A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1)

Parajes, Silvia; Kamrath, Clemens; Rose, Ian T.; Taylor, Angela E.; Mooij, Christiaan F.; Dhir, Vivek; Grötzinger, Joachim; Arlt, Wiebke; Krone, Nils

doi:10.1210/jc.2011-1277

Cited by 59Adrenal Hormones and DisordersSexual Differentiation and DisordersMetabolism and Genetic Disorders

A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1)

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Parajes, Silvia, Kamrath, Clemens, Rose, Ian T., Taylor, Angela E., Mooij, Christiaan F., Dhir, Vivek, Grötzinger, Joachim, Arlt, Wiebke +1 more·2011·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2011-1277

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CONTEXT: Cytochrome P450 side-chain cleavage enzyme (CYP11A1) facilitates the first and rate-limiting step of steroidogenesis. Only nine patients with CYP11A1 deficiency have been described. All patients presented with adrenal insufficiency (AI) and disorder of sex development in 46,XY individuals. OBJECTIVE: Our objective was to define the pathogenic consequences of a novel CYP11A1 mutation (p.R451W) found in two brothers with isolated adrenal insufficiency. PATIENTS: The two brothers (46,XY) presented with AI and normal male genital development. The older boy first presented with signs and symptoms suggestive of AI at the age of 2.8 yr but was only diagnosed at the age of 4.1 yr during an adrenal crisis. The younger brother was diagnosed with AI at the age of 2.5 yr while being clinically asymptomatic. Both boys had entirely normal appearance of their external genitalia. RESULTS: The novel p.R451W mutation and five published missense CYP11A1 mutations were characterized employing two in vitro approaches using the natural substrate cholesterol and the intermediate 22R-hydroxycholesterol, respectively. Pregnenolone generation was measured by highly specific liquid chromatography tandem mass spectrometry. p.R451W had 30% of wild-type activity consistent with the clinical phenotype in our patients. Two previously published mutations (p.L222P and p.A359V) had 2- to 3-fold higher in vitro activities than originally reported, correlating better with the associated phenotypes. CONCLUSIONS: We provide the first evidence that partial CYP11A1 deficiency has to be considered as a differential diagnosis in clinically isolated adrenal insufficiency. Our assays demonstrate a tighter genotype-phenotype correlation in CYP11A1 deficiency than previous in vitro studies.

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A nonclassic form of lipoid CAH was first described in 2006 associated with mutations that retain approximately 20-30% of StAR activity.
“A nonclassic form was first described in 2006 52 associated with mutations that retain approximately 20-30% of StAR activity.”
From Congenital adrenal hyperplasia (2017) · cites this paper as [52]

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Authors: Parajes, S., Kamrath, C., Rose, I. T., Taylor, A. E., Mooij, C. F., Dhir, V., Grötzinger, J., Arlt, W., & Krone, N.
Affiliations: University of Birmingham (GB)
Justus-Liebig-Universität Gießen (DE)
Christian-Albrechts-Universität zu Kiel (DE)
Corresponding author: Krone, Nils
ORCID: Kamrath, Clemens
Taylor, Angela E.
Mooij, Christiaan F.
Dhir, Vivek
Arlt, Wiebke
Krone, Nils
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2011-11
Volume: 96
Issue: 11
Pages: E1798-E1806
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2011-1277
OpenAlex: W2159760570
Cited by: 59
References: 33
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 1 · 2013: 7 · 2012: 6
FWCI: 3.93
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Funders: Wellcome Trust (GR079865MA)
European Commission (255424, 201444)
ZonMw
Consellería de Economía, Emprego e Industria, Xunta de Galicia
Xunta de Galicia
Medical Research Council (0900567)
FP7 Coordination of Non-Community Research Programmes (201444)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords: CYP11A1, adrenal insufficiency, missense mutations, genotype-phenotype correlation, steroidogenesis, 22R-hydroxycholesterol, pregnenolone, adrenal crisis, 46,XY disorders of sex development, differential diagnosis
MeSH terms: Adrenal Insufficiency, Child, Preschool, Cholesterol Side-Chain Cleavage Enzyme, Genotype, Humans, Male, Phenotype, Mutation, Missense

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A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1)

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