A Diagnosis Not to Be Missed: Nonclassic Steroid 11β-Hydroxylase Deficiency Presenting With Premature Adrenarche and Hirsutism
Abstract
CONTEXT: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Milder nonclassic forms are rare and at risk to be missed. OBJECTIVE: The objective of the study was to demonstrate the challenges in diagnosing nonclassic 11OHD. PATIENTS AND METHODS: Patient 1, a 10-year-old boy, presented with high-normal blood pressure and previously unexplained exaggerated adrenarche from age 4 years. Previous tests at the age of 8 years showed normal 17-hydroxyprogesterone concentrations with increased androgens. Patient 2, a 14-year-old female, presented with facial hirsutism, primary amenorrhea, and high-normal blood pressure. Novel CYP11B1 mutations were functionally analyzed in transiently transfected COS7 cells measuring the conversion of 11-deoxycortisol to cortisol by liquid chromatography-tandem mass spectrometry. RESULTS: Biochemical findings including urinary steroid metabolite analysis by gas chromatography-mass spectrometry were suggestive of 11OHD in all patients. CYP11B1 mutation analysis revealed compound heterozygosity in patient 1 (g.235T>A, p.F79I/g.2608C>T, p.R138C) and a homozygous mutation in patient 2 and two siblings (g.2623C>T, p.R143W). Functional in vitro analysis demonstrated partially impaired CYP11B1 activity compared with wild-type (p.F79I: 8.8% ± 0.8% (SEM); p.R138C: 9.8% ± 0.8%; p.R143W: 10.6% ± 1.2%). CONCLUSION: In addition to nonclassic 21-hydroxylase deficiency and steroid-secreting tumors, nonclassic 11OHD should be considered as an important differential diagnosis in patients with unexplained hyperandrogenism without 46,XX disorder of sex development. Nonclassic 11OHD is likely to be missed when relying on measuring standard steroid hormone panels. This diagnosis needs to be established early in life to avoid long-term health problems such as short stature, hyperandrogenism-related metabolic complications, potentially severe arterial hypertension, and cardiovascular consequences.
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The diagnosis of POR can be best made with a urinary steroid profile, revealing characteristic precursor accumulation that can be captured by steroid ratios, while serum steroid analysis often yields confusing results due to the overlapping effects of combined 17OH and 21OH deficiency.
“The diagnosis of POR can be best made with a urinary steroid profile, revealing characteristic precursor accumulation that can be captured by steroid ratios 32 while serum steroid analysis often yields confusing results due to the overlapping effects of combined 17OH and 21OH deficiency.”
From Congenital adrenal hyperplasia (2017) · cites this paper as [32]
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- Authors
- Reisch, N., Högler, W., Parajes, S., Rose, I. T., Dhir, V., Götzinger, J., Arlt, W., & Krone, N.
- Affiliations
- LMU Klinikum (DE)
- Birmingham Children's Hospital (GB)
- University of Birmingham (GB)
- Christian-Albrechts-Universität zu Kiel (DE)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2013-10
- Volume
- 98
- Issue
- 10
- Pages
- E1620-E1625
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2027244067
- Cited by
- 73
- References
- 25
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 2 · 2019: 2 · 2018: 10 · 2017: 4 · 2016: 8 · 2015: 7 · 2014: 5
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (GR079865MA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- CYP11B1, congenital adrenal hyperplasia, premature adrenarche, hirsutism, hyperandrogenism, compound heterozygosity, differential diagnosis, primary amenorrhea, short stature, 17-hydroxyprogesterone
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Child, Female, Hirsutism, Humans, Male, Steroid 11-beta-Hydroxylase, Adrenarche
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