan J, Walsh M, Thornton C, Hadden D, Bingham EA

The British journal of dermatology. 1992 ; 126 (4) : 367-371.

PMID 1571257

Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: dynamic endocrine studies and treatment with the somatostatin analogue octreotide.

Garcia MB, Koppeschaar HP, Lips CJ, Thijssen JH, Krenning EP

Journal of endocrinological investigation. 1994 ; 17 (1) : 59-65.

PMID 7911814

Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas.

Carney JA

Seminars in dermatology. 1995 ; 14 (2) : 90-98.

PMID 7640202

The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism.

Carney JA

The American journal of surgical pathology. 1995 ; 19 (1) : 100-108.

PMID 7802129

Ductal adenoma of the breast and the Carney complex.

Carney JA, Stratakis CA

The American journal of surgical pathology. 1996 ; 20 (9) : 1154-1155.

PMID 8764753

Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene.

DeMarco L, Stratakis CA, Boson WL, Jakbovitz O, Carson E, Andrade LM, Amaral VF, Rocha JL, Choursos GP, Nordenskj��ld M, Friedman E

Human genetics. 1996 ; 98 (2) : 185-188.

PMID 8698339

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

Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP

The Journal of clinical investigation. 1996 ; 97 (3) : 699-705.

PMID 8609225

Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).

Stratakis CA, Jenkins RB, Pras E, Mitsiadis CS, Raff SB, Stalboerger PG, Tsigos C, Carney JA, Chrousos GP

The Journal of clinical endocrinology and metabolism. 1996 ; 81 (10) : 3607-3614.

PMID 8855810

Genetic heterogeneity of familial atrial myxoma syndromes (Carney complex).

Basson CT, MacRae CA, Korf B, Merliss A

The American journal of cardiology. 1997 ; 79 (7) : 994-995.

PMID 9104925

Spectrum of malignancy and premalignancy in Carney syndrome.

Nwokoro NA, Korytkowski MT, Rose S, Gorin MB, Penles Stadler M, Witchel SF, Mulvihill JJ

American journal of medical genetics. 1997 ; 73 (4) : 369-377.

PMID 9415461

Testicular ultrasound in Carney complex: report of three cases.

Premkumar A, Stratakis CA, Shawker TH, Papanicolaou DA, Chrousos GP

Journal of clinical ultrasound : JCU. 1997 ; 25 (4) : 211-214.

PMID 9142622

Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy.

Sarlis NJ, Chrousos GP, Doppman JL, Carney JA, Stratakis CA

The Journal of clinical endocrinology and metabolism. 1997 ; 82 (4) : 1274-1278.

PMID 9100606

Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex)

Stratakis CA, Courcoutsakis NA, Abati A, Filie A, Doppman JL, Carney JA, Shawker T

The Journal of clinical endocrinology and metabolism. 1997 ; 82 (7) : 2037-2043.

PMID 9215269

Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex.

Carney JA, Stratakis CA

Seminars in diagnostic pathology. 1998 ; 15 (3) : 216-224.

PMID 9711672

Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.

Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT

Circulation. 1998 ; 98 (23) : 2560-2566.

PMID 9843463

Evidence for a second genetic locus in Carney complex.

Irvine AD, Armstrong DK, Bingham EA, Hadden DR, Nevin NC, Hughes AE

The British journal of dermatology. 1998 ; 139 (4) : 572-576.

PMID 9892898

Characterization of the adrenal gland pathology of Carney complex, and molecular genetics of the disease.

Kirschner LS, Taymans SE, Stratakis CA

Endocrine research. 1998 ; 24 (3-4) : 863-864.

PMID 9888588

Syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).

Legius E, Daenen W, Vandenbergh V, Verbeeck G, Bex M, Fryns JP

Genetic counseling (Geneva, Switzerland). 1998 ; 9 (4) : 287-290.

PMID 9894167

Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome.

Stratakis CA, Kirschner LS

Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et metabolisme. 1998 ; 30 (6-7) : 456-463.

PMID 9694579

Carney complex: diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas.

Stratakis CA, Kirschner LS, Carney JA

American journal of medical genetics. 1998 ; 80 (2) : 183-185.

PMID 9805140

Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.

Stratakis CA, Kirschner LS, Taymans SE, Tomlinson IP, Marsh DJ, Torpy DJ, Giatzakis C, Eccles DM, Theaker J, Houlston RS, Blouin JL, Antonarakis SE, Basson CT, Eng C, Carney JA

The Journal of clinical endocrinology and metabolism. 1998 ; 83 (8) : 2972-2976.

PMID 9709978

Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex).

Goldstein MM, Casey M, Carney JA, Basson CT

American journal of medical genetics. 1999 ; 86 (1) : 62-65.

PMID 10440831

Genomic mapping of chromosomal region 2p15-p21 (D2S378-D2S391): integration of Genemap'98 within a framework of yeast and bacterial artificial chromosomes.

Kirschner LS, Taymans SE, Pack S, Pak E, Pike BL, Chandrasekharappa SC, Zhuang Z, Stratakis CA

Genomics. 1999 ; 62 (1) : 21-33.

PMID 10585764

Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease.

Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP, Papanicolaou DA

Annals of internal medicine. 1999 ; 131 (8) : 585-591.

PMID 10523219

Radiation hybrid mapping of chromosomal region 2p15-p16: integration of expressed and polymorphic sequences maps at the Carney complex (CNC) and Doyne honeycomb retinal dystrophy (DHRD) loci.

Taymans SE, Kirschner LS, Giatzakis C, Stratakis CA

Genomics. 1999 ; 56 (3) : 344-349.

PMID 10087203

Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA

Nature genetics. 2000 ; 26 (1) : 89-92.

PMID 10973256

Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.

Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA

Human molecular genetics. 2000 ; 9 (20) : 3037-3046.

PMID 11115848

Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas (Carney complex).

Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis CA

The Journal of clinical endocrinology and metabolism. 2000 ; 85 (10) : 3860-3865.

PMID 11061550

Prolactin secretion abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas (Carney complex).

Raff SB, Carney JA, Krugman D, Doppman JL, Stratakis CA

Journal of pediatric endocrinology & metabolism : JPEM. 2000 ; 13 (4) : 373-379.

PMID 10776991

Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy.

Stratakis CA, Papageorgiou T, Premkumar A, Pack S, Kirschner LS, Taymans SE, Zhuang Z, Oelkers WH, Carney JA

The Journal of clinical endocrinology and metabolism. 2000 ; 85 (11) : 4359-4366.

PMID 11095480

Neurosurgical implications of Carney complex.

Watson JC, Stratakis CA, Bryant-Greenwood PK, Koch CA, Kirschner LS, Nguyen T, Carney JA, Oldfield EH

Journal of neurosurgery. 2000 ; 92 (3) : 413-418.

PMID 10701527

Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.

Carney JA, Boccon-Gibod L, Jarka DE, Tanaka Y, Swee RG, Unni KK, Stratakis CA

The American journal of surgical pathology. 2001 ; 25 (2) : 164-176.

PMID 11176065

Multiple lentigines associated with cutaneous myxomas.

Egan CA, Stratakis CA, Turner ML

Journal of the American Academy of Dermatology. 2001 ; 44 (2) : 282-284.

PMID 11174387

Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.

Stratakis CA, Kirschner LS, Carney JA

The Journal of clinical endocrinology and metabolism. 2001 ; 86 (9) : 4041-4046.

PMID 11549623

Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.

Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J

American journal of human genetics. 2002 ; 71 (6) : 1433-1442.

PMID 12424709

Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.

Kurtkaya-Yapicier O, Scheithauer BW, Carney JA, Kovacs K, Horvath E, Stratakis CA, Vidal S, Vella A, Young WF Jr, Atkinson JL, Lloyd RV, Kontogeorgos G

Ultrastructural pathology. 2002 ; 26 (6) : 345-353.

PMID 12537759

Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease).

Papageorgiou T, Stratakis CA

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2002 ; 12 (4) : 337-347.

PMID 12144681

PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex.

Sandrini F, Kirschner LS, Bei T, Farmakidis C, Yasufuku-Takano J, Takano K, Prezant TR, Marx SJ, Farrell WE, Clayton RN, Groussin L, Bertherat J, Stratakis CA

Journal of medical genetics. 2002 ; 39 (12) : page e78.

PMID 12471216

Chromosome 2 (2p16) abnormalities in Carney complex tumours.

Matyakhina L, Pack S, Kirschner LS, Pak E, Mannan P, Jaikumar J, Taymans SE, Sandrini F, Carney JA, Stratakis CA

Journal of medical genetics. 2003 ; 40 (4) : 268-277.

PMID 12676898

Clinical and molecular genetics of Carney complex.

Sandrini F, Stratakis C

Molecular genetics and metabolism. 2003 ; 78 (2) : 83-92.

PMID 12666684

Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease!

Stergiopoulos SG, Stratakis CA

FEBS letters. 2003 ; 546 (1) : 59-64.

PMID 12829237

A typical Korean case of Carney complex.

Yoon HD, Shon HS

The Korean journal of internal medicine. 2003 ; 18 (4) : 260-265.

PMID 14717239

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Contributor(s)

Written	08-2004	Constantine A Stratakis, Ludmila Matyakhina

Citation

This paper should be referenced as such :

Stratakis CA, Matyakhina L . Carney complex (CNC). Atlas Genet Cytogenet Oncol Haematol. August 2004 .

URL : http://AtlasGeneticsOncology.org/Kprones/CarneyComplexID10080.html

The various updated versions of this paper are referenced and archived by INIST as such :

http://documents.irevues.inist.fr/bitstream/2042/38142/1/08-2004-CarneyComplexID10080.pdf   [ Bibliographic record ]

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