Familial Recurrent Atrial Myxoma: Carney's Complex

Abstract

We report on a family of 4 members, all of whom have had multifocal, recurrent atrial myxomas associated with skin pigmentation, melanotic schwannomas, mucocutaneous myxomas, and tumors of the ovary and pituitary, adrenal, and thyroid glands. Immunochemistry of the myxoma cells is positive for calretinin, confirming their neuroendocrine origin. Genetic studies confirmed mutations in the gene coding protein kinase A, regulatory subunit 1‐α (PRKAR1α). This is Carney's complex, characterized by multiple, mucocutaneous myxomas; pigmented lesions over the lips, conjunctiva, and genitalia; adenomas of the breast and thyroid; schwannomas; and endocrinal abnormalities including Cushing syndrome and acromegaly. Members of the family require vigorous screening, including urinary free cortisol, plasma transforming growth factor‐β ₁ and thyrotropin‐releasing hormone, testicular ultrasound, routine echocardiographic screening, searches for cardiac and mucocutaneous myxomas in multiple locations, and genetic studies for the PRKAR1α gene sequence. Copyright © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Family History

Of Croatian ancestry, M.S. is a white female age 38 years who presented with recurrent episodes of visual disturbances in the right eye. The patient had episodes of amaurosis fugax1 and flashing lights2 in her left eye associated with firework‐type3 scotomas and electrical squiggles in her left eye. She exhibited constitutional symptoms4 of palpitation, headache, anxiety, decreased exercise tolerance, and a choking sensation5 in her neck. Her private cardiologist ordered transthoracic echocardiography6 (Figures 1, 2), transesophageal echocardiography,7., 8., 9. and T2‐weighted10., 11. gadolinium‐enhanced9., 12. magnetic resonance imaging (MRI).13., 14., 15. (Figure 3). Relevant past history includes a right cilioretinal artery occlusion (central retinal artery) and resection of the left atrial myxoma in 2003.16., 17. She had a melanotic schwannoma18 dissected from her left fifth metacarpal bone in 1999 and pigmented nevi removed from her back. Ganglion cysts were removed from both feet and ankles in 2000 and a cyst was removed from the right side of her neck in 2002. A physical examination revealed a tall, white female with no evidence of skin pigmentation; a cardiac examination did not reveal any murmurs. Previous genetic testing19., 20., 21. was positive for a mutation of the protein kinase A, regulatory subunit 1‐α (PRKAR1α) gene.

Figure 1.

Echocardiographic image of left atrial myxoma.

Figure 2.

Echocardiographic image of right and left atrial myxoma.

Figure 3.

Gadolinium‐enhanced MRI image. Abbreviations: MRI, magnetic resonance imaging.

Her father emigrated from Croatia and died of a bleeding aneurysm at age 63. Her mother was of German origin and died of a malignant melanoma at age 45. Her eldest sister had an atrial myxoma removed and is currently healthy. Her second‐eldest sister had a pituitary tumor, tumors of the ovary, melanoma, and an atrial myxoma, and died at the age of 27. Her younger brother, who currently is 22, had liver carcinoma, a pituitary tumor, and an atrial myxoma.

After initial evaluation, the patient underwent open heart surgery in 2010.22 This revealed a left atrial myxoma3 of 2.5 cm attached to the fossa ovalis and posterior left atrial wall, and a right atrial myxoma of 4 cm. After resection of both the right and left atrial myxomas,23 both the atrial walls and the interatrial septum were reconstructed24 with bovine pericardial patches. The postoperative course25 was uneventful and the patient currently is doing well.

Discussion

Great credit should be given to Dr. J. Aidan Carney, who in 1985 described multiple familial myxomas, spotty pigmentation, and endocrine overactivity.26 Previously, these conditions were known as the nevi, atrial myxoma, myxoid neurofibroma, and ephelides (NAME),27 and the lentigines, atrial myxoma, and blue nevi (LAMB) syndromes.28

Cardiac myxomas are the most common cardiac tumor,29 accounting for 90% of the surgical series and 50% of the medical series.30 Two‐thirds of the patients are females, and 75% of myxomas31 occur in the left atrium in the region of the limbus32 of the fossa ovalis. Approximately 15% –20% occur in the right atrium. Ninety percent of myxomas are solitary. Familial myxomas constitute 10% of all myxomas and are likely to have multiple and atypical locations17 and recur after surgery. Histologically, myxomas contain polygonal33 cells and are multipotential mesenchymal cells34., 35. that are found in the subendocardium, especially in the atria and atrial septum. These cells are cytokeratin‐negative and vimentin‐positive markers34 for endothelial cells. It is suggested that they are neuroendocrine36 in origin based upon positivity with neuroendocrine markers. These cells are able to differentiate into fibroblasts, smooth‐muscle cells, endothelial cells,37 and neuroendocrine38 cells. They are also known to elaborate the acid mucopolysaccharide33 matrix. Figure 4 shows myxoma cells as dark clusters4 with a pale myxoid. Figure 5 shows calretinin‐positive cells of neuroendocrinal origin.

Figure 4.

H&E histology of myxoma cells. Abbreviations: H&E: Hematoxylin and eosin.

Figure 5.

Immunochemistry of calretinin‐positive myxoma cells.

Carney's Complex

Carney's complex is a novel neuroendocrine‐cardiac syndrome characterized by: (1) familial recurrent myxomas; (2) pigmented skin lesions, schwannomas, and multiple recurrent mucocutaneous myxomas; and (3) various endocrinal overactivity and neoplasms.

One‐third of the patients with this syndrome have a mucocutaneous myxomas at presentation, with classic sites being the eyelid, external ear canal, breast, and oropharynx. Sixty‐seven percent of these patients have cardiac tumors, and 75% have various skin pigmentations, including blue nevi,27., 39. caféau lait28 spots, and depigmented40 legions. Lentigines (macular melanosis) develop early in the prepubertal period, and typically involve lips, conjunctiva, inner or outer canthi, and vaginal and penile mucosa. Endocrine abnormalities include nodular adenocortical tumors, growth hormones, prolactin‐producing adenomas, and large cell calcifying Sertoli cell tumors.

Carney's complex demonstrates autosomal dominant transmission with incomplete penetrance. Linkage studies have revealed genetic foci34., 37. at 2p1641., 42. and 17q22–24.19., 43. Among the families mapping to 17q, mutations in the gene encoding PRKAR1α have been identified.20 Immunochemistry44 has revealed positivity in vimentin, indicative of mesenchymal origin, as well as several neuroendocrine markers, including S‐100 and calretinin.33., 45. Cardiac tumors recur35 in 22% of patients, and account for more than 50% of deaths.40

Patients with established Carney's complex require vigorous screening,46 measurements of urinary‐free cortisol, testicular ultrasound, and careful search of cardiac myxomas in multiple locations. Routine echocardiography47 screenings of the first‐degree relatives are appropriate in searching for familial myxomas.

Diagnostic Criteria for Carney Complex

Clinical Criteria:

• 1.Spotty skin pigmentation with typical distribution (lips, conjunctiva, and inner or outer canthi, vaginal and penile mucosa);
• 2.Myxoma (cutaneous and mucosal);
• 3.Cardiac myxoma;
• 4.Breast myxomatosis or fat‐suppressed MRI findings suggestive of this diagnosis;
• 5.Primary pigmented nodular adrenocortical disease or paradoxical positive response of urinary glucocorticosteroids to dexamethasone administration during the Liddle test;
• 6.Acromegaly due to growth hormone–producing adenoma;
• 7.Large cell calcifying Sertoli cell tumors or characteristic calcification on testicular ultrasonography;
• 8.Thyroid carcinoma or multiple, hyperechoic nodules on thyroid ultrasonography, in a young patient;
• 9.Psammomatous melanotic schwannoma;
• 10.Blue nevus, epithelioid blue nevus (multiple);
• 11.Breast ductal adenoma (multiple);
• 12.Osteochondromyxoma.

Supplemental Genetic Criteria:

• 1.Affected first‐degree relative;
• 2.Inactivating mutation of the PRKAR1α gene.