ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.


CONTEXT Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH. OBJECTIVE To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS. PATIENTS AND METHODS ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed. RESULTS ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively). CONCLUSIONS ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.

DOI: 10.1210/jc.2014-4204
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@article{Espiard2015ARMC5MI, title={ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.}, author={St{\'e}phanie Espiard and Ludivine Drougat and Rossella Lib{\'e} and Guillaume Assi{\'e} and Karine Perlemoine and Laurence Guignat and Gaelle Barrande and Françoise Brucker-Davis and Françoise Doullay and Stephanie Lopez and Emmanuel Sonnet and Florence Torremocha and Denis Pinsard and Nathalie Chabbert-Buffet and Marie-Laure Raffin-Sanson and Lionel Groussin and Françoise Borson-Chazot and Jo{\"{e}l Coste and Xavier Y Bertagna and Constantine A. Stratakis and Felix Beuschlein and Bruno Ragazzon and J er{\^o}me Bertherat}, journal={The Journal of clinical endocrinology and metabolism}, year={2015}, volume={100 6}, pages={E926-35} }