Christiaan F Mooij1,2, Silvia Parajes1, Ian T Rose1, Angela E Taylor1, Taner Bayraktaroglu3, John A H Wass4, John M C Connell5, David W Ray6, Wiebke Arlt1, Nils Krone1. 1. Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. 2. Department of Pediatric Endocrinology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Division of Endocrinology, Department of Internal Medicine, Bulent Ecevıt University, Zonguldak, Turkey. 4. Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK. 5. School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. 6. Endocrine Sciences Research Group, University of Manchester, Manchester, UK.
Abstract
OBJECTIVE: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. PATIENTS AND METHODS: Five patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2 years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an in vitro expression system. RESULTS: CYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. CONCLUSION: Mutations causing partial impairment of 11β-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.
OBJECTIVE: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. PATIENTS AND METHODS: Five patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2 years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an in vitro expression system. RESULTS: CYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. CONCLUSION: Mutations causing partial impairment of 11β-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.
Authors: Gabriela P Finkielstain; Ana Vieites; Ignacio Bergadá; Rodolfo A Rey Journal: Front Endocrinol (Lausanne) Date: 2021-12-20 Impact factor: 5.555
Authors: Connar S J Westgate; Keira Markey; James L Mitchell; Andreas Yiangou; Rishi Singhal; Paul Stewart; Jeremy W Tomlinson; Gareth G Lavery; Susan P Mollan; Alexandra J Sinclair Journal: Eur J Endocrinol Date: 2022-07-04 Impact factor: 6.558
Authors: Keira Markey; James Mitchell; Hannah Botfield; Ryan S Ottridge; Tim Matthews; Anita Krishnan; Rebecca Woolley; Connar Westgate; Andreas Yiangou; Zerin Alimajstorovic; Pushkar Shah; Caroline Rick; Natalie Ives; Angela E Taylor; Lorna C Gilligan; Carl Jenkinson; Wiebke Arlt; William Scotton; Rebecca J Fairclough; Rishi Singhal; Paul M Stewart; Jeremy W Tomlinson; Gareth G Lavery; Susan P Mollan; Alexandra J Sinclair Journal: Brain Commun Date: 2020-01-10