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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Carney Complex

Synonyms: Carney Syndrome, Familial Myxoma

, MD, DSc and , PhD.

Author Information
, MD, DSc
Chief, Unit on Genetics and Endocrinology, DEB/NICHD
Director, Inter-Institute Pediatric Endocrinology Program
National Institutes of Health
Scientific Director, NICHD
Bethesda, Maryland
, PhD
NICHD, DEB, SEGEN
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: September 20, 2012.

Summary

Disease 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. Mutations in PRKAR1A are causative. Sequence analysis of the PRKAR1A coding region has a mutation detection rate of approximately 60%.

Management. Treatment of manifestations: Open-heart surgery for cardiac myxomas; surgical excision of cutaneous and mammary myxoma; bilateral adrenolectomy for Cushing syndrome; transsphenoidal surgery for pituitary adenoma; surgery for cancerous thyroid adenomas; orchiectomy for boys with LCCSCT and gynecomastia to avoid premature epiphyseal fusion and induction of central precocious puberty; 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 mutation 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 mutation. Each child of an individual with CNC has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

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 here; 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 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

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

Molecular Genetic Testing

Genes. PRKAR1A is the only gene in which mutations are known to cause CNC [Schoenberg-Fejzo 1999, Stratakis et al 1999a, Kirschner et al 2000b].

Evidence for locus heterogeneity

Clinical testing. See Table 1.

Research testing

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

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
PRKAR1ASequence analysis 2PRKAR1A point mutations60% 3
Deletion / duplication analysis 4Large PRKAR1A deletions~2% 5
Linkage analysisNANA

NA= not applicable

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. 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].

4. Testing that identifies deletions/duplications not readily 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 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 and a 4,165-bp deletion that eliminated exon 3.

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.

Clinical Description

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 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 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. 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 mutations is summarized [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 a 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 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, 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, neurofibromatosis type 1, neurofibromatosis type 2, and Watson syndrome. 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 mutation 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 mutations [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 mutations in PRKAR1A [Groussin et al 2002]. Isolated micronodular adrenocortical hyperplasia may be associated with inactivating mutations 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 mutations [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 in which schwannomas occur.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 for ovarian malignancy.
  • Medical genetics consultation

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

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 [1999b])
    • Adrenal computed tomography
  • For gigantism/acromegaly, in addition to serum IGF-1 levels:
    • Pituitary magnetic resonance imaging
    • 3-hour oral glucose tolerance test (oGTT)
    • 90-minute thyroid releasing hormone (TRH) testing
  • For psammomatous melanotic schwannoma:
    • Magnetic resonance imaging (brain, spine, chest, abdomen, retroperitoneum, pelvis)

Evaluation 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.

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 mutation.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation 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 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 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 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, Evaluation 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.

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 an option for some families in which the disease-causing mutation has been identified.

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.

  • 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

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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 demonstrated in loss of heterozygosity (LOH) studies. Indeed, LOH was essential in identifying PRKAR1A as the involved 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-q24 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 (see PRKAR1A Mutation Database) in 387 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]. 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 PRKAR1A [Kirschner et al 2000a, Groussin et al 2006].

Table 2. PRKAR1A Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change 2 Number of AllelesReference SequencesReference
Normal c.87G>Ap.(=)--NM_212472​.1
NP_997637​.1
Not reported
c.204A>Gp.(=)--Not reported
c.318G>Cp.(=)--Not reported
c.349-5dupT
(IVS3-5dupT)
----Not reported
c.892-43G>T
(IVS9-34G>T)
----Not reported
c.973-102A>T
(IVS10-102A>T)
----Not reported
Pathologicc.1A>Gp.Met1Val9Kirschner et al [2000a]
c.82C>Tp.Gln28X2Kirschner et al [2000b]
c.109C>Tp.Gln37X1Cazabat et al [2006]
c.124C>T--5Kirschner et al [2000b]
c.286C>Tp.Arg96X8Urban et al [2007]
c.682C>Tp.Arg227X9Kirschner et al [2000b]
c.786_787delGGinsCTp.Trp262Cysfs*23Kirschner et al [2000b]
c.638C>Ap.Ala213Asp8Perdigao et al [2005]
c.85_95del11p.Ala29Argfs*121Cazabat et al [2006]
c.101_105del5p.Ser34Cysfs*93Kirschner et al [2000b]
c.139delAp.Met46Trpfs*821Imai et al [2005]
c.491_492delTGp.Val164Argfs*538Kirschner et al [2000a]
c.530delTTATp.Val117fs26X1Kirschner et al [2000a]
c.566_567delAAinsCACp.Glu188Alafs*443Kirschner et al [2000b]
c.693insTp.Arg232X1Kirschner et al [2000b]
c.712insAAp.Ser238Lysfs*42Kirschner et al [2000b]
c.846insAp.Val282Serfs*91Cazabat et al [2006]
c.178-2A>G----Kirschner et al [2000b]
c.348+1G>C----Kirschner et al [2000b]
c.550-2_550-9 delATTTCACG
(c.550 (-9-2)del8)
----Kirschner et al [2000b]
c.708+1G>T----Kirschner et al [2000b]
c.709-2_709-7 delATTTTT
(c.709 (-7-2) del 6)
----Groussin et al [2006]
c.891+3A>G----Kirschner et al [2000b]
c.178_348del171----Horvath et al [2008]

Note on variant classification: Variants listed in the table have been provided by the author(s). 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. The designation p.(=) means that the protein has not been analyzed but no change is expected (Human Genome Variation Society).

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 creation of a new premature stop codon by nonsense or frameshift changes upstream of the last exon. Such mutations predict degradation of the mutant mRNAs through a mechanism of nonsense-mediated decay (NMD). Similarly, the majority of the splice variants – disrupted donor or acceptor sequences leading to skipping an exon and/or retaining a partial intron – create nonsense or frameshift changes resulting in 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 an in-frame change.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  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]

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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 online. Accessed 9-11-12.
  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 Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 47.1. Available online. Accessed 9-11-12.

Chapter Notes

Revision History

  • 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

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