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.
Cushing Syndrome and Nodular Primary Pigmented Adrenocortical Disease (PPNAD)
Gonadal Tumors (Testicular and Ovarian Lesions)
Three most common skin manifestations are very frequent and are seen early in patients with Carney complex.
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
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.
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%)
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.
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