A Feminizing Adrenocortical Carcinoma in the Context of a Late Onset 21-Hydroxylase Deficiency
Rossella Libé, Wiebke Arlt, Estelle Louiset, Charlotte Waintrop, Jean Guibourdenche, Mathilde Sibony, Eric Clauser, and Lionel Groussin
French COMETE Network (R.L.), 75014 Paris, France; Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; INSERM U982 (E.L.), Différenciation & Communication Neuronale & Neuroendocrine, Université de Rouen, 76821 Mont-Saint-Aignan, France; Departments of Endocrinology (C.W., L.G.), Hormonal Biology (J.G.), Pathology (M.S.), and Oncogenetics (E.C.), Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and INSERM U1016 (L.G.), Institut Cochin, 75014 Paris, France
A 77-year-old man was referred for breast enlarge- ment. Clinical examination suggested true gyneco- mastia, visualized by computed tomography (CT) (Figure 1A). An endocrine assessment (1) showed high estradiol levels (624 pmol/L [normal range, 36-239]) with normal gonadotropins. Testicular ultrasound did not show any tumor. A left adrenal mass was found (Figure 1B) at the CT scan. Further hormonal assessment revealed high levels of serum 17-hydroxyprogesterone (17OHP) (42 nmol/L [normal range, 4.5-8.5]) with normal cortisol and corti- cotropin levels. The 17OHP excess could derive from al- tered intratumoral steroidogenesis or, much less likely, result from undiagnosed adrenal hyperplasia due to non- classic 21-hydroxylase deficiency (21OHD). After left ad- renalectomy, histopathological assessment documented an adrenocortical carcinoma (Figure 2A) with a Weiss score of 3 (2). Immunohistochemistry showed aromatase positivity limited to malignant cells (Figure 2B). After sur-
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gery, estradiol promptly normalized. By contrast, 17OHP (18.9 nmol/L) remained elevated. Assuming an underlying diagnosis of 21OHD, we carried out genetic analysis; se- quencing of the 21-hydroxylase gene (CYP21A2) coding regions revealed no mutations. The persistent increase of a steroid precursor may be the sign of residual tumor. Steroid profiling, using urine metabolomics (3), was not in favor of malignancy but revealed only high levels of the 21-deoxycortisol metabolite pregnanetriolone, which is pathognomonic for 21OHD (4). Because the diagnosis of 21OHD was strongly supported by the plasma and urine data, we extended the CYP21A2 genetic analysis beyond the coding regions. This confirmed 21OHD caused by biallelic microconversion between the promoter regions of CYP21A2 and the 21-hydroxylase pseudogene CYP21A1; the pseudogene promoter carrying four mutations is 80% less
Abbreviations: CT, computed tomography; 21OHD, 21-hydroxylase deficiency; 17OHP, 17-hydroxyprogesterone.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A.
Received February 5, 2014. Accepted March 10, 2014.
First Published Online March 21, 2014
doi: 10.1210/jc.2014-1342
active than the CYP21A2 promoter (5). Investigations of gynecomastia led us to discover a feminizing adrenocortical carcinoma in the context of late onset 21OHD. This unique situation cannot be interpreted as evidence of causality.
Acknowledgments
Address all correspondence and requests for reprints to: Profes- sor Lionel Groussin, Department of Endocrinology, Cochin Teaching Hospital, Université Paris Descartes, 75006 Paris, France. E-mail: lionel.groussin@cch.aphp.fr.
This research was supported by the Medical Research Coun- cil UK (Program Grant G0900567, to W.A.).
Disclosure Summary: The authors have no conflicts of inter- est to declare.
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