Clinical case

A 33-year-old woman with a history of high blood pressure since she was 8 years old, hypothyroidism, polycystic ovary syndrome, metabolic syndrome, multiple nevi, and a maternal family history of death at age 50 due to malignant high blood pressure and a possible Cushing Syndrome (CS). Also, char acteristically she presented multiple nevi on the face and back, and a blue nevus. The patient was medicated with valsartan, metformin, levothyroxine, lercanidipine and atorvastatin.

Renal artery stenosis and aortic coarctation were ruled out by doppler. A transthoracic echocardiogram was performed, which showed preserved left ventricular diameters, thickness and function, and the presence of a rounded mass of 15 mm in diameter in the left atrium. Transesophageal echocardiography was made, and it confirmed the presence of this heteroge neous mass with irregular borders and independent mobility (a rounded portion of 17 × 22 × 13 mm and a filiform mobile portion of 16 mm in length), inserted in the septal face of the left atrium, compatible with AM (Fig. 1A y 1B).

Fig. 1 Atrial myxoma (AM) and pituitary microadenoma in the patient with Carney Complex. AM sited in the left atrium, assessed by bi-dimensional TEE in apical 5C view in 1A image and by three-dimensional TEE in mid-esophageal 0° 4C view in 1B image (the insertion site in green arrows, the rounded portion in yellow arrows, and the filiform mobile portion in red arrows). Pituitary microadenoma evaluated by brain magnetic resonance imaging in 1C (blue arrow). Resected AM in 1D (the insertion site in green arrows, the rounded portion in yellow arrows, and the filiform mobile portion in red arrows). 

The study of hypertension was completed by serum labo ratory examination, which showed cortisol 1267 ug/dL (high value), adrenocorticotrophin 44 pg/ml (high value). Thyrotro phin, insulin, triglycerides, HDL-c, LDL-c, urinary ions and metanephrines were normal. The diagnosis of CS was made due to the presence of compatible clinical manifestations and serum laboratory alterations. A brain magnetic resonance de tected a posterior pituitary microadenoma of 6 mm diameter (ruling out embolic events associated with AM) (Fig. 1C). Adrenal glands were normal in abdomen magnetic resonance. A gynecologic ultrasound revealed benign ovarian cysts. In the presence of AM, polycystic ovary syndrome and CS due to hypersecretory pituitary microadenoma, with a family his tory of malignant hypertension, a diagnosis of CC was made according to the Stratakis criteria (Table 1).

Table 1 Diagnostic criteria for Carney complex (CC) 

Given the high embolic risk of AM, it was decided to perform surgery as soon as possible. Coronary and carotid atherosclerotic obstructions were ruled out by Doppler ul trasound and coronary tomography. AM resection without a patch was performed. It required dobutamine 5 mg/kg/min and nitroglycerin 10 μg/min in the postoperative period, without complications. Pathological anatomy confirmed that it was an AM (Figure 1D). The PRKAR1A gene mutation by next gen eration deoxyribonucleic acid sequencing techniques (Illumina technology) was negative. It was evaluated in a peripheral blood sample, and then corroborated by Sanger technique and in an external database. However, CC diagnosis was still confirmed by clinical Stratakis criteria.

The patient evolved clinically stable in outpatient controls during 6 months of follow up, and her blood pressure was controlled with valsartan 160 mg and lercanidipine 10 mg daily. Surgical resection of pituitary microadenoma will be performed as a curative treatment for CS and secondary hypertension.

Discussion

AM are the most frequent benign CT in adults, usually sporadic, but sometimes they can be associated with endocrine disorders as part of CC^1-3. CC was described in 1985 as a rare disease characterized by the presence of AM, skin hyperpigmentation, and endocrine hyperactiv ity^2-4. The Mayo Clinic series reported 353 CC patients, 63% females, aged between the second and third de cade of life. The presence of inactivating mutations of the PRKAR1A gene was detected in 73% of cases⁵. The reported patient is a young woman that present an AM, CS, skin hyperpigmentation with atypical distribution and a history of malignant secondary hypertension, so the suspicion of CC was high. CC can be inherited with an autosomal dominant pattern, and the PRKAR1A gene is the most frequently compromised, although this is not the only one affected^2-7. PRKAR1A gene encodes the 1-al pha regulatory subunit of protein kinase A, related to the signaling pathway of the cAMP, and it is responsible for tumorigenesis in CC^4-7. PRKACA and PRKACB genes ac tivating mutations have also been related with CC, the first is associated with CS and the second with acromegaly, that could be altered in our patient⁶. Diagnosis of CC is made according to the Stratakis criteria (Table 1), with the presentation of two typical manifestations confirmed by histology, laboratory or imaging tests, or with detection of the inactivating mutation of the PRKAR1A gene⁴. The main cardiovascular manifestation of CC is AM that could be responsible for more than 50% of mortality because of embolic phenomena, heart failure or valvular occlu sion, therefore surgical treatment of AM is mandatory^2-4. The most frequent cutaneous manifestations are blue lentigines and nevi around lips, conjunctiva and oral and genital mucosa. Our patient had multiple nevi and a blue nevus without classical distribution in her face^2-4. The most prevalent endocrinological manifestations are acromegaly, benign thyroid tumors and CS, this last present in this case, due to an hypersecretory pituitary microadenoma^2-4. Ovarian cysts are generally benign, usually polycystic ovary as in the reported case, and the ovarian adenocarcinoma is exceptional^2-4,8-10. Although genetic study is not a necessary criterion for diagnosis, and in fact the PRKAR1A gene mutation was negative in the presented case, genetic screening must be performed in all index cases in order to allow family diagnosis^2-4. CC requires a close follow-up due to the risk of tumor recurrence^2-4. The association of AM and endocrinological disorders should lead to suspicion of the diagnosis of CC and require an interdisciplinary management for an early treatment of its manifestations.