Clinical-hormonal-radiological and genetic characterization of patients with Primary Pigmentary Nodular Adrenocortical Disease (PPNAD) associated or not with Carney Complex

Abstract

Primary Bilateral Pigmented Nodular Adrenocortical Disease can be classified into Isolated Adrenocortical Micronodular Disease (i-MAD) and Primary Pigmented Nodular Adrenocortical Disease (PPNAD). PPNAD may or may not be associated with Carney Complex (CNC), a hereditary syndrome, with autosomal dominant inheritance and variable penetrance, composed of multiple neoplasms, such as benign and malignant, endocrine and non-endocrine tumors (cardiac, cutaneous and neural). PPNAD is the most common endocrine neoplasia occurring in more than 60% of patients. The diagnosis of CNC is based on clinical and/or molecular criteria. The most frequent genetic cause is the presence of germline pathogenic variants of the protein kinase A regulatory subunit 1± tumor suppressor gene (PRKAR1A). However, other rare germline variants have already been associated with CNC involving the following genes PDE11A, PDE8. From a somatic point of view, variants were identified in the PDE8 genes and in the CTNNB1 gene, which may have some role in modulating the phenotype of these patients. Usually, the clinical presentation of index cases is severe Cushing's Syndrome (CS), however, among family members, there is clinical variability in cortisol secretion and, consequently, in their clinical presentation. To date, more than 130 different pathogenic allelic variants in the PRKAR1A gene have been described in patients with CNC. Surgical treatment is directly related to the severity of hypercortisolism. For patients with periodic dyshormonogenesis and subclinical hypercortisolism, treatment is still challenging. For patients with PPNAD and classic SC, bilateral adrenalectomy is the treatment of choice, and unilateral adrenalectomy has been proposed when there is asymmetry between the glands, in an attempt to delay as much as possible permanent adrenal insufficiency due to adrenalectomy for adult patients. According to the clinical characteristics presented by the patients, we propose to investigate the genotype phenotype correlation of the following genes that may be involved in the molecular pathogenesis of the disease: PRKAR1A, PDE11A, PDE8, ARMC5, ARMC5, CTNNB1, in addition to the protein expression of PRKAC±, PRKAC² . The following methodologies will be used: customized panel of target genes, exome, MLPA and paraffin-embedded immunohistochemistry. With this study, we hope to establish the influence of pathogenic variants of the genes evaluated on the biological behavior of the disease in our cohort of patients, in addition to evaluating new possible pathogenic variants and comparing them with cohorts already described in the literature. (AU)