Are You Confident of the Diagnosis?
What you should be alert for in the history
A personal or family history of multiple pigmented lesions, myxomas (cutaneous, cardiac or mammary) endocrine abnormalities and/or unusual tumors strongly suggests the diagnosis of the Carney complex.
Characteristic findings on physical examination
The old acronyms of NAME (nevi, atrial myxoma, myxoid neurofibromas, ephelides [freckles]) and LAMB (lentigines, atrial myxoma, mucocutaneous myxomas, blue nevi) help one remember the major features.
Patients have multiple pigmented macules (Figure 1, Figure 2), most commonly on the face and trunk. Some are brown-black while others are tan. All have an irregular border. Pigmented macules on the lips, conjunctiva, inner canthus and genitalia are particularly suggestive. The lesions start in childhood and increase gradually in number; they fade to some extent in late adult life.
About 75% of patients have multiple pigmented spots (Figure 3). Another 40% may have darkly pigmented nodules admixed with the diffuse macules. In addition, some have café-au-lait macules. About 30% have cutaneous myxomas which are soft skin-colored or waxy papules. They are most common in the periorbital region and about the external ear, but can occur anywhere. Mucosal and nipple myxomas are also common.
Dermatopathology: The nodular lesions are often excised and almost invariably turn out to be heavily pigmented epithelioid blue nevi, although some are compound melanocytic nevi. The flat lesions are rarely biopsied or excised, but have been described variously as lentigines (with increased numbers of melanocytes at the dermoepidermal junction) and freckles (with increased amounts of melanin, but normal numbers of melanocytes. Most likely the darker lesions are lentigines and the tan ones, freckles, but this has not been proven in a large rigorous study. The distinction is subtle and of no clinical importance.
The myxomas feature lacy strands of epithelium admixed with generous deposits of mucin; they have been designated epithelioid myxomas. The old term of myxoid neurofibroma from NAME syndrome turned out to be incorrect; the lesions are not neurofibromas.
Expected results of diagnostic studies
Histopathology: The soft tissue schwannomas are a very unusual variant known as psammomatous melanotic schwannoma. They are pigmented with melanin and contain concretions. The adrenal glands feature heavily pigmented nodules.
There are many other tumors, discussed below, which are identical to their sporadic counterparts under the microscope.
Serologic: The primary pigmented nodular adrenocortical disease (PPNAD) that causes Cushing syndrome can be confirmed by a dexamethasone suppression test (Liddle test). There is often a paradoxical increase in urinary glucocorticosteroid levels following administration of dexamethasone.
Imaging: There are many clues to the diagnosis of Carney complex with imaging studies.
-Cardiac myxomas are best identified with echocardiography.
-Testicular ultrasonography may identify microcalcifications suggesting large-cell calcifying Sertoli cell tumor (LCCSCT)
-Thyroid nodules are usually identified with ultrasonography
-Breast myxomas are best spotted with fat-suppressed magnetc resonance imaging (MRI)
-Pituitary MRI is used to identify adenomas.
Genetic tests: Mutations can be identified in PPKAR1A in about 80% of cases; the balance of cases seem to be caused by mutations in an as yet unidentified gene at 2p16.
The diagnostic criteria for Carney complex include the following (Table I). The diagnosis can be made when two major criteria are fulfilled. If not otherwise specified, the tumors must be diagnosed histologically.
Spotty skin pigmentation (especially lips, canthi and genitalia)
Myxomas (cutaneous or mucosal)
Mammary myxomas (or imaging studies suggesting this diagnosis)
Primary pigmented nodular adrenocortical disease
Acromegaly secondary to a growth hormone-secreting pituitary adenoma
Large-cell calcifying Sertoli cell tumor or characteristic testicular calcifications with ultrasonography
Thyroid carcinoma or multiple hypoechoic nodules on ultrasonography in a patient <18 years of age
Psammomatous melanotic schwannoma
Blue nevi, usually epithelioid
Ductal adenoma of breast
Affected first-degree relative
Mutation in PPKAR1A gene
|Based on Mateus et al, 2008|
Other disorders with multiple pigmented lesions include:
-Peutz-Jeghers syndrome: Labial and mucosal macules, intestinal polyps which are frequently symptomatic, gonadal tumors including LCCSCT. Extensive cutaneous macules almost unheard of; no myxomas.
-LEOPARD syndrome: Only similarity is multiple lentigines. LEOPARD refers both to the large spotted cat and serves as an acronym (lentigines, EKG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, deafness). LEOPARD patients are generally far more “spotted” than Carney complex patients.
– Noonan syndrome features multiple melanocytic nevi, as well as cardiac defects, mental retardation and a host of dysmorphologic features.
There are other even more uncommon lentiginosis syndromes, both with and without systemic features. Café-au-lait macules suggest neurofibromatosis, McCune-Albright syndrome and Watson syndrome. Epithelioid blue nevi may occur sporadically.
The differential diagnostic considerations for all the different tumors are too complex to consider in detail but a few points deserve attention:
-Some pedigrees just have cardiac myxomas.
-Cowden syndrome also has thyroid tumors.
-Eighty percent of patients with bilateral micronodular adrenocortical hyperplasia have Carney complex. In some pedigrees, adrenal disease is the only manifestation of the complex.
-While schwannomas also occur in neurofibromatosis 1, neurofibromatosis 2, and isolated familial schwannomatosis, psammomatous melanotic schwannomas are almost diagnostic of Carney complex.
Who is at Risk for Developing this Disease?
Carney complex is a rare disorder; less than 1000 patients have been reported. Estimates of incidence and prevalence are not available. The number is undoubtedly higher as pedigrees with only adrenal, pituitary or cardiac disease may not be captured as Carney complex.
What is the Cause of the Disease?
Carney complex is inherited in autosomal dominant fashion. At least two genes are involved.
Carney complex 1: Around 80% of pedigrees have a mutation in the PPKAR1A (protein kinase A regulatory subunit-1-alpha) gene. This protein kinase plays a key role in regulating cAMP activity. Almost all Carney complex patients with adrenal disease have mutations in this gene.
Carney complex 2: Around 20% of patients have mutations in an as yet unidentified gene at chromosome 2p16.
Carney complex variant: Families with trismus, pseudocamptodactyly, freckling and cardiac myxomas have been described with mutations in the MYH8 (myosin heavy chain 8) gene. The relationship of this disorder to classic Carney complex remains controversial.
Type 1 protein kinase (PKA) is the main regulator of cAMP. PKA is a tetramer with regulatory and catalytic subunits. PPKAR1A encodes a regulatory subunit. Phosphorylation mediated by the cAMP/PKA signaling pathway helps regulate many aspects of the cell function.
Systemic Implications and Complications
Carney complex has a myriad of systemic manifestations. Only those mentioned in the diagnostic criteria will be discussed.
Cardiac myxoma: Cardiac myxomas are the most common heart tumor; around 10% of them occur in patients with Carney complex. Cardiac myxomas in Carney complex tend to present at an early age, with two peaks in infancy and early 20s. They are often multiple and may involve any chamber of the heart, in contrast to sporadic cardiac myxomas which are solitary and strongly favor the left atrium.
Primary pigmented nodular adrenocortical disease: The hallmark of PPNAD is excessive production of cortisol, independent of ACTH levels. Cushing syndrome is seen in 70% of middle-aged women with Carney complex but only 45% of men. Cushing syndrome in general is more common in women but why this is true in Carney complex patients is unclear. Almost every patient with Carney complex has autopsy evidence of PPNAD.
Cushing syndrome usually presents in adolescence or young adult life with its classic features such as abnormal fat distribution, striae, easy bruising and hypertension; in children it may cause weight gain and growth arrest. There is good evidence that Cushing’s first patient with Cushing syndrome actually had Carney complex.
Pituitary adenoma: About 10% of adults with Carney complex have acromegaly caused by growth-hormone-producing pituitary adenomas. Gigantism is rare, suggesting the tumors are hardly ever functional prior to puberty. Over two-thirds of patients have biochemical evidence of pituitary disease with elevated levels of growth hormone, insulin-like growth factor type 1 (IGF-1), or prolactin.
Large-cell calcifying Sertoli cell tumor: One-third of male patients present with LCCSCT in adolescence or young adult life. The tumors may produce male hormones, leading to gynecomastia and premature fusion of epiphyses in prepubertal boys. Almost all adult men have some evidence of LCCSCT. The tumors are usually multicentric and often bilateral. They are almost never malignant. Patients may be infertile but there is some evidence that PPKAR1A mutations contribute to infertility independent of LCCSCT.
Thyroid tumors: While 75% of patients have multiple thyroid nodules, most are harmless adenomas without metabolic impact. On rare occasions, thyroid carcinomas may develop.
Psammomatous melanotic schwannoma: This rare and histologically unique nerve sheath tumor occurs in about 10% of Carney complex patients. In 10% of this group, the tumor is malignant and potentially life-threatening. It usually affects either the gastrointestinal tract (60%) or the paraspinal sympathetic tract (30%) where it can present with easily misdiagnosed painful radiculopathy in young adults.
Mammary myxoma: These benign tumors are generally bilateral and develop after puberty.
Ductal adenoma of breast: This benign circumscribed breast tumor features both a tubular component and prominent capsule. It can appear sporadically but is far more common in Carney complex patients.
Osteochondromyxoma: A rare congenital bone tumor usually involving the nasal bones, osteochondromyxoma is almost pathognomonic for Carney complex. It can be locally aggressive but does not metastasize.
Considering this long list of tumors, it is not surprising that the average life expectancy in Carney complex is only 50 years. The main threats are cardiac myxomas and complications associated with their surgical removal, as well as metastatic schwannomas.
Treatment options are summarized in Table II.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Excision of cutaneous myxomas, blue nevi and suspicious flat pigmented lesions|
Optimal Therapeutic Approach for this Disease
The dermatologic management of Carney complex is straightforward. The mucocutaneous myxomas may be annoying, especially when they are located about the eyes or block the ear canal. They can be easily removed with shave excision; if the location seems problematic, patients can be referred to ophthalmology or ENT. Myxomas on glabrous skin can be simply excised.
The epithelioid blue nevi are generally excised. While they are often suspected of being malignant, melanoma is an extremely rare entity in Carney complex. While choroidal and maxillary sinus melanomas have been described, they were not aggressive. The risk of cutaneous melanomas is almost zero.
While the pigmented mucosal lesions are generally irregular and often alarming, they too are benign and can usually be diagnosed clinically with confidence. On some occasions, the pigmented mucocutaneous lesions may be the presenting feature and biopsied for diagnostic help.
The treatment for the systemic problems is generally surgical:
-Cardiac myxoma: Open heart surgery
-Primary pigmented nodular adrenocortical disease: Bilateral adrenalectomy and replacement therapy
-Pituitary adenoma: Transsphenoidal surgery
-Large-cell calcifying Sertoli cell tumor: Orchiectomy if hormone-producing in boys.
-Thyroid tumors: Surgery only if malignant
-Psammomatous melanotic schwannoma: Surgery
-Mammary myxoma and ductal adenoma of the breast: Surgery
Patients in whom the diagnosis is suspected should be offered genetic testing and counseling. If the diagnosis is confirmed, then family members at risk should also be tested and counseled. About 70% of patients have an affected parent, while 30% represent new mutations. Prenatal diagnosis is possible if a specific mutation has been identified in one parent.
There are relatively strict guidelines for monitoring patients with or at risk for Carney complex.
– Echocardiography at 6 months and annually thereafter
-Testicular ultrasonography to look for microcalcifications. If positive or if LCCSCT has developed, then close monitoring of hormonal status, bone age and growth.
-Testicular ultrasonography annually in those men with testicular microcalcifications, which are an early manifestation of LCCSCT.
-Annual assessment of adrenal function (urinary free cortisol, diurnal serum cortisol levels or overnight mini ( 1mg) dexamethasone suppression test.
-Annual plasma IGF-1 level.
-Annual thyroid ultrasonography if adenomas are present.
-Clinical examination of breasts yearly, combined with age-appropriate mammography.
-If there is suspicion of adrenal or pituitary disease on screening tests, then very complex detailed protocols are available.
Unusual Clinical Scenarios to Consider in Patient Management
At least 10% of patients have no pigmentary lesions or mucocutaneous myxomas. Carney complex is often not considered in these patients, even when they present with classic systemic findings. Dermatologists may worsen the problem by stating “no evidence for Carney complex” when patients have no mucocutaneous findings suggesting the disorder.
Another tricky issue is the subtle way in which many of the systemic features may present, such as a psammomatous melanotic schwannoma presenting with back pain or a LCCSCT presenting with weight gain in a boy.
What is the Evidence?
Boikos SA, Stratakis , CA. “Carney complex: the first 20 years”. Curr Opin Oncol . vol. 19. 2007. pp. 24-9. (Good overview of oncologic problems.)
Carney , JA, Gordon , H, Carpenter , PC. “The complex of myxomas, spotty pigmentation and endocrine overactivity”. Medicine (Baltimore) . vol. 64. 1985. pp. 270-83. (Classic old paper which gave the disorder its name; still full of useful details.)
Carney , JA. “The search for Harvey Cushing's patient, Minnie G, and the cause of her hypercortisolism”. Am J Surg Pathol . vol. 19. 1995. pp. 100-8. (Fascinating paper showing Cushing syndrome may actually be Carney complex.)
Carney , JA, Stratakis , CA. “Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex”. Semin Diagn Pathol . vol. 15. 1998. pp. 216-24. (Classic paper addressing the two troublesome pigmented lesions.)
Ferreiro , JA, Carney , JA. “Myxomas of the external ear and their significance”. Am J Surg Pathol. vol. 18. 1994. pp. 274-80. (Emphasizes importance of myxomas of external ear and periorbital region.)
Mateus , C, Palangie , A, Franck , N. “Heterogeneity of skin manifestations in patients with Carney complex”. J Am Acad Dermatol . vol. 59. 2008. pp. 801-10. (Detailed data on cutaneous findings in large French series.)
(Stratakis , CA, Kirschner , LS, Carney , JA. “Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation”. J Clin Endocrinol Metab . vol. 86. 2001. pp. 4041-6. (Initial source of the diagnostic criteria.)
Stratakis , CA, Horvath , A. “Carney complex”. Gene Reviews. (Detailed, regularly-updated website.)
Veugelers , M, Bressan , M, McDermott , DA. “Mutation of perinatal myosin heavy chain associated with a Carney complex variant”. N Engl J Med . vol. 351. 2004. pp. 460-9. (First description of the possible Carney variant.)
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