ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome

adrenal-hyperplasia

 

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D.

N Engl J Med 2013; 369:2105-2114 November 28, 2013 DOI: 10.1056/NEJMoa1304603

BACKGROUND

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.

METHODS

We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.

RESULTS

The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.

CONCLUSIONS

Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), Corticomedullosurrénale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique–Hôpitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d’Interface, to Dr. Assié), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Assié, Libé, Espiard, Rizk-Rabin, Ragazzon, and Bertherat contributed equally to this article.

We thank Drs. J. Chelly and M. Delpech of the cell bank of Cochin Hospital and Dr. B. Terris of the tumor bank of Cochin Hospital for their help in sample collection; Dr. E. Clauser of the oncogenetic unit of Cochin Hospital for help in microsatellite analysis; Drs. J. Guibourdenche and E. Clauser of the hormone biology unit of Cochin Hospital for cortisol assays; Drs. F. Tissier and Pierre Colin for pathological analysis; Anne Audebourg for technical assistance; J. Metral and A. de Reynies of the Cartes d’Identité des Tumeurs program of Ligue Nationale contre le Cancer for help in genomics studies and fruitful discussions; Dr. P. Nietschke of the bioinformatics platforms of Paris Descartes University for helpful discussions; all the members of the Genomics and Signaling of Endocrine Tumors team and of the genomic platform of Cochin Institute for their help in these studies; and the patients and their families, as well as the physicians and staff involved in patient care, for their active participation.

SOURCE INFORMATION

From INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, Hôpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério, Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).

Address reprint requests to Dr. Bertherat at Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75014 Paris, France, or at jerome.bertherat@cch.aphp.fr.

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Happy Thanksgiving!

thanksgiving

 

Happy Thanksgiving to US Cushies!

Are you carrying adrenal Cushing’s syndrome without knowing it?

Genetic research that will be published tomorrow in the New England Journal of Medicine suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease.

“Screening family members of bilateral adrenal Cushing’s syndrome patients with  may identify affected silent carriers,” Lacroix said in an editorial in the Journal. “The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualized specific therapies for hypercortisolism, eliminate the current practice of removing both , and possibly prevent disease progression in genetically affected .”

Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, , diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.

Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumor on the adrenal glands, or a  that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.

Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he published today, he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place.

 Explore further: Scientists discover a curable cause for some cases of high blood pressure

More information: André Lacroix, M.D., Heredity and Cortisol Regulation in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Estelle Louiset, Ph.D., Céline Duparc, Ph.D., Jacques Young, M.D., Ph.D., Sylvie Renouf, Ph.D., Milène Tetsi Nomigni, M.Sc., Isabelle Boutelet, Ph.D., Rossella Libé, M.D., Zakariae Bram, M.Sc., Lionel Groussin, M.D., Ph.D., Philippe Caron, M.D., Antoine Tabarin, M.D., Ph.D., Fabienne Grunenberger, M.D., Sophie Christin-Maitre, M.D., Ph.D., Xavier Bertagna, M.D., Ph.D., Jean-Marc Kuhn, M.D., Youssef Anouar, Ph.D., Jérôme Bertherat, M.D., Ph.D., and Hervé Lefebvre, M.D., Ph.D., Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D., ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome, New England Journal of Medicine 369;22, November 28, 2013

The Current Role Of Transcranial Surgery In The Management Of Pituitary Adenomas

Pituitary. 2013 Dec;16(4):419-34. doi: 10.1007/s11102-012-0439-z.

The current role of transcranial surgery in the management of pituitary adenomas.

Source

Section of Neurosurgery, Department of Neurological Sciences, Christian Medical College, Vellore, 632004, Tamil Nadu, India.

Abstract

The aim of this study was to determine the factors influencing the use of a transcranial (TC) approach in pituitary adenomas and suggest a decision-making tree for the surgical strategy.

The data for 23 (4.6 %) patients who underwent TC surgery from amongst 494 pituitary adenomas were retrospectively analyzed. Eight factors on magnetic resonance imaging (MRI) that could predict a difficult transsphenoidal (TS) surgery were noted.

Adverse findings at TS surgery leading to a 2nd stage TC surgery were documented. Eighteen of the 23 cases were giant adenomas. Thirteen patients underwent TC surgery alone or as an initial approach when combined with TS while 10 underwent 2nd stage TC surgery following a TS approach. Most cases in the first group had 3 or more radiological factors in combination with a small sella. The 2nd group had higher sellar tumor volumes and fewer unfavourable radiological factors that led to the initial use of the TS approach.

A hard, fibrous consistency or a significant residue obscured from the surgeon’s view, and difficulty in hemostasis were additional factors prompting the use of a TC approach. Tumor excision ≥90 % could be achieved in 13 cases (56.5 %). Post-operative RT was administered in 12 patients. There were 2 deaths (8.7 %) and the major morbidity rate was 43 %. Despite advances in endoscopic surgery the TC approach may be required in 5 % of cases.

A study of the preoperative MRI for factors that predict difficulty with the TS approach might encourage the surgeon to consider a TC surgery either as an initial approach or combined with a TS surgery.

PMID:
23076713
[PubMed – in process]

Is Diabetes in Cushing’s Syndrome a Consequence of Hypercortisolism?

Eur J Endocrinol. 2013 Nov 19. [Epub ahead of print]

Is Diabetes in Cushing syndrome only a consequence of hypercortisolism?

Source

C Giordano, Dipartimento di Medicina Interna e Specialistica (Di.Bi.Mi.S) Sezione di Endocrinologia e Malattie del Metabolismo, University of Palermo, Palermo, Italy.

Abstract

OBJECTIVE:

Diabetes mellitus (DM) is one of the most frequent complications of Cushing syndrome (CS). Aim of the study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients.

DESIGN:

Cross-sectional study on 140 patients with CS.

METHODS:

113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 yr) and 27 men (19 with pituitary disease and 8 with adrenal disease, aged 38.1±20.01 yr) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes) and diabetes (CS/DM).

RESULTS:

71 patients belonged to CS/NGT (49.3%), 26 (18.5%) to CS/prediabetes and 43 (30.8%) to CS/DM. Significant increasing trends in the prevalence of family history of diabetes (p<0.001), metabolic syndrome (p<0.001), age (p<0.001) and waist circumference (p=0.043) and decreasing trends in HOMAβ (p<0.001)and Oral Dispositional Index (DIo) (p<0.002) were observed among the groups. No significant trend in fasting insulin, AUC INS, ISI-Matsuda and VAI was detected.

CONCLUSIONS:

Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in the natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of patients at high risk for metabolic complications.

PMID:
24255133
[PubMed – as supplied by publisher]
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