{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:03:59Z","timestamp":1793822639255,"version":"4.6.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:sec>\n<jats:title>Context<\/jats:title>\n<jats:p>17\u03b1-Hydroxylase\/17,20-lyase deficiency (17OHD) caused by mutations in the <jats:italic>CYP17A1<\/jats:italic> gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding <jats:italic>in silico<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> functional analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Design<\/jats:title>\n<jats:p>Case series.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Patients and results<\/jats:title>\n<jats:p>We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic <jats:italic>CYP17A1<\/jats:italic> analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53\/54del, p.Tyr60Ile<jats:italic>fs<\/jats:italic>Lys88X). <jats:italic>In vitro<\/jats:italic> functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17\u03b1-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17\u03b1-hydroxylase activity correlated well with clinical phenotype severity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17\u03b1-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Significance statement<\/jats:title>\n<jats:p>Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17\u03b1-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-21-0152","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T16:06:42Z","timestamp":1631722002000},"page":"729-741","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":30,"title":["The broad phenotypic spectrum of 17\u03b1-hydroxylase\/17,20-lyase (CYP17A1) deficiency: a case series"],"prefix":"10.1093","volume":"185","author":[{"given":"Min","family":"Sun","sequence":"first","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan W","family":"Mueller","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna C","family":"Gilligan","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela E","family":"Taylor","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fozia","family":"Shaheen","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Noczy\u0144ska","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"T\u2019Sjoen","sequence":"additional","affiliation":[{"name":"4Department of Endocrinology, Ghent University Hospital, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Denvir","sequence":"additional","affiliation":[{"name":"5Department of Paediatric Endocrinology and Diabetes, Queen\u2019s Medical Centre, Nottingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savitha","family":"Shenoy","sequence":"additional","affiliation":[{"name":"6Children\u2019s and Adolescent Services, University Hospitals of Leicester NHS Trust, Leicester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piers","family":"Fulton","sequence":"additional","affiliation":[{"name":"7West Midlands Regional Genetics Service, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy D","family":"Cheetham","sequence":"additional","affiliation":[{"name":"8Newcastle University c\/o Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Gleeson","sequence":"additional","affiliation":[{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"},{"name":"9Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mushtaqur","family":"Rahman","sequence":"additional","affiliation":[{"name":"10Department of Endocrinology, Northwick Park Hospital, London Northwest University Healthcare NHS Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils P","family":"Krone","sequence":"additional","affiliation":[{"name":"11Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman F","family":"Taylor","sequence":"additional","affiliation":[{"name":"12Department of Clinical Biochemistry, King\u2019s College Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric H L","family":"Shackleton","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"},{"name":"13Benioff Children\u2019s Hospital, University of California San Francisco, Oakland, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-9719","authenticated-orcid":true,"given":"Wiebke","family":"Arlt","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Idkowiak","sequence":"additional","affiliation":[{"name":"1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"},{"name":"14Department of Endocrinology and Diabetes, Birmingham Children\u2019s Hospital, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","container-title":["European Journal of 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