Expanding Genetic Spectrum And Discriminatory Role Of Steroid Profiling By Lc-Ms/Ms In 11 Beta-Hydroxylase Deficiency

Objective: To report clinical, hormonal and structural effects of CYP11B1 pathogenic variations in Indian patients with 11 beta-hydroxylase deficiency (11 beta OHD) and find hormonal criteria that accurately distinguish 11 beta OHD from 21 alpha-hydroxylase deficiency (21OHD).Design: Retrospective record review of genetically diagnosed patients with 11 beta OHD.Patients and Measurements: Clinical features, hormonal parameters at diagnosis (by immunoassay) and recent follow-up of 13 genetically proven 11 beta OHD patients managed at our centre were retrospectively reviewed. ACTH-stimulated serum adrenal steroids (measured by LC-MS/MS) of 11 beta OHD were compared with those of simple virilizing and non-classic 21OHD. Structural analysis of the observed pathogenic variations was performed by computational modelling.Results: Nine (four females) and four (all females) patients had classic and non-classic disease, respectively. All 11 beta OHD patients had elevated ACTH-stimulated serum 11-deoxycortisol (26.5-342.7 nmol/L) whereas none had elevated serum 17-hydroxyprogesterone (4.2-21.2 nmol/L); both hormonal parameters distinguished 11 beta OHD from 21OHD with 100% accuracy. ACTH-stimulated serum cortisol, but not 11-deoxycortisol, clearly distinguished classic (<70 nmol/L) from non-classic (>160 nmol/L) disease. Thirteen (eight novel, two recurrent) pathogenic variants were observed. Only missense mutations were observed among patients with non-classic disease. Computational modelling predicted the possible affection of enzyme structure and function for all the observed missense mutations.Conclusions: This first Indian study describes 13 11 beta OHD patients, including four with the rarer non-classic variant. A total of eight novel pathogenic variants were identified in our study, highlighting regional genetic heterogeneity. Measurement of ACTH-stimulated adrenal steroids by LC-MS/MS will help avoid the misdiagnosis of 11 beta OHD as 21OHD and has potential to distinguish classic from non-classic 11 beta OHD.