Carney complex (CNC)

2004-08-01 Constantine A Stratakis , Ludmila Matyakhina Affiliation

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

Identity

Name

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 ID	Last Year	Title	Authors
7437308	1980	A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome.	Atherton DJ et al
3713260	1986	"Carney's complex".	Bain J et al
9104925	1997	Genetic heterogeneity of familial atrial myxoma syndromes (Carney complex).	Basson CT et al
7802129	1995	The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism.	Carney JA et al
11176065	2001	Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.	Carney JA et al
4010501	1985	The complex of myxomas, spotty pigmentation, and endocrine overactivity.	Carney JA et al
3945116	1986	Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity.	Carney JA et al
9711672	1998	Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex.	Carney JA et al
9843463	1998	Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.	Casey M et al
2498385	1989	Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.	Cuttler L et al
8698339	1996	Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene.	DeMarco L et al
11174387	2001	Multiple lentigines associated with cutaneous myxomas.	Egan CA et al
7911814	1994	Acromegaly and hyperprolactinemia in a patient with polyostotic fibrous dysplasia: dynamic endocrine studies and treatment with the somatostatin analogue octreotide.	Garcia MB et al
10440831	1999	Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex).	Goldstein MM et al
12424709	2002	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 et al
1571257	1992	Multiple lentigines, myxoid tumours and endocrine overactivity; four cases of Carney's complex.	Handley J et al
9892898	1998	Evidence for a second genetic locus in Carney complex.	Irvine AD et al
3674187	1987	Ocular pigmented spots and eyelid myxomas.	Kennedy RH et al
11115848	2000	Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.	Kirschner LS et al
1997386	1991	Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity).	Koopman RJ et al
12537759	2002	Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.	Kurtkaya-Yapicier O et al
9894167	1998	Syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).	Legius E et al
12676898	2003	Chromosome 2 (2p16) abnormalities in Carney complex tumours.	Matyakhina L et al
9415461	1997	Spectrum of malignancy and premalignancy in Carney syndrome.	Nwokoro NA et al
11061550	2000	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 et al
12144681	2002	Ovarian 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
9142622	1997	Testicular ultrasound in Carney complex: report of three cases.	Premkumar A et al
7446466	1980	Large-cell calcifying Sertoli cell tumor of the testis.	Proppe KH et al
10776991	2000	Prolactin secretion abnormalities in patients with the "syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex).	Raff SB et al
4729862	1973	Lentiginosis and left atrial myxoma.	Rees JR et al
6693605	1984	Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the "LAMB" syndrome.	Rhodes AR et al
12666684	2003	Clinical and molecular genetics of Carney complex.	Sandrini F et al
9100606	1997	Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy.	Sarlis NJ et al
7179736	1982	Primary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas. A peculiar familial disease.	Schweizer-Cagianut M et al
6329005	1984	Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome.	Shenoy BV et al
12829237	2003	Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease!	Stergiopoulos SG et al
11549623	2001	Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.	Stratakis CA et al
10087203	1999	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 et al
3566983	1987	"Syndrome myxoma": a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasms.	Vidaillet HJ Jr et al
10701527	2000	Neurosurgical implications of Carney complex.	Watson JC et al
3465316	1986	A familial syndrome of cardiac myxomas, myxoid neurofibromata, cutaneous pigmented lesions, and endocrine abnormalities.	Wilsher ML et al
14717239	2003	A typical Korean case of Carney complex.	Yoon HD et al
2586567	1989	Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later.	Young WF Jr et al