Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up

Abstract

Introduction Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. Methods This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. Results The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. Conclusion This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

Predicting the risk of cardiac myxoma in Carney complex

“…They are the leading cause of death in patients with CNC 3 , 17 , 18 . In our population, 42.6% of the patients with CNC developed a cardiac tumor, which is a higher number than what has previously been reported 3 , 4 , 19 .…”

“…Thyroid involvement in CNC patients has been described before 4 , 6 , 19 , 21 , 22 as a feature of the syndrome, ranging from benign lesions (i.e. follicular/nodular hyperplasia) to carcinoma 21 , 22 What is interesting in our findings is that thyroid gland manifestations occurred in 8.1% of CNC patients without cardiac myxoma versus 25.7% of CNC patients with cardiac myxoma (p=0.001).…”

MANAGEMENT OF ENDOCRINE DISEASE: Carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene

“…Frequencies of the major clinical features met in CNC are summarized in Table 2. We focused on three different series of CNC patients: the original retrospective series described by Carney et al in 1985 (2), the largest retrospective series investigating retrospectively patients that were all genotyped at the NIH or Cochin Hospital published in 2009 (7), and the only prospective series of CNC patients to date, conducted at the national level in France and recently published (8).…”

“…Cardiac myxomas are benign tumours characterized by stellate mesenchymal cells in a myxoid stroma. With a penetrance of 20 to 40% of patients (7,8), they are not the most frequent feature diagnosed in CNC patients, but their diagnosis is crucial because of its high morbidity and lethality. In CNC, cardiac myxomas can arise in any cardiac cavity, are often multiple and/or recurrent (31,32) and occur at a median age of 50 (7); on the contrary, isolated cardiac myxomas grow much later in life, classically in the sixth or seventh decade, mostly in left atria, and are generally unique, recurrence being exceptional (33).…”

“…The largest international series reports 353 patients (7), and a recent national prospective study reports on 70 patients (8). In its initial description of CNC, Dr Carney speculated that the disease could be an autosomal dominantly inherited disorder (2).…”