Molecular Genetic and Genomic Alterations in Cushing's Syndrome and Primary Aldosteronism.

The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing's syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.

First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing Syndrome.

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating PRKAR1A defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease. CASE DESCRIPTION: A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different PRKAR1A variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. "Deep" NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect. CONCLUSIONS: We present a case of PPNAD due to low-level mosaicism for a PRKAR1A defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic PRKAR1A mutation. The identification of mosaicism for PRKAR1A, depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with PRKAR1A mosaicism, PPNAD, and an adenoma forming due to complete inactivation of PRKAR1A in adrenal tissue from a second, somatic-only, PRKAR1A coding sequence mutation.

Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia.

CONTEXT: Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated. OBJECTIVE: We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed. DESIGN: A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019. SETTING: Tertiary care clinical research center. PATIENTS: Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics. INTERVENTION: Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota). MAIN OUTCOME AND MEASURES: 17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume. RESULTS: A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ±â€…11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P = 0.028), urinary free cortisol (R = 0.70, P = 0.035), and 17-OHS (R = 0.87, P = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P = 0.018; R = 0.65, P = 0.042; and R = 0.73, P = 0.016, respectively). CONCLUSIONS: Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.

Endocrine Conditions and COVID-19.

COVID-19 was declared a global pandemic by the WHO and has affected millions of patients around the world. COVID-19 disproportionately affects persons with endocrine conditions, thus putting them at an increased risk for severe disease. We discuss the mechanisms that place persons with endocrine conditions at an additional risk for severe COVID-19 and review the evidence. We also suggest precautions and management of endocrine conditions in the setting of global curfews being imposed and offer practical tips for uninterrupted endocrine care.

Adrenocortical tumorigenesis: Lessons from genetics.

Advances in genomics over the past two decades have allowed for elucidation of the genetic alterations leading to the development of adrenocortical tumors and/or hyperplasias. These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, with the identification of alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic tumors. Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, that lead to aberrant cyclic adenosine monophosphate-protein (cAMP) kinase A signaling, were found to play a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling. Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenocortical hyperplasia with glucocorticoid and/or mineralocorticoid oversecretion. Adrenocortical carcinoma was linked primarily to aberrant p53 signaling and/or Wnt-ß-catenin signaling, as well as IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15. This review focuses on the genetic underpinnings of benign cortisol- and aldosterone-producing adrenocortical tumors/hyperplasias and adrenocortical carcinoma.

Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis.

Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.

Carney Complex.

Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the PRKAR1A gene, which encodes the regulatory subunit type 1α of protein kinase A. Inactivating defects of PRKAR1A lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer.

An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade.

The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.