Molecular Genetics of Adrenocortical Tumors and Related Disorders
- Constantine Stratakis, MD, D(med)Sci, Head, Section on Endocrinology and Genetics
- Maria Nesterova, PhD, Staff Scientist
- Sosipatros Boikos, MD, Visiting Fellow
- Anelia Horvath, PhD, Visiting Fellow
- Michael Muchow, PhD, Postdoctoral Fellow1
- Andrew Bauer, MD, Guest Researcher2
- Audrey Robinson-White, PhD, Researcher
- Eirini Bimpaki, MD, Visiting Scientist3
- Limor Drori-Harishanu, MD, Visiting Scientist4
- Hui-Pin Hsiao, MD, Visiting Scientist5
- Maya Lodish, MD, Clinical Associate
- Somya Verma, MD, Clinical Associate
- Linda Kotz, RN, Clinical Assistant, Nursing Coordinator
- Elizabeth Levine, BS, Predoctoral Fellow
- Yianna Patronas, BA, MS, Predoctoral Fellow
- Kit-Man Tsang, BS, Predoctoral Fellow
- Jason Papademetriou, BA, MS, Special Volunteer
- Michelle Haran, NIH Summer Student Program
We aim to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those disorders that are developmental, hereditary, and associated with adrenal hypoplasia or hyperplasia, multiple tumors, and abnormalities in other endocrine glands. We study congenital adrenal hypoplasia caused by triple A syndrome and several endocrine deficiencies; familial hyperaldosteronism; adrenocortical and thyroid cancer; pituitary tumors; multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid, and adrenal glands; and Carney complex (CNC), an autosomal dominant disease. We focus on cyclic AMP (cAMP)/protein kinase A (PKA) stimulated signaling pathways and PKA effects on tumor suppression, development, and the cell cycle. The prkar1a and pde11a gene mouse models, in which we have knocked out the respective genes, facilitate our research. Genome-wide searches for other genes responsible for CNC and related diseases of the adrenal and pituitary glands are ongoing. We described a new disease (Carney-Stratakis syndrome, or CSS) and observed adrenocortical tumors in association with tumors of the peripheral nervous system and gastrointestinal system (Carney Triad, or CT). The laboratory identified mutations in the succinate dehydrogenase subunits B, C, and D in CSS and, in collaboration with other investigators and the NCI, is currently looking for gene(s) responsible for CT and related tumors.
Carney complex genetics
Horvath, Patronas, Tsang, Boikos, Giatzakis,6 Levine, Stratakis; in collaboration with Carney, Kirschner, Bertherat
We have collected families with CNC and related syndromes from several collaborating institutions worldwide. Through genetic linkage analysis, we identified loci harboring genes for CNC on chromosomes 2 (2p16) and 17 (17q22–24) and are currently searching for other possible loci for this genetically heterogeneous condition. With the application of state-of-the-art molecular cytogenetic techniques, we are investigating the participation of these currently identified genomic loci in the expression of the disease and have constructed a comprehensive genetic and physical map of the 2p16 chromosomal region for cloning the CNC-associated sequences from this region. Studies in cultured primary tumor cell lines (established from our patients) identified a region of genomic amplification in CNC tumors in the center of the map. The PRKAR1A gene on 17q22–24, which is the gene responsible for CNC in most cases of the disease, appears to undergo loss of heterozygosity in at least some CNC tumors. PRKAR1A is also the main regulatory subunit (subunit type 1-α) of PKA, a central signaling pathway for many cellular functions and hormonal responses. We have increased the number of CNC patients in genotype-phenotype correlation studies, which are expected to provide insight into the complex biochemical and molecular pathways regulated by PRKAR1A and PKA. We expect to identify new genes by ongoing genome-wide searches for patients and families who do not carry PRKAR1A mutations.
- Greene EL, Horvath AD, Nesterova M, Giatzakis C, Bossis I, Stratakis CA. In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay. Hum Mutat 2008;29:633-639.
- Horvath A, Bossis I, Giatzakis C, Levine E, Weinberg F, Meoli E, Siegel J, Soni P, Groussin L, Matyakhina L, Verma S, Carney JA, Bertherat J, Stratakis CA. Large deletions of the PRKAR1A gene in Carney complex: phenotype correlations and implications for laboratory and diagnostic testing. Clin Cancer Res 2008;14:388-395.
- Horvath A, Stratakis CA. Unraveling the molecular basis of micronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2008;15:227-233.
- Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin-independent Cushing syndrome). In: Flück CE, Miller WL, eds. Disorders of the Human Adrenal Cortex. Karger, Endocr Dev 2008;13:117-132.
- Stratakis CA, Horvath A. How the new tools to analyze the human genome are opening new perspectives: the use of gene expression in investigations of the adrenal cortex. Ann Endocrinol (Paris) 2008;69:123-129.
PRKAR1A, protein kinase A activity, and endocrine and other tumor development
Levine, Horvath, Boikos, Muchow, Robinson-White, Nesterova, Stratakis; in collaboration with Bertherat, Grimberg
We are investigating the functional and genetic consequences of PRKAR1A mutations in cell lines established from CNC patients and their tumors. We measure both cAMP and PKA activity in these cell lines, along with the expression of the other subunits of the PKA tetramer. In addition, we are seeking mutations of the PRKAR1A gene in sporadic endocrine and non-endocrine tumors (thyroid adenomas and carcinomas, adrenocortical adenomas and carcinomas, ovarian carcinomas, melanomas and other benign and malignant pigmented lesions, and myxomas in the heart and other sites)—mutations that would further establish the gene’s role as a general tumor suppressor. Many investigators within the NIH and around the world provide specimens on a collaborative basis.
- Gennari M, Stratakis CA, Horvath A, Pirazzoli P, Cicognani A. A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations. Clin Endocrinol (Oxf) 2008; [E-pub ahead of print].
- Robinson-White AJ, Hsiao HP, Leitner WW, Greene E, Bauer A, Krett NL, Nesterova M, Stratakis CA. PKA-independent inhibition of proliferation and induction of apoptosis in human thyroid cancer cells by 8-Cl-adenosine. J Clin Endocrinol Metab 2008;93:1020-1029.
- Shi Z, Henwood MJ, Bannerman P, Batista D, Horvath A, Guttenberg M, Stratakis CA, Grimberg A. Primary pigmented nodular adrenocortical disease reveals insulin-like growth factor binding protein-2 regulation by protein kinase A. Growth Horm IGF Res 2007;17:113-121.
- Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Bourdeau I. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease. Clin Endocrinol (Oxf) 2008;69:367-373.
- Zembowicz A, Knoepp SM, Bei T, Stergiopoulos S, Eng C, Mihm MC, Stratakis CA. Loss of expression of protein kinase A regulatory subunit 1a in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol 2007;31:1764-1775.
Prkar1a+/− and antisense (AS) Prkar1a transgenic animal models
Tsang, Muchow, Bauer, Boikos, Nesterova, Stratakis; in collaboration with Griffin, Westphal, Kirschner, Batista
In collaboration with Heiner Westphal, Lawrence Kirschner, while in our laboratory, developed a Prkar1a knockout mouse floxed by a lox-P system for the purpose of generating, first, a novel Prkar1a+/− and, second, knockouts of the Prkar1a gene in a tissue-specific manner after crossing the new mouse model with mice expressing the cre protein in the adrenal cortex, anterior lobe of the pituitary, and thyroid gland (Kirschner et al., Cancer Res 2005;65:4506). The heterozygote mouse develops several tumors reminiscent of the equivalent human disease. Ongoing crosses with mice such as the transgenic GHRH–expressing mouse attempt to identify tissue-specific effects (in the case of the GHRH-expressing mouse, the pituitary) or specific signaling events (such as involvement of the p53 and Rb proteins in Prkara1a-related tumorigenesis). We also created a transgenic mouse carrying an antisense transgene for exon 2 of the mouse Prkar1a gene (X2AS) under the control of a regulable promoter. As in human CNC tumors, tissues from mice with the X2AS transgene showed elevated cAMP-stimulated kinase activity. The mice had several CNC-compatible histologic and clinical changes, including obesity attributed to subclinical Cushing syndrome.
- Nadella KS, Jones GN, Trimboli A, Stratakis CA, Leone G, Kirschner LS. Targeted deletion of Prkar1a reveals a role for protein kinase A in mesenchymal-to-epithelial transition. Cancer Res 2008;68:2671-2677.
PRKAR1A, the cell cycle, and other signaling pathways
Robinson-White, Hsiao, Patronas, Levine, Nesterova, Stratakis; in collaboration with Lippincott-Schwartz
We work to identify PRKAR1A-interacting mitogenic and other growth-signaling pathways in cell lines expressing PRKAR1A constructs and/or mutations. Several genes that regulate PKA function and increase cAMP-dependent proliferation and related signals may be altered in the process of endocrine tumorigenesis initiated by a mutant PRKAR1A, a gene with important functions in the cell cycle and in chromosomal stability. Recently, we found an interaction with the mTOR pathway in both human and mouse cells with altered PKA function.
- Heyerdahl SL, Boikos S, Horvath A, Giatzakis C, Bossis I, Stratakis CA. Protein kinase A subunit expression is altered in Bloom syndrome fibroblasts and the BLM protein is increased in adrenocortical hyperplasias: inverse findings for BLM and PRKAR1A. Horm Metab Res 2008;40:391-397.
- Mavrakis M, Lippincott-Schwartz J, Stratakis CA, Bossis I. mTOR kinase and the regulatory subunit of protein kinase A (PRKAR1A) spatially and functionally interact during autophagosome maturation. Autophagy 2007;3:151-153.
- Meoli E, Bossis I, Cazabat L, Mavrakis M, Horvath A, Shiferaw M, Fumey G, Perlemoine K, Muchow M, Robinson-White A, Weinberg F, Nesterova M, Patronas Y, Groussin L, Bertherat J, Stratakis CA. Protein kinase A (PKA) effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res 2008;68:3133-3141.
- Nesterova M, Bossis I, Wen F, Horvath A, Matyakhina L, Stratakis CA. An immortalized human cell line bearing a PRKAR1A-inactivating mutation: effects of over-expression of the wild-type allele and other protein kinase A (PKA) subunits. J Clin Endocrinol Metab 2008;93:565-571.
Phosphodiesterase (PDE) genes in endocrine and other tumors
Horvath, Tsang, Patronas, Giatzakis,6 Boikos, Levine, Stratakis; in collaboration with Bertherat
In patients who did not exhibit CNC or PRKAR1A mutations but presented with bilateral adrenal tumors similar to those in CNC, we found inactivating mutations of the PDE11A gene, which encodes phosphodiesterase-11A and regulates PKA in the normal physiologic state. Phosphodiesterase 11A is a member of a 22 gene–encoded family of proteins that break down cyclic nucleotides that control PKA. PDE11A appears to act as a tumor suppressor such that tumors develop when its action is abolished. In fact, in what proved to be the first time that mutated PDE was observed in a genetic disorder predisposing to tumors, we found pediatric and adult patients with bilateral adrenal tumors. Recent data indicate that PDE11A sequence polymorphisms may be present in the general population. The finding that genetic alterations of such a major biochemical pathway may be associated with tumors in humans raises the reasonable hope that drugs that modify PKA and/or PDE activity may eventually undergo development for use in both CNC and patients with other, non-genetic, adrenal tumors—and perhaps other endocrine tumors. Most recently, we identified a patient with a PDE8B mutation and Cushing syndrome (Figure 4.10), with the PDE8B transcript and protein seemingly expressed widely in the endocrine system (Figure 4.11).
- Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White A, Bossis I, Bertherat J, Carney JA, Stratakis CA. Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Horm Metab Res 2008;40:347-353.
- Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libè R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet 2006;38:794-800.
- Horvath A, Giatzakis C, Tsang K, Greene E, Osorio P, Boikos S, Libè R, Patronas Y, Robinson-White A, Remmers E, Bertherat J, Nesterova M, Stratakis CA. A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet 2008;16:1245-1253.
- Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cAMP-specific Phosphodiesterase in Adrenal Hyperplasia. N Engl J Med 2008;358:750-752.
- Libè R, Fratticci A, Coste J, Tissier F, Horvath A, Ragazzon B, Rene-Corail F, Groussin L, Bertagna X, Raffin-Sanson ML, Stratakis CA, Bertherat J. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res 2008;14:4016-4024.
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Figure 4.10 A genetic defect in PDE8B
A. Female patient CAR 559.03 with Cushing syndrome: (1) characteristic facial plethora and roundness (“moon” facies); (2) body fat in the upper back, known as “buffalo” hump, and supraclavicular fat pads and lipomastia; and (3) hirsutism. B. Family CAR 559: the mutant allele (C) of the proband (CAR559.03) was inherited from mildly affected father (CAR559.01) while unaffected mother (CAR550.02) had normal PDE8B alleles. C. Midnight cortisol levels (in mg/dl) in patients with adrenocortical tumors (N = 23) and control individuals (N = 7) recently studied at the NIH and levels of the proband (CAR 559.03) and patient’s father (CAR 559.01) as indicated by a full circle and a full square, respectively. D. Imaging and pathological findings in the proband: (left panel) adrenal computed tomography of CAR 559.03, with mild enlargement of both the left and right adrenal glands; (center panel) hematoxylin and eosin staining (5× magnification) of the adrenal gland of the proband, with disturbed adrenocortical zonation pattern and both nodular tissue and hyperplasia of the surrounding cortex visible; and (right panel) pigment (lipofuscin) in adrenocortical nodules (visible at 40x magnification. E. Computed tomography of the adrenal glands of patient’s father (CAR 559.01): (left panel) right and (right panel) left adrenal gland. F. Electrophoregram showing the A→T substitution in patient CAR 559.03 with the arrow pointing to the position of the mutation. G. Conservation of histidine (H) at position 305 of PDE8B across species. H. In vitro expression of constructs employing the normal (wild-type; wt) and mutant (H305P) coding sequence of the PDE8B gene in HEK293 cells, leading to significant decrease of cyclic AMP levels or no change, respectively, compared with the “mock” transfection; thus, the H305P mutation abolishes the ability of PDE8B to degrade cyclic AMP.
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Figure 4.11 Mouse expression of PDE8B
(A) PDE8B immunostaining (arrows) in the mouse embryo on day 15.5 seen in a whole-body section (Br = brain; H = heart; Li = liver; Ad = adipose tissue, with upper arrow indicating the hibernating gland); (B) PDE8B immunostaining (arrows) in the adipose tissue, with arrows indicating the hibernating gland (B = bone; M = skeletal muscle; Sk = skin); (C) Immunostaining in embryonic liver showing labeling forming the islets in between the liver cells (arrows); (D) PDE8B in the heart ventricle (HV) forming small spots between muscle fibers (arrows) while the atria (Au) do not show any labeling; (E) PDE8B immunostaining in the adipose tissue of the hibernating gland of a newborn mouse, with arrow indicating the hibernating gland; (F) PDE8B immunostaining (arrows) in the heart ventricle and liver of a newborn mouse; (G) The wall of the heart ventricle, with PDE8B labeling (arrow) forming a network around the muscle fibers; (H) Liver, with PDE8B labeling (arrow) as a heterogeneous distribution throughout the liver parenchyma; (I) Kidney tubules, most likely distal tubules, but not glomeruli, showing PDE8B labeling (arrow) (Gl = glomerulus; K = kidney; T = tubules); (J) Intense PDE8B immunostaining (arrow) in adipose tissue (R = rib); (K) PDE8B immunostaining (arrow) in the liver parenchyma with blood vessels, including branches of the portal vein and hepatic artery, and bile duct remaining unlabeled (BD = bile duct; H = hepatocyte; HA = hepatic artery; PV = portal vein branch); (L) PDE8B immunostaining (arrow) in the adipose tissue surrounding the thymus, with thymus and blood vessels remaining unstained (BV = blood vessel; Th = thymus); (M) Light PDE8B immunostaining (arrow) in the epithelial cells of the bronchioles (Br = bronchiole); (N) PDE8B immunostaining (arrow) in the seminiferous tubules of the adult mouse testis, showing spermatogonia to be slightly labeled and spermatozoa seeming to be unstained (SfT = seminiferous tubule; Sg = spermatogonia; Sz = spermatozoa).
Genetic investigations into other adrenocortical diseases and related tumors
Boikos, Hsiao, Horvath, Muchow, Nesterova, Stratakis; in collaboration with Libutti, Chan, Voutetakis, Carney, Hammer, Stowasser, Lacroix, Bertherat
Through collaborations, we (1) apply general and pathway-specific microarrays to a variety of adrenocortical tumors, including single adenomas and massive macronodular adrenocortical disease (MMAD), to identify genes with important functions in adrenal oncogenetics; (2) examine candidate genes for their roles in adrenocortical tumors and development; and (3) identify additional genes that play a role in inherited adrenocortical and related diseases, such as Allgrove syndrome.
- Pack S, Boikos SA, Stratakis CA. Medullary thyroid carcinoma, RET mutations, and the multiple endocrine neoplasia-2 syndromes. In: Govindan R, ed. American Society of Clinical Oncology 2007 Educational Book. American Society of Clinical Oncology, 2007;668-672.
- Perl S, Kotz L, Keil M, Patronas NJ, Stratakis CA. Calcified adrenals associated with perinatal adrenal hemorrhage and adrenal insufficiency. J Clin Endocrinol Metab 2007;92:754.
- Ribeiro RC, Rodriguez-Galindo C, Zambetti GP, Figueiredo BC, Pacak K, Bauer A, Stratakis CA. Uncommon endocrine tumors in children and adolescents. In: Raghavan D, Brecher ML, Johnson DH, Meropol NJ, Moots PL, Rose PG, eds.; Mayer IA, assoc. ed. Textbook of Uncommon Cancers, 3rd Edition; Section 11: Pediatric Malignancies; Chapter 70. John Wiley & Sons, 2006;775-797.
- Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushing’s syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Clin Pract Endocrinol Metab 2007;3:748-757.
- Stratakis CA, Bornstein SR. Symposium on cortisol secretion abnormalities honoring Dr. George P. Chrousos. Horm Metab Res 2007;39:401-403.
Genetic investigations into pituitary tumors, other endocrine neoplasias, and related syndromes
Horvath, Boikos, Stratakis; in collaboration with Marx, Carney
In collaboration with several other investigators at the NIH and elsewhere, we are investigating the genetics of CNC- and adrenal-related endocrine tumors, including childhood pituitary tumors, related or unrelated to PRKAR1A mutations. As part of this work, we have identified novel genetic abnormalities in other endocrine glands.
- Boikos SA, Stratakis CA. Molecular genetics of the cAMP-dependent protein kinase pathway and of sporadic pituitary tumorigenesis. Hum Mol Genet 2007;16:R80-87.
- Bowden SA, Sotos JF, Stratakis CA, Weil RJ. Successful treatment of an invasive growth hormone-secreting pituitary macroadenoma in an 8-year-old boy. J Pediatr Endocrinol Metab 2007;20:643-647.
- Keil MF, Stratakis CA. Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics. Expert Rev Neurother 2008;8:563-574.
- Mai PL, Korde L, Kramer J, Peters J, Mueller CM, Pfeiffer S, Stratakis CA, Pinto PA, Bratslavsky G, Merino M, Choyke P, Linehan WM, Greene MH. A possible new syndrome with growth-hormone secreting pituitary adenoma, colonic polyposis, lipomatosis, lentigines and renal carcinoma in association with familial testicular germ cell malignancy: a case report. J Med Case Reports (BMC) 2007;1:9-15.
- Nandagopal R, Vortmeyer A, Oldfield EH, Keil MF, Stratakis CA. Cushing’s syndrome due to a pituitary corticotropinoma in a child with tuberous sclerosis: an association or a coincidence? Clin Endocrinol (Oxford) 2007;67:639-641.
Genetic investigations into other endocrine neoplasias and related syndromes; hereditary paragangliomas and related conditions
Muchow, Boikos, Stratakis; in collaboration with Carney
As part of a collaboration with other investigators at the NIH and elsewhere (including an international consortium organized by our laboratory), we are studying the genetics of a rare syndrome that predisposes to adrenal and other tumors, the Carney Triad, and related conditions (associated with gastrointestinal stromal tumors, or GIST). In the course of our work, we identified a patient with a new syndrome, known as the paraganglioma and gastrointestinal stromal tumor syndrome (or Carney-Stratakis syndrome), for which we found mutations in the genes encoding succinate dehydrogenase (SDH) subunits B, C, and D. In another patient, we found a novel germline mutation of the PDFGRA gene (Figure 4.12).
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Several small intestinal tumors of a patient studied in the context of cases of multiple endocrine tumors: formalin-fixed specimens of small intestine showed several polypoid tumors covered by intact mucosa; the tumors were generally hemispherical and protruded into the bowel lumen while some were confluent. The cut surface was white and homogeneous. The patient had a germline mutation in the PDFGRA gene; the mutation was V561D (GTC→GAC) in exon 12. Both the normal gastric mucosa and the tumor cells exhibited the mutation (J Clin Endocrinol Metab 2007;92:3728).
- Matyakhina L, Bei TA, McWhinney SR, Pasini B, Cameron S, Gunawan B, Stergiopoulos SG, Boikos S, Muchow M, Dutra A, Pak E, Campo E, Cid MC, Gomez F, Gaillard RC, Assie G, Fuzesi L, Baysal BE, Eng C, Carney JA, Stratakis CA. Genetics of Carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab 2007;92:2938-2943.
- McWhinney SR, Pasini B, Stratakis CA, International Carney Triad and Carney-Stratakis Syndrome Consortium. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007;357:1054-1056.
- Pasini B, Matyakhina L, Bei T, Muchow M, Boikos S, Ferrando B, Carney JA, Stratakis CA. Multiple gastrointestinal stromal tumors caused by platelet-derived growth factor receptor-alpha (PDGFRA) gene mutations: a case associated with a germline V561D defect. J Clin Endocrinol Metab 2007;92:3728-3732.
- Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 2007;16:79-88.
- Timmers HJ, Pacak K, Bertherat J, Lenders JW, Duet M, Eisenhofer G, Stratakis CA, Niccoli-Sire P, Huy PT, Burnichon N, Gimenez-Roqueplo AP. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf) 2008;68:561-566.
Clinical investigations into the diagnosis and treatment of adrenal and pituitary tumors
Verma, Hsiao, Stratakis; in collaboration with Keil, Patronas, Batista
Patients with adrenal tumors and other types of Cushing syndrome (and occasionally other pituitary tumors) come to the NIH Clinical Center for diagnosis and treatment. Ongoing investigations focus on (1) the prevalence of ectopic hormone receptor expression in adrenal adenomas and massive macronodular adrenocortical disease; (2) the diagnostic use of high-sensitivity magnetic resonance imaging for the earlier detection of pituitary tumors; and (3) the diagnosis, management, and post-operative care of children with Cushing syndrome and other pituitary tumors.
- Batista DL, Riar J, Keil M, Stratakis CA. Diagnostic tests for children referred for the investigation of Cushing syndrome. Pediatrics 2007;120:e575-86.
- Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B, Stratakis CA, Hedley-Whyte ET, Klibanski A. Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 2008;93:4119-4125.
- Hsiao HP, Iglesias ML, Keil MF, Boikos S, Robinson-White A, Stratakis CA. Differences in cortisol levels and body mass index between East Asians and Caucasians with Cushing’s syndrome: an ‘East Asian’ phenotype for Cushing syndrome. Clin Endocrinol (Oxford) 2007;66:753-755.
- Powell AC, Stratakis CA, Patronas NJ, Steinberg SM, Batista D, Alexander HR, Pingpank JF, Keil M, Bartlett DL, Libutti SK. Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia. Surgery 2008;143:750-758.
Clinical and molecular investigations into other pediatric genetic syndromes
Kotz, Lodish, Verma, Horvath, Hsiao, Boikos, Stratakis; in collaboration with Keil, Raygada, Rennert
Largely in collaboration with a number of other investigators at the NIH and elsewhere, we are conducting work on pediatric genetic syndromes seen in our clinics and wards.
- De Ravin SS, Shum E, Zarember KA, Rezvani G, Rosenfeld RG, Stratakis CA, Malech HL. Short stature in partially corrected X-linked severe combined immunodeficiency-suboptimal response to growth hormone. J Pediatr Endocrinol Metabol 2008, in press.
- Giri N, Batista DL, Alter BP, Stratakis CA. Endocrine abnormalities in patients with Fanconi anemia. J Clin Endocrinol Metab 2007;92:2624-2631.
- Mussai FJ, Cunningham LC, Rezvani G, Stratakis CA, Reynolds JC, Nesterova G, Henshaw RM, Levine JE, Helman LJ, Arthur DC, Kim SY. Hypocalcemia in a patient with osteosarcoma and 22q11.2 deletion syndrome. J Pediatr Hematol Oncol 2008;30:612-617.
1 Intramural Research Training Award Program of the NIH
2 Director, Pediatric Endocrinology Program, Walter Reed Army Medical Center
3 Special Volunteer from Greece
4 Special Volunteer from Israel
5 Special Volunteer from Taiwan
6 Christopher Giatzakis, PhD, former Visiting Fellow
- Dalia Batista, MD, Massachusetts General Hospital, Harvard University, Boston, MA
- Jérôme Bertherat, MD, PhD, Service des Maladies Endocriniennes et Mètaboliques, Hôpital Cochin, Paris, France
- Stephan Bornstein, MD, PhD,Universität Dresden, Dresden, Germany
- Isabelle Bourdeau, MD, Universitè of Montrèal, Montrèal, Canada
- Brian Brooks, MD, PhD, Ophthalmic Genetics and Clinical Services Branch, NEI, Bethesda, MD
- J. Aidan Carney, MD, PhD, Mayo Clinic, Rochester, MN
- Wai-Yee Chan, PhD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
- Adrian Clark, MD, PhD, St. Bartholomew’s Hospital, London, UK
- Nickolas Courkoutsakis, MD, PhD, University of Thrace, Alexandroupolis, Greece
- Jacques Drouin, PhD, Institut de Recherches Cliniques de Montrèal (IRCM), Montrèal, Canada
- Kurt Griffin, MD, PhD, University of Arizona, Tucson, AZ
- Adda Grimberg, MD, Children’s Hospital of Philadelphia, Philadelphia, PA
- Gary Hammer, MD, PhD, University of Michigan, Ann Arbor, MI
- Meg Keil, RN, PNP, Program in Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
- Lawrence Kirschner, MD, PhD, James Cancer Hospital, Ohio State University, Columbus, OH
- Anne Klibanski, MD, Massachusetts General Hospital, Harvard University, Boston, MA
- Andre Lacroix, MD, PhD, Centre Hospitalier de l’Universitè de Montrèal, Montrèal, Canada
- Stephen Libutti, MD, Center for Cancer Research, NCI, Bethesda, MD
- Jennifer Lippincott-Schwartz, PhD, Cell Biology and Metabolism Program, NICHD, Bethesda, MD
- Stephen Marx, PhD, Surgery Branch, NCI, Bethesda, MD
- Ludmila Matyakhina, PhD, Medical Genetics Branch, NHGRI, Bethesda, MD
- Nickolas Patronas, MD, Diagnostic Radiology, Clinical Center, NIH, Bethesda, MD
- Margarita Raygada, PhD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
- Owen M. Rennert, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
- Matthew Ringel, MD, PhD, Ohio State University, Columbus, OH
- Michael Stowasser, MD, University of Queensland, Brisbane, Australia
- David Torpy, MD, University of Queensland, Brisbane, Australia
- Antonis Voutetakis, MD, Gene Therapy and Therapeutics Branch, NIDCR, Bethesda, MD
- Heiner Westphal, MD, PhD, Program in Genomics of Differentiation, NICHD, Bethesda, MD