AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome. Historically, the complex involved the association of the following conditions: (1) primary pigmented nodular adrenocortical disease (PPNAD), a pituitary-independent, primary adrenal form of hypercortisolism; (2) lentigines, ephelides, and blue nevi of the skin and mucosae; and (3) a variety of nonendocrine and endocrine tumors. The latter include myxomas of the skin, heart, breast, and other sites; psammomatous melanotic schwannoma; growth hormone–producing pituitary adenoma; testicular Sertoli-cell tumor; and, possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenoma of the breast and acromegaly due to somatomammotroph hyperplasia and adenoma not dependent on growth hormone–releasing hormone.

Although the existence of the complex as an unrecognized inherited syndrome was first suggested in 1985, combinations of several components of the syndrome and their familial occurrence were reported earlier.

The pathologic findings of multiple, small, pigmented adrenocortical nodules and internodular cortical atrophy were described as early as 1949 in the adrenal glands of children and young adults with Cushing syndrome. In 1980, Atherton and colleagues¹ described a patient with a vast number of macular pigmented lesions on the skin, which involved the lips; myxoid neurofibroma; and domed blue nevi. Echocardiograms revealed dense echoes arising from the space between the mitral leaflets; these findings were consistent with the histologic features of a myxoma. Atherton suggested the term nevi, atrial myxoma, myxoid neurofibromas, and ephelides (NAME) syndrome.

Rhodes and colleagues² then described a similar condition for which the term lentigines, atrial myxomas, and blue nevi (LAMB) syndrome was suggested.

Carney³ conducted a review of cases in 40 patients with cardiac myxomas. He found that many of these patients also had multiple pigmented lesions (lentigines and several types of nevi), which affected the lips, as well as PPNAD, which presented as Cushing syndrome. Some of these patients also presented with testicular tumors, fibroadenomas, and pituitary adenomas. He concluded that these rare conditions were unlikely to occur together by chance and that they represented a unique syndrome. Endocrine overactivity is also part of this syndrome.⁴ In fact, corticotropin hormone–independent Cushing syndrome due to primary pigmented nodular adrenocortical disease is an important syndrome characteristic.

The eMedicine article Carney Complex also may be of interest.

Pathophysiology

The Carney myxoma-endocrine complex is believed to exist in at least 2 genetically distinct forms: One form can be mapped to chromosome 17, and the other, to chromosome 2. The chromosome 17 form, designated CNC type I, is due to mutations in the PRKAR1A gene. Further research is needed to delineate the exact genetic mutations in CNC type II.

CNC genes are associated with genomic instability as cell lines established from CNC tumors accumulate chromosomal changes, including telomeric associations (tas) and dicentric chromosomes. Myxomas in CNC show a high rate of apoptosis, in concordance with the cytogenetic abnormalities in these tumors. Both PPNAD (a primary bilateral adrenal disorder leading to Cushing syndrome) and myxomatous tumors from patients with CNC stain positive for synaptophysin, a neuroendocrine (NE) marker, and the lesions have NE properties on electron microscopy.

An inherited disposition to cardiac myxoma development is seen in these CNC patients.⁵ They have a mutation in the PRKAR1A gene, which encodes the regulatory R1alpha subunit of protein kinase A—a significant component of the cyclic adenosine monophosphate (cAMP) signaling pathway. Genetically engineered mutant Prkar1a mouse models also show a tendency to develop tumors. PPNAD, a rare cause of corticotropin-independent Cushing syndrome, may be part of CNC. A small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly PPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.⁶ PPNAD and pituitary adenoma in a boy with sporadic CNC was found to be due to a novel, de novo paternal PRKAR1A mutation (R96X).⁷

Frequency

United States

Cardiac myxomas are the most common primary cardiac tumor in the general population and occur with a frequency of 7 cases per 10,000 individuals. Myxomas occurring as part of CNC account for 7% of all cardiac myxomas.

International

More than 150 patients have been identified as having Carney syndrome since its recognition as a complex in 1985. Cases in persons with only limited involvement may not be reported. The syndrome is distributed worldwide.

Mortality/Morbidity

• Cardiac myxomas account for a mortality rate of 25% in patients with this syndrome.
• Cardiac myxomas are a silent killer, causing major disability with its embolic capacity and even sudden death.
• The psammomatous melanotic schwannomas are typically benign; however, as many as 10% of cases can metastasize.

Race

Most patients who are affected with CNC are white, although the disease has been described in blacks.

Sex

Males and females are affected equally.

Age

The mean patient age at diagnosis is 10-20 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Cutaneous manifestations are a major clue in the diagnosis of this condition. These manifestations include Cushing syndrome and skin changes associated with pigmentation.

• Symptoms of Cushing syndrome may develop in young patients.
• • The skin is fragile and thin.
  • Patients bruise easily and heal poorly.
  • The bones are weakened, and routine activities such as bending, lifting, or rising from a chair may lead to backaches and rib and spinal column fractures.
  • Severe fatigue, muscle weakness, high blood pressure, and high blood sugar levels may be present.
  • Irritability, anxiety, and depression are also common.
  • Women may have menstrual periods that become irregular or stop.
  • Men have decreased fertility with a diminished or absent desire for sex.
• Symptoms of a prolactin-secreting tumor include hypogonadism (eg, amenorrhea, impotence) associated with symptoms of increased prolactin levels (eg, galactorrhea) in female patients.
• Symptoms of acromegaly include headaches and visual abnormalities.
• Symptoms of hyperparathyroidism include fatigue, anemia, muscle weakness, joint pain, constipation with nausea, frequent urination (sometimes bloody), mood change with confusion, abdominal pain due to ulcers, flank or back pain due to stones, bone pain due to bone erosions or fractures, and hypertension.
• Atrial myxomas may create ball-valve obstructions that cause unexpected syncopal attacks, cardiac insufficiency, and sudden death in apparently healthy young children and adults.
• Right-sided myxomas with extramedullary hematopoiesis and ossification in CNC has been described in a patient who also had a tiny eyelid cutaneous myxoma, multiple hypoechoic thyroid follicular adenomas, and multiple small testicular tumors.⁸

Physical

Myxomas recur in approximately 12-22% of familial cases and in about 1-2% of sporadic cases.

• Atrial myxomas
• • On physical examination, an accentuated first heart sound can be appreciated in patients with cardiac myxomas.
  • In adults, myxomas are the most common primary tumor of the heart. They arise in any of the 4 chambers or on the heart valves; however, about 90% are located in the atria. Myxomas in the atria have a left-to-right ratio of approximately 4:1.
  • Myxomas are mostly single and rarely multiple in several chambers.
  • Tumors can be 1-10 cm or larger in diameter.
  • The tumors can be sessile or pedunculated. In addition, the pedunculated form of atrial myxomas is often sufficiently mobile to move into or sometimes through the atrioventricular valves during diastole. Sometimes, such mobility exerts a wrecking-ball effect on the valve leaflets.
• Multiple nevi, diffuse facial lentigines, and mucosal labial pigmentation
• • The classic presentation is a spotty pigmentation on the face, the chest and shoulders, and the vermilion border of the lips and conjunctiva.
  • The pigmentation can be tan or dark brown to black.
  • The lesions can be irregularly shaped or sharply delineated, and they can be small or several millimeters in diameter.
• Subcutaneous myxoid neurofibromas and mammary fibroadenosis
• • Cutaneous myxomas have a predilection for the eyelids and external ear canals, although they may affect any part of the skin.
  • The mammary myxoid fibroadenomas in the complex are often multiple and bilateral; these fibroadenomas are an unusual finding in an otherwise normal breast.
• Signs of acromegaly
• • Macroglossia may be present.
  • Prominent jaw and frontal bossing may be observed.
  • The patient may have large spadelike hands.
  • Skin tags may be observed.
  • Hyperhidrosis may occur.
• Signs of Cushing syndrome
• • The skin is fragile and thin.
  • Patients bruise easily and heal poorly.
  • Purplish pink stretch marks are noted on the abdomen, thighs, buttocks, arms, and breasts.
  • Upper-body obesity, a rounded face, increased fat around the neck, and thin arms and legs are observed.
  • Children tend to be obese, with slowed growth rates.
  • Women usually have excessive hair growth on their face, neck, chest, abdomen, and thighs.
• Endocrine involvement in CNC also includes 3 types of testicular tumors: large-cell calcifying Sertoli-cell tumor (one of the rarest testicular neoplasms), adrenocortical rests, and Leydig-cell tumor.
• • These tumors appear with testicular masses, and about one third of affected male patients have them.
  • Large-cell calcifying Sertoli-cell tumors may also appear as bilateral masses. They can also secrete estrogens, resulting in precocious puberty, gynecomastia, or both.
• As many as 75% of patients with CNC may have multiple thyroid nodules.
• • The nodules can appear as a goiter or thyroid mass when palpated on physical examination.
  • Patients can also present with symptoms of hyperthyroidism or hypothyroidism.
• Psammomatous melanotic schwannoma most frequently occurs in the gastrointestinal tract (esophagus and stomach) and paraspinal sympathetic chain. Masses can be palpated on abdominal or paraspinal examination.

Causes

CNC is inherited as an autosomal dominant trait, and the genes responsible have been mapped to bands 2p16 and 17q22-24.

• Because the features of CNC, such as the paradoxical responses to endocrine signals, are similar to those of McCune-Albright syndrome and other conditions, the genes implicated in cyclic nucleotide-dependent signaling have been implicated.
• Kirschner and colleagues⁹ examined families with CNC.
• • They first detected a loss of heterozygosity (LOH) in the vicinity of the PRKAR1A gene that encoded the protein kinase A regulatory subunit 1-alpha (R1alpha), which was mapped to chromosome 17q.
  • They subsequently identified 3 unrelated kindreds with an identical mutation in the coding region of PRKAR1A.
  • An analysis of PRKAR1A activity demonstrated that basal activity is decreased and cAMP-stimulated activity is increased in CNC tumors compared with non-CNC tumors.
  • Kirschner et al concluded from these findings that germline mutations in PRKAR1A, an apparent tumor suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.
• Kirschner et al¹⁰ also screened the mutations present in 54 CNC kindreds.
• • In 14 of the mutations that were mapped to the PRKAR1A locus, they found a premature stop codon; one altered the initiator ATG codon.
  • The messenger RNAs (mRNAs) resulting from this mutation were unstable, and they rapidly decayed.
  • The PRKAR1A products were absent in the affected cells.
  • These studies were the first to show a disease with mutations in the protein kinase A holoenzymes, critical components of the signaling pathway.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Adrenal adenoma
Adrenal carcinoma
Rhabdomyomas
Intracardiac thrombus
Metastatic neoplasm to the heart
Breast adenoma
Breast carcinoma
Testicular adenoma
Testicular carcinoma

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• A 24-hour urinary cortisol excretion test and a dexamethasone stimulation test should be performed to evaluate for PPNAD.
• Plasma somatomedin C levels should be measured to evaluate possible growth hormone excess.
• Thyrotropin hormone levels should be obtained.
• Corticotropin hormone levels should be determined.

Imaging Studies

• Echocardiography should be performed to evaluate cardiac myxomas.
• Transesophageal echocardiography may be helpful.
• Testicular sonography can be used to assess large-cell calcifying Sertoli-cell tumor of the testes.
• Computed tomography or MRI may depict extrathoracic tumors.

Other Tests

• ECGs may reflect the presence of left atrial enlargement or pulmonary hypertension.
• Mutational analysis of the PRKAR1A gene may be a useful adjunctive diagnostic test, but such DNA-based testing currently remains the province of research laboratories.

Histologic Findings

Myxomas

In general, myxomas are globular, hard, and mottled lesions with hemorrhage. Histologically, they are composed of stellate or globular myxoma cells, endothelial cells, macrophages, mature or immature smooth muscle cells, and a variety of intermediate forms embedded in an abundant acid mucopolysaccharide ground substance.

Freckles

Freckles are small (1- to 10-mm), tan-red or light brown macules that first appear in early childhood after sun exposure. Once present, they fade and reappear in a cyclic fashion with winter and summer. The observed hyperpigmentation of the freckle is the result of increased amounts of melanin pigment in the basal keratinocytes. Melanocytes are relatively normal in number, although they may be slightly enlarged.

Lentigo

The term lentigo refers to a common benign hyperplasia of the melanocytes. Lentigo can occur in individuals of all ages, but often occurs in infants and children. Unlike freckles, lentigines do not darken when exposed to sunlight. The essential histologic feature of the lentigo is melanocytic hyperplasia that produces a hyperpigmented basal cell layer in the epidermis in a linear fashion. Elongation and thinning of the rete ridges are also common in a lentigo.

Blue nevi

Blue nevi are characterized by highly dendritic nevus cells (as opposed to the rounded cell typical of most melanocytic nevi) that are heavily pigmented. When these cells are in the middle-to-deep dermis, they are blue to gray-blue at clinical examination. Carney described an additional histopathologic variant of the blue nevus that is called an epithelioid blue nevus. It is a heavily pigmented dermal lesion composed of 2 types of melanocytes: One type is intensely pigmented, globular, and fusiform, whereas the other type is lightly pigmented and polygonal with large amounts of cytoplasm. Most patients with an epithelioid blue nevus have CNC. However, cases of epithelioid blue nevi are also reported in children and adults with no evidence of CNC.

Schwannomas

Schwannomas are typically solitary, circumscribed, and encapsulated tumors that are eccentrically located on the proximal nerves or spinal nerve roots. Microscopically, the tumors have regions of high and low cellularity called Antoni A and Antoni B areas, respectively. In the Antoni A tissue, foci of palisaded nuclei called Verocay bodies may be present, and the blood vessels in schwannomas often have hyaline thickening around them, indicating that pseudopalisading of the tumor nuclei may be present. Psammomatous melanotic schwannoma is a particular schwannoma in Carney syndrome that is distinctive because of its heavy melanotic pigmentation and calcification. Multicentricity also frequently occurs in this tumor.

Sertoli-cell tumors

Sertoli-cell tumors may be composed of entirely Sertoli cells, or they may have a component of granulosa cells. These neoplasms may appear as firm, small nodules or, rarely, as bulky masses that cause considerable testicular enlargement. On cross sections, the surface is homogeneously gray-white to yellow. On histologic examination, the cells in the classic form are distinctive and tall, columnar, or polyhedral, with abundant and usually vacuolated cytoplasm. The tendency for these cells to grow in cords that are highly reminiscent of spermatic tubules is distinctive.

Primary pigmented nodular adrenocortical tumors

PPNAD tumors are characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors are unclear. On gross examination, the surfaces show multiple small nodules, usually with a black-to-brown discoloration. In addition, the extranodular cortex is atrophic. On histologic examination, multiple nodules are observed deep in the cortex. The cells in these nodules stain positively with periodic acid-Schiff. Outside the cortex, intense disorganization is present without normal zonation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• In CNC, medical care is restricted to the treatment of the endocrine overactivity that is commonly present.
• See Acromegaly, Cushing Syndrome, Hyperparathyroidism, and Hyperprolactinemia for the treatment of these conditions.
• No medical treatment for myxomas exists.

Surgical Care

A primary cardiac tumor requires prompt surgical excision.

• Large or symptomatic skin myxomas can be excised.
• Other tumors (eg, schwannoma, Sertoli-cell tumors, parathyroid tumors, adrenal tumors) should be surgically treated, and adjuvant radiation therapy and/or chemotherapy should be administered if necessary.

Consultations

• Cardiologist
• Geneticist
• Cardiothoracic surgeon
• Endocrinologist
• Oncologist

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Monitor patients annually with echocardiography to detect new cardiac myxomas.
• Annual history taking and physical examination are also recommended to detect extracardiac myxomas, other tumors, and signs or symptoms of endocrine dysfunction.

In/Out Patient Meds

• The medical management of endocrine dysfunction is indicated.

Complications

• Stroke can be a complication.
• Recurrent myxomas are common in patients with CNC.
• The most common postoperative complication is atrial dysrhythmia.
• Atrial myxomas may create ball-valve obstructions that cause unexpected syncopal attacks, cardiac insufficiency, and sudden death in apparently healthy young children and adults.
• Cerebellar ischemic stroke can result from emboli from an atrial myxoma.
• Embolization to the brain, kidneys, and lungs can also occur.

Prognosis

• The prognosis largely depends on the success of the surgical procedure to remove the myxomas.
• The mortality rate is less than 2% during excisions of primary cardiac tumors.

Patient Education

• Educate patients about the genetics of this condition and the fact that the disease is inherited in an autosomal dominant pattern.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize endocrine dysfunction in a patient with CNC
• Failure to recognize other tumors associated with this disease
• Failure to recognize the potential for myxoma formation in family members of an individual affected by CNC

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  A pedunculated flesh-colored nodule that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.
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Media type:  Photo

Media file 2:  Polypoid neoplasm of fibrillary collagen and uniform stellate cells within abundant connective tissue mucin. Note telangiectasia and ramification of tumor as strands through a myxoid dermis (hematoxylin-eosin). Courtesy of Dermatology, NYU School of Medicine; photography by Anca Croitoru, MD, and Scott Sanders, MD.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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36. Moreno C, Requena L, Kutzner H, de la Cruz A, Jaqueti G, Yus ES. Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex. J Cutan Pathol. May 2000;27(5):218-23. [Medline].
37. Nwokoro NA, Korytkowski MT, Rose S, Gorin MB, Penles Stadler M, Witchel SF, et al. Spectrum of malignancy and premalignancy in Carney syndrome. Am J Med Genet. Dec 31 1997;73(4):369-77. [Medline].
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Article Last Updated: May 16, 2008