Carney Complex

Etiology

Approximately 25% of cases occur sporadically due to a de novo mutation. CNC was initially thought to be autosomal dominant, but genetic loci have been linked to Carney complex. CNC gene 1 is a germline mutation in a regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24 observed in about two-thirds of patients with CNC.[3][4] The second locus has been seen on chromosome 2p16, but no specific gene has been identified. Alterations in a locus at 2p16 have been reported in patients with PRKAR1A gene mutations.[5] Inactivating mutations of the phosphodiesterase genes PDE11A and, less commonly, PDE8B have been identified in patients with isolated micronodular pigmented adrenal disease or nonpigmented adrenal hyperplasia. These mutations result in premature stop codons or single-base substitutions in the catalytic domain of the encoded proteins, thereby contributing to the pathogenesis of Carney complex.[6]

Epidemiology

The exact prevalence of Carney complex is unknown. Around 750 cases from many ethnicities have been reported worldwide since 1985. The prevalence can be underestimated because the diagnosis is challenging, and the awareness of this rare and complex disorder is lacking in the medical community.[7]

Pathophysiology

The constellation of symptoms includes 4 major criteria:

1. Spotty skin pigmentation: Pigmented lentigines and blue nevi on the face, neck, and trunk, including the lips, conjunctivae, and sclera. Abnormal skin pigmentation may be present at birth, but lentigines develop during puberty.
2. Endocrine tumors: Primary pigmented nodular adrenocortical disease (PPNAD) is the most common endocrine finding in CNC. Less common findings include growth hormone-secreting pituitary adenomas, thyroid adenomas, and thyroid carcinomas.
3. Myxomas: These include cardiac myxomas (most significant), breast myxomatosis, osteochondromyxomas, and cutaneous and mucosal myxomas. 
4. Nonendocrine tumors: These include psammomatous melanotic schwannomas, breast ductal adenomas, testicular large cell calcifying Sertoli cells, and ovarian cysts.[8]

A definitive diagnosis of CNC requires 2 or more of these manifestations. Diagnosis may also be made if one of the above major criteria is present and a first-degree relative has CNC or an inactivating mutation of PRKAR1A. About 80% of patients with PPNAD show a variant in the PRKAR1A gene. Cardiac myxomas and psammomatous schwannomas are the most common causes of mortality. Cushing syndrome is the most common clinical syndrome present in about 25% of patients with CNC. This requires treatment due to the long-term deleterious effects of prolonged corticosteroid exposure.[7]

Histopathology

The skin biopsy is usually not performed for lentiginous pigmentation unless there is a suspicion of malignancy. Histologically, lentigines are characterized by the elongation of epidermal ridges, accompanied by increased pigmentation in the basal layer of the epidermis. Cutaneous myxomas exhibit a nonencapsulated proliferation of spindled or stellate dermal fibroblasts within a loose, mucinous stroma in the dermis, characterized by the presence of bizarre, multinucleated cells and regular mitotic figures.

Blue nevi characteristically demonstrate highly pigmented melanocytes in the superficial and reticular dermis. Large epithelioid cells with minimal pigmentation and abundant cytoplasm, arranged in nests within the dermis, are characteristic features of an epithelioid blue nevus. If PPNAD is present, the adrenal glands may be normal-sized or slightly enlarged, with numerous small micronodules that appear brown, black, or yellow in color. The nodules are generally 1 to 4 mm in size.[7] Heart myxoma can have a gelatinous or hemorrhagic appearance. They arise from subendocardial mesenchymal precursor cells.[9][10]

History and Physical

Endocrine Manifestations

Cushing syndrome and nodular primary pigmented adrenocortical disease

Cushing syndrome due to nodular PPNAD is more frequent in females and young adults. The incidence peaks during the second and third decades of life. Clinical signs are similar to those observed in patients presenting with other causes of increased cortisol levels. Furthermore, in patients with histological evidence for PPNAD, 60% to 70% of patients with CNC exhibit Cushing syndrome. The disease was named after the macroscopic appearance of the adrenal cortex, characterized by the small pigmented nodules less than 10 mm in diameter, most often surrounded by the atrophic cortex. The disease is bilateral, with primary involvement of both adrenal glands.[1] Case reports showed that adrenocortical carcinoma can also be seen in patients with CNC.[11][12][13][14]

Pituitary

Pituitary tumors typically involve the growth hormone-producing cells and can cause acromegaly. Acromegaly in CNC has a slow, progressive course and does not appear until the third decade of life. Clinical acromegaly is a rare condition, affecting approximately 10% to 15% of patients. About 75% of patients with CNC may have an asymptomatic elevation of insulin-like growth factor 1 and growth hormone.[15][16][17]

Thyroid

Thyroid nodules are relatively common in patients with CNC. Almost 75% of patients are found to have cystic or multinodular disease on ultrasound. Thyroid nodules are often follicular-type, benign, nontoxic adenomas. About 3% of patients will have thyroid cancer; it is most often papillary carcinoma that can be multiple and sometimes quite aggressive, indicating the need for chronic surveillance of the thyroid. Follicular carcinoma can also be seen.[18][19]

Gonadal tumors (testicular and ovarian lesions)

• Testicular tumors: The most common types are large-cell calcifying Sertoli cell tumors (LCCST), nodular adrenocortical rests, and Leydig cell tumors. Between 20% and 50% of patients with CNC will have at least 1 of the tumors. LCCST, a benign stromal tumor, is a very rare tumor; however, it occurs frequently in male patients with CNC. LCCST may be bilateral and multifocal in about 50% of patients. The tumors progress gradually with age, replacing the normal testicular tissue. LCCSTs can cause replacement and obstruction of seminiferous tubules, leading to reduced fertility in men. Malignant changes have rarely been described, particularly when the primary tumor exceeds 6 cm in diameter. Nodular adrenocortical rests and Leydig cell tumors are observed less frequently. These 3 types of tumors are frequently asymptomatic. However, precocious puberty or male feminization has rarely been reported. These masses are often asymptomatic and not palpable, but have been reported to have sperm abnormalities when associated with Carney complex.[20]
• Ovarian tumors: Carney complex can present as ovarian cysts and tumors of the ovarian surface epithelium, including serous cystadenomas and cystic teratomas. Ovarian lesions were described at autopsy in about 60% of the patients, which can occasionally progress to ovarian carcinoma (mucinous adenocarcinoma or endometrioid carcinoma) and is usually seen during the fifth decade of life.[10][21]

Non-Endocrine Manifestations

Cardiac myxomas

These are benign neoplasms with an equal distribution among all ages and genders. They are found in about 20% to 40% of patients with CNC. These myxomas can be located within any chamber of the heart, can be multiple, and require surgical removal. They can cause a stroke due to embolism and cardiac deficiency. However, they often recur despite seemingly adequate excision, thus rendering surgical cure problematic. These tumors are the most frequent cause of death in patients with CNC, either related to the tumors themselves, surgical complications occurring during removal, or embolic stroke. Cardiac myxomas may also be responsible for the high rate of sudden death reported in patients with CNC.[15][22][23]

Skin

The 3 most common skin manifestations occur frequently and are seen at a young age in patients with Carney complex. These are lentiginosis, blue nevi, and cutaneous myxoma. Lentiginosis is seen in about 50% to 80% of patients with CNC. Lentigines are typically flat, poorly circumscribed, brownish to black macules located around the lips, eyelids, ears, and genital area. They usually are small (<5 mm) and do not change with sun exposure. The density of pigmented spots can vary from a few lesions to profuse pigmentation. These can be present at birth and often appear during childhood and the prepubertal period. Lentigines usually do not acquire their typical intensity and distribution until early adolescence. CNC lentigines are challenging to distinguish from solar lentigines. However, in contrast to age-related skin lesions, CNC-associated lentigines tend to fade with age.[24][25]

Blue nevi are, after lentigines, the second most frequent skin lesions in patients with CNC. They are seen in about 40% of patients. They are bluish-black colored marks with an ovoid or star-shaped appearance, exhibiting variable distribution. Cutaneous myxoma is the third most common skin manifestation of CNC, reported in 20% to 55% of patients. They typically appear before the age of 18 and tend to recur. The lesions vary, ranging from asymptomatic to sessile, small (rarely exceeding 1 cm in diameter), opalescent, or dark pink papules, and can also include large, finger-like, pedunculated lesions.

They can occur anywhere but usually affect the eyelids, ears, nipples, external ear canal, trunk, and perineum. Myxoma is the most specific dermatological criterion for diagnosing CNC. These can be used for the early detection of the disease, thus preventing life-threatening complications of CNC related to heart myxomas and endocrine abnormalities.[26][27] Café-au-lait spots or other birthmarks (depigmented lesions) are also seen in Carney complex patients and are usually present at birth. The molecular causes underlying the formation of pigmented skin lesions in Carney complex are not fully understood.[27]

Breast lesions

Lesions include lobular or nodular myxomatosis, myxoid fibroadenomas, or ductal adenomas. They are often bilateral and occur in 20% of the female patients.[28][29][30]

Melanotic schwannoma

These are typically observed in 5% to 10% of patients and can be mistaken for malignant melanomas, which exhibit spindle cell morphology but display clinical characteristics of schwannomas. They usually present with frequent calcifications and multicentricity. They can be observed anywhere, but their most frequent site is the gastrointestinal tract (esophagus, stomach, and rectum) and the paraspinal sympathetic chain. Malignancy may be observed in 10% of the cases with frequent metastasis to the lung, liver, or brain.

Osteochondromyxoma

These are typically reported early in life, usually before the age of 2, when sporadic bone tumors are rare. Clinically, the tumors are painless masses found in distal long bones (diaphyseal) and small flat bones (nasal). Osteochondromyxomas are usually benign, but local invasiveness has also been seen. Some case reports have shown that giant cell tumors of the bones can also be associated with CNC. [31][32]

Other Lesions

Other lesions can be associated with CNC but are less frequent. Some of these are hepatocellular carcinoma, intraductal papillary mucinous tumor of the pancreas, and multiple fusiform myxomatous cerebral aneurysms.[10]

Evaluation

Once the diagnosis is made, the patient requires lifelong surveillance. A clinical workup for all manifestations of CNC should be conducted at least annually in all patients. These workups should start in infancy for some manifestations.[33]

Adrenal: Urinary cortisol usually increases, but can be variable. The dexamethasone suppression test fails to suppress cortisol secretion even after high doses of dexamethasone are administered. Most patients respond to dexamethasone with a contradictory rise in cortisol production. The dexamethasone suppression test may be used diagnostically to identify PPNAD, even in patients who have normal baseline cortisol levels and do not have clinical stigmata of Cushing syndrome. Plasma adrenocorticotropic hormone levels are usually low, and adrenal glands appear normal on computerized tomography scans in one-third of the patients, whereas the other patients present with micronodules (generally <6 mm) or, rarely, macronodules larger than 10 mm. Pathology reports typically indicate that the adrenal glands are normal in size and weight, and are characterized by black or brown nodules within the cortex, which is often atrophic.

Pituitary: Biochemical abnormalities of the growth hormone (GH) axis are present in up to 80% of the patients. These biochemical abnormalities develop before radiological evidence of a frank pituitary tumor. They may be secondary to hyperplasia of GH cells, as characterized by pathological examination of poorly delineated regions with increased cellularity. Most remaining patients exhibit abnormal responses to the oral glucose tolerance test, but have normal pituitary imaging. Follow-up on these patients should include magnetic resonance imaging and an oral glucose tolerance test. If a tumor develops, it is typically treated surgically. Conversely, if insulin-like growth factor 1 levels increase without a visible tumor, somatostatin analogs or GH receptor antagonist treatment may be used.

Thyroid: Around 75% of patients are found to have cystic or multinodular disease. An annual clinical examination, including thyroid ultrasonography, is recommended for postpubertal pediatric and adult patients. Fine-needle aspiration of thyroid nodules helps establish the diagnosis.

Gonadal: Sonographic evaluation of the testes and ovaries often shows microcalcifications and hypoechogenic lesions. Suspicious or large lesions should be monitored for possible malignancy, especially LCCST larger than 6 cm.

Cardiac myxoma: Early diagnosis of these tumors is important and should start within the first 6 months of life. Annual screening with an echocardiogram should follow. Patients with cardiac myxoma should be screened every 6 months. In difficult cases, transesophageal ultrasound and cardiac magnetic resonance imaging can be helpful.

Breast lesions: Although regular mammograms do not show clear evidence of improved mortality, breast magnetic resonance imaging is performed in patients with previously diagnosed lesions. Treatment and follow-up are not well standardized.

Treatment / Management

Cushing syndrome due to PPNAD must be treated to control the consequences of cortisol oversecretion. Bilateral adrenalectomy is the most common treatment, although, under certain circumstances, ketoconazole or mitotane have been used as anti-cortisol treatment.

• Fine-needle aspiration is indicated for patients with thyroid nodules. Patients with lesions suspicious of malignancy should be referred for surgery.
• Few patients with CNC and acromegaly have an aggressively growing tumor that will require surgery with possible radiation treatment. Treatment of acromegaly with somatostatin analogs may also be used either as a primary treatment or as an adjuvant to transsphenoidal surgery.
• LCCSCTs, especially when bilateral, are benign and require imaging surveillance alone. If measures of tumor markers or imaging features indicate a suspicion of malignancy, then testicle-sparing surgery may be considered for small tumors to allow for histopathologic examination. There are a few reports of prepubertal boys with LCCSCT treated with aromatase inhibitors.
• Malignant LCCSCTs typically occur in older patients and those with unilateral and unifocal disease. Orchiectomy is the treatment of choice for malignant LCCSCTs.
• Surgical resection is the treatment of choice for cardiac myxomas. They often recur in affected patients, so follow-up monitoring is required.
• Psammomatous melanotic schwannomas are treated with complete surgical resection with tumor-free margins. Chemotherapy and radiation therapy may be required for malignant tumors.

Differential Diagnosis

The differential diagnosis included Cushing disease, adrenal carcinoma, adrenal incidentaloma, breast cancer, intracardiac thrombus, lentigo, melanotic nevi, primary cardiac neoplasms, and rhabdomyoma.

Prognosis

The most significant risk of mortality in CNC is associated with cardiac disease (57%), specifically cardiac myxomas and complications of cardiac surgery. Other significant causes of mortality include metastatic or intracranial psammomatous melanotic schwannoma (14%), carcinoma or metastatic tumor (14%), and noncardiac postoperative complications (12%).

Complications

The most significant complication of CNC is the mortality associated with cardiac myxomas, psammomatous melanotic schwannoma, carcinomas, or metastatic disease. These are especially common when part of the multiple endocrine neoplasia syndrome. Treatment often involves adrenalectomy, leaving patients with lifelong dependence on exogenous steroid replacement and the risks of hypocortisolism.