Anne Thiel1, Anna-Carinna Reis2, Matthias Haase1, Gerald Goh2, Matthias Schott1, Holger S Willenberg2, Ute I Scholl3. 1. Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany. 2. Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany. 3. Departments of NephrologyPathologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of PathologyUniversity Hospital Essen, 45147 Essen, GermanyDivision of Specific EndocrinologySchool of Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, GermanyDepartment of GeneticsYale University School of Medicine, New Haven, Connecticut 06520, USAUniversity College London Cancer InstituteLondon WC1E 6BT, UKDivision of Endocrinology and Metabolic DiseaseUniversity Medical Center, 18057 Rostock, Germany ute.scholl@med.uni-duesseldorf.de.
Abstract
OBJECTIVE: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA(L206R) mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone. DESIGN, PATIENTS, AND METHODS: In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone. RESULTS: Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA(L206R) mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions. CONCLUSIONS: PRKACA(L206R) is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.
OBJECTIVE:Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA(L206R) mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone. DESIGN, PATIENTS, AND METHODS: In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone. RESULTS: Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1+GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA(L206R) mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions. CONCLUSIONS:PRKACA(L206R) is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.
Authors: Ute I Scholl; James M Healy; Anne Thiel; Annabelle L Fonseca; Taylor C Brown; John W Kunstman; Matthew J Horne; Dimo Dietrich; Jasmin Riemer; Seher Kücükköylü; Esther N Reimer; Anna-Carinna Reis; Gerald Goh; Glen Kristiansen; Amit Mahajan; Reju Korah; Richard P Lifton; Manju L Prasad; Tobias Carling Journal: Clin Endocrinol (Oxf) Date: 2015-09-23 Impact factor: 3.478
Authors: Kazutaka Nanba; Kei Omata; Tobias Else; Peter C C Beck; Aya T Nanba; Adina F Turcu; Barbra S Miller; Thomas J Giordano; Scott A Tomlins; William E Rainey Journal: J Clin Endocrinol Metab Date: 2018-10-01 Impact factor: 5.958
Authors: Kazutaka Nanba; Andrew X Chen; Kei Omata; Michelle Vinco; Thomas J Giordano; Tobias Else; Gary D Hammer; Scott A Tomlins; William E Rainey Journal: J Clin Endocrinol Metab Date: 2016-01-14 Impact factor: 5.958
Authors: Christina Tatsi; Andrea G Maria; Cole Malloy; Lin Lin; Edra London; Nick Settas; Chelsi Flippo; Meg Keil; Fady Hannah-Shmouni; Dax A Hoffman; Constantine A Stratakis Journal: J Clin Endocrinol Metab Date: 2021-05-13 Impact factor: 5.958