The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands (especially the pituitary gland and to a lesser extent the thyroid gland). We have studied congenital adrenal hypoplasia caused by triple A syndrome and other defects, other multiple endocrine deficiencies, familial hyperaldosteronism, adrenocortical and thyroid cancer, pituitary tumors and multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid and adrenal glands, and Carney complex (CNC), an autosomal dominant disease. CNC is a MEN syndrome affecting the pituitary, adrenal cortex, thyroid, and the gonads, and is associated with a variety of other tumors, including myxomas and schwannomas, and skin pigmentation defects (lentigines, cafe-au-lait spots, and nevi). We have identified the regulatory subunit type 1-A of protein kinase A (PKA), which is coded by the PRKAR1A gene as the gene responsible for most CNC patients. Thus, a significant part of our work is now focused on PKA-stimulated signaling pathways, PKA effects on tumor suppression and/or development, the cell cycle and chromosomal stability. Prkar1a-specific animal models have also been created to address the tumor-promoting effects of this gene and serve as models for possible therapies. In addition, genes that are mutated in patients with CNC-like and other froms of inherited adrenal tumors are being investigated. Most recently, mutations in PRKACA, PRKACB and ARMC5, as well as in phosphodiesterase genes - phosphodiesterase 11A (PDE11A) and PDE8B - were identified in patients with various forms of bilateral adrenocortical hyperplasias. Mouse models of PDE11A and PDE8B deficiency are being studied, and mutations of these genes are being sought in other endocrine tumors. We have also elucidated the causative genetic defects in Carney-Stratakis syndrome (CSS) and we continue our search for genes that are related to tumors that develop in association with CSS and a similar condition (Carney Triad).

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3
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2014
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U.S. National Inst/Child Hlth/Human Dev
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Tirosh, Amit; Valdés, Nuria; Stratakis, Constantine A (2018) Genetics of micronodular adrenal hyperplasia and Carney complex. Presse Med 47:e127-e137
Makri, Angeliki; Bonella, Maria Belen; Keil, Margaret F et al. (2018) Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease. Clin Endocrinol (Oxf) 89:437-443
Rossi, Á D; Faucz, F R; Melo, A et al. (2018) Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil. J Intern Med :
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Stratakis, Constantine A (2018) Cyclic AMP-dependent protein kinase catalytic subunit A (PRKACA): the expected, the unexpected, and what might be next. J Pathol 244:257-259
Makri, Angeliki; Boyce, Alison M; Stratakis, Constantine A et al. (2018) Irreversible Primary Amenorrhea Secondary to Uterine Damage and Premature Ovarian Failure in 2 Patients with Ewing Sarcoma. J Pediatr Adolesc Gynecol :
Pasternak-Pietrzak, Katarzyna; Stratakis, Constantine A; Moszczy?ska, El?bieta et al. (2018) Detection of new potentially pathogenic mutations in 2 patients with primary pigmented nodular adrenocortical disease (PPNAD) - case reports with literature review. Endokrynol Pol :
Jha, Abhishek; Ling, Alexander; Millo, Corina et al. (2018) Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population. Eur J Nucl Med Mol Imaging 45:787-797
Hannah-Shmouni, Fady; Moraitis, Andreas G; Romero, Vladimir Valera et al. (2018) Successful Treatment of Estrogen Excess in Primary Bilateral Macronodular Adrenocortical Hyperplasia with Leuprolide Acetate. Horm Metab Res 50:124-132
Chatain, Grégoire P; Patronas, Nicholas; Smirniotopoulos, James G et al. (2018) Potential utility of FLAIR in MRI-negative Cushing's disease. J Neurosurg 129:620-628

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