Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

Author:

Vouillarmet Julien1,Fernandes-Rosa Fabio234,Graeppi-Dulac Julia1,Lantelme Pierre1567,Decaussin-Petrucci Myriam187,Thivolet Charles179,Peix Jean-Louis110,Boulkroun Sheerazed23,Clauser Eric2311,Zennaro Maria-Christina234

Affiliation:

1. Hospices Civils de Lyon (J.V., J.G.-D., C.T.), Centre Hospitalier Lyon-Sud, Service d’Endocrinologie, Diabète et Obésité, 69310 Pierre Bénite, France;

2. Inserm, UMRS_970 (F.F.-R., S.B., E.C., M.-C.Z.), Paris Cardiovascular Research Center, 75015 Paris, France;

3. Université Paris Descartes (F.F.-R., S.B., E.C., M.-C.Z.), Sorbonne Paris Cité, 75006 Paris, France;

4. Assistance Publique-Hôpitaux de Paris (F.F.-R., M.-C.Z.), Hôpital Européen Georges Pompidou, Service de Génétique, 75015 Paris, France;

5. Hospices Civils de Lyon (P.L.), Hôpital de la Croix-Rousse, Service de Cardiologie, European Society of Hypertension Excellence Center, 69317 Lyon, France;

6. Université de Lyon (P.L.), CREATIS; CNRS UMR5220; Inserm U1044; INSA-Lyon; Université Claude Bernard Lyon 1, 69100 Lyon, France;

7. Université Claude Bernard Lyon I (P.L., M.D.-P., C.T.), 69100 Lyon, France;

8. Hospices Civils de Lyon (M.D.-P.), Centre Hospitalier Lyon-Sud, Service d’anatomo-pathologie, université Claude Bernard Lyon I, 69310 Pierre Bénite, France;

9. Inserm U1060 (C.T.), Faculté de médecine Lyon sud, 69921 Oullins, France;

10. Hospices Civils de Lyon (J.-L.P.), Centre Hospitalier Lyon-Sud, Service de chirurgie digestive et endocrinienne, 69495 Pierre Bénite, France;

11. Assistance Publique-Hôpitaux de Paris (E.C.), Hôpital Cochin, Service de Biologie Hormonale, 75014 Paris, France

Abstract

Context: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. Case Description: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. Conclusions: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.

Publisher

The Endocrine Society

Subject

Biochemistry, medical,Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference17 articles.

1. An update on novel mechanisms of primary aldosteronism;Zennaro;J Endocrinol,2015

2. Different somatic mutations in multinodular adrenals with aldosterone-producing adenoma;Fernandes-Rosa;Hypertension,2015

3. Adrenal cortex remodeling and functional zona glomerulosa hyperplasia in primary aldosteronism;Boulkroun;Hypertension,2010

4. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival;de Reyniès;J Clin Oncol,2009

5. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management;Leoz;Appl Clin Genet,2015

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