Carney complex (CNC)

2004-08-01   Constantine A Stratakis  , Ludmila Matyakhina  

Unit on Genetics &Endocrinology (UGEN), DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862, USA

Identity

Name

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.

Omim

160980 , 605244

Mesh

D056733

Orphanet

1359 Carney complex

Umls

C0406810;C2607929

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

    Alias

    CARCNC1MGC17251PKR1PRKAR1TSE1

    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.

    Description

    10 exons

    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.

    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.

    Description

    Unknown

    Function

    Unknown

    Somatic

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

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    74373081980A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome.Atherton DJ et al
    37132601986"Carney's complex".Bain J et al
    91049251997Genetic heterogeneity of familial atrial myxoma syndromes (Carney complex).Basson CT et al
    78021291995The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism.Carney JA et al
    111760652001Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.Carney JA et al
    40105011985The complex of myxomas, spotty pigmentation, and endocrine overactivity.Carney JA et al
    39451161986Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity.Carney JA et al
    97116721998Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex.Carney JA et al
    98434631998Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.Casey M et al
    24983851989Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.Cuttler L et al
    86983391996Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene.DeMarco L et al
    111743872001Multiple lentigines associated with cutaneous myxomas.Egan CA et al
    79118141994Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: dynamic endocrine studies and treatment with the somatostatin analogue octreotide.Garcia MB et al
    104408311999Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex).Goldstein MM et al
    124247092002Molecular 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 et al
    15712571992Multiple lentigines, myxoid tumours and endocrine overactivity; four cases of Carney's complex.Handley J et al
    98928981998Evidence for a second genetic locus in Carney complex.Irvine AD et al
    36741871987Ocular pigmented spots and eyelid myxomas.Kennedy RH et al
    111158482000Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.Kirschner LS et al
    19973861991Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity).Koopman RJ et al
    125377592002Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.Kurtkaya-Yapicier O et al
    98941671998Syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).Legius E et al
    126768982003Chromosome 2 (2p16) abnormalities in Carney complex tumours.Matyakhina L et al
    94154611997Spectrum of malignancy and premalignancy in Carney syndrome.Nwokoro NA et al
    110615502000Genetic 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 et al
    121446812002Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease).Papageorgiou T et al
    91426221997Testicular ultrasound in Carney complex: report of three cases.Premkumar A et al
    74464661980Large-cell calcifying Sertoli cell tumor of the testis.Proppe KH et al
    107769912000Prolactin secretion abnormalities in patients with the "syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex).Raff SB et al
    47298621973Lentiginosis and left atrial myxoma.Rees JR et al
    66936051984Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the "LAMB" syndrome.Rhodes AR et al
    126666842003Clinical and molecular genetics of Carney complex.Sandrini F et al
    91006061997Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy.Sarlis NJ et al
    71797361982Primary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas. A peculiar familial disease.Schweizer-Cagianut M et al
    63290051984Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome.Shenoy BV et al
    128292372003Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease!Stergiopoulos SG et al
    115496232001Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.Stratakis CA et al
    100872031999Radiation 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 et al
    35669831987"Syndrome myxoma": a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasms.Vidaillet HJ Jr et al
    107015272000Neurosurgical implications of Carney complex.Watson JC et al
    34653161986A familial syndrome of cardiac myxomas, myxoid neurofibromata, cutaneous pigmented lesions, and endocrine abnormalities.Wilsher ML et al
    147172392003A typical Korean case of Carney complex.Yoon HD et al
    25865671989Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later.Young WF Jr et al

    Citation

    Constantine A Stratakis ; Ludmila Matyakhina

    Carney complex (CNC)

    Atlas Genet Cytogenet Oncol Haematol. 2004-08-01

    Online version: http://atlasgeneticsoncology.org/cancer-prone-disease/10080/carney-complex-(cnc)