Clinical Diagnosis

Since the first description of Carney complex (CNC), numerous individuals with CNC have been reported from all ethnic groups and presenting with varying numbers, combinations, and severity of manifestations. The most recently reevaluated diagnostic criteria for CNC are listed in below; a definite diagnosis is given when two or more major manifestations are present:

Major diagnostic criteria for Carney complex (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 magnetic resonance imaging 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*

* After histologic confirmation [Mateus et al 2008]

Supplementary criteria

• Affected first-degree relative

• Inactivating mutation of the PRKAR1A gene

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 Journal of the American Academy of Dermatology: Mateus C, Palangie A, Franck N, Groussin L, Bertagna X, Avril M-F, Bertherat J, Dupin N. Heterogeneity of skin manifestations in patients with Carney complex. 59:801-10 (2008), with permission from Elsevier Publishing

Molecular Genetic Testing

Genes. PRKAR1A is the only gene currently known to be associated with CNC [Schoenberg-Fejzo 1999, Stratakis et al 1999, Kirschner et al 2000b].

Other loci

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

• It is possible that a third as-yet unidentified locus exists.

Clinical testing

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

• Deletion/duplication analysis. In a study of 36 unrelated individuals with CNC who were negative for PRKAR1A point mutations, two large PRKAR1A deletions were identified [Horvath et al 2008]:

  • A 3876-bp deletion including part of sequences regulating transcription and exon 1 splicing, without affecting PRKAR1A ORF

  • A 4,165-bp deletion that eliminated exon 3

Research testing

• Linkage analysis. For those individuals without an identifiable PRKAR1A mutation, linkage analysis may be available on a research basis.

Table 1. Summary of Molecular Genetic Testing Used in Carney Complex

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PRKAR1A	Sequence analysis	PRKAR1A point mutations	60%	Clinical
	Deletion/duplication analysis 2	Large PRKAR1A mutations	~2%
	Linkage analysis	NA	NA	Research 3

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

NA= not applicable

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

3. No laboratories offering clinical testing for this test method are listed in the GeneTests Laboratory Directory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing of PRKAR1A involves:

• Bidirectional sequencing of all coding sequences and exon-intron junctions;

• Deletion/duplication analysis in families with typical clinical manifestations of Carney complex in whom no PRKAR1A point mutation has been identified.

Predictive testing for young at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The following phenotypes are also associated with mutations in PRKAR1A:

• Sporadic isolated (not CNC-associated) PPNAD [Groussin et al 2002]

• Sporadic undifferentiated thyroid cancers and sporadic papillary thyroid cancers [Sandrini et al 2002b]

• Adrenal tumors [Bertherat et al 2003]

Odontogenic myxomas, which have never been seen in the context of CNC, have been associated with somatic PRKAR1A mutations [Perdigao et al 2005].

Natural History

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 70s.

• 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 mutation, 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.

Age at presentation. CNC may present at any age; it most commonly presents in the teen years and early adulthood.

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.

Genotype-Phenotype Correlations

Until recently, genotype-phenotype correlation studies were limited by the variability of the CNC phenotype, the number and combinations of manifestations, and the limited number of affected individuals available for study. However, clinical and genotypic data on more than 380 affected individuals are now 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 mutations is summarized below [Bertherat et al 2009].

A PRKAR1A mutation 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’’ mutation, c.491_492delTG, was more likely to be associated with lentigines, cardiac myxoma, and thyroid tumors than all other PRKAR1A mutations combined (p=0.03).

Individuals with CNC heterozygous for a PRKAR1A mutation presented more frequently and earlier in life with pigmented skin lesions, myxomas, thyroid tumors, and gonadal tumors than those without an identifiable mutation. Tumors that presented at significantly younger age in PRKAR1A heterozygotes than in individuals with CNC without an identifiable mutation included cardiac myxomas (p=0.02), thyroid tumors (p=0.03), and LCCSCTs (p=0.04).

Those with isolated PPNAD (which was in some cases accompanied by lentiginosis) diagnosed before age eight years were rarely heterozygous for a PRKAR1A mutation. The two PRKAR1A mutations commonly seen in those with isolated PPNAD were c.709-2_709-7 delATTTTT (p=0.0001) and c.1A>G substitution affecting the initiation codon of the protein.

PRKAR1A exonic mutations were associated more frequently with lentigines, PMS, acromegaly, and cardiac myxomas than were intronic mutations (p=0.04), consistent with the observation that milder phenotypes are more likely to be associated with splice variants than other types of mutations.

Penetrance

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

Thus far only two PRKAR1A mutations 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 mutations 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 gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma.

Prevalence

More than 600 individuals with CNC are known to the authors. These include Caucasians, African Americans, and Asians, from North and South America, Europe, Australia, and Asia.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 of ovarian malignancy.

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 LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty

• PMS. Surgery to remove primary and/or metastatic lesions

Surveillance

The following are recommended for prepubertal children:

• Echocardiography during the first six months of life and annually thereafter; closer follow-up may be necessary for children following excision of a cardiac myxoma.

• In children with LCCSCT (or microcalcifications observed on testicular ultrasonography), close monitoring of linear growth rate and pubertal status; some may require bone age determination and further laboratory evaluation for possible aromatase excess resulting in increased estrogen levels.

The following are recommended for postpubertal children and adults of both sexes with established CNC:

• Annual echocardiogram

• Annual measurement of urinary free cortisol concentration (which may be supplemented by diurnal measurement of serum cortisol concentration) or the overnight 1-mg dexamethasone testing

• Annual measurement of plasma IGF-1 concentration

• Thyroid ultrasonography repeated as needed

• Annual ultrasonography for males in whom minute testicular calcifications (presumably a manifestation of LCCSCT) are present

• Clinical follow-up of breast ductal adenoma

More elaborate clinical studies and imaging studies may be necessary for the detection of PPNAD and GH-producing pituitary adenoma in those without overt clinical manifestations of adrenal or pituitary disease:

• For PPNAD, a dexamethasone stimulation test is recommended in addition to adrenal computed tomography (CT) to detect PPNAD-associated subclinical, atypical, or periodic Cushing syndrome. Diurnal plasma cortisol concentrations may also be obtained.

• For the early detection of a GH-producing pituitary adenoma, oral glucose tolerance (OGT) and thyrotrophin-releasing hormone (TRH) testing may be obtained in addition to plasma IGF-1 concentration and pituitary MRI.

If findings suggestive of PMS are present, imaging of the brain, spine, chest, abdomen (in particular the retroperitoneum), and the pelvis may be necessary.

Testing of Relatives at Risk

When a clinically diagnosed relative has undergone molecular genetic testing and is found to have a mutation in PRKAR1A, molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members so that they can be evaluated promptly for treatable manifestations of CNC (see Evaluations Following Initial Diagnosis and Surveillance).

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 mutation.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include eliciting pertinent family history, physical examination for evidence of cutaneous pigmented spots or lumps or both and for signs of endocrine disease, and imaging and/or biochemical screening. If a mutation in PRKAR1A has been identified in the proband, molecular genetic testing of the parents should be considered.

Note: Although most individuals diagnosed with CNC have an affected parent, the family history 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.

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 approximately 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 mutation.

• Fertility may be impaired in males with CNC.

• It is possible that pregnancies in which a PRKAR1A-inactivating mutation 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, Testing of Relatives at Risk).

When a clinically diagnosed relative has undergone molecular genetic testing and is found to have a mutation 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 disease-causing mutation 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 disease-causing mutation in an at-risk family member does not eliminate the possibility that a PRKAR1A disease-causing mutation 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

PRKAR1A appears to function as a classic tumor suppressor gene in tumors from individuals with Carney complex (CNC) as demonstrated in loss of heterozygosity (LOH) studies. Indeed, LOH was essential in identifying PRKAR1A as the causative gene in the families mapping 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]. In some tumors, LOH is not detected [Bertherat et al 2003, Tsilou et al 2004]. Recently, a mouse model of the disease was made available [Griffin et al 2004a]; LOH was not a consistent feature in the mouse tumors [Griffin et al 2004b].

Western blot testing of protein lysates from CNC cells demonstrated that foreshortened forms of the protein encoded for by PRKAR1A are not produced. In addition, analysis of mRNA in these cells has demonstrated selective degradation of mutant mRNA, a phenomenon known as nonsense-mediated mRNA decay. Thus, it has been demonstrated at both the protein and mRNA levels that these mutant alleles are functionally null, indicating that loss of one allele of PRKAR1A is key in disease pathogenesis. In CNC tumors, loss of the PRKAR1A protein 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.

Normal allelic variants. PRKAR1A is located on chromosome 17q23-17q24 and extends to a total genomic length of approximately 21 kb. The gene is composed of 11 exons, ten of which (2-11) are coding, with a total encoding region of 1143 bp.

Pathologic allelic variants. To date, a total of 117 different PRKAR1A mutations have been identified (online PRKAR1A Mutation Database) in 387 unrelated families of various 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]. The mutations 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 mutations have been found in more than three unrelated pedigrees: c.82C>T, c.491_492delTG, and c.709-2_709-7 delATTTTT; these mutations 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 mutations confirmed that these mutations arose de novo in what appear to be ‘‘hot spots’’ for sequence changes in the PRKAR1A gene [Kirschner et al 2000a, Groussin et al 2006].

Normal gene product. The PRKAR1A protein consists of 384 amino acid residues organized in a dimerization/docking domain at the aminoterminal, 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 vast majority of mutations (>80%) result in premature stop codon generation caused by nonsense and frameshift changes upstream of the last gene exon; the mutant mRNAs are degraded through nonsense-mediated decay (NMD). In this group fall also the majority of the splice variants – disrupted donor or acceptor sequences leading to exon skip and/or retention of part of the intron, and, thus, direct or by frame-shift incorporation of a premature stop codon. A relatively small proportion of unique mutations result in the expression of an altered protein; this group comprises missense substitutions, frameshift mutations affecting the last exon of the gene and thus escaping NMD, in-frame deletions, and one splice variant that leads to in-frame change.

Literature Cited

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12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. Kjellman M, Larsson C, Backdahl M. Genetic background of adrenocortical tumor development. World J Surg. 2001;25:948–56. [PubMed: 11572037]
18. 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]
19. Perdigao 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]
20. 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]
21. 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]
22. Schoenberg-Fejzo M. Integrated map of chromosome 17q critical region in multiple sclerosis. Am J Hum Genet. 1999;65:A442.
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24. 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]
25. 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]
26. Stratakis CA, Kirschner LS, Taymans SE, Carney JA, Basson CT. Genetic heterogeneity in Carney complex (OMIM 160980): contributions of loci at chromosomes 2 and 17 in its genetics. Am J Hum Genet. 1999;65:A447.
27. 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]
28. Tsilou ET, Chan CC, Sandrini F, Rubin BI. Eyelid myxoma in Carney complex without PRKAR1A allelic loss. Am J Med Genet A. 2004;130A:395–7. [PubMed: 15368482]
29. 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]
30. 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]
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32. 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]
33. 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]

Published Statements and Policies Regarding Genetic Testing

1. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology; American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28:893–901. [PubMed: 20065170]

Suggested Reading

1. Boikos SA, Stratakis CA. Carney complex: pathology and molecular genetics. Neuroendocrinology. 2006;83:189–99. [PubMed: 17047382]
2. 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]
3. Stratakis CA, Matyakhina L (2004) Carney complex (CNC). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available at atlasgeneticsoncology.org. Accessed 6-17-10.
4. Veugelers M, Vaughan CJ, Basson CT. Familial cardiac myxomas and Carney complex. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 47.1. Available at www.ommbid.com. Accessed 6-17-10.

Author Notes

Section on Endocrinology and Genetics Web site

Revision History

• 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