Carney complex (ORPHA:1359)
A rare endocrine disease characterized by lentigines with a specific peri-orifical distribution, blue nevus, myxomas, various endocrine tumors including primary pigmented nodular adrenocortical disease (PPNAD), acromegaly, thyroid tumors, and a wide range of other tumors.
Epidemiology
Carney complex (CNC) is a rare disease with more than 750 cases reported in the scientific and medical literature.
Clinical description
Lentigines with a specific peri-orifical distribution, blue nevus (particularly epithelioid blue nevus), and cutaneous myxomas, with a classical distribution in the eyelids, nipples, external ear canal or genitalia, are frequent and very suggestive of the diagnosis. The most common endocrine gland manifestations are of Cushing syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD), large cell calcifying Sertoli cell tumors, thyroid tumors, and acromegaly. Myxomas can also be observed in the heart and breast. Cardiac myxomas are diagnosed at a median age of 50 but may occur in early childhood, can develop in any cardiac chamber, and may be multiple and/or recurrent.
Etiology
In more than 70% of cases, CNC is related to mutations of the PRKAR1A gene coding for regulatory subunit R1alpha of protein kinase A. The mutation c.709-7del6 is mostly associated with isolated PPNAD, and the mutation c.491-492del is associated with more frequent cardiac myxomas, lentigines and thyroid tumors. Deleterious PDE11A variants have been described in patients with PRKAR1A mutations, with more frequent PPNAD and testicular tumors. A germline triplication mutation involving PRKACB, the gene encoding the catalytic subunit beta of the protein kinase A, has been described in a young woman with acromegaly, lentigines and myxomas who did not harbor a PRKAR1A mutation.
Diagnostic methods
Diagnosis is made if two major features are present (e.g. peri-orifical lentigines, myxomas, PPNAD), or one major feature with a supplementary criterion such as a PRKAR1A mutation or an affected first-degree relative. Patients with CNC, or with a genetic predisposition to CNC, should have regular screening for manifestations of the disease. Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy.
Differential diagnosis
The heterogeneity of the manifestations of CNC implies that differential diagnosis should be discussed for each of its numerous manifestations: i.e. differential diagnosis of PPNAD can be the others causes of adrenal Cushing syndrome; PPNAD can be isolated without others manifestations of CNC and no genetic variant of PRKAR1A, or be part of a classic CNC associated with another main feature like lentiginosis and/or myxoma.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in one of the 2 parents.
Genetic counseling
About 70% of the cases are familial with an autosomal dominant transmission. Genetic analysis should be proposed to all patients with CNC. In a second step, a genome-wide study may be discussed. Genetic counseling should be proposed in families with a known disease-causing mutation.
Management and treatment
Cardiac myxomas require surgical removal. Treatment of the other manifestations of CNC should be discussed and may include follow-up, surgery, or medical treatment depending on the location of the tumor, it's size, existence of hormonal excess or volume-related clinical signs, and the suspicion of malignancy. Bilateral adrenalectomy is the most common treatment for CS due to PPNAD.
Prognosis
Cardiac myxoma complications and other tumors development can greatly impact the lifespan of CNC patients.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Pr Jérôme BERTHERAT | Endo-ERN*


                                * European Reference Network