Carney Complex

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 can manifest as intracardiac obstruction of blood flow, embolic phenomenon, 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 most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning 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 is established in a proband with two or more major diagnostic criteria and/or by identification of a heterozygous germline pathogenic variant in PRKAR1A on molecular genetic testing.

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 may be treated medically); surgery to remove primary and/or metastatic PMS.

Prevention of primary manifestations: Surgical removal of a cardiac myxoma prior to the development of heart dysfunction, stroke, or other embolism.

Prevention of secondary complications: Medical or surgical treatment of endocrine manifestations may prevent the metabolic abnormalities from Cushing syndrome or arthropathy and complications from acromegaly.

Surveillance:

• For prepubertal children: echocardiography annually or biannually for those with a history of excised myxoma; testicular ultrasound with 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; 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.

Suggestive Findings

Carney complex (CNC) should be suspected in individuals with the following features.

Major diagnostic criteria for CNC

• Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
• Myxoma* (cutaneous and mucosal)
• Cardiac myxoma*
• Breast myxomatosis* or fat-suppressed MRI findings suggestive of this diagnosis
• Primary pigmented nodular adrenocortical disease (PPNAD)* or paradoxic 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

• Affected first-degree relative
• Inactivating pathogenic variant in PRKAR1A

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 macules or other "birthmarks"
• Elevated IGF-I levels, abnormal glucose tolerance test (GTT), or paradoxic 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 diagnostic criteria (see Suggestive Findings). Identification of a heterozygous germline pathogenic variant in PRKAR1A by molecular genetic testing (see Table 1) can confirm the diagnosis in individuals with two or more major diagnostic criteria and establishes the diagnosis if clinical features are inconclusive.

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of PRKAR1A detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• A multigene panel that includes PRKAR1A and other genes of interest (see Differential Diagnosis) may 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 are likely to change 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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 macules, 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 phenomenon (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 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, long-standing 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.
• Growth hormone (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 an individual age 62 years. 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.

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).

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; e.g., skin, heart, and breast), psammomatous melanotic schwannomas (PMS), thyroid tumors, and large-cell calcifying Sertoli cell tumors (LCCSCTs) 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 accompanied by lentiginosis in some individuals) 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.709-7_709-2delATTTTT 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" (OMIM 604287) 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.

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 if they have not already been completed:

• 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, regardless of age.
• Consultation 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 and at-risk relatives include the following:

Prepubertal 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)

Postpubertal 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 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.
• If 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 (see Surveillance).

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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.