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Carney complex (CNC)

Identity

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 NamePRKARIA
    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 NameCNC2
    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

    OrphanetCarney complex

    Bibliography

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    Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.
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    Evidence for a second genetic locus in Carney complex.
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    Characterization of the adrenal gland pathology of Carney complex, and molecular genetics of the disease.
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    Carney complex: diagnosis and management of the complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas.
    Stratakis CA, Kirschner LS, Carney JA
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    Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.
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    Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex).
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    Genomic mapping of chromosomal region 2p15-p21 (D2S378-D2S391): integration of Genemap'98 within a framework of yeast and bacterial artificial chromosomes.
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    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.
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    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.
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    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
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    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)

    Written08-2004Constantine A Stratakis, Ludmila Matyakhina

    Citation

    This paper should be referenced as such :
    Stratakis, CA ; Matyakhina, L
    Carney complex (CNC)
    Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):336-339.
    Free journal version : [ pdf ]   [ DOI ]
    URL : http://AtlasGeneticsOncology.org/Kprones/CarneyComplexID10080.html

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