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Cited by 139Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc

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Kim, Chan Jong, Lin, Lin, Huang, Ningwu, Quigley, Charmian A., AvRuskin, Theodore W., Achermann, John C., Miller, Walter L.·2008·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2007-2330PMC PMC2266942
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Abstract

CONTEXT: Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues. Although progesterone production from the fetally-derived placenta is necessary to maintain pregnancy to term, four patients with mutations in the gene encoding P450scc (CYP11A1), have been described, one in a 46,XX female and three in underandrogenized 46,XY individuals, all with primary adrenal failure. OBJECTIVE: Our aim was to determine whether P450scc mutations might be found in other children and to explore genotype/phenotype correlations. METHODS AND PATIENTS: We performed mutational analysis of CYP11A1 in individuals with 46,XY disorders of sex development and primary adrenal failure, followed by functional studies of P450scc activity and of P450scc RNA splicing. RESULTS: Among nine 46,XY infants with adrenal failure and disordered sexual differentiation, two infants had compound heterozygous mutations in CYP11A1. One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38 and 0% activity, respectively. The other carried a CYP11A1 frameshift mutation c835delA (0% activity) and a splice site mutation [IVS3+(2-3)insT] that prevented correct splicing of P450scc mRNA. CONCLUSIONS: P450scc deficiency is a recently recognized disorder that may be more frequent than originally thought. The phenotypic spectrum ranges from severe loss-of-function mutations associated with prematurity, complete underandrogenization, and severe, early-onset adrenal failure, to partial deficiencies found in children born at term with clitoromegaly and later-onset adrenal failure. In contradistinction to congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein mutations, adrenal hyperplasia has not been reported in any of the six patients with P450scc deficiency.

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Crossref · 10.1210/jc.2007-2330

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  • P450scc mutations can cause lipoid CAH and establish a recently recognized human endocrine disorder.

    “P450scc mutations can also cause lipoid CAH and establish a recently recognized human endocrine disorder.”

    From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [35]

    The Abstract Conclusions call P450scc deficiency a recently recognized disorder, supporting that part of the claim. But the Introduction attributes congenital lipoid adrenal hyperplasia to StAR mutations, and the Discussion distinguishes it from P450scc deficiency; the paper does not say P450scc mutations cause lipoid CAH. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • P450scc deficiency is a novel, rare disorder that can present as acute adrenal insufficiency at any time from infancy to early childhood.

    “P450scc deficiency is a novel, rare disorder that can present as acute adrenal insufficiency at any time from infancy to early childhood35).”

    From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [35]

  • 46,XY patients with P450scc deficiency have female external genitalia, sometimes with clitoromegaly.

    “the 46,XY patients have female external genitalia, sometimes with clitoromegaly35).”

    From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [35]

  • In all cases of P450scc deficiency, ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent.

    “In all cases, ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent”

    From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [35]

  • Several patients have been described with mutations in P450scc.

    “Several patients have now been described with mutations in P450scc (136, 137, 153-155).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [137]

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  1. [4]Prader A Gurtner HP Das Syndrom des Pseudohermaphroditismus masculinus bei kongenitaler Nebennierenrindenhyperplasie ohne Androgenuberproduktion (adrenaler Pseudohermaphroditismus masculinus) Helv Paed Acta 1955 10 397 412 13285832

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Authors
Kim, C. J., Lin, L., Huang, N., Quigley, C. A., AvRuskin, T. W., Achermann, J. C., & Miller, W. L.
Affiliations
  • University of California, San Francisco (US)
  • University College London (GB)
  • Lilly Research Laboratories (C.A.Q.), US Medical, Indianapolis, Indiana 46285
  • State University of New York (US)
Corresponding author
  • Achermann, John C.
  • Miller, Walter L.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2008-03-01
Volume
93
Issue
3
Pages
696-702
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2007-2330
PMC
PMC2266942
OpenAlex
W2099492603
Semantic Scholar
e50208e681318846c6c0b597460495270ec2ed2c
Cited by
139
References
44
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 10 · 2017: 5 · 2016: 7 · 2015: 12 · 2014: 5 · 2013: 14 · 2012: 10
FWCI
5.21
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (079666)
  • Chonnam National University
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, R01DK037922)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
CYP11A1, cholesterol side-chain cleavage enzyme, Addison's disease, disorders of sex development, 46,XY disorders of sex development, compound heterozygosity, missense mutations, frameshift mutation, splice site mutation, genotype-phenotype correlation, clitoromegaly, adrenal hyperplasia, pregnenolone synthesis, congenital lipoid adrenal hyperplasia
MeSH terms
Adrenal Insufficiency, Cholesterol Side-Chain Cleavage Enzyme, Female, Gonadal Dysgenesis, 46,XY, Humans, Mutation, Disorders of Sex Development

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