Carney complex (CNC) is a rare genetic disorder associated with one of the multiple endocrine neoplasia syndromes. Carney complex affects multiple glands in the body such as such as thyroid, pituitary, and adrenal glands. Carney complex is also known to cause cardiac myxomas, abnormal pigmentation or myxomas of the skin, breast myxomatosis, melanotic schwannoma, and testicular tumors.
Approximately 25% of cases occur sporadically, as a result of a de novo mutation. Carney complex initially was thought to be autosomal dominant, but recently two 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 CNC patients.
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.
Inactivating mutations of phosphodiesterase genes PDE11A and more rarely PDE8B have also been observed in patients with isolated micronodular pigmented (PPNAD) or non-pigmented hyperplasia. These mutations result in premature stop codon generation or single-base substitutions in the catalytic domain of the protein resulting in Carney complex.
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 insufficient among the medical community.
The skin biopsy is usually not performed for lentiginous pigmentation unless there is a suspicion of malignancy. Histologically, lentigines are characterized by elongation of epidermal ridges with increased pigmentation of the basal layer.
Cutaneous myxomas demonstrate a non-encapsulated proliferation of spindled or stellate dermal fibroblasts in a loose, mucinous stroma in the dermis. Bizarre multinucleated cells and regular mitotic figures can be seen.
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 in the dermis are features suggestive of epithelioid blue nevus.
History and Physical
Cushing Syndrome and Nodular Primary Pigmented Adrenocortical Disease (PPNAD)
Cushing syndrome due to PPNAD is more frequent in females and young adults. The incidence peaks during the second and third decade of life. Clinical signs are similar to those observed in patients presenting with other causes of increased cortisol levels.
Primary pigmented adrenocortical disease (PPNAD): ACTH-independent Cushing syndrome. In patients with histological evidence for PPNAD, only 60% to 70% of patients with Carney complex exhibit Cushing syndrome. The disease was named after the macroscopic appearance of the adrenal cortex that is characterized by the small-pigmented nodules less than 10 mm in their greatest diameter most often surrounded by the atrophic cortex. The disease is bilateral with primary involvement of both adrenals.
Pituitary tumors typically involve the growth hormone-producing cells and cause acromegaly. Acromegaly in Carney complex has a slow, progressive course. It does not appear until the third decade of life. Clinical acromegaly is uncommon, is seen in approximately 10% to 15% of patients.
Thyroid nodules are fairly common in patients with Carney complex. 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 the patients 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.
Gonadal Tumors (Testicular and Ovarian Lesions)
Testicular tumors: Large-cell calcifying Sertoli cell tumor (LCCST), nodular adrenocortical rests, and Leydig cell tumors are the most common types. Twenty percent to 50% of Carney patients have at least one of the tumors. LCCST, a benign stromal tumor, is among the rarest of lesion tumor whereas it frequently occurs in male patients with Carney complex. LCCST may be bilateral and multifocal in about 50% of the patients. They progress gradually with age to replace the normal testicular tissue. As they can cause replacement and obstruction of seminiferous tubules, they can be the cause of reduced fertility observed in men with Carney complex. Malignant changes have rarely been described particularly when the primary tumor is large, above 6-cm diameter. Nodular adrenocortical rests and Leydig cell tumors are observed less frequently. These 3 types of tumor are frequently asymptomatic. However, precocious puberty or male feminization have rarely been reported. These masses are often asymptomatic and not palpable but have been reported to have sperm abnormalities in Carney complex.
Ovarian tumors: Carney complex presents 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 may progress occasionally to ovarian carcinoma (mucinous adenocarcinoma or endometrioid carcinoma) and is usually seen during their fifth decade of life.
Benign neoplasm with equal distribution among all ages and genders. They are found in about 20% to 40% of Carney complex patients. Carney complex-associated myxomas can be located within any chamber of the heart and can be multiple and require surgical removal. They can be the cause of stroke due to embolism and cardiac deficiency. However, they can recur despite seemingly adequate excision, thus rendering surgical cure problematic. These tumors are the most frequent cause of death in Carney complex patients, either related to the tumors themselves or to surgical complications that occur during or after their removal. It is likely the cause of the high rate of sudden death reported in Carney complex patients.
Three most common skin manifestations are very frequent and are seen early in patients with Carney complex.
Lentiginosis is seen in about 50% to 80% of patients with Carney complex. Lentiginosis are typically flat, poorly circumscribed, brownish to black macules located around the lips, eyelids, ears, and the genital area. They usually are small (less than 5 mm) and do not change with sun exposure. The density of pigmented spots can vary from a few lesions to profuse pigmentation. It may be observed at birth in some cases and often appears during childhood and the prepubertal period. Lentigines usually do not acquire their typical intensity and distribution until the early adolescent period. Carney complex lentigines are difficult to distinguish from solar lentigines. However, in contrast to the age-related skin lesions, Carney complex-associated lentigines tend to fade as one age.
Blue nevi are, after lentigines, the second most frequent skin lesions in patients with Carney complex as they are seen in about 40% of patients. They are bluish-black-colored marks with an ovoid or star-shaped appearance with their distribution being variable.
Cutaneous myxoma, the third most common skin manifestation of Carney complex is reported in 20% to 55% of patients. They typically appear before the age of 18 years and tend to recur. The lesions vary between asymptomatic, sessile, small (rarely exceeding 1 cm in diameter), opalescent or dark pink papules and 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 Carney complex diagnosis. They can be used for the early detection of the disease and, thus, the prevention of life-threatening complications of Carney complex related to heart myxomas and endocrine abnormalities.
Café-au-lait spots or other birthmarks (depigmented lesions) are also seen in Carney complex patients and are usually present at birth. To date, the molecular causes underlying the formation of pigmented skin lesions in Carney complex are not fully understood.
Lesions include lobular or nodular myxomatosis, myxoid fibroadenomas or ductal adenomas. They are often bilateral and occur in 20% of the female patients.
Usually seen 5% to 10% of patients and can be mistaken for malignant melanomas which demonstrate spindle cell morphology but exhibit 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.
They have reported occurring early in life, usually before the age of two when sporadic bone tumors are rare. Clinically, the tumors are painless masses that occurred in distal long bones (diaphyseal) and small flat bones (nasal). Osteochondromyxoma is usually benign, but local invasiveness has also been seen.
Other lesions can be associated with Carney complex but are less frequent as hepatocellular carcinoma, an intra-ductal papillary mucinous tumor of the pancreas or multiple fusiform myxomatous cerebral aneurysms.
CLinicians make a diagnosis when there are 2 or more cardinal manifestations confirmed by histology, biochemical testing, or imaging. If the patient has a demonstrated germline PRKAR1A mutation and/or a first-degree relative affected by Carney complex, a single manifestation is sufficient for the diagnosis. Once the diagnosis is demonstrated, the patient will require life-long surveillance. Clinical work-up for all the manifestations of Carney complex should be done at a minimum of once a year in all patients. These work-ups should start in infancy for some manifestations
Adrenal: Urinary cortisol is usually increased in but can be variable in most patients. Dexamethasone suppression test fails to suppress cortisol secretion even after high doses. Most patients respond to dexamethasone with a contradictory rise of cortisol production. Dexamethasone suppression test may be used diagnostically for the identification of PPNAD, even in patients that have normal baseline cortisol levels and do not have clinical stigmata of Cushing syndrome. Plasma ACTH levels are usually low, and adrenals appear normal on CT-scan in 1 out of 3 of the patients whereas the other patients present with micro-nodules (usually less than 6 mm) or more rarely macro-nodules larger than 10 mm. Path reports usually show that the adrenal glands are being normal in size and weight and are peppered with black or brown nodules set in a cortex which is often atrophic.
Pituitary: Biochemical abnormalities of the GH axis as alterations in the rhythm of GH secretion may be higher if carefully screened, up to 80% of the patients. These biochemical abnormalities develop before radiological evidence of a frank pituitary tumor and might be secondary to hyperplasia of GH cells, characterized by the pathological examination by poorly delineated regions with increased cellularity. Most remaining patients have abnormal responses to oral glucose tolerant test but normal IGF-1 (insulin-like growth factor 1) and normal pituitary imaging. Follow-up on these patients can with magnetic resonance imaging and oral glucose tolerance test. If a tumor develops, it is treated surgically, whereas if IGF-1 levels increase without a visible tumor, somatostatin analogs or GH receptor antagonist treatment can be discussed.
Thyroid: Usually around 75% of patients are found to have a cystic or multinodular disease. In post-pubertal pediatric and adult patients, an annual clinical examination is recommended with a thyroid ultrasound. Fine needle investigation of the thyroid nodule helps with the diagnosis.
Gonadal: Sonographic evaluation of testis and ovaries shows micro-calcifications and hypo-echogenic lesions.
Cardiac myxoma: Early diagnosis of these tumors is important and should start within the first 6-months of life. Annual screening with cardiac ultrasound 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: Regular mammograms showed no clear evidence, but breast magnetic resonance imaging was performed in patients who had previous lesions diagnosed. Treatment and follow-up are not well standardized.
Treatment / Management
Cushing syndrome due to PPNAD must be treated to control the consequences of cortisol over-secretion. Bilateral adrenalectomy is the most common treatment although, under certain circumstances, ketoconazole or mitotane has been used as anti-cortisol treatment.
Fine needle aspiration is indicated for patients with thyroid nodules. Patients with lesions suspicious for malignancy should be referred for surgery.
Few Carney patients with acromegaly have an aggressively growing tumor that will require surgery followed or not with irradiation treatment. Treatment of acromegaly with somatostatin analogs may also be used either as a primary treatment or as an adjuvant to trans-sphenoidal surgery.
Large cell calcifying Sertoli cell tumors (LCCSCTs), especially when bilateral, are benign and require imaging surveillance alone. If measures of tumor markers or imaging features indicate a suspicion for malignancy, then testicle-sparing surgery may be considered for small tumors to allow for histopathologic examination. There are a few reports of pre-pubertal boys with LCCSCT treated with aromatase inhibitors
Malignant LCCSCTs usually occur in older patients and in those who have the unilateral and unifocal disease. Orchiectomy is the treatment of choice for malignant LCCSCTs.
Cardiac myxoma: Surgical resection is the treatment of choice for cardiac myxomas. They may recur in affected patients; 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
Genetic testing for mutations in the protein kinase A type I-alpha regulatory subunit (PRKAR1A) is indicated for other potentially affected family members of patients with Carney complex. However, clinical surveillance is advisable for at-risk family members even when a PRKAR1A pathogenic variant is not identified.
When neither parent of an individual with Carney complex has the pathogenic gene variant or any clinical features of Carney complex, the affected patient has likely a de novo mutation.
The greatest risk of mortality in Carney complex is associated with cardiac disease (57%), specifically cardiac myxomas and complications of cardiac surgery. Other major causes of mortality include metastatic or intracranial psammomatous melanotic schwannoma (14%), carcinoma or metastatic tumor (14%), and non-cardiac postoperative complications (12%)
Pearls and Other Issues
Counseling regarding the potential risks for the offspring should be offered to adults and children before childbearing age with or at risk for Carney complex. The availability of prenatal and preimplantation genetic diagnosis should also be discussed.