NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Carney Complex

Synonym: Carney Syndrome

, MD, DSc, , PhD, and , MSc, PhD.

Author Information

Initial Posting: ; Last Update: January 29, 2015.

Summary

Clinical characteristics.

Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and manifest as intracardiac obstruction of blood flow, embolic phenomena, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in almost all adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.

Diagnosis/testing.

The diagnosis of CNC usually relies on clinical diagnostic criteria. Pathogenic variants in PRKAR1A are causative. Sequence analysis of the PRKAR1A coding region has a variant detection rate of approximately 60%.

Management.

Treatment of manifestations: Open-heart surgery for cardiac myxomas; surgical excision of cutaneous and mammary myxomas; bilateral adrenalectomy for Cushing syndrome; transsphenoidal surgery for pituitary adenoma; surgery for cancerous thyroid adenomas; orchiectomy for boys with aggressive LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty (mild gynecomastia can be treated medically); surgery to remove primary and/or metastatic PMS.

Surveillance:

  • For prepubertal children: echocardiography annually or biannually for those with a history of excised myxoma.
  • For boys with LCCSCT: testicular ultrasound; close monitoring of linear growth rate and annual pubertal staging.
  • For postpubertal children and adults: echocardiogram annually or biannually for those with a history of excised myxoma; annual testicular ultrasound; baseline thyroid ultrasound with repeat as necessary; baseline transabdominal ultrasound of the ovaries with repeat as necessary; annual urinary free cortisol levels; and annual serum IGF-1 levels.

Further evaluation in all age groups may include: diurnal cortisol levels, dexamethasome stimulation test, and adrenal computed tomography for primary pigmented nodular adrenocortical disease; pituitary MRI, 3-hour oral glucose tolerance test, and 90-minute thyroid releasing hormone testing for gigantism/acromegaly; MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis) for psammamotous melanotic schwannoma.

Evaluation of relatives at risk: When the family-specific pathogenic variant is known, molecular genetic testing to clarify the genetic status of at-risk family members so that appropriate evaluation and surveillance can enable early diagnosis of treatable manifestations.

Genetic counseling.

CNC is inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a de novo pathogenic variant. Each child of an individual with CNC has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

Suggestive Findings

Diagnosis of Carney complex (CNC) should be suspected in individuals with the following features; a definite diagnosis is given when two or more major manifestations are present:

Major diagnostic criteria for CNC

  • Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosal)
  • Myxoma* (cutaneous and mucosal)
  • Cardiac myxoma*
  • Breast myxomatosis* or fat-suppressed MRI findings suggestive of this diagnosis
  • Primary pigmented nodular adrenocortical disease (PPNAD)* or paradoxical positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle's test
  • Acromegaly as a result of growth hormone (GH)-producing adenoma*
  • Large-cell calcifying Sertoli cell tumor (LCCSCT)* or characteristic calcification on testicular ultrasound
  • Thyroid carcinoma* or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
  • Psammomatous melanotic schwannomas (PMS)*
  • Blue nevus, epithelioid blue nevus*
  • Breast ductal adenoma*
  • Osteochondromyxoma*

Note: * denotes after histologic confirmation [Mateus et al 2008]

Supplementary criteria

Findings suggestive of or possibly associated with CNC, but not diagnostic for the disease

  • Intense freckling (without darkly pigmented spots or typical distribution)
  • Blue nevus, common type (if multiple)
  • Café-au-lait spots or other ‘birthmarks’
  • Elevated IGF-I levels, abnormal glucose tolerance test (GTT), or paradoxical GH response to TRH (thyrotropin-releasing hormone) testing in the absence of clinical acromegaly
  • Cardiomyopathy
  • Pilonidal sinus
  • History of Cushing's syndrome, acromegaly, or sudden death in extended family
  • Multiple skin tags or other skin lesions; lipomas
  • Colonic polyps (usually in association with acromegaly)
  • Hyperprolactinemia (usually mild and almost always combined with clinical or subclinical acromegaly)
  • Single, benign thyroid nodule in a child younger than age 18 years; multiple thyroid nodules in an individual older than age 18 years (detected on ultrasound examination)
  • Family history of carcinoma, in particular of the thyroid, colon, pancreas, and ovary; other multiple benign or malignant tumors

[Criteria reprinted from Mateus et al [2008] with permission of Elsevier Publishing]

Establishing the Diagnosis

The diagnosis of CNC is established in a proband with two or more major clinical manifestations (see Suggestive Findings) and/or when a pathogenic variant is identified in PRKAR1A (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of PRKAR1A is performed first and followed by deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes PRKAR1A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, or mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes PRKAR1A) fails to confirm a diagnosis in an individual with features of CNC.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Carney Complex

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
PRKAR1ASequence analysis 260% 3
Deletion/duplication analysis 4~10% 5
Unknown 6, 7, 8NA

NA= not applicable

1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

In the largest study to date, 114 (62%) of 185 families studied had an identifiable PRKAR1A pathogenic variant [Bertherat et al 2009]. The variant detection frequency increases to 80% in individuals with CNC presenting with Cushing syndrome caused by PPNAD [Cazabat et al 2007].

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

In a study of 36 unrelated individuals with CNC who were negative for PRKAR1A single nucleotide variants, two large PRKAR1A deletions were identified [Horvath et al 2008]. Recent study revealed that 21.6% (51 tested) of individuals with CNC who were negative for other PRKAR1A pathogenic variants were positive for PRKAR1A deletions [Salpea et al 2014] (see Table 2). The deletions ranged from 328 bp to 3 Mb affecting part or all of PRKAR1A and in all cases leading to PRKAR1A haploinsufficiency.

6.

Approximately 20% of families with CNC have been linked to 2p16 [Stratakis et al 1996].

7.

PRKACA pathogenic germline gene duplication has been detected in five individuals(4 kindreds) with CNC who have adrenal tumors and Cushing syndrome (<1% of CNC affected families) [Beuschlein et al 2014]. In one of these kindreds, the variant was inherited, as both mother and son were carriers; in another individual, the amplification was de novo, as neither parent was a carrier [Beuschlein et al 2014].

8.

One individual with CNC (<1% of CNC affected families) had a germline rearrangement resulting in four copies of PRKACB [Forlino et al 2014]. PRKACB encodes the catalytic subunit Cβ of the cyclic AMP-dependent protein kinase A (PKA). Levels of Cβ and PKA activity were increased in the individual’s lymphoblasts and fibroblasts; the authors propose that this is a CNC-causing gain-of-function variant.

Clinical Characteristics

Clinical Description

The Carney complex (CNC) of skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas may be evident at birth, although the median age of diagnosis is 20 years.

Skin pigment abnormalities

  • Pale brown to black lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number and appear anywhere on the body including the face, the lips, and mucosa around puberty. These lentigines tend to fade after the fourth decade, but may still be evident in the eighth decade.
  • Additional pigmentary abnormalities that develop over time are epithelioid-type blue nevi (small bluish domed papules with a smooth surface), combined nevi, café au lait spots, and depigmented lesions.

Myxomas

  • Cutaneous myxomas are papules or subcutaneous nodules that usually have a smooth surface and are white, flesh-colored, opalescent, or pink. They appear between birth and the fourth decade. Most individuals with CNC have multiple lesions. Myxomas occur on any part of the body except the hands and feet and typically affect the eyelids, external ear canal, and nipples.
  • Cardiac myxomas occur at a young age and may occur in any or all cardiac chambers. Cardiac myxomas present with symptoms related to intracardiac obstruction of blood flow, embolic phenomenona (into the systemic circulation), and/or heart failure. Myxomas that completely occlude a valvular orifice can cause sudden death.
  • Breast myxomas, often bilateral, occur in females after puberty. Both males and females may develop breast nipple myxomas at any age.
  • Other sites for myxomas include the oropharynx (tongue, hard palate, pharynx) and the female genital tract (uterus, cervix, vagina).
  • Osteochondromyxoma is a rare myxomatous tumor of the bone that affects nasal sinuses and long bones.

Endocrine tumors

  • Primary pigmented nodular adrenocortical disease (PPNAD) is associated with adrenocorticotropic hormone (ACTH)-independent overproduction of cortisol (hypercortisolism). PPNAD is the most frequently observed endocrine tumor in individuals with CNC, occurring in an estimated 25% of affected individuals. Among those with a PRKAR1A pathogenic variant, Cushing syndrome caused by PPNAD is seen in 70% of affected females before age 45 years but in only 45% of affected males, likely reflecting the generally higher frequency of Cushing syndrome in females. Histologic evidence of PPNAD has been found in almost every individual with CNC undergoing autopsy.
    Symptomatic individuals have Cushing syndrome. The hypercortisolism of PPNAD is usually insidious in onset. In children, hypercortisolism is manifest first as weight gain and growth arrest. In adults, longstanding hypercortisolism results in central obesity, "moon facies," hirsutism, striae, hypertension, buffalo hump fat distribution, weakness, easy bruising, and psychological disturbance. In a minority of individuals, PPNAD presents in the first two to three years; in the majority it presents in the second or third decade.
  • GH-producing adenoma. Clinically evident acromegaly is a relatively frequent manifestation of CNC, occurring in approximately 10% of adults at the time of presentation. Gigantism, resulting from excess GH secretion prior to puberty, is rare. However, asymptomatic increased serum concentration of GH and insulin-like growth factor type-1 (IGF-1), as well as subtle hyperprolactinemia, may be present in up to 75% of individuals with CNC. Somatomammotroph hyperplasia, a putative precursor of GH-producing adenoma, may explain the protracted period of onset of clinical acromegaly in individuals with CNC.
  • Testicular tumors. Large-cell calcifying Sertoli cell tumors (LCCSCT) are observed in one third of affected males at the time of presentation, which is often within the first decade. Most adult males with CNC have evidence of LCCSCT. The tumors are often multicentric and bilateral. LCCSCT is almost always benign; malignancy has been reported only once, in a 62-year-old. LCCSCT may be hormone producing; gynecomastia in prepubertal and peripubertal boys may result from increased P-450 aromatase expression. Other testicular tumors observed in individuals with LCCSCT include Leydig cell tumors and (pigmented nodular) adrenocortical rest tumors.
  • Thyroid adenoma or carcinoma. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Thyroid carcinomas, both papillary and follicular, can occur and occasionally may develop in a person with a long history of multiple thyroid adenomas.

Schwannomas

  • Psammomatous melanotic schwannoma (PMS). This rare tumor of the nerve sheath occurs in approximately 10% of individuals with CNC. Malignant degeneration occurs in approximately 10% of those with CNC [Watson et al 2000]. PMS may occur anywhere in the central and peripheral nervous system; it is most frequently found in the nerves of the gastrointestinal tract (esophagus and stomach) and paraspinal sympathetic chain (28%). The spinal tumors present as pain and radiculopathy in adults (mean age 32 years).

Other

  • Breast ductal adenoma is a benign tumor of the mammary gland ducts.

Life span. Most individuals with CNC have a normal life span. However, because some die at an early age, the average life expectancy for individuals with CNC is 50 years. Causes of death include complications of cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors.

Fertility. LCCSCT causes replacement and obstruction of seminiferous tubules, macroorchidism, oligoasthenospermia, and inappropriate hormone production or aromatization. Despite these findings, fertility is frequently preserved.

Genotype-Phenotype Correlations

Clinical and genotypic data on more than 380 affected individuals are available from more than 20 years of study at the National Institutes of Health (Bethesda, MD) and the Hospital Côchin (Paris). Phenotype analysis in 353 individuals with 80 different PRKAR1A pathogenic variants is summarized [Bertherat et al 2009]:

  • A PRKAR1A pathogenic variant was seen more often in individuals with the combination of myxomas (affecting multiple locations such as skin, heart, and breast), psammomatous melanotic schwannomas (PMS), thyroid tumors, and large-cell calcifying Sertoli cell tumor (LCCSCT) than in individuals with CNC without this combination of findings.
  • The ‘‘hot spot’’ pathogenic variant, c.491_492delTG, was more likely to be associated with lentigines, cardiac myxoma, and thyroid tumors than all other PRKAR1A pathogenic variants combined.
  • Individuals with CNC heterozygous for a PRKAR1A pathogenic variant presented more frequently and earlier in life with pigmented skin lesions, myxomas, thyroid tumors, and gonadal tumors than those without an identifiable pathogenic variant. Tumors that presented at a significantly younger age in PRKAR1A heterozygotes than in individuals with CNC without an identifiable pathogenic variant included cardiac myxomas, thyroid tumors, and LCCSCTs.
  • Those with isolated primary pigmented nodular adrenocortical disease (PPNAD) (which was in some cases accompanied by lentiginosis) diagnosed before age eight years were rarely heterozygous for a PRKAR1A pathogenic variant. The two PRKAR1A pathogenic variants commonly seen in those with isolated PPNAD were c.709-2_709-7 delATTTTT and c.1A>G substitution affecting the initiation codon of the protein.
  • PRKAR1A exon variants were associated more frequently with lentigines, PMS, acromegaly, and cardiac myxomas than were intron variants, consistent with the observation that milder phenotypes are more likely to be associated with splice variants than other types of pathogenic variants.
  • Large PRKAR1A deletions (328 bp to 3 Mb) were found to lead to a phenotype that varied but was generally severe and unusual, presumably as a result of haploinsufficiency of additional genes [Salpea et al 2014].

Penetrance

The overall penetrance of CNC in those with a PRKAR1A pathogenic variant is greater than 95% by age 50 years.

Thus far only two PRKAR1A pathogenic variants are known to result in incomplete penetrance of CNC: the splice variant c.709-7_709-2del and the initiation-alternating substitution p.Met1Val. When expressed, these two pathogenic variants lead to relatively mild CNC, manifest mostly as PPNAD, which can be accompanied by lentigines [Groussin et al 2006].

Nomenclature

Carney complex has also been designated by the following acronyms:

  • NAME (nevi, atrial myxomas, ephelides)
  • LAMB (lentigines, atrial myxoma, blue nevi)

"Carney triad" is a completely different entity consisting of a triad of gastrointestinal stromal tumors, pulmonary chondroma, and extra-adrenal paraganglioma.

Prevalence

More than 700 individuals with CNC are known to the authors. These include whites, African Americans, and Asians, from North and South America, Europe, Australia, and Asia.

Differential Diagnosis

Skin. Disorders in which lentigines occur include benign familial lentiginosis (OMIM 151001), Peutz-Jeghers syndrome, LEOPARD syndrome, Noonan syndrome with lentiginosis, and the Bannayan-Riley-Ruvalcaba syndrome, which is one of the phenotypes observed in the PTEN hamartoma tumor syndrome. The café au lait spots of Carney complex (CNC) can resemble those of McCune-Albright syndrome (OMIM 174800), neurofibromatosis type 1, neurofibromatosis type 2, and Watson syndrome (OMIM 193520). Epithelioid blue nevi may occur as solitary lesions in individuals who have no findings to suggest CNC.

Cardiac myxoma. Cardiac myxoma is the most common type of cardiac tumor in adults and accounts for approximately 30% of cardiac tumors in children. Genetic studies reveal no apparent association between CNC and sporadic myxomas [Fogt et al 2002].

Kindreds have been described with familial myxomas, CNC, and cardiomyopathy associated with a single pathogenic variant of a protein that belongs to the family of myosins [Veugelers et al 2004]. This condition is distinct from CNC and is either a separate disorder or the concurrence of two genetic disorders in one family [Stratakis et al 2004].

Endocrine tumors. Thyroid tumors also occur in Cowden syndrome, one of the phenotypes observed in the PTEN hamartoma tumor syndrome. Rarely, sporadic thyroid tumors may harbor somatic PRKAR1A pathogenic variants [Sandrini et al 2002b].

Large-cell calcifying Sertoli cell tumor (LCCSCT) is also seen in Peutz-Jeghers syndrome, in which the tumor may also be hormone producing. Ovarian tumors similar to those seen in Peutz-Jeghers syndrome are not observed in CNC [Stratakis et al 2000].

CNC accounts for approximately 80% of bilateral micronodular adrenal hyperplasia; sporadic isolated (not CNC-associated) primary pigmented nodular adrenocortical disease (PPNAD) can also be caused by pathogenic variants in PRKAR1A [Groussin et al 2002]. Isolated micronodular adrenocortical hyperplasia may be associated with inactivating pathogenic variants in PDE11A, the gene encoding dual-specificity phosphodiesterase [Horvath et al 2006].

Adrenal cortical tumors are also seen in Beckwith-Wiedemann syndrome, Li-Fraumeni syndrome, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency, and the McCune-Albright syndrome [Kjellman et al 2001].

GH-secreting pituitary adenomas (somatotropinomas) can also be seen in multiple endocrine neoplasia type 1 (MEN1) or isolated familial somatotropinomas (IFS), which maps to 11q13.1-q13.3 or 2p16 [Stratakis & Kirschner 2000, Frohman 2003]. Sporadic somatotropinomas or non-CNC- and non-MEN1-associated somatotropinomas do not appear to be frequently associated with PRKAR1A pathogenic variants [Sandrini et al 2002a, Yamasaki et al 2003].

Schwannomas. CNC is the only genetic condition other than neurofibromatosis type 1, neurofibromatosis type 2, and isolated familial schwannomatosis (OMIM 162091) in which schwannomas occur.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Carney complex (CNC), the following evaluations are recommended:

  • Imaging or biochemical screening for endocrine tumors for diagnostic purposes only
  • Thyroid ultrasonography, recommended as a satisfactory, cost-effective method for determining thyroid involvement in pediatric and young adults with CNC. Its value, however, is questionable in older individuals.
  • In males, testicular ultrasonography at the initial evaluation
  • In females, transabdominal ultrasonography during the first evaluation. Unless an abnormality is detected initially, the test need not be repeated because of the low risk for ovarian malignancy.
  • Consultaiton with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following interventions are routine:

  • Cardiac myxoma. Open-heart surgery
  • Cutaneous and mammary myxoma. Surgical excision
  • Cushing syndrome. Bilateral adrenalectomy
  • Pituitary adenoma. Transsphenoidal surgery
  • Thyroid adenomas. Surgery if cancerous
  • LCCSCT. Orchiectomy usually required for boys with aggressively growing LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty. Tumors with lack of growth and mild gynecomastia can be treated medically with aromatase inhibitors.
  • PMS. Surgery to remove primary and/or metastatic lesions

Prevention of Primary Manifestations

The only preventive measure in an asymptomatic individual is surgical removal of a heart tumor (cardiac myxoma) prior to the development of heart dysfunction, stroke, or other embolism.

Prevention of Secondary Complications

Development of metabolic abnormalities from Cushing syndrome or arthropathy and other complications from acromegaly may be prevented by medical or surgical treatment of the respective endocrine manifestations.

Surveillance

Recommended clinical surveillance for individuals with CNC include the following:

Pre-pubertal pediatric individuals

  • Echocardiogram (annually; biannually for those with a history of excised myxoma)
  • Testicular ultrasound for boys; close monitoring of growth rate and pubertal staging (annually)

Post-pubertal pediatric and adult individuals

  • Echocardiogram (annually or biannually for adolescent individuals with a history of excised myxoma)
  • Testicular ultrasound (annually)
  • Thyroid ultrasound (baseline examination; may be repeated as needed)
  • Transabdominal ultrasound of the ovaries (baseline examination; may be repeated as needed)
  • Urinary free cortisol levels (annually)
  • Serum IGF-1 levels (annually)

Further evaluation of affected individuals of all age groups, as needed

  • For primary pigmented nodular adrenocortical disease, in addition to urinary free cortisol levels:
    • Diurnal cortisol levels (11:30 pm, 12:00 am and 7:30 am, 8:00 am sampling)
    • Dexamethasone-stimulation test (modified Liddle’s test, as per Stratakis et al [1999])
    • Adrenal computed tomography
  • For gigantism/acromegaly, in addition to serum IGF-1 levels:
    • Pituitary MRI
    • Three-hour oral glucose tolerance test (oGTT)
    • 90-minute thyroid releasing hormone (TRH) testing
  • For psammomatous melanotic schwannoma: MRI (brain, spine, chest, abdomen, retroperitoneum, pelvis)

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures (see Evaluations Following Initial Diagnosis and Surveillance).

If the PRKAR1A pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Carney complex (CNC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 70% of individuals diagnosed with CNC have an affected parent.
  • Approximately 20% of individuals have CNC as the result of a de novo PRKAR1A pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include elicitation of pertinent family history, physical examination for evidence of cutaneous pigmented spots and/or lumps and for signs of endocrine disease, and imaging and/or biochemical screening. If a pathogenic variant in PRKAR1A has been identified in the proband, molecular genetic testing of the parents should be considered.
  • The family history of some individuals diagnosed with CNC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected, the risk to the sibs is 50%.
  • In the absence of known family history, the risk to sibs of the proband is less than 1%.
  • Germline mosaicism has not been observed in individuals with CNC.

Offspring of a proband

  • Each child of an individual with CNC has a 50% chance of inheriting the PRKAR1A pathogenic variant.
  • Fertility may be impaired in males with CNC.
  • It is possible that pregnancies in which a PRKAR1A-inactivating variant is present are more likely to end in spontaneous abortion; however, no data are yet available.

Other family members of a proband. The risk to the other family members depends on the status of the proband's parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Testing at-risk asymptomatic adults and children. Consideration of molecular genetic testing of young at-risk family members is appropriate for guiding medical management (see Management, Evaluation of Relatives at Risk).

When a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in PRKAR1A, molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members.

When a clinically diagnosed relative is not available for testing, the use of molecular genetic testing for determining the genetic status of at-risk relatives is problematic, and test results need to be interpreted with caution.

  • Identification of a PRKAR1A pathogenic variant in an at-risk family member indicates that the same molecular genetic testing method can be used to assess the genetic status of other at-risk family members.
  • Failure to identify a pathogenic variant in an at-risk family member does not eliminate the possibility that a PRKAR1A pathogenic variant is present; such individuals need to follow the recommendations for clinical surveillance of at-risk family members.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with CNC has the pathogenic variant or clinical evidence of the disorder, the PRKAR1A pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the PRKAR1A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CNC are possible.

Requests for prenatal testing for conditions which (like CNC) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Fetal ultrasound examination. A fetal heart tumor detected prenatally by ultrasound examination in an at-risk fetus may suggest the diagnosis; however, absence of such prenatal ultrasound findings does not rule out the diagnosis.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • CancerNetwork.com
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Carney Complex: Genes and Databases

Locus NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CNC1PRKAR1A17q24​.2cAMP-dependent protein kinase type I-alpha regulatory subunitPRKAR1A database
PRKAR1A Mutation Database
PRKAR1APRKAR1A
CNC2Unknown2p16Unknown

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Carney Complex (View All in OMIM)

160980CARNEY COMPLEX, TYPE 1; CNC1
188830PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A
605244CARNEY COMPLEX, TYPE 2; CNC2

Molecular Genetic Pathogenesis

PRKAR1A appears to function as a classic tumor suppressor gene in tumors from individuals with Carney complex (CNC) as suggested by loss of heterozygosity (LOH) studies. Indeed, LOH was essential in identifying PRKAR1A as the causal gene in the families whose CNC phenotype mapped to 17q22-24 [Kirschner et al 2000a]. Subsequent studies, however, have shown that demonstrating LOH can be difficult because of significant admixture of tumor cells with normal cells in the mostly benign, hyperplastic tissue that either surrounds tumors (as is the case in the pituitary and adrenal glands) or in the primary lesion in CNC [Stratakis, unpublished data]. As expected, in some tumors LOH is not detected [Bertherat et al 2003, Tsilou et al 2004]. Recently, a murine model of CNC was reported [Griffin et al 2004a]; LOH was not a consistent feature in the murine tumors [Griffin et al 2004b].

It has been demonstrated at both the protein and mRNA levels that PRKAR1A alleles with either nonsense or frameshift alterations are functionally null [Kirschner et al 2000a, Kirschner et al 2000b, Groussin et al 2002], indicating that loss of one allele of PRKAR1A is key in disease pathogenesis. The mRNA of such alleles is degraded selectively, a phenomenon known as nonsense-mediated mRNA decay. In tumors of individuals affected with CNC, biallelic inactivation of leads to enhanced intracellular signaling by protein kinase A (PKA), as evidenced by an almost twofold greater response to cAMP in CNC tumors than in non-CNC tumors [Groussin et al 2002]

Gene structure. PRKAR1A has a genomic length of approximately 21 kb. The longest transcript variant NM_212472.1 is composed of 11 exons; codon 1 is non-coding. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A total of 125 different PRKAR1A pathogenic variants have been identified (see PRKAR1A Mutation Database) in 401 unrelated families of diverse ethnic origin; they are summarized in Table 2 [Horvath et al 2010]. The molecular changes involve single base substitutions and small (≤15 bp) deletions, insertions, or combined rearrangements that are spread along the whole open reading frame (ORF) of the gene; in addition, several relatively large deletions have been reported [Horvath et al 2008, Salpea et al 2014]. The pathogenic variants in PRKAR1A are spread along the whole coding sequence, without preference for an exon or a domain. Most of them are unique – identified in single families [Bertherat et al 2009]. To date, only three pathogenic variants have been found in more than three unrelated pedigrees: c.82C>T, c.491_492delTG, and c.709-2_709-7 delATTTTT; these pathogenic variants occurred in kindreds with different racial and ethnic backgrounds, suggesting that they are likely to result from more than one independent mutation event. Allelotyping of several families for at least the c.491_492delTG and c.709-2_709-7 delATTTTT pathogenic variants confirmed that these pathogenic variants arose de novo in what appear to be ‘‘hot spots’’ for sequence changes in PRKAR1A [Kirschner et al 2000a, Groussin et al 2006].

Table 2.

PRKAR1A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change# of
Alleles
Reference
Sequences
c.1A>G 2p.Met1Val9NM_212472​.1
NP_997637​.1
c.82C>T 2p.Gln28Ter2
c.109C>T 3p.Gln37Ter1
c.124C>T 2--5
c.286C>T 4p.Arg96Ter8
c.682C>T 2p.Arg227Ter9
c.786_787delGGinsCT 2p.Trp262CysfsTer23
c.638C>A 5p.Ala213Asp8
c.85_95del11 3p.Ala29ArgfsTer121
c.101_105del5 2p.Ser34CysfsTer93
c.139delA 6p.Met46TrpfsTer821
c.177+3A>G--1
c.491_492delTG 2p.Val164ArgfsTer538
c.530delTTAT 2p.Val117fs26Ter1
c.566_567delAAinsCAC 2p.Glu188AlafsTer443
c.693insT 2p.Arg232Ter1
c.712insAA 2p.Ser238LysfsTer42
c.846insA 3p.Val282SerfsTer91
c.178-2A>G 2----
c.348+1G>C 2----
c.550-2_550-9delATTTCACG 2
(c.550(-9-2)del8)
----
c.708+1G>T 2----
c.709-2_709-7delATTTTT 7
(c.709(-7-2)del6)
----
c.891+3A>G 2----
c.178_348del171 8----
Whole-gene deletion 9--6
Exon 1 deletion 9--2
Exon 2 deletion 9--1
Exon 9-11 deletion 9--1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.
3.
4.
5.
6.
7.
8.
9.

Normal gene product. The PRKAR1A protein consists of 381 amino acid residues organized in a dimerization/docking domain at the amino terminus, followed by a PKA inhibitor site, two tandem binding domains for cAMP at the carboxyl terminus (cAMP:A and cAMP:B), and a linker region that contains the main docking site for the C subunit [Zawadzki & Taylor 2004].

Abnormal gene product. The majority of pathogenic variants (>80%) predict or result in creation of a premature stop codon by nonsense, frameshift, or splicing changes upstream of the last exon. Such variants predict degradation of the mutant mRNAs through a mechanism of nonsense-mediated decay (NMD). A relatively small proportion of pathogenic variants result in the expression of an altered protein; this group comprises missense substitutions, frameshift variants affecting the last exon of the gene (and thus escaping NMD), in-frame deletions, and one splice variant that leads to an in-frame change (c.177+3A>G).

Cancer and Benign Tumors

PRKACA somatic pathogenic variants have been detected in 37% of unilateral adenomas from individuals with overt Cushing’s syndrome [Beuschlein et al 2014].

References

Published Guidelines/Consensus Statements

  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 3-30-18.

Literature Cited

  • Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, René-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab. 2009;94:2085–91. [PMC free article: PMC2690418] [PubMed: 19293268]
  • Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res. 2003;63:5308–19. [PubMed: 14500362]
  • Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014;370:1019–28. [PMC free article: PMC4727447] [PubMed: 24571724]
  • Cazabat L, Libè R, Perlemoine K, René-Corail F, Burnichon N, Gimenez-Roqueplo AP, Dupasquier-Fediaevsky L, Bertagna X, Clauser E, Chanson P, Bertherat J, Raffin-Sanson ML. Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol. 2007;157:1–8. [PubMed: 17609395]
  • Cazabat L, Ragazzon B, Groussin L, Bertherat J. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary. 2006;9:211–9. [PubMed: 17036196]
  • Fogt F, Zimmerman RL, Hartmann CJ, Brown CA, Narula N. Genetic alterations of Carney complex are not present in sporadic cardiac myxomas. Int J Mol Med. 2002;9:59–60. [PubMed: 11744997]
  • Forlino A, Vetro A, Garavelli L, Ciccone R, London E, Stratakis CA, Zuffardi O.N. PRKACB and Carney complex. N Engl J Med. 2014;370:1065–7. [PubMed: 24571725]
  • Frohman LA. Isolated familial somatotropinomas: clinical and genetic considerations. Trans Am Clin Climatol Assoc. 2003;114:165–77. [PMC free article: PMC2194520] [PubMed: 12813918]
  • Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S, Weinberg FD, Claflin E, Meoli E, Cho-Chung YS, Stratakis CA. Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res. 2004a;64:8811–5. [PubMed: 15604237]
  • Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos SG, Robinson-White A, Lenherr SM, Weinberg FD, Claflin ES, Batista D, Bourdeau I, Voutetakis A, Sandrini F, Meoli EM, Bauer AJ, Cho-Chung YS, Bornstein SR, Carney JA, Stratakis CA. A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. J Med Genet. 2004b;41:923–31. [PMC free article: PMC1735656] [PubMed: 15591278]
  • Groussin L, Horvath A, Jullian E, Boikos S, Rene-Corail F, Lefebvre H, Cephise-Velayoudom FL, Vantyghem MC, Chanson P, Conte-Devolx B, Lucas M, Gentil A, Malchoff CD, Tissier F, Carney JA, Bertagna X, Stratakis CA, Bertherat J. A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab. 2006;91:1943–9. [PubMed: 16464939]
  • 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. 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. Am J Hum Genet. 2002;71:1433–42. [PMC free article: PMC378588] [PubMed: 12424709]
  • Horvath A, Bertherat J, Groussin L, Guillaud-Bataille M, Tsang K, Cazabat L, Libé R, Remmers E, René-Corail F, Faucz FR, Clauser E, Calender A, Bertagna X, Carney JA, Stratakis CA. Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum Mutat. 2010;31:369–79. [PMC free article: PMC2936101] [PubMed: 20358582]
  • Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libe R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006;38:794–800. [PubMed: 16767104]
  • Horvath A, Bossis I, Giatzakis C, Levine E, Weinberg F, Meoli E, Robinson-White A, Siegel J, Soni P, Groussin L, Matyakhina L, Verma S, Remmers E, Nesterova M, Carney JA, Bertherat J, Stratakis CA. Large deletions of the PRKAR1A gene in Carney complex. Clin Cancer Res. 2008;14:388–95. [PubMed: 18223213]
  • Imai Y, Taketani T, Maemura K, Takeda N, Harada T, Nojiri T, Kawanami D, Monzen K, Hayashi D, Murakawa Y, Ohno M, Hirata Y, Yamazaki T, Takamoto S, Nagai R. Genetic analysis in a patient with recurrent cardiac myxoma and endocrinopathy. Circ J. 2005;69:994–5. [PubMed: 16041174]
  • Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000a;26:89–92. [PubMed: 10973256]
  • Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Hum Mol Genet. 2000b;9:3037–46. [PubMed: 11115848]
  • Kjellman M, Larsson C, Backdahl M. Genetic background of adrenocortical tumor development. World J Surg. 2001;25:948–56. [PubMed: 11572037]
  • Mateus C, Palangié A, Franck N, Groussin L, Bertagna X, Avril MF, Bertherat J, Dupin N. Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 2008;59:801–10. [PubMed: 18804312]
  • Perdigão PF, Stergiopoulos SG, De Marco L, Matyakhina L, Boikos SA, Gomez RS, Pimenta FJ, Stratakis CA. Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (PRKAR1A) in odontogenic myxomas. Genes Chromosomes Cancer. 2005;44:204–11. [PubMed: 16001434]
  • Salpea P, Horvath A, London E, Faucz FR, Vetro A, Levy I, Gourgari E, Dauber A, Holm IA, Morrison PJ, Keil MF, Lyssikatos C, Smith ED, Sanidad MA, Kelly JC, Dai Z, Mowrey P, Forlino A, Zuffardi O, Stratakis CA. Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing. J Clin Endocrinol Metab. 2014;99:E183–8. [PMC free article: PMC3879675] [PubMed: 24170103]
  • 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. PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex. J Med Genet. 2002a;39:e78. [PMC free article: PMC1757227] [PubMed: 12471216]
  • Sandrini F, Matyakhina L, Sarlis NJ, Kirschner LS, Farmakidis C, Gimm O, Stratakis CA. Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer. Genes Chromosomes Cancer. 2002b;35:182–92. [PubMed: 12203783]
  • Stratakis CA, Bertherat J, Carney JA. Mutation of perinatal myosin heavy chain. N Engl J Med. 2004;351:2556–8. [PubMed: 15590965]
  • Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest. 1996;97:699–705. [PMC free article: PMC507106] [PubMed: 8609225]
  • Stratakis CA, Kirschner LS. Isolated familial somatotropinomas: does the disease map to 11q13 or to 2p16? J Clin Endocrinol Metab. 2000;85:4920–1. [PubMed: 11134164]
  • Stratakis CA, Papageorgiou T, Premkumar A, Pack S, Kirschner LS, Taymans SE, Zhuang Z, Oelkers WH, Carney JA. Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J Clin Endocrinol Metab. 2000;85:4359–66. [PubMed: 11095480]
  • Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP, Papanicolaou DA. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med. 1999;131:585–91. [PubMed: 10523219]
  • Tsilou ET, Chan CC, Sandrini F, Rubin BI, Shen DF, Carney JA, Kaiser-Kupfer M, Stratakis CA. Eyelid myxoma in Carney complex without PRKAR1A allelic loss. Am J Med Genet A. 2004;130A:395–7. [PubMed: 15368482]
  • Urban C, Weinhausel A, Fritsch P, Sovinz P, Weinhandl G, Lackner H, Moritz A, Haas OA. Primary pigmented nodular adrenocortical disease (PPNAD) and pituitary adenoma in a boy with sporadic Carney complex due to a novel, de novo paternal PRKAR1A mutation (R96X). J Pediatr Endocrinol Metab. 2007;20:247–52. [PubMed: 17396442]
  • Veugelers M, Bressan M, McDermott DA, Weremowicz S, Morton CC, Mabry CC, Lefaivre JF, Zunamon A, Destree A, Chaudron JM, Basson CT. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med. 2004;351:460–9. [PubMed: 15282353]
  • Watson JC, Stratakis CA, Bryant-Greenwood PK, Koch CA, Kirschner LS, Nguyen T, Carney JA, Oldfield EH. Neurosurgical implications of Carney complex. J Neurosurg. 2000;92:413–8. [PubMed: 10701527]
  • Yamasaki H, Mizusawa N, Nagahiro S, Yamada S, Sano T, Itakura M, Yoshimoto K. GH-secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23-24. Clin Endocrinol (Oxf). 2003;58:464–70. [PubMed: 12641630]
  • Zawadzki KM, Taylor SS. cAMP-dependent protein kinase regulatory subunit type IIbeta: active site mutations define an isoform-specific network for allosteric signaling by cAMP. J Biol Chem. 2004;279:7029–36. [PubMed: 14625280]

Suggested Reading

  • Boikos SA, Stratakis CA. Carney complex: pathology and molecular genetics. Neuroendocrinology. 2006;83:189–99. [PubMed: 17047382]
  • Pereira AM, Hes FJ, Horvath A, Woortman S, Greene E, Bimpaki E, Alatsatianos A, Boikos S, Smit JW, Romijn JA, Nesterova M, Stratakis CA. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. J Clin Endocrinol Metab. 2010;95:338–42. [PMC free article: PMC2805491] [PubMed: 19915019]
  • Stratakis CA, Matyakhina L. Carney complex (CNC). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2004. Accessed 3-30-18.
  • Veugelers M, Vaughan CJ, Basson CT. Familial cardiac myxomas and Carney complex. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 46. McGraw-Hill.

Chapter Notes

Author History

Anelia Horvath, PhD; National Institutes of Health (2003-2015)
Margarita Raygada, MSc, PhD (2015-present)
Paraskevi Salpea, PhD (2015-present)
Constantine A Stratakis, MD, DSc (2003-present)

Revision History

  • 29 January 2015 (me) Comprehensive update posted live
  • 20 September 2012 (me) Comprehensive update posted live
  • 22 June 2010 (me) Comprehensive update posted live
  • 10 January 2008 (me) Comprehensive update posted to live Web site
  • 22 March 2005 (me) Comprehensive update posted to live Web site
  • 5 February 2003 (me) Review posted to live Web site
  • 7 October 2002 (cs) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview ‘Carney Complex’ is in the public domain in the United States of America.

Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1286PMID: 20301463

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...