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Adrenocortical Growth and Cancer

Lucile Lefèvre, Jérôme Bertherat, Bruno Ragazzon

10.1002/cphy.c140010

Source: Volume 5, Issue 1, January 2015

Published online: December 2014

Full Article on Wiley Online Library



Abstract

The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/β‐catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes current knowledge of adrenocortical development, growth, and tumorigenesis. © 2015 American Physiological Society. Compr Physiol 5:293‐326, 2015.

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Figure 1. Figure 1. Comparison of fetal and adult adrenal. (A) Fetal adrenal gland histology. The fetal gland is composed of two types of tissue, the fetal zone and the definitive zone. The fetal zone constitutes more than 80% of the fetal gland. Under the capsule lies the definitive zone. (B) Adult adrenal gland histology. The adult adrenal is constituted by two distinct tissues, the outer cortex and the inner medulla. These two tissues have different cellular origin and produce corticosteroid and catecholamines, respectively. The cortex is composed of three distinct cell layers: the glomerulosa, fasciculata and reticularis. The adrenal gland is encapsulated. Originally published, with permission, by Nat Rev Endocrinol (236).
Figure 2. Figure 2. Steroidogenic pathways in human adult adrenal cortex. The adrenal cortex produces zone‐specific steroids due to specific steroidogenic enzyme expression. There are three distinct steroids: mineralocorticoids produced by zona glomerulosa, glucocorticoids synthesized by zona fasciculata, and androgen produced by zona reticularis. Cholesterol, which is the common precursor, is internalized by StAR protein in the inner mitochondrial membrane. Abbreviations: CYP11B2, aldosterone synthase; CYP17, 17‐hydroxylase, CYP17, 17,20‐lyase; CYP11B1, 11β‐hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD3B2, type II 3β‐hydroxysteroid dehydrogenase; CYP11A1, cholesterol side‐chain cleveage; CYP21, 21‐hydroxylase; 17βHSD, 17β‐hydroxysteroid dehydrogenase; p450Aro, aromatase; StAR, steroidogenic acute regulatory protein; CS, corticosterone; DOC, deoxycortisol; DOCS, deoxycorticosterone; 18OHCS, 18‐hydroxylase corticosterone.
Figure 3. Figure 3. Development of adrenal gland from urogenital ridge to adult adrenal. (A) Transversal section of an embryo at four weeks in human or at embryonic day nine in mouse. (B) (1) The urogenital ridge corresponds to longitudinal elevation of the intermediate mesoderm. (2) The adrenogonadal primordium (AGP) is formed by condensation of coelomic epithelium and/or intermediate mesoderm. AGP separates into adrenal primordium and gonadal primordium in which germ cells accumulate. (3) Fetal adrenal is localized cranial to the kidney. (4) The adult adrenal gland is formed by fetal adrenal proliferation and differentiation in steroidogenic cells and by migration of chromaffin cells inner the cortex. Factors involved in each step have been annotated. (C) Adrenal gland organogenesis in human and mouse. At the eighth week of gestation in humans (E10.5 in mice), the adrenal primordial/fetal zone (grey cells) derives from the AGP. At the ninth week of gestation in humans (E11.5‐12.5 in mice), chromaffin cells (red cells) colonize the inner layer of the fetal cortex to form the future medulla. At 14.5 days in mice, there is an encapsulation of the fetal zone by mesenchymal cells (blue cells) followed by the formation of definitive cells (orange cells). There is a proliferation of the fetal zone until the birth. At birth, the adrenal cortex undergoes profound structural modification: the definitive zone begins to differentiate in zona fasciculata (yellow cells) and zona glomerulosa (orange cells). The fetal zone regresses after birth in humans, while in mice the fetal zone persists until puberty for males and the first pregnancy in females. In humans, at the age of 6 to 8 years, the zona reticularis (green cells) is formed. Abbreviation: E, embryonic day. Adapted, with permission, from (127).
Figure 4. Figure 4. Model of adrenal development. Subcapsular progenitor cells (dark grey) give rise to definitive adrenal cells by centripedal differentiation (major pathway) based on works by (58,101,149,176). Some alternative pathways could participate or are activated to maintain the zona fasciculata in certain conditions. Blue: capsular cells; dark‐gray: progenitor cells; orange: zona glomerulosa cells; yellow: zona fasciculata cells; light‐gray: X‐zone cells; white: medulla cells.
Figure 5. Figure 5. Alterations of 11p15 locus and IGF2 overexpression in ACC. The imprinted 11p15 locus contains the CDKN1C (p57kip2), IGF2, and H19 genes. In a normal adrenal (on the left), only the paternal allele of the IGF2 gene is expressed, whereas only the maternal alleles of CDKN1C and H19 are expressed. Paternal isodisomy is usually observed in adrenal cancers (on the right) with loss of the maternal allele at 11p15. This leads to the overexpression of IGF2 and decreased expression of CDKN1C and H19.
Figure 6. Figure 6. The Wnt signaling pathway. Left: In the absence of Wnt ligand, β‐catenin is low, owing to degradation by the ubiquitin‐proteasome system after phosphorylation by the GSK3β‐APC‐AXIN‐WTX complex. Right: Stimulation by Wnt ligand leads to the inactivation of the degradation complex, which leads to the stabilization of β‐catenin in the cytoplasm. After translocation to the nucleus, β‐catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of β‐catenin abolish phosphorylation of β‐catenin, which leads to its accumulation by preventing its degradation by the ubiquitin‐proteasome system.


Figure 1. Comparison of fetal and adult adrenal. (A) Fetal adrenal gland histology. The fetal gland is composed of two types of tissue, the fetal zone and the definitive zone. The fetal zone constitutes more than 80% of the fetal gland. Under the capsule lies the definitive zone. (B) Adult adrenal gland histology. The adult adrenal is constituted by two distinct tissues, the outer cortex and the inner medulla. These two tissues have different cellular origin and produce corticosteroid and catecholamines, respectively. The cortex is composed of three distinct cell layers: the glomerulosa, fasciculata and reticularis. The adrenal gland is encapsulated. Originally published, with permission, by Nat Rev Endocrinol (236).


Figure 2. Steroidogenic pathways in human adult adrenal cortex. The adrenal cortex produces zone‐specific steroids due to specific steroidogenic enzyme expression. There are three distinct steroids: mineralocorticoids produced by zona glomerulosa, glucocorticoids synthesized by zona fasciculata, and androgen produced by zona reticularis. Cholesterol, which is the common precursor, is internalized by StAR protein in the inner mitochondrial membrane. Abbreviations: CYP11B2, aldosterone synthase; CYP17, 17‐hydroxylase, CYP17, 17,20‐lyase; CYP11B1, 11β‐hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HSD3B2, type II 3β‐hydroxysteroid dehydrogenase; CYP11A1, cholesterol side‐chain cleveage; CYP21, 21‐hydroxylase; 17βHSD, 17β‐hydroxysteroid dehydrogenase; p450Aro, aromatase; StAR, steroidogenic acute regulatory protein; CS, corticosterone; DOC, deoxycortisol; DOCS, deoxycorticosterone; 18OHCS, 18‐hydroxylase corticosterone.


Figure 3. Development of adrenal gland from urogenital ridge to adult adrenal. (A) Transversal section of an embryo at four weeks in human or at embryonic day nine in mouse. (B) (1) The urogenital ridge corresponds to longitudinal elevation of the intermediate mesoderm. (2) The adrenogonadal primordium (AGP) is formed by condensation of coelomic epithelium and/or intermediate mesoderm. AGP separates into adrenal primordium and gonadal primordium in which germ cells accumulate. (3) Fetal adrenal is localized cranial to the kidney. (4) The adult adrenal gland is formed by fetal adrenal proliferation and differentiation in steroidogenic cells and by migration of chromaffin cells inner the cortex. Factors involved in each step have been annotated. (C) Adrenal gland organogenesis in human and mouse. At the eighth week of gestation in humans (E10.5 in mice), the adrenal primordial/fetal zone (grey cells) derives from the AGP. At the ninth week of gestation in humans (E11.5‐12.5 in mice), chromaffin cells (red cells) colonize the inner layer of the fetal cortex to form the future medulla. At 14.5 days in mice, there is an encapsulation of the fetal zone by mesenchymal cells (blue cells) followed by the formation of definitive cells (orange cells). There is a proliferation of the fetal zone until the birth. At birth, the adrenal cortex undergoes profound structural modification: the definitive zone begins to differentiate in zona fasciculata (yellow cells) and zona glomerulosa (orange cells). The fetal zone regresses after birth in humans, while in mice the fetal zone persists until puberty for males and the first pregnancy in females. In humans, at the age of 6 to 8 years, the zona reticularis (green cells) is formed. Abbreviation: E, embryonic day. Adapted, with permission, from (127).


Figure 4. Model of adrenal development. Subcapsular progenitor cells (dark grey) give rise to definitive adrenal cells by centripedal differentiation (major pathway) based on works by (58,101,149,176). Some alternative pathways could participate or are activated to maintain the zona fasciculata in certain conditions. Blue: capsular cells; dark‐gray: progenitor cells; orange: zona glomerulosa cells; yellow: zona fasciculata cells; light‐gray: X‐zone cells; white: medulla cells.


Figure 5. Alterations of 11p15 locus and IGF2 overexpression in ACC. The imprinted 11p15 locus contains the CDKN1C (p57kip2), IGF2, and H19 genes. In a normal adrenal (on the left), only the paternal allele of the IGF2 gene is expressed, whereas only the maternal alleles of CDKN1C and H19 are expressed. Paternal isodisomy is usually observed in adrenal cancers (on the right) with loss of the maternal allele at 11p15. This leads to the overexpression of IGF2 and decreased expression of CDKN1C and H19.


Figure 6. The Wnt signaling pathway. Left: In the absence of Wnt ligand, β‐catenin is low, owing to degradation by the ubiquitin‐proteasome system after phosphorylation by the GSK3β‐APC‐AXIN‐WTX complex. Right: Stimulation by Wnt ligand leads to the inactivation of the degradation complex, which leads to the stabilization of β‐catenin in the cytoplasm. After translocation to the nucleus, β‐catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of β‐catenin abolish phosphorylation of β‐catenin, which leads to its accumulation by preventing its degradation by the ubiquitin‐proteasome system.
References
 1. Achermann JC , Ito M , Ito M , Hindmarsh PC , Jameson JL . A mutation in the gene encoding steroidogenic factor‐1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22: 125‐126, 1999.
 2. Achermann JC , Ozisik G , Ito M , Orun UA , Harmanci K , Gurakan B , Jameson JL . Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor‐1, in a dose‐dependent manner. J Clin Endocrinol Metab 87: 1829‐1833, 2002.
 3. Anderson DJ and Axel R . A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids. Cell 47: 1079‐1090, 1986.
 4. Anselmo J , Medeiros S , Carneiro V , Greene E , Levy I , Nesterova M , Lyssikatos C , Horvath A , Carney JA , Stratakis CA . A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab 97: 351‐359, 2012.
 5. Arboleda VA , Lee H , Parnaik R , Fleming A , Banerjee A , Ferraz‐de‐Souza B , Delot EC , Rodriguez‐Fernandez IA , Braslavsky D , Bergada I , Dell'Angelica EC , Nelson SF , Martinez‐Agosto JA , Achermann JC , Vilain E . Mutations in the PCNA‐binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 44: 788‐792, 2012.
 6. Arnold J. Ein Beitrag zur feineren Struktur und dem Chemismus der Nebennieren. Virchow Arch Patholog Anatomie Physiol Klin Med 35: 64‐107, 1866.
 7. Asai M , Ramachandrappa S , Joachim M , Shen Y , Zhang R , Nuthalapati N , Ramanathan V , Strochlic DE , Ferket P , Linhart K , Ho C , Novoselova TV , Garg S , Ridderstrale M , Marcus C , Hirschhorn JN , Keogh JM , O'Rahilly S , Chan LF , Clark AJ , Farooqi IS , Majzoub JA . Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341: 275‐278, 2013.
 8. Assie G , Giordano TJ , Bertherat J . Gene expression profiling in adrenocortical neoplasia. Mol Cell Endocrinol 351: 111‐117, 2012.
 9. Assie G , Guillaud‐Bataille M , Ragazzon B , Bertagna X , Bertherat J , Clauser E . The pathophysiology, diagnosis and prognosis of adrenocortical tumors revisited by transcriptome analyses. Trends Endocrinol Metab 21: 325‐334, 2010.
 10. Assie G , Letouze E , Fassnacht M , Jouinot A , Luscap W , Barreau O , Omeiri H , Rodriguez S , Perlemoine K , Rene‐Corail F , Elarouci N , Sbiera S , Kroiss M , Allolio B , Waldmann J , Quinkler M , Mannelli M , Mantero F , Papathomas T , De Krijger R , Tabarin A , Kerlan V , Baudin E , Tissier F , Dousset B , Groussin L , Amar L , Clauser E , Bertagna X , Ragazzon B , Beuschlein F , Libe R , de Reynies A , Bertherat J . Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 46: 607‐612, 2014.
 11. Assumpcao JG , Seidinger AL , Mastellaro MJ , Ribeiro RC , Zambetti GP , Ganti R , Srivastava K , Shurtleff S , Pei D , Zeferino LC , Dufloth RM , Brandalise SR , Yunes JA . Association of the germline TP53 R337H mutation with breast cancer in southern Brazil. BMC Cancer 8: 357, 2008.
 12. Babu PS , Bavers DL , Beuschlein F , Shah S , Jeffs B , Jameson JL , Hammer GD . Interaction between Dax‐1 and steroidogenic factor‐1 in vivo: Increased adrenal responsiveness to ACTH in the absence of Dax‐1. Endocrinology 143: 665‐673, 2002.
 13. Baker BY , Lin L , Kim CJ , Raza J , Smith CP , Miller WL , Achermann JC . Nonclassic congenital lipoid adrenal hyperplasia: A new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab 91: 4781‐4785, 2006.
 14. Bamforth SD , Braganca J , Eloranta JJ , Murdoch JN , Marques FI , Kranc KR , Farza H , Henderson DJ , Hurst HC , Bhattacharya S . Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co‐activator. Nat Genet 29: 469‐474, 2001.
 15. Bandiera R , Vidal VP , Motamedi FJ , Clarkson M , Sahut‐Barnola I , von Gise A , Pu WT , Hohenstein P , Martinez A , Schedl A . WT1 maintains adrenal‐gonadal primordium identity and marks a population of AGP‐like progenitors within the adrenal gland. Dev Cell 27: 5‐18, 2013.
 16. Baquedano MS , Berensztein E , Saraco N , Dorn GV , de Davila MT , Rivarola MA , Belgorosky A . Expression of the IGF system in human adrenal tissues from early infancy to late puberty: Implications for the development of adrenarche. Pediatr Res 58: 451‐458, 2005.
 17. Barbaux S , Niaudet P , Gubler MC , Grunfeld JP , Jaubert F , Kuttenn F , Fekete CN , Souleyreau‐Therville N , Thibaud E , Fellous M , McElreavey K . Donor splice‐site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17: 467‐470, 1997.
 18. Bardoni B , Zanaria E , Guioli S , Floridia G , Worley KC , Tonini G , Ferrante E , Chiumello G , McCabe ER , Fraccaro M , et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 7: 497‐501, 1994.
 19. Barreau O , Assie G , Wilmot‐Roussel H , Ragazzon B , Baudry C , Perlemoine K , Rene‐Corail F , Bertagna X , Dousset B , Hamzaoui N , Tissier F , de Reynies A , Bertherat J . Identification of a CpG island methylator phenotype in adrenocortical carcinomas. J Clin Endocrinol Metab 98: E174‐184, 2013.
 20. Barreau O , de Reynies A , Wilmot‐Roussel H , Guillaud‐Bataille M , Auzan C , Rene‐Corail F , Tissier F , Dousset B , Bertagna X , Bertherat J , Clauser E , Assie G . Clinical and pathophysiological implications of chromosomal alterations in adrenocortical tumors: An integrated genomic approach. J Clin Endocrinol Metab 97: E301‐311, 2012.
 21. Bashamboo A , Ferraz‐de‐Souza B , Lourenco D , Lin L , Sebire NJ , Montjean D , Bignon‐Topalovic J , Mandelbaum J , Siffroi JP , Christin‐Maitre S , Radhakrishna U , Rouba H , Ravel C , Seeler J , Achermann JC , McElreavey K . Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 87: 505‐512, 2010.
 22. Beamer WG , Sweet HO , Bronson RT , Shire JG , Orth DN , Davisson MT . Adrenocortical dysplasia: A mouse model system for adrenocortical insufficiency. J Endocrinol 141: 33‐43, 1994.
 23. Bendavid C , Dubourg C , Gicquel I , Pasquier L , Saugier‐Veber P , Durou MR , Jaillard S , Frebourg T , Haddad BR , Henry C , Odent S , David V . Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet 119: 1‐8, 2006.
 24. Bergada I , Del Rey G , Lapunzina P , Bergada C , Fellous M , Copelli S . Familial occurrence of the IMAGe association: Additional clinical variants and a proposed mode of inheritance. J Clin Endocrinol Metab 90: 3186‐3190, 2005.
 25. Berthon A , Sahut‐Barnola I , Lambert‐Langlais S , de Joussineau C , Damon‐Soubeyrand C , Louiset E , Taketo MM , Tissier F , Bertherat J , Lefrancois‐Martinez AM , Martinez A , Val P . Constitutive beta‐catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet 19: 1561‐1576, 2010.
 26. Beuschlein F , Looyenga BD , Bleasdale SE , Mutch C , Bavers DL , Parlow AF , Nilson JH , Hammer GD . Activin induces x‐zone apoptosis that inhibits luteinizing hormone‐dependent adrenocortical tumor formation in inhibin‐deficient mice. Mol Cell Biol 23: 3951‐3964, 2003.
 27. Beuschlein F , Mutch C , Bavers DL , Ulrich‐Lai YM , Engeland WC , Keegan C , Hammer GD . Steroidogenic factor‐1 is essential for compensatory adrenal growth following unilateral adrenalectomy. Endocrinology 143: 3122‐3135, 2002.
 28. Beuschlein F , Reincke M , Koniger M , D'Orazio D , Dobbie Z , Rump LC . Cortisol producing adrenal adenoma–a new manifestation of Gardner's syndrome. Endocr Res 26: 783‐790, 2000.
 29. Bhattacharya S , Michels CL , Leung MK , Arany ZP , Kung AL , Livingston DM . Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF‐1. Genes Dev 13: 64‐75, 1999.
 30. Biason‐Lauber A , De Filippo G , Konrad D , Scarano G , Nazzaro A , Schoenle EJ . WNT4 deficiency–a clinical phenotype distinct from the classic Mayer‐Rokitansky‐Kuster‐Hauser syndrome: A case report. Hum Reprod 22: 224‐229, 2007.
 31. Biason‐Lauber A , Konrad D , Navratil F , Schoenle EJ . A WNT4 mutation associated with Mullerian‐duct regression and virilization in a 46,XX woman. N Engl J Med 351: 792‐798, 2004.
 32. Biason‐Lauber A , Schoenle EJ . Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF‐1) and adrenocortical insufficiency. Am J Hum Genet 67: 1563‐1568, 2000.
 33. Bicknell AB , Lomthaisong K , Woods RJ , Hutchinson EG , Bennett HP , Gladwell RT , Lowry PJ . Characterization of a serine protease that cleaves pro‐gamma‐melanotropin at the adrenal to stimulate growth. Cell 105: 903‐912, 2001.
 34. Blaker H , Sutter C , Kadmon M , Otto HF , Von Knebel‐Doeberitz M , Gebert J , Helmke BM . Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli. Gene Chromosome Canc 41: 93‐98, 2004.
 35. Bland ML , Jamieson CA , Akana SF , Bornstein SR , Eisenhofer G , Dallman MF , Ingraham HA . Haploinsufficiency of steroidogenic factor‐1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci U S A 97: 14488‐14493, 2000.
 36. Bliek J , Snijder S , Maas SM , Polstra A , van der Lip K , Alders M , Knegt AC , Mannens MM . Phenotypic discordance upon paternal or maternal transmission of duplications of the 11p15 imprinted regions. Eur J Med Genet 52: 404‐408, 2009.
 37. Bonnet S , Gaujoux S , Launay P , Baudry C , Chokri I , Ragazzon B , Libe R , Rene‐Corail F , Audebourg A , Vacher‐Lavenu MC , Groussin L , Bertagna X , Dousset B , Bertherat J , Tissier F . Wnt/beta‐catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1‐activating mutations, which are associated with larger and nonsecreting tumors: A study in cortisol‐secreting and ‐nonsecreting tumors. J Clin Endocrinol Metab 96: E419‐426, 2011.
 38. Bose J , Grotewold L , Ruther U . Pallister‐Hall syndrome phenotype in mice mutant for Gli3. Hum Mol Genet 11: 1129‐1135, 2002.
 39. Botrugno OA , Fayard E , Annicotte JS , Haby C , Brennan T , Wendling O , Tanaka T , Kodama T , Thomas W , Auwerx J , Schoonjans K . Synergy between LRH‐1 and beta‐catenin induces G1 cyclin‐mediated cell proliferation. Mol Cell 15: 499‐509, 2004.
 40. Bougeard G , Sesboue R , Baert‐Desurmont S , Vasseur S , Martin C , Tinat J , Brugieres L , Chompret A , de Paillerets BB , Stoppa‐Lyonnet D , Bonaiti‐Pellie C , Frebourg T . Molecular basis of the Li‐Fraumeni syndrome: An update from the French LFS families. J Med Genet 45: 535‐538, 2008.
 41. Boulle N , Baudin E , Gicquel C , Logie A , Bertherat J , Penfornis A , Bertagna X , Luton JP , Schlumberger M , Le Bouc Y. Evaluation of plasma insulin‐like growth factor binding protein‐2 as a marker for adrenocortical tumors. Eur J Endocrinol 144: 29‐36, 2001.
 42. Boulle N , Logie A , Gicquel C , Perin L , Le Bouc Y. Increased levels of insulin‐like growth factor II (IGF‐II) and IGF‐binding protein‐2 are associated with malignancy in sporadic adrenocortical tumors. J Clin Endocrinol Metab 83: 1713‐1720, 1998.
 43. Bourcigaux N , Gaston V , Logie A , Bertagna X , Le Bouc Y , Gicquel C . High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. J Clin Endocrinol Metab 85: 322‐330, 2000.
 44. Bourdeau I , Antonini SR , Lacroix A , Kirschner LS , Matyakhina L , Lorang D , Libutti SK , Stratakis CA . Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 23: 1575‐1585, 2004.
 45. Braganca J , Swingler T , Marques FI , Jones T , Eloranta JJ , Hurst HC , Shioda T , Bhattacharya S . Human CREB‐binding protein/p300‐interacting transactivator with ED‐rich tail (CITED) 4, a new member of the CITED family, functions as a co‐activator for transcription factor AP‐2. J Biol Chem 277: 8559‐8565, 2002.
 46. Bragulla H , Hirschberg RM , Schlotfeldt U , Stede M , Budras KD . On the structure of the adrenal gland of the common seal (Phoca vitulina vitulina). Anat Histol Embryol 33: 263‐272, 2004.
 47. Bremner R and Zacksenhaus E . Cyclins, Cdks, E2f, Skp2, and more at the first international RB Tumor Suppressor Meeting. Cancer Res 70: 6114‐6118, 2010.
 48. Brisken C , Heineman A , Chavarria T , Elenbaas B , Tan J , Dey SK , McMahon JA , McMahon AP , Weinberg RA . Essential function of Wnt‐4 in mammary gland development downstream of progesterone signaling. Genes Dev 14: 650‐654, 2000.
 49. Burglin TR . Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 25: 4173‐4180, 1997.
 50. Cadigan KM , Nusse R . Wnt signaling: A common theme in animal development. Genes Dev 11: 3286‐3305, 1997.
 51. Call KM , Glaser T , Ito CY , Buckler AJ , Pelletier J , Haber DA , Rose EA , Kral A , Yeger H , Lewis WH , et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60: 509‐520, 1990.
 52. Carney JA , Gordon H , Carpenter PC , Shenoy BV , Go VL . The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64: 270‐283, 1985.
 53. Caron de Fromentel C , Soussi T . TP53 tumor suppressor gene: A model for investigating human mutagenesis. Gene Chromosome Canc 4: 1‐15, 1992.
 54. Caron KM , Soo SC , Wetsel WC , Stocco DM , Clark BJ , Parker KL . Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 94: 11540‐11545, 1997.
 55. Chabre O , Libe R , Assie G , Barreau O , Bertherat J , Bertagna X , Feige JJ , Cherradi N . Serum miR‐483‐5p and miR‐195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr Relat Cancer 20: 579‐594, 2013.
 56. Chiang JM , Chou YH , Chen TC , Ng KF , Lin JL . Nuclear beta‐catenin expression is closely related to ulcerative growth of colorectal carcinoma. Br J Cancer 86: 1124‐1129, 2002.
 57. Chida D , Nakagawa S , Nagai S , Sagara H , Katsumata H , Imaki T , Suzuki H , Mitani F , Ogishima T , Shimizu C , Kotaki H , Kakuta S , Sudo K , Koike T , Kubo M , Iwakura Y . Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A 104: 18205‐18210, 2007.
 58. Ching S , Vilain E . Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis 47: 628‐637, 2009.
 59. Chompret A , Abel A , Stoppa‐Lyonnet D , Brugieres L , Pages S , Feunteun J , Bonaiti‐Pellie C . Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38: 43‐47, 2001.
 60. Chompret A , Brugieres L , Ronsin M , Gardes M , Dessarps‐Freichey F , Abel A , Hua D , Ligot L , Dondon MG , Bressac‐de Paillerets B , Frebourg T , Lemerle J , Bonaiti‐Pellie C , Feunteun J . P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 82: 1932‐1937, 2000.
 61. Clark AJ , Chan LF , Chung TT , Metherell LA . The genetics of familial glucocorticoid deficiency. Best Pract Res Clin Endocrinol Metab 23: 159‐165, 2009.
 62. Clark AJ , McLoughlin L , Grossman A . Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 341: 461‐462, 1993.
 63. Clement K , Dubern B , Mencarelli M , Czernichow P , Ito S , Wakamatsu K , Barsh GS , Vaisse C , Leger J . Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab 93: 4955‐4962, 2008.
 64. Clements WM , Wang J , Sarnaik A , Kim OJ , MacDonald J , Fenoglio‐Preiser C , Groden J , Lowy AM . beta‐Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 62: 3503‐3506, 2002.
 65. Clipsham R , McCabe ER . DAX1 and its network partners: Exploring complexity in development. Mol Genet Metab 80: 81‐120, 2003.
 66. Coll AP , Challis BG , Yeo GS , Snell K , Piper SJ , Halsall D , Thresher RR , O'Rahilly S . The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin. Endocrinology 145: 4721‐4727, 2004.
 67. Conkrite K , Sundby M , Mu D , Mukai S , MacPherson D . Cooperation between Rb and Arf in suppressing mouse retinoblastoma. J Clin Invest 122: 1726‐1733, 2012.
 68. Correa FH , Gomes MB . Diabetic pregnancy: Outpatient follow‐up in a Brazilian University Hospital. Arq Bras Endocrinol Metabol 48: 499‐504, 2004.
 69. Coulter CL. Fetal adrenal development: Insight gained from adrenal tumors. Trends Endocrinol Metab 16: 235‐242, 2005.
 70. Coutant R , Mallet D , Lahlou N , Bouhours‐Nouet N , Guichet A , Coupris L , Croue A , Morel Y . Heterozygous mutation of steroidogenic factor‐1 in 46,XY subjects may mimic partial androgen insensitivity syndrome. J Clin Endocrinol Metab 92: 2868‐2873, 2007.
 71. Crawford PA , Dorn C , Sadovsky Y , Milbrandt J . Nuclear receptor DAX‐1 recruits nuclear receptor corepressor N‐CoR to steroidogenic factor 1. Mol Cell Biol 18: 2949‐2956, 1998.
 72. Crowder RE . The development of the adrenal gland in man, with special reference to origin and ultimate location of cell types and evidence in favor of the “cell migration” theory. Contemp Embryol 251: 195‐209, 1957.
 73. Cui S , Ross A , Stallings N , Parker KL , Capel B , Quaggin SE . Disrupted gonadogenesis and male‐to‐female sex reversal in Pod1 knockout mice. Development 131: 4095‐4105, 2004.
 74. Custodio G , Komechen H , Figueiredo FR , Fachin ND , Pianovski MA , Figueiredo BC . Molecular epidemiology of adrenocortical tumors in southern Brazil. Mol Cell Endocrinol 351: 44‐51, 2012.
 75. Custodio G , Parise GA , Kiesel Filho N , Komechen H , Sabbaga CC , Rosati R , Grisa L , Parise IZ , Pianovski MA , Fiori CM , Ledesma JA , Barbosa JR , Figueiredo FR , Sade ER , Ibanez H , Arram SB , Stinghen ST , Mengarelli LR , Figueiredo MM , Carvalho DC , Avilla SG , Woiski TD , Poncio LC , Lima GF , Pontarolo R , Lalli E , Zhou Y , Zambetti GP , Ribeiro RC , Figueiredo BC . Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31: 2619‐2626, 2013.
 76. de Fraipont F , El Atifi M , Cherradi N , Le Moigne G , Defaye G , Houlgatte R , Bertherat J , Bertagna X , Plouin PF , Baudin E , Berger F , Gicquel C , Chabre O , Feige JJ . Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 90: 1819‐1829, 2005.
 77. De Martino MC , Al Ghuzlan A , Aubert S , Assie G , Scoazec JY , Leboulleux S , Do Cao C , Libe R , Nozieres C , Lombes M , Pattou F , Borson‐Chazot F , Hescot S , Mazoyer C , Young J , Borget I , Colao A , Pivonello R , Soria JC , Bertherat J , Schlumberger M , Lacroix L , Baudin E . Molecular screening for a personalized treatment approach in advanced adrenocortical cancer. J Clin Endocrinol Metab 98: 4080‐4088, 2013.
 78. de Reynies A , Assie G , Rickman DS , Tissier F , Groussin L , Rene‐Corail F , Dousset B , Bertagna X , Clauser E , Bertherat J . Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J Clin Oncol 27: 1108‐1115, 2009.
 79. Demars J , Gicquel C . Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith‐Wiedemann and Silver‐Russell syndromes. Clin Genet 81: 350‐361, 2012.
 80. DiGiammarino EL , Lee AS , Cadwell C , Zhang W , Bothner B , Ribeiro RC , Zambetti G , Kriwacki RW . A novel mechanism of tumorigenesis involving pH‐dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9: 12‐16, 2002.
 81. Doghman M , Cazareth J , Lalli E . The T cell factor/beta‐catenin antagonist PKF115‐584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab 93: 3222‐3225, 2008.
 82. Doghman M , El Wakil A , Cardinaud B , Thomas E , Wang J , Zhao W , Peralta‐Del Valle MH , Figueiredo BC , Zambetti GP , Lalli E . Regulation of insulin‐like growth factor‐mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 70: 4666‐4675, 2010.
 83. Dohna M , Reincke M , Mincheva A , Allolio B , Solinas‐Toldo S , Lichter P . Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high‐level amplifications. Genes Chromosomes Cancer 28: 145‐152, 2000.
 84. Drelon C , Berthon A , Ragazzon B , Tissier F , Bandiera R , Sahut‐Barnola I , de Joussineau C , Batisse‐Lignier M , Lefrancois‐Martinez AM , Bertherat J , Martinez A , Val P . Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models. PLoS One 7: e44171, 2012.
 85. Dubourg C , Lazaro L , Pasquier L , Bendavid C , Blayau M , Le Duff F , Durou MR , Odent S , David V . Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype‐phenotype correlations. Hum Mutat 24: 43‐51, 2004.
 86. Else T , Hammer GD . Genetic analysis of adrenal absence: Agenesis and aplasia. Trends Endocrinol Metab 16: 458‐468, 2005.
 87. Else T , Trovato A , Kim AC , Wu Y , Ferguson DO , Kuick RD , Lucas PC , Hammer GD . Genetic p53 deficiency partially rescues the adrenocortical dysplasia phenotype at the expense of increased tumorigenesis. Cancer Cell 15: 465‐476, 2009.
 88. Estivariz FE , Carino M , Lowry PJ , Jackson S . Further evidence that N‐terminal pro‐opiomelanocortin peptides are involved in adrenal mitogenesis. J Endocrinol 116: 201‐206, 1988.
 89. Estivariz FE , Iturriza F , McLean C , Hope J , Lowry PJ . Stimulation of adrenal mitogenesis by N‐terminal proopiocortin peptides. Nature 297: 419‐422, 1982.
 90. Estivariz FE , Morano MI , Carino M , Jackson S , Lowry PJ . Adrenal regeneration in the rat is mediated by mitogenic N‐terminal pro‐opiomelanocortin peptides generated by changes in precursor processing in the anterior pituitary. J Endocrinol 116: 207‐216, 1988.
 91. Evelyn HM . A transitory zone in the adrenal cortex which shows age and sex relationships. Am J Anat 40: 251‐293, 1927.
 92. Fabbri HC , de Andrade JG , Soardi FC , de Calais FL , Petroli RJ , Maciel‐Guerra AT , Guerra‐Junior G , de Mello MP . The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency. BMC Med Genet 15: 7, 2014.
 93. Farooqi IS , Drop S , Clements A , Keogh JM , Biernacka J , Lowenbein S , Challis BG , O'Rahilly S . Heterozygosity for a POMC‐null mutation and increased obesity risk in humans. Diabetes 55: 2549‐2553, 2006.
 94. Fassnacht M , Hahner S , Hansen IA , Kreutzberger T , Zink M , Adermann K , Jakob F , Troppmair J , Allolio B . N‐terminal proopiomelanocortin acts as a mitogen in adrenocortical tumor cells and decreases adrenal steroidogenesis. J Clin Endocrinol Metab 88: 2171‐2179, 2003.
 95. Fernandez‐Ranvier GG , Weng J , Yeh RF , Khanafshar E , Suh I , Barker C , Duh QY , Clark OH , Kebebew E . Identification of biomarkers of adrenocortical carcinoma using genomewide gene expression profiling. Arch Surg 143: 841‐846; discussion 846, 2008.
 96. Fernandez‐Ranvier GG , Weng J , Yeh RF , Shibru D , Khafnashar E , Chung KW , Hwang J , Duh QY , Clark OH , Kebebew E . Candidate diagnostic markers and tumor suppressor genes for adrenocortical carcinoma by expression profile of genes on chromosome 11q13. World J Surg 32: 873‐881, 2008.
 97. Ferraz‐de‐Souza B , Martin F , Mallet D , Hudson‐Davies RE , Cogram P , Lin L , Gerrelli D , Beuschlein F , Morel Y , Huebner A , Achermann JC . CBP/p300‐interacting transactivator, with Glu/Asp‐rich C‐terminal domain, 2, and pre‐B‐cell leukemia transcription factor 1 in human adrenal development and disease. J Clin Endocrinol Metab 94: 678‐683, 2009.
 98. Ferruzzi P , Ceni E , Tarocchi M , Grappone C , Milani S , Galli A , Fiorelli G , Serio M , Mannelli M . Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J Clin Endocrinol Metab 90: 1332‐1339, 2005.
 99. Fonseca AL , Kugelberg J , Starker LF , Scholl U , Choi M , Hellman P , Akerstrom G , Westin G , Lifton RP , Bjorklund P , Carling T . Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors. Genes Chromosomes Cancer 51: 949‐960, 2012.
 100. Fragoso MC , Almeida MQ , Mazzuco TL , Mariani BM , Brito LP , Goncalves TC , Alencar GA , Lima Lde O , Faria AM , Bourdeau I , Lucon AM , Freire DS , Latronico AC , Mendonca BB , Lacroix A , Lerario AM . Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: Validation in a Brazilian cohort of adult and pediatric patients. Eur J Endocrinol 166: 61‐67, 2012.
 101. Freedman BD , Kempna PB , Carlone DL , Shah MS , Guagliardo NA , Barrett PQ , Gomez‐Sanchez CE , Majzoub JA , Breault DT . Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell 26: 666‐673, 2013.
 102. Freeman H , Shimomura K , Cox RD , Ashcroft FM . Nicotinamide nucleotide transhydrogenase: A link between insulin secretion, glucose metabolism and oxidative stress. Biochem Soc Trans 34: 806‐810, 2006.
 103. Fuhrman SA , Lasky LC , Limas C . Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6: 655‐663, 1982.
 104. Gatta‐Cherifi B , Chabre O , Murat A , Niccoli P , Cardot‐Bauters C , Rohmer V , Young J , Delemer B , Du Boullay H , Verger MF , Kuhn JM , Sadoul JL , Ruszniewski P , Beckers A , Monsaingeon M , Baudin E , Goudet P , Tabarin A . Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database. Eur J Endocrinol 166: 269‐279, 2012.
 105. Gaujoux S , Grabar S , Fassnacht M , Ragazzon B , Launay P , Libe R , Chokri I , Audebourg A , Royer B , Sbiera S , Vacher‐Lavenu MC , Dousset B , Bertagna X , Allolio B , Bertherat J , Tissier F . beta‐catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma. Clin Cancer Res 17: 328‐336, 2011.
 106. Gaujoux S , Hantel C , Launay P , Bonnet S , Perlemoine K , Lefevre L , Guillaud‐Bataille M , Beuschlein F , Tissier F , Bertherat J , Rizk‐Rabin M , Ragazzon B . Silencing mutated beta‐catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R. PLoS One 8: e55743, 2013.
 107. Gaujoux S , Pinson S , Gimenez‐Roqueplo AP , Amar L , Ragazzon B , Launay P , Meatchi T , Libe R , Bertagna X , Audebourg A , Zucman‐Rossi J , Tissier F , Bertherat J . Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers. Clin Cancer Res 16: 5133‐5141, 2010.
 108. Gekle M , Grossmann C . Actions of aldosterone in the cardiovascular system: The good, the bad, and the ugly? Pflugers Arch 458: 231‐246, 2009.
 109. Gessler M , Poustka A , Cavenee W , Neve RL , Orkin SH , Bruns GA . Homozygous deletion in Wilms tumours of a zinc‐finger gene identified by chromosome jumping. Nature 343: 774‐778, 1990.
 110. Giacomazzi J , Koehler‐Santos P , Palmero EI , Graudenz MS , Rivero LF , Lima E , Putten AC , Hainaut P , Camey SA , Michelli RD , Neto CS , Fitarelli‐Kiehl M , Geyer G , Meurer L , Geiger A , Azevedo MB , da Silva VD , Ashton‐Prolla P . A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil. Virchows Arch 463: 17‐22, 2013.
 111. Gicquel C , Bertagna X , Gaston V , Coste J , Louvel A , Baudin E , Bertherat J , Chapuis Y , Duclos JM , Schlumberger M , Plouin PF , Luton JP , Le Bouc Y . Molecular markers and long‐term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61: 6762‐6767, 2001.
 112. Gicquel C , Bertagna X , Schneid H , Francillard‐Leblond M , Luton JP , Girard F , Le Bouc Y . Rearrangements at the 11p15 locus and overexpression of insulin‐like growth factor‐II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 78: 1444‐1453, 1994.
 113. Gicquel C , Raffin‐Sanson ML , Gaston V , Bertagna X , Plouin PF , Schlumberger M , Louvel A , Luton JP , Le Bouc Y . Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: Study on a series of 82 tumors. J Clin Endocrinol Metab 82: 2559‐2565, 1997.
 114. Giles RH , van Es JH , Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653: 1‐24, 2003.
 115. Giordano TJ , Kuick R , Else T , Gauger PG , Vinco M , Bauersfeld J , Sanders D , Thomas DG , Doherty G , Hammer G . Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res 15: 668‐676, 2009.
 116. Giordano TJ , Thomas DG , Kuick R , Lizyness M , Misek DE , Smith AL , Sanders D , Aljundi RT , Gauger PG , Thompson NW , Taylor JM , Hanash SM . Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162: 521‐531, 2003.
 117. Gray ES , Abramovich DR . Morphologic features of the anencephalic adrenal gland in early pregnancy. Am J Obstet Gynecol 137: 491‐495, 1980.
 118. Grumbach MM , Biller BM , Braunstein GD , Campbell KK , Carney JA , Godley PA , Harris EL , Lee JK , Oertel YC , Posner MC , Schlechte JA , Wieand HS . Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 138: 424‐429, 2003.
 119. Guaragna MS , Lutaif AC , Piveta CS , Belangero VM , Maciel‐Guerra AT , Guerra G, Jr , De Mello MP . Two distinct WT1 mutations identified in patients and relatives with isolated nephrotic proteinuria. Biochem Biophys Res Commun 441: 371‐376, 2013.
 120. Guimier A , Ragazzon B , Assie G , Tissier F , Dousset B , Bertherat J , Gaujoux S . AXIN genetic analysis in adrenocortical carcinomas updated. J Endocrinol Invest 36: 1000‐1003, 2013.
 121. Gummow BM , Scheys JO , Cancelli VR , Hammer GD . Reciprocal regulation of a glucocorticoid receptor‐steroidogenic factor‐1 transcription complex on the Dax‐1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex. Mol Endocrinol 20: 2711‐2723, 2006.
 122. Gummow BM , Winnay JN , Hammer GD . Convergence of Wnt signaling and steroidogenic factor‐1 (SF‐1) on transcription of the rat inhibin alpha gene. J Biol Chem 278: 26572‐26579, 2003.
 123. Guo X , Deng Y , Lin Y , Cosme‐Blanco W , Chan S , He H , Yuan G , Brown EJ , Chang S . Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis. EMBO J 26: 4709‐4719, 2007.
 124. Haber DA , Buckler AJ , Glaser T , Call KM , Pelletier J , Sohn RL , Douglass EC , Housman DE . An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 61: 1257‐1269, 1990.
 125. Haegel H , Larue L , Ohsugi M , Fedorov L , Herrenknecht K , Kemler R . Lack of beta‐catenin affects mouse development at gastrulation. Development 121: 3529‐3537, 1995.
 126. Hammer GD , Ingraham HA . Steroidogenic factor‐1: Its role in endocrine organ development and differentiation. Front Neuroendocrinol 20: 199‐223, 1999.
 127. Hammer GD , Parker KL , Schimmer BP . Minireview: Transcriptional regulation of adrenocortical development. Endocrinology 146: 1018‐1024, 2005.
 128. Hanley NA , Rainey WE , Wilson DI , Ball SG , Parker KL . Expression profiles of SF‐1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation. Mol Endocrinol 15: 57‐68, 2001.
 129. Hao HX , Xie Y , Zhang Y , Charlat O , Oster E , Avello M , Lei H , Mickanin C , Liu D , Ruffner H , Mao X , Ma Q , Zamponi R , Bouwmeester T , Finan PM , Kirschner MW , Porter JA , Serluca FC , Cong F . ZNRF3 promotes Wnt receptor turnover in an R‐spondin‐sensitive manner. Nature 485: 195‐200, 2012.
 130. Harding B , Lemos MC , Reed AA , Walls GV , Jeyabalan J , Bowl MR , Tateossian H , Sullivan N , Hough T , Fraser WD , Ansorge O , Cheeseman MT , Thakker RV . Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer 16: 1313‐1327, 2009.
 131. Hasegawa T , Fukami M , Sato N , Katsumata N , Sasaki G , Fukutani K , Morohashi K , Ogata T . Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor‐1. J Clin Endocrinol Metab 89: 5930‐5935, 2004.
 132. Hatano O , Takakusu A , Nomura M , Morohashi K . Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF‐1. Genes Cells 1: 663‐671, 1996.
 133. Hatano O , Takayama K , Imai T , Waterman MR , Takakusu A , Omura T , Morohashi K . Sex‐dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P‐450 genes in the gonads during prenatal and postnatal rat development. Development 120: 2787‐2797, 1994.
 134. Hattangady NG , Olala LO , Bollag WB , Rainey WE . Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350: 151‐162, 2012.
 135. Heaton JH , Wood MA , Kim AC , Lima LO , Barlaskar FM , Almeida MQ , Fragoso MC , Kuick R , Lerario AM , Simon DP , Soares IC , Starnes E , Thomas DG , Latronico AC , Giordano TJ , Hammer GD . Progression to adrenocortical tumorigenesis in mice and humans through insulin‐like growth factor 2 and beta‐catenin. Am J Pathol 181: 1017‐1033, 2012.
 136. Heikkila M , Peltoketo H , Leppaluoto J , Ilves M , Vuolteenaho O , Vainio S . Wnt‐4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143: 4358‐4365, 2002.
 137. Henry I , Jeanpierre M , Couillin P , Barichard F , Serre JL , Journel H , Lamouroux A , Turleau C , de Grouchy J , Junien C . Molecular definition of the 11p15.5 region involved in Beckwith‐Wiedemann syndrome and probably in predisposition to adrenocortical carcinoma. Hum Genet 81: 273‐277, 1989.
 138. Heppner C , Reincke M , Agarwal SK , Mora P , Allolio B , Burns AL , Spiegel AM , Marx SJ . MEN1 gene analysis in sporadic adrenocortical neoplasms. J Clin Endocrinol Metab 84: 216‐219, 1999.
 139. Herrmann LJ , Heinze B , Fassnacht M , Willenberg HS , Quinkler M , Reisch N , Zink M , Allolio B , Hahner S . TP53 germline mutations in adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 97: E476‐485, 2012.
 140. Hershkovitz L , Beuschlein F , Klammer S , Krup M , Weinstein Y . Adrenal 20alpha‐hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11‐deoxycorticosterone and is restricted to the X‐zone. Endocrinology 148: 976‐988, 2007.
 141. Hisada M , Garber JE , Fung CY , Fraumeni JF, Jr , Li FP . Multiple primary cancers in families with Li‐Fraumeni syndrome. J Natl Cancer Inst 90: 606‐611, 1998.
 142. Hockemeyer D , Palm W , Else T , Daniels JP , Takai KK , Ye JZ , Keegan CE , de Lange T , Hammer GD . Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol 14: 754‐761, 2007.
 143. Holland JD , Klaus A , Garratt AN , Birchmeier W . Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 25: 254‐264, 2013.
 144. Hollstein M , Sidransky D , Vogelstein B , Harris CC . p53 mutations in human cancers. Science 253: 49‐53, 1991.
 145. Honda S , Morohashi K , Nomura M , Takeya H , Kitajima M , Omura T . Ad4BP regulating steroidogenic P‐450 gene is a member of steroid hormone receptor superfamily. J Biol Chem 268: 7494‐7502, 1993.
 146. Hosogi H , Nagayama S , Kanamoto N , Yoshizawa A , Suzuki T , Nakao K , Sakai Y . Biallelic APC inactivation was responsible for functional adrenocortical adenoma in familial adenomatous polyposis with novel germline mutation of the APC gene: Report of a case. Jpn J Clin Oncol 39: 837‐846, 2009.
 147. Hossain A , Saunders GF . Synergistic cooperation between the beta‐catenin signaling pathway and steroidogenic factor 1 in the activation of the Mullerian inhibiting substance type II receptor. J Biol Chem 278: 26511‐26516, 2003.
 148. Houghtaling BR , Cuttonaro L , Chang W , Smith S . A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14: 1621‐1631, 2004.
 149. Huang CC , Miyagawa S , Matsumaru D , Parker KL , Yao HH . Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology 151: 1119‐1128, 2010.
 150. Hughes CR , Guasti L , Meimaridou E , Chuang CH , Schimenti JC , King PJ , Costigan C , Clark AJ , Metherell LA . MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest 122: 814‐820, 2012.
 151. Hutz JE , Krause AS , Achermann JC , Vilain E , Tauber M , Lecointre C , McCabe ER , Hammer GD , Keegan CE . IMAGe association and congenital adrenal hypoplasia: No disease‐causing mutations found in the ACD gene. Mol Genet Metab 88: 66‐70, 2006.
 152. Ikeda Y , Lala DS , Luo X , Kim E , Moisan MP , Parker KL . Characterization of the mouse FTZ‐F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol 7: 852‐860, 1993.
 153. Ikeda Y , Luo X , Abbud R , Nilson JH , Parker KL . The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol 9: 478‐486, 1995.
 154. Ikeda Y , Shen WH , Ingraham HA , Parker KL . Developmental expression of mouse steroidogenic factor‐1, an essential regulator of the steroid hydroxylases. Mol Endocrinol 8: 654‐662, 1994.
 155. Ilvesmaki V , Blum WF , Voutilainen R . Insulin‐like growth factor‐II in human fetal adrenals: Regulation by ACTH, protein kinase C and growth factors. J Endocrinol 137: 533‐542, 1993.
 156. Ilvesmaki V , Blum WF , Voutilainen R . Insulin‐like growth factor binding proteins in the human adrenal gland. Mol Cell Endocrinol 97: 71‐79, 1993.
 157. Ingraham HA , Lala DS , Ikeda Y , Luo X , Shen WH , Nachtigal MW , Abbud R , Nilson JH , Parker KL . The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8: 2302‐2312, 1994.
 158. Inui M , Martello G , Piccolo S . MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 11: 252‐263, 2010.
 159. Ito M , Yu R , Jameson JL . DAX‐1 inhibits SF‐1‐mediated transactivation via a carboxy‐terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17: 1476‐1483, 1997.
 160. Jackson RS , Creemers JW , Ohagi S , Raffin‐Sanson ML , Sanders L , Montague CT , Hutton JC , O'Rahilly S . Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16: 303‐306, 1997.
 161. Jacobs Y , Schnabel CA , Cleary ML . Trimeric association of Hox and TALE homeodomain proteins mediates Hoxb2 hindbrain enhancer activity. Mol Cell Biol 19: 5134‐5142, 1999.
 162. Jadhav U , Harris RM , Jameson JL . Hypogonadotropic hypogonadism in subjects with DAX1 mutations. Mol Cell Endocrinol 346: 65‐73, 2011.
 163. Jeays‐Ward K , Hoyle C , Brennan J , Dandonneau M , Alldus G , Capel B , Swain A . Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 130: 3663‐3670, 2003.
 164. Jordan BK , Mohammed M , Ching ST , Delot E , Chen XN , Dewing P , Swain A , Rao PN , Elejalde BR , Vilain E . Up‐regulation of WNT‐4 signaling and dosage‐sensitive sex reversal in humans. Am J Hum Genet 68: 1102‐1109, 2001.
 165. Jordan BK , Shen JH , Olaso R , Ingraham HA , Vilain E . Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta‐catenin synergy. Proc Natl Acad Sci U S A 100: 10866‐10871, 2003.
 166. Kang S , Graham JM, Jr , Olney AH , Biesecker LG . GLI3 frameshift mutations cause autosomal dominant Pallister‐Hall syndrome. Nat Genet 15: 266‐268, 1997.
 167. Karamurzin Y , Zeng Z , Stadler ZK , Zhang L , Ouansafi I , Al‐Ahmadie HA , Sempoux C , Saltz LB , Soslow RA , O'Reilly EM , Paty PB , Coit DG , Shia J , Klimstra DS . Unusual DNA mismatch repair‐deficient tumors in Lynch syndrome: A report of new cases and review of the literature. Hum Pathol 43: 1677‐1687, 2012.
 168. Karpac J , Ostwald D , Bui S , Hunnewell P , Shankar M , Hochgeschwender U . Development, maintenance, and function of the adrenal gland in early postnatal proopiomelanocortin‐null mutant mice. Endocrinology 146: 2555‐2562, 2005.
 169. Keegan CE , Hammer GD . Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab 13: 200‐208, 2002.
 170. Keegan CE , Hutz JE , Else T , Adamska M , Shah SP , Kent AE , Howes JM , Beamer WG , Hammer GD . Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Hum Mol Genet 14: 113‐123, 2005.
 171. Kelly VR , Xu B , Kuick R , Koenig RJ , Hammer GD . Dax1 up‐regulates Oct4 expression in mouse embryonic stem cells via LRH‐1 and SRA. Mol Endocrinol 24: 2281‐2291, 2010.
 172. Khalfallah O , Rouleau M , Barbry P , Bardoni B , Lalli E . Dax‐1 knockdown in mouse embryonic stem cells induces loss of pluripotency and multilineage differentiation. Stem Cells 27: 1529‐1537, 2009.
 173. Kikuchi A. Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci 94: 225‐229, 2003.
 174. Kim AC , Barlaskar FM , Heaton JH , Else T , Kelly VR , Krill KT , Scheys JO , Simon DP , Trovato A , Yang WH , Hammer GD . In search of adrenocortical stem and progenitor cells. Endocr Rev 30: 241‐263, 2009.
 175. Kim AC , Reuter AL , Zubair M , Else T , Serecky K , Bingham NC , Lavery GG , Parker KL , Hammer GD . Targeted disruption of beta‐catenin in Sf1‐expressing cells impairs development and maintenance of the adrenal cortex. Development 135: 2593‐2602, 2008.
 176. King P , Paul A , Laufer E . Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A 106: 21185‐21190, 2009.
 177. Kjellman M , Kallioniemi OP , Karhu R , Hoog A , Farnebo LO , Auer G , Larsson C , Backdahl M . Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56: 4219‐4223, 1996.
 178. Kjellman M , Roshani L , Teh BT , Kallioniemi OP , Hoog A , Gray S , Farnebo LO , Holst M , Backdahl M , Larsson C . Genotyping of adrenocortical tumors: Very frequent deletions of the MEN1 locus in 11q13 and of a 1‐centimorgan region in 2p16. J Clin Endocrinol Metab 84: 730‐735, 1999.
 179. Kohler B , Lin L , Ferraz‐de‐Souza B , Wieacker P , Heidemann P , Schroder V , Biebermann H , Schnabel D , Gruters A , Achermann JC . Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat 29: 59‐64, 2008.
 180. Kohler B , Lin L , Mazen I , Cetindag C , Biebermann H , Akkurt I , Rossi R , Hiort O , Gruters A , Achermann JC . The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF‐1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol 161: 237‐242, 2009.
 181. Kreidberg JA , Sariola H , Loring JM , Maeda M , Pelletier J , Housman D , Jaenisch R . WT‐1 is required for early kidney development. Cell 74: 679‐691, 1993.
 182. Krude H , Biebermann H , Luck W , Horn R , Brabant G , Gruters A . Severe early‐onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155‐157, 1998.
 183. Krude H , Biebermann H , Schnabel D , Tansek MZ , Theunissen P , Mullis PE , Gruters A . Obesity due to proopiomelanocortin deficiency: Three new cases and treatment trials with thyroid hormone and ACTH4‐10. J Clin Endocrinol Metab 88: 4633‐4640, 2003.
 184. Kuhl SJ , Kuhl M . On the role of Wnt/beta‐catenin signaling in stem cells. Biochim Biophys Acta 1830: 2297‐2306, 2013.
 185. Lala DS , Rice DA , Parker KL . Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu‐factor I. Mol Endocrinol 6: 1249‐1258, 1992.
 186. Lalli E , Bardoni B , Zazopoulos E , Wurtz JM , Strom TM , Moras D , Sassone‐Corsi P . A transcriptional silencing domain in DAX‐1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol 11: 1950‐1960, 1997.
 187. Lalli E , Melner MH , Stocco DM , Sassone‐Corsi P . DAX‐1 blocks steroid production at multiple levels. Endocrinology 139: 4237‐4243, 1998.
 188. Lalli E , Sassone‐Corsi P . DAX‐1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. Mol Endocrinol 17: 1445‐1453, 2003.
 189. Lam WW , Hatada I , Ohishi S , Mukai T , Joyce JA , Cole TR , Donnai D , Reik W , Schofield PN , Maher ER . Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith‐Wiedemann syndrome (BWS) provides a novel genotype‐phenotype correlation. J Med Genet 36: 518‐523, 1999.
 190. Lamolet B , Pulichino AM , Lamonerie T , Gauthier Y , Brue T , Enjalbert A , Drouin J . A pituitary cell‐restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104: 849‐859, 2001.
 191. Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: A comprehensive review. Am J Med Genet C Semin Med Genet 137C: 53‐71, 2005.
 192. Latronico AC , Pinto EM , Domenice S , Fragoso MC , Martin RM , Zerbini MC , Lucon AM , Mendonca BB . An inherited mutation outside the highly conserved DNA‐binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. J Clin Endocrinol Metab 86: 4970‐4973, 2001.
 193. Lau SK , Weiss LM . The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol 40: 757‐768, 2009.
 194. Laurell C , Velazquez‐Fernandez D , Lindsten K , Juhlin C , Enberg U , Geli J , Hoog A , Kjellman M , Lundeberg J , Hamberger B , Larsson C , Nilsson P , Backdahl M . Transcriptional profiling enables molecular classification of adrenocortical tumours. Eur J Endocrinol 161: 141‐152, 2009.
 195. Laurent‐Puig P , Legoix P , Bluteau O , Belghiti J , Franco D , Binot F , Monges G , Thomas G , Bioulac‐Sage P , Zucman‐Rossi J . Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 120: 1763‐1773, 2001.
 196. Lazaro L , Dubourg C , Pasquier L , Le Duff F , Blayau M , Durou MR , de la Pintiere AT , Aguilella C , David V , Odent S . Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A 129A: 21‐24, 2004.
 197. Lee FY , Faivre EJ , Suzawa M , Lontok E , Ebert D , Cai F , Belsham DD , Ingraham HA . Eliminating SF‐1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Dev Cell 21: 315‐327, 2011.
 198. Lefrancois‐Martinez AM , Bertherat J , Val P , Tournaire C , Gallo‐Payet N , Hyndman D , Veyssiere G , Bertagna X , Jean C , Martinez A . Decreased expression of cyclic adenosine monophosphate‐regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors. J Clin Endocrinol Metab 89: 3010‐3019, 2004.
 199. Lehmann SG , Lalli E , Sassone‐Corsi P . X‐linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX‐1 protein. Proc Natl Acad Sci U S A 99: 8225‐8230, 2002.
 200. Li FP , Fraumeni JF, Jr . Soft‐tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71: 747‐752, 1969.
 201. Li FP , Fraumeni JF, Jr , Mulvihill JJ , Blattner WA , Dreyfus MG , Tucker MA , Miller RW . A cancer family syndrome in twenty‐four kindreds. Cancer Res 48: 5358‐5362, 1988.
 202. Li M , Squire JA , Weksberg R . Molecular genetics of Beckwith‐Wiedemann syndrome. Curr Opin Pediatr 9: 623‐629, 1997.
 203. Li M , Squire JA , Weksberg R . Molecular genetics of Wiedemann‐Beckwith syndrome. Am J Med Genet 79: 253‐259, 1998.
 204. Libe R , Bertherat J . Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153: 477‐487, 2005.
 205. Libe R , Groussin L , Tissier F , Elie C , Rene‐Corail F , Fratticci A , Jullian E , Beck‐Peccoz P , Bertagna X , Gicquel C , Bertherat J . Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin Cancer Res 13: 844‐850, 2007.
 206. Lienhardt A , Mas JC , Kalifa G , Chaussain JL , Tauber M . IMAGe association: Additional clinical features and evidence for recessive autosomal inheritance. Horm Res 57(Suppl 2): 71‐78, 2002.
 207. Lin L , Philibert P , Ferraz‐de‐Souza B , Kelberman D , Homfray T , Albanese A , Molini V , Sebire NJ , Einaudi S , Conway GS , Hughes IA , Jameson JL , Sultan C , Dattani MT , Achermann JC . Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab 92: 991‐999, 2007.
 208. Liu D , Safari A , O'Connor MS , Chan DW , Laegeler A , Qin J , Songyang Z . PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6: 673‐680, 2004.
 209. Logan CY , Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781‐810, 2004.
 210. Logie A , Boulle N , Gaston V , Perin L , Boudou P , Le Bouc Y , Gicquel C . Autocrine role of IGF‐II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J Mol Endocrinol 23: 23‐32, 1999.
 211. Lombardi CP , Raffaelli M , Pani G , Maffione A , Princi P , Traini E , Galeotti T , Rossi ED , Fadda G , Bellantone R . Gene expression profiling of adrenal cortical tumors by cDNA macroarray analysis. Results of a preliminary study. Biomed Pharmacother 60: 186‐190, 2006.
 212. Lourenco D , Brauner R , Lin L , De Perdigo A , Weryha G , Muresan M , Boudjenah R , Guerra‐Junior G , Maciel‐Guerra AT , Achermann JC , McElreavey K , Bashamboo A . Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360: 1200‐1210, 2009.
 213. Lowry PJ , Silas L , McLean C , Linton EA , Estivariz FE . Pro‐gamma‐melanocyte‐stimulating hormone cleavage in adrenal gland undergoing compensatory growth. Nature 306: 70‐73, 1983.
 214. Lu J , Getz G , Miska EA , Alvarez‐Saavedra E , Lamb J , Peck D , Sweet‐Cordero A , Ebert BL , Mak RH , Ferrando AA , Downing JR , Jacks T , Horvitz HR , Golub TR . MicroRNA expression profiles classify human cancers. Nature 435: 834‐838, 2005.
 215. Lu J , Richardson JA , Olson EN . Capsulin: A novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs. Mech Dev 73: 23‐32, 1998.
 216. Luo X , Ikeda Y , Parker KL . A cell‐specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77: 481‐490, 1994.
 217. Luo X , Ikeda Y , Schlosser DA , Parker KL . Steroidogenic factor 1 is the essential transcript of the mouse Ftz‐F1 gene. Mol Endocrinol 9: 1233‐1239, 1995.
 218. Luton JP , Martinez M , Coste J , Bertherat J . Outcome in patients with adrenal incidentaloma selected for surgery: An analysis of 88 cases investigated in a single clinical center. Eur J Endocrinol 143: 111‐117, 2000.
 219. Lynch HT , Shaw MW , Magnuson CW , Larsen AL , Krush AJ . Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 117: 206‐212, 1966.
 220. Mallet D , Bretones P , Michel‐Calemard L , Dijoud F , David M , Morel Y . Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: A case of SF1 haploinsufficiency. J Clin Endocrinol Metab 89: 4829‐4832, 2004.
 221. Mantero F , Terzolo M , Arnaldi G , Osella G , Masini AM , Ali A , Giovagnetti M , Opocher G , Angeli A . A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 85: 637‐644, 2000.
 222. Marchesa P , Fazio VW , Church JM , McGannon E . Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum 40: 1023‐1028, 1997.
 223. Marini F , Falchetti A , Luzi E , Tonelli F , Maria Luisa B . Multiple endocrine neoplasia type 1 (MEN1) syndrome. In: Riegert‐Johnson DL , Boardman LA , Hefferon T , Roberts M , editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information, 2009.
 224. Marney AM , Brown NJ . Aldosterone and end‐organ damage. Clin Sci (Lond) 113: 267‐278, 2007.
 225. Masi G , Lavezzo E , Iacobone M , Favia G , Palu G , Barzon L . Investigation of BRAF and CTNNB1 activating mutations in adrenocortical tumors. J Endocrinol Invest 32: 597‐600, 2009.
 226. Meeks JJ , Weiss J , Jameson JL . Dax1 is required for testis determination. Nat Genet 34: 32‐33, 2003.
 227. Meimaridou E , Hughes CR , Kowalczyk J , Guasti L , Chapple JP , King PJ , Chan LF , Clark AJ , Metherell LA . Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol 371: 195‐200, 2013.
 228. Meimaridou E , Kowalczyk J , Guasti L , Hughes CR , Wagner F , Frommolt P , Nurnberg P , Mann NP , Banerjee R , Saka HN , Chapple JP , King PJ , Clark AJ , Metherell LA . Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet 44: 740‐742, 2012.
 229. Melo KF , Martin RM , Costa EM , Carvalho FM , Jorge AA , Arnhold IJ , Mendonca BB . An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: Predominantly male ambiguous genitalia and absence of gonadal dysgenesis. J Clin Endocrinol Metab 87: 2500‐2505, 2002.
 230. Mendiratta MS , Yang Y , Balazs AE , Willis AS , Eng CM , Karaviti LP , Potocki L . Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinol 2011: 5, 2011.
 231. Mesiano S , Jaffe RB . Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 18: 378‐403, 1997.
 232. Mesiano S , Mellon SH , Jaffe RB . Mitogenic action, regulation, and localization of insulin‐like growth factors in the human fetal adrenal gland. J Clin Endocrinol Metab 76: 968‐976, 1993.
 233. Metherell LA , Chan LF , Clark AJ . The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab 20: 547‐560, 2006.
 234. Metherell LA , Chapple JP , Cooray S , David A , Becker C , Ruschendorf F , Naville D , Begeot M , Khoo B , Nurnberg P , Huebner A , Cheetham ME , Clark AJ . Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 37: 166‐170, 2005.
 235. Metherell LA , Naville D , Halaby G , Begeot M , Huebner A , Nurnberg G , Nurnberg P , Green J , Tomlinson JW , Krone NP , Lin L , Racine M , Berney DM , Achermann JC , Arlt W , Clark AJ . Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab 94: 3865‐3871, 2009.
 236. Monticone S , Auchus RJ , Rainey WE . Adrenal disorders in pregnancy. Nat Rev Endocrinol 8: 668‐678, 2012.
 237. Moore AW , McInnes L , Kreidberg J , Hastie ND , Schedl A . YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126: 1845‐1857, 1999.
 238. Morin E , Mete O , Wasserman JD , Joshua AM , Asa SL , Ezzat S . Carney complex with adrenal cortical carcinoma. J Clin Endocrinol Metab 97: E202‐206, 2012.
 239. Morohashi K , Honda S , Inomata Y , Handa H , Omura T . A common trans‐acting factor, Ad4‐binding protein, to the promoters of steroidogenic P‐450s. J Biol Chem 267: 17913‐17919, 1992.
 240. Morohashi K , Iida H , Nomura M , Hatano O , Honda S , Tsukiyama T , Niwa O , Hara T , Takakusu A , Shibata Y , et al. Functional difference between Ad4BP and ELP, and their distributions in steroidogenic tissues. Mol Endocrinol 8: 643‐653, 1994.
 241. Morohashi K , Tsuboi‐Asai H , Matsushita S , Suda M , Nakashima M , Sasano H , Hataba Y , Li CL , Fukata J , Irie J , Watanabe T , Nagura H , Li E . Structural and functional abnormalities in the spleen of an mFtz‐F1 gene‐disrupted mouse. Blood 93: 1586‐1594, 1999.
 242. Nachtigal MW , Hirokawa Y , Enyeart‐VanHouten DL , Flanagan JN , Hammer GD , Ingraham HA . Wilms' tumor 1 and Dax‐1 modulate the orphan nuclear receptor SF‐1 in sex‐specific gene expression. Cell 93: 445‐454, 1998.
 243. Naylor EW , Gardner EJ . Adrenal adenomas in a patient with Gardner's syndrome. Clin Genet 20: 67‐73, 1981.
 244. Nedumaran B , Hong S , Xie YB , Kim YH , Seo WY , Lee MW , Lee CH , Koo SH , Choi HS . DAX‐1 acts as a novel corepressor of orphan nuclear receptor HNF4alpha and negatively regulates gluconeogenic enzyme gene expression. J Biol Chem 284: 27511‐27523, 2009.
 245. Nickerson PA , Brownie AC , Skelton FR . An electron microscopic study of the regenerating adrenal gland during the development of adrenal regeneration hypertension. Am J Pathol 57: 335‐364, 1969.
 246. Ogawa O , Eccles MR , Szeto J , McNoe LA , Yun K , Maw MA , Smith PJ , Reeve AE . Relaxation of insulin‐like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362: 749‐751, 1993.
 247. Ohgaki H , Kleihues P , Heitz PU . p53 mutations in sporadic adrenocortical tumors. Int J Cancer 54: 408‐410, 1993.
 248. Ozata DM , Caramuta S , Velazquez‐Fernandez D , Akcakaya P , Xie H , Hoog A , Zedenius J , Backdahl M , Larsson C , Lui WO . The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer 18: 643‐655, 2011.
 249. Painter TA , Jagelman DG . Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum. Cancer 55: 2001‐2004, 1985.
 250. Patterson EE , Holloway AK , Weng J , Fojo T , Kebebew E . MicroRNA profiling of adrenocortical tumors reveals miR‐483 as a marker of malignancy. Cancer 117: 1630‐1639, 2011.
 251. Pedreira CC , Savarirayan R , Zacharin MR . IMAGe syndrome: A complex disorder affecting growth, adrenal and gonadal function, and skeletal development. J Pediatr 144: 274‐277, 2004.
 252. Pellegrino C , Ricci PD , Tongiani R . A quantitative cytochemical and physiological study of the rat adrenal cortex in hypertrophy after unilateral adrenalectomy. Exp Cell Res 31: 167‐182, 1963.
 253. Pelletier J , Bruening W , Kashtan CE , Mauer SM , Manivel JC , Striegel JE , Houghton DC , Junien C , Habib R , Fouser L , et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys‐Drash syndrome. Cell 67: 437‐447, 1991.
 254. Pelletier J , Bruening W , Li FP , Haber DA , Glaser T , Housman DE . WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 353: 431‐434, 1991.
 255. Perrone RD , Bengele HH , Alexander EA . Sodium retention after adrenal enucleation. Am J Physiol 250: E1‐12, 1986.
 256. Phelan JK , McCabe ER . Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Hum Mutat 18: 472‐487, 2001.
 257. Philibert P , Biason‐Lauber A , Rouzier R , Pienkowski C , Paris F , Konrad D , Schoenle E , Sultan C . Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: A French collaborative study. J Clin Endocrinol Metab 93: 895‐900, 2008.
 258. Philibert P , Leprieur E , Zenaty D , Thibaud E , Polak M , Frances AM , Lespinasse J , Raingeard I , Servant N , Audran F , Paris F , Sultan C . Steroidogenic factor‐1 (SF‐1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration. Reprod Biol Endocrinol 8: 28, 2010.
 259. Philibert P , Zenaty D , Lin L , Soskin S , Audran F , Leger J , Achermann JC , Sultan C . Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: A French collaborative study. Hum Reprod 22: 3255‐3261, 2007.
 260. Quaggin SE , Vanden Heuvel GB , Igarashi P . Pod‐1, a mesoderm‐specific basic‐helix‐loop‐helix protein expressed in mesenchymal and glomerular epithelial cells in the developing kidney. Mech Dev 71: 37‐48, 1998.
 261. Ragazzon B , Assie G , Bertherat J . Transcriptome analysis of adrenocortical cancers: From molecular classification to the identification of new treatments. Endocr Relat Cancer 18: R15‐27, 2011.
 262. Ragazzon B , Libe R , Assie G , Tissier F , Barreau O , Houdayer C , Perlemoine K , Audebourg A , Clauser E , Rene‐Corail F , Bertagna X , Dousset B , Bertherat J , Groussin L . Mass‐array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas. Eur J Endocrinol 170: 385‐391, 2014.
 263. Ragazzon B , Libe R , Gaujoux S , Assie G , Fratticci A , Launay P , Clauser E , Bertagna X , Tissier F , de Reynies A , Bertherat J . Transcriptome analysis reveals that p53 and {beta}‐catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res 70: 8276‐8281, 2010.
 264. Rainey WE. Adrenal zonation: Clues from 11beta‐hydroxylase and aldosterone synthase. Mol Cell Endocrinol 151: 151‐160, 1999.
 265. Rainey WE , Nakamura Y . Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol 108: 281‐286, 2008.
 266. Rainey WE , Rehman KS , Carr BR . Fetal and maternal adrenals in human pregnancy. Obstet Gynecol Clin North Am 31: 817‐835, x, 2004.
 267. Rainey WE , Rehman KS , Carr BR . The human fetal adrenal: Making adrenal androgens for placental estrogens. Semin Reprod Med 22: 327‐336, 2004.
 268. Rainier S , Johnson LA , Dobry CJ , Ping AJ , Grundy PE , Feinberg AP . Relaxation of imprinted genes in human cancer. Nature 362: 747‐749, 1993.
 269. Raymond VM , Else T , Everett JN , Long JM , Gruber SB , Hammer GD . Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab 98: E119‐125, 2013.
 270. Raymond VM , Everett JN , Furtado LV , Gustafson SL , Jungbluth CR , Gruber SB , Hammer GD , Stoffel EM , Greenson JK , Giordano TJ , Else T . Adrenocortical carcinoma is a lynch syndrome‐associated cancer. J Clin Oncol 31: 3012‐3018, 2013.
 271. Rechache NS , Wang Y , Stevenson HS , Killian JK , Edelman DC , Merino M , Zhang L , Nilubol N , Stratakis CA , Meltzer PS , Kebebew E . DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors. J Clin Endocrinol Metab 97: E1004‐E1013, 2012.
 272. Refaie S , Gagnon S , Gagnon H , Desjardins R , D'Anjou F , D'Orleans‐Juste P , Zhu X , Steiner DF , Seidah NG , Lazure C , Salzet M , Day R . Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. J Biol Chem 287: 14703‐14717, 2012.
 273. Reincke M , Beuschlein F , Lalli E , Arlt W , Vay S , Sassone‐Corsi P , Allolio B . DAX‐1 expression in human adrenocortical neoplasms: Implications for steroidogenesis. J Clin Endocrinol Metab 83: 2597‐2600, 1998.
 274. Reincke M , Karl M , Travis WH , Mastorakos G , Allolio B , Linehan HM , Chrousos GP . p53 mutations in human adrenocortical neoplasms: Immunohistochemical and molecular studies. J Clin Endocrinol Metab 78: 790‐794, 1994.
 275. Reincke M , Mora P , Beuschlein F , Arlt W , Chrousos GP , Allolio B . Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: Implications for tumorigenesis. J Clin Endocrinol Metab 82: 3054‐3058, 1997.
 276. Reuter AL , Goji K , Bingham NC , Matsuo M , Parker KL . A novel mutation in the accessory DNA‐binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency. Eur J Endocrinol 157: 233‐238, 2007.
 277. Ribeiro RC , Sandrini F , Figueiredo B , Zambetti GP , Michalkiewicz E , Lafferty AR , DeLacerda L , Rabin M , Cadwell C , Sampaio G , Cat I , Stratakis CA , Sandrini R . An inherited p53 mutation that contributes in a tissue‐specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98: 9330‐9335, 2001.
 278. Roessler E , Ward DE , Gaudenz K , Belloni E , Scherer SW , Donnai D , Siegel‐Bartelt J , Tsui LC , Muenke M . Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly. Hum Genet 100: 172‐181, 1997.
 279. Ronchi CL , Sbiera S , Leich E , Henzel K , Rosenwald A , Allolio B , Fassnacht M . Single nucleotide polymorphism array profiling of adrenocortical tumors–evidence for an adenoma carcinoma sequence? PLoS One 8: e73959, 2013.
 280. Rosenberg D , Groussin L , Jullian E , Perlemoine K , Medjane S , Louvel A , Bertagna X , Bertherat J . Transcription factor 3′,5′‐cyclic adenosine 5′‐monophosphate‐responsive element‐binding protein (CREB) is decreased during human adrenal cortex tumorigenesis and fetal development. J Clin Endocrinol Metab 88: 3958‐3965, 2003.
 281. Sablin EP , Woods A , Krylova IN , Hwang P , Ingraham HA , Fletterick RJ . The structure of corepressor Dax‐1 bound to its target nuclear receptor LRH‐1. Proc Natl Acad Sci U S A 105: 18390‐18395, 2008.
 282. Sadovsky Y , Crawford PA , Woodson KG , Polish JA , Clements MA , Tourtellotte LM , Simburger K , Milbrandt J . Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side‐chain‐cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A 92: 10939‐10943, 1995.
 283. Sahut‐Barnola I , de Joussineau C , Val P , Lambert‐Langlais S , Damon C , Lefrancois‐Martinez AM , Pointud JC , Marceau G , Sapin V , Tissier F , Ragazzon B , Bertherat J , Kirschner LS , Stratakis CA , Martinez A . Cushing's syndrome and fetal features resurgence in adrenal cortex‐specific Prkar1a knockout mice. PLoS Genet 6: e1000980, 2010.
 284. Sasano H , Shizawa S , Suzuki T , Takayama K , Fukaya T , Morohashi K , Nagura H . Ad4BP in the human adrenal cortex and its disorders. J Clin Endocrinol Metab 80: 2378‐2380, 1995.
 285. Scheys JO , Heaton JH , Hammer GD . Evidence of adrenal failure in aging Dax1‐deficient mice. Endocrinology 152: 3430‐3439, 2011.
 286. Schmitz KJ , Helwig J , Bertram S , Sheu SY , Suttorp AC , Seggewiss J , Willscher E , Walz MK , Worm K , Schmid KW . Differential expression of microRNA‐675, microRNA‐139‐3p and microRNA‐335 in benign and malignant adrenocortical tumours. J Clin Pathol 64: 529‐535, 2011.
 287. Schnabel CA , Selleri L , Cleary ML . Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 37: 123‐130, 2003.
 288. Schulte DM , Shapiro I , Reincke M , Beuschlein F . Expression and spatio‐temporal distribution of differentiation and proliferation markers during mouse adrenal development. Gene Expr Patterns 7: 72‐81, 2007.
 289. Schulte KM , Heinze M , Mengel M , Simon D , Scheuring S , Kohrer K , Roher HD . MEN I gene mutations in sporadic adrenal adenomas. Hum Genet 105: 603‐610, 1999.
 290. Schulte KM , Mengel M , Heinze M , Simon D , Scheuring S , Kohrer K , Roher HD . Complete sequencing and messenger ribonucleic acid expression analysis of the MEN I gene in adrenal cancer. J Clin Endocrinol Metab 85: 441‐448, 2000.
 291. Seidinger AL , Mastellaro MJ , Paschoal Fortes F , Godoy Assumpcao J , Aparecida Cardinalli I , Aparecida Ganazza M , Correa Ribeiro R , Brandalise SR , Dos Santos Aguiar S , Yunes JA . Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. Cancer 117: 2228‐2235, 2011.
 292. Seki M , Tanaka K , Kikuchi‐Yanoshita R , Konishi M , Fukunari H , Iwama T , Miyaki M . Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis. Hum Genet 89: 298‐300, 1992.
 293. Sherr CJ , McCormick F . The RB and p53 pathways in cancer. Cancer Cell 2: 103‐112, 2002.
 294. Shimizu M , Takai K , Moriwaki H . Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. Cancer Sci 100: 369‐374, 2009.
 295. Shin SH , Kogerman P , Lindstrom E , Toftgard R , Biesecker LG . GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci U S A 96: 2880‐2884, 1999.
 296. Shinoda K , Lei H , Yoshii H , Nomura M , Nagano M , Shiba H , Sasaki H , Osawa Y , Ninomiya Y , Niwa O , et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz‐F1 disrupted mice. Dev Dyn 204: 22‐29, 1995.
 297. Sidhu S , Marsh DJ , Theodosopoulos G , Philips J , Bambach CP , Campbell P , Magarey CJ , Russell CF , Schulte KM , Roher HD , Delbridge L , Robinson BG . Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab 87: 3467‐3474, 2002.
 298. Sidhu S , Martin E , Gicquel C , Melki J , Clark SJ , Campbell P , Magarey CJ , Schulte KM , Roher HD , Delbridge L , Robinson BG . Mutation and methylation analysis of TP53 in adrenal carcinogenesis. Eur J Surg Oncol 31: 549‐554, 2005.
 299. Skelton FR. Adrenal regeneration and adrenal‐regeneration hypertension. Physiol Rev 39: 162‐182, 1959.
 300. Slater EP , Diehl SM , Langer P , Samans B , Ramaswamy A , Zielke A , Bartsch DK . Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. Eur J Endocrinol 154: 587‐598, 2006.
 301. Smith TG , Clark SK , Katz DE , Reznek RH , Phillips RK . Adrenal masses are associated with familial adenomatous polyposis. Dis Colon Rectum 43: 1739‐1742, 2000.
 302. Soon PS , Gill AJ , Benn DE , Clarkson A , Robinson BG , McDonald KL , Sidhu SB . Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki‐67 as useful in differentiating carcinomas from adenomas. Endocr Relat Cancer 16: 573‐583, 2009.
 303. Soon PS , Tacon LJ , Gill AJ , Bambach CP , Sywak MS , Campbell PR , Yeh MW , Wong SG , Clifton‐Bligh RJ , Robinson BG , Sidhu SB . miR‐195 and miR‐483‐5p identified as predictors of poor prognosis in adrenocortical cancer. Clin Cancer Res 15: 7684‐7692, 2009.
 304. Spencer SJ , Mesiano S , Lee JY , Jaffe RB . Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: Implications for growth and remodeling. J Clin Endocrinol Metab 84: 1110‐1115, 1999.
 305. Sperling S , Grimm CH , Dunkel I , Mebus S , Sperling HP , Ebner A , Galli R , Lehrach H , Fusch C , Berger F , Hammer S . Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 26: 575‐582, 2005.
 306. Stark K , Vainio S , Vassileva G , McMahon AP . Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt‐4. Nature 372: 679‐683, 1994.
 307. Stephan EA , Chung TH , Grant CS , Kim S , Von Hoff DD , Trent JM , Demeure MJ . Adrenocortical carcinoma survival rates correlated to genomic copy number variants. Mol Cancer Ther 7: 425‐431, 2008.
 308. Sucheston ME , Cannon MS . Development of zonular patterns in the human adrenal gland. J Morphol 126: 477‐491, 1968.
 309. Sucheston ME , Cannon MS . Microscopic comparison of the normal and anencephalic human adrenal gland with emphasis on the transient‐zone. Obstet Gynecol 35: 544‐553, 1970.
 310. Swain A , Narvaez V , Burgoyne P , Camerino G , Lovell‐Badge R . Dax1 antagonizes Sry action in mammalian sex determination. Nature 391: 761‐767, 1998.
 311. Szabo DR , Baghy K , Szabo PM , Zsippai A , Marczell I , Nagy Z , Varga V , Eder K , Toth S , Buzas EI , Falus A , Kovalszky I , Patocs A , Racz K , Igaz P . Antitumoral effects of 9‐cis retinoic acid in adrenocortical cancer. Cell Mol Life Sci 71: 917‐932, 2013.
 312. Szabo PM , Tamasi V , Molnar V , Andrasfalvy M , Tombol Z , Farkas R , Kovesdi K , Patocs A , Toth M , Szalai C , Falus A , Racz K , Igaz P . Meta‐analysis of adrenocortical tumour genomics data: Novel pathogenic pathways revealed. Oncogene 29: 3163‐3172, 2010.
 313. Tadjine M , Lampron A , Ouadi L , Bourdeau I . Frequent mutations of beta‐catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf) 68: 264‐270, 2008.
 314. 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) 69: 367‐373, 2008.
 315. Takayama K , Sasano H , Fukaya T , Morohashi K , Suzuki T , Tamura M , Costa MJ , Yajima A . Immunohistochemical localization of Ad4‐binding protein with correlation to steroidogenic enzyme expression in cycling human ovaries and sex cord stromal tumors. J Clin Endocrinol Metab 80: 2815‐2821, 1995.
 316. Tamura M , Kanno Y , Chuma S , Saito T , Nakatsuji N . Pod‐1/Capsulin shows a sex‐ and stage‐dependent expression pattern in the mouse gonad development and represses expression of Ad4BP/SF‐1. Mech Dev 102: 135‐144, 2001.
 317. Tan TY , Jameson JL , Campbell PE , Ekert PG , Zacharin M , Savarirayan R . Two sisters with IMAGe syndrome: Cytomegalic adrenal histopathology, support for autosomal recessive inheritance and literature review. Am J Med Genet A 140: 1778‐1784, 2006.
 318. Tien ES , Davis JW , Vanden Heuvel JP . Identification of the CREB‐binding protein/p300‐interacting protein CITED2 as a peroxisome proliferator‐activated receptor alpha coregulator. J Biol Chem 279: 24053‐24063, 2004.
 319. Tinat J , Bougeard G , Baert‐Desurmont S , Vasseur S , Martin C , Bouvignies E , Caron O , Bressac‐de Paillerets B , Berthet P , Dugast C , Bonaiti‐Pellie C , Stoppa‐Lyonnet D , Frebourg T . 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27: e108‐109; author reply e110, 2009.
 320. Tissier F , Cavard C , Groussin L , Perlemoine K , Fumey G , Hagnere AM , Rene‐Corail F , Jullian E , Gicquel C , Bertagna X , Vacher‐Lavenu MC , Perret C , Bertherat J . Mutations of beta‐catenin in adrenocortical tumors: Activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65: 7622‐7627, 2005.
 321. Tombol Z , Szabo PM , Molnar V , Wiener Z , Tolgyesi G , Horanyi J , Riesz P , Reismann P , Patocs A , Liko I , Gaillard RC , Falus A , Racz K , Igaz P . Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue‐specific target prediction, and pathway analysis. Endocr Relat Cancer 16: 895‐906, 2009.
 322. Toye AA , Lippiat JD , Proks P , Shimomura K , Bentley L , Hugill A , Mijat V , Goldsworthy M , Moir L , Haynes A , Quarterman J , Freeman HC , Ashcroft FM , Cox RD . A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48: 675‐686, 2005.
 323. Traill Z , Tuson J , Woodham C . Adrenal carcinoma in a patient with Gardner's syndrome: Imaging findings. AJR Am J Roentgenol 165: 1460‐1461, 1995.
 324. Treier M , Gleiberman AS , O'Connell SM , Szeto DP , McMahon JA , McMahon AP , Rosenfeld MG . Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev 12: 1691‐1704, 1998.
 325. Vainio S , Heikkila M , Kispert A , Chin N , McMahon AP . Female development in mammals is regulated by Wnt‐4 signalling. Nature 397: 405‐409, 1999.
 326. Val P , Martinez‐Barbera JP , Swain A . Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf‐1 dosage. Development 134: 2349‐2358, 2007.
 327. van Amerongen R , Nusse R . Towards an integrated view of Wnt signaling in development. Development 136: 3205‐3214, 2009.
 328. Varley JM , McGown G , Thorncroft M , James LA , Margison GP , Forster G , Evans DG , Harris M , Kelsey AM , Birch JM . Are there low‐penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet 65: 995‐1006, 1999.
 329. Velazquez‐Fernandez D , Laurell C , Geli J , Hoog A , Odeberg J , Kjellman M , Lundeberg J , Hamberger B , Nilsson P , Backdahl M . Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138: 1087‐1094, 2005.
 330. Vidal V , Schedl A . Requirement of WT1 for gonad and adrenal development: Insights from transgenic animals. Endocr Res 26: 1075‐1082, 2000.
 331. Vilain E , Le Merrer M , Lecointre C , Desangles F , Kay MA , Maroteaux P , McCabe ER . IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. J Clin Endocrinol Metab 84: 4335‐4340, 1999.
 332. Vlangos CN , O'Connor BC , Morley MJ , Krause AS , Osawa GA , Keegan CE . Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53‐dependent apoptosis. Dev Biol 334: 418‐428, 2009.
 333. Volante M , Buttigliero C , Greco E , Berruti A , Papotti M . Pathological and molecular features of adrenocortical carcinoma: An update. J Clin Pathol 61: 787‐793, 2008.
 334. Voutilainen R , Miller WL . Coordinate tropic hormone regulation of mRNAs for insulin‐like growth factor II and the cholesterol side‐chain‐cleavage enzyme, P450scc [corrected], in human steroidogenic tissues. Proc Natl Acad Sci U S A 84: 1590‐1594, 1987.
 335. Wagner J , Portwine C , Rabin K , Leclerc JM , Narod SA , Malkin D . High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86: 1707‐1710, 1994.
 336. Wakatsuki S , Sasano H , Matsui T , Nagashima K , Toyota T , Horii A . Adrenocortical tumor in a patient with familial adenomatous polyposis: A case associated with a complete inactivating mutation of the APC gene and unusual histological features. Hum Pathol 29: 302‐306, 1998.
 337. Wang B , Fallon JF , Beachy PA . Hedgehog‐regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100: 423‐434, 2000.
 338. Warman DM , Costanzo M , Marino R , Berensztein E , Galeano J , Ramirez PC , Saraco N , Baquedano MS , Ciaccio M , Guercio G , Chaler E , Maceiras M , Lazzatti JM , Bailez M , Rivarola MA , Belgorosky A . Three new SF‐1 (NR5A1) gene mutations in two unrelated families with multiple affected members: Within‐family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr 75: 70‐77, 2011.
 339. Warthin AS . Classics in oncology. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895‐1913. By Aldred Scott Warthin. 1913. CA Cancer J Clin 35: 348‐359, 1913.
 340. West AN , Neale GA , Pounds S , Figueredo BC , Rodriguez Galindo C , Pianovski MA , Oliveira Filho AG , Malkin D , Lalli E , Ribeiro R , Zambetti GP . Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67: 600‐608, 2007.
 341. Wood MA , Acharya A , Finco I , Swonger JM , Elston MJ , Tallquist MD , Hammer GD . Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140: 4522‐4532, 2013.
 342. Wood MA , Hammer GD . Adrenocortical stem and progenitor cells: Unifying model of two proposed origins. Mol Cell Endocrinol 336: 206‐212, 2011.
 343. Wrobel KH , Suss F . On the origin and prenatal development of the bovine adrenal gland. Anat Embryol (Berl) 199: 301‐318, 1999.
 344. WuQiang F , Yanase T , Wei L , Oba K , Nomura M , Okabe T , Goto K , Nawata H . Functional characterization of a new human Ad4BP/SF‐1 variation, G146A. Biochem Biophys Res Commun 311: 987‐994, 2003.
 345. Xin H , Liu D , Wan M , Safari A , Kim H , Sun W , O'Connor MS , Songyang Z . TPP1 is a homologue of ciliate TEBP‐beta and interacts with POT1 to recruit telomerase. Nature 445: 559‐562, 2007.
 346. Xu M , Wu X , Li Y , Yang X , Hu J , Zheng M , Tian J . CITED2 Mutation and methylation in children with congenital heart disease. J Biomed Sci 21: 7, 2014.
 347. Yamakita N , Murai T , Ito Y , Miura K , Ikeda T , Miyamoto K , Onami S , Yoshida T . Adrenocorticotropin‐independent macronodular adrenocortical hyperplasia associated with multiple colon adenomas/carcinomas which showed a point mutation in the APC gene. Intern Med 36: 536‐542, 1997.
 348. Yano T , Linehan M , Anglard P , Lerman MI , Daniel LN , Stein CA , Robertson CN , LaRocca R , Zbar B . Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81: 518‐523, 1989.
 349. Yates LA , Norbury CJ , Gilbert RJ . The long and short of microRNA. Cell 153: 516‐519, 2013.
 350. Ye JZ , Hockemeyer D , Krutchinsky AN , Loayza D , Hooper SM , Chait BT , de Lange T . POT1‐interacting protein PIP1: A telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev 18: 1649‐1654, 2004.
 351. Yu RN , Ito M , Jameson JL . The murine Dax‐1 promoter is stimulated by SF‐1 (steroidogenic factor‐1) and inhibited by COUP‐TF (chicken ovalbumin upstream promoter‐transcription factor) via a composite nuclear receptor‐regulatory element. Mol Endocrinol 12: 1010‐1022, 1998.
 352. Yu RN , Ito M , Saunders TL , Camper SA , Jameson JL . Role of Ahch in gonadal development and gametogenesis. Nat Genet 20: 353‐357, 1998.
 353. Zazopoulos E , Lalli E , Stocco DM , Sassone‐Corsi P . DNA binding and transcriptional repression by DAX‐1 blocks steroidogenesis. Nature 390: 311‐315, 1997.
 354. Zhang P , Liegeois NJ , Wong C , Finegold M , Hou H , Thompson JC , Silverman A , Harper JW , DePinho RA , Elledge SJ . Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith‐Wiedemann syndrome. Nature 387: 151‐158, 1997.
 355. Zhao J , Roth J , Bode‐Lesniewska B , Pfaltz M , Heitz PU , Komminoth P . Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosomes Cancer 34: 48‐57, 2002.
 356. Zhao J , Speel EJ , Muletta‐Feurer S , Rutimann K , Saremaslani P , Roth J , Heitz PU , Komminoth P . Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 155: 1039‐1045, 1999.
 357. Zubair M , Ishihara S , Oka S , Okumura K , Morohashi K . Two‐step regulation of Ad4BP/SF‐1 gene transcription during fetal adrenal development: Initiation by a Hox‐Pbx1‐Prep1 complex and maintenance via autoregulation by Ad4BP/SF‐1. Mol Cell Biol 26: 4111‐4121, 2006.
 358. Zubair M , Parker KL , Morohashi K . Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol 28: 7030‐7040, 2008.
 359. Zwermann O , Beuschlein F , Mora P , Weber G , Allolio B , Reincke M . Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol 142: 689‐695, 2000.

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Article Title: Adrenocortical Growth and Cancer
 

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Lucile Lefèvre, Jérôme Bertherat, Bruno Ragazzon. Adrenocortical Growth and Cancer. Compr Physiol 2014, 5: 293-326. doi: 10.1002/cphy.c140010