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Cited by 160Sexual Differentiation and DisordersAdrenal Hormones and DisordersOvarian function and disorders

Spontaneous Feminization in a 46,XX Female Patient with Congenital Lipoid Adrenal Hyperplasia Due to a Homozygous Frameshift Mutation in the Steroidogenic Acute Regulatory Protein*

Bose, Himangshu S., Pescovitz, Ora Hirsch, Miller, Walter L.·1997·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.82.5.3962
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Abstract

The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.

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Crossref · 10.1210/jcem.82.5.3962

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  • Although net ovarian steroidogenesis is impaired in lipoid CAH, enough estrogen is produced to induce breast development, feminization, monthly estrogen withdrawal, and cyclic vaginal bleeding.

    “Although net ovarian steroidogenesis is impaired, enough estrogen is produced to induce breast development (especially in the absence of androgens), feminization, monthly estrogen withdrawal, and cyclic vaginal bleeding (67, 109, 110).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [109]

  • The two-hit model explains the spontaneous feminization of affected 46,XX females who are treated in infancy and reach adolescence.

    “The two-hit model also explains the spontaneous feminization of affected 46,XX females who are treated in infancy and reach adolescence (109, 110).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [109]

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Authors
Bose, H. S., Pescovitz, O. H., & Miller, W. L.
Affiliations
  • Department of Pediatrics (H.S.B., W.L.M.), San Francisco, California 94143;
  • Indiana University (US)
  • University of California, San Francisco (US)
Corresponding author
Miller, Walter L.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1997-05-01
Volume
82
Issue
5
Pages
1511-1515
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.82.5.3962
OpenAlex
W2063795177
Cited by
160
References
8
Citations by year
2025: 1 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 6 · 2017: 2 · 2016: 9 · 2015: 5 · 2014: 6 · 2013: 10 · 2012: 4
FWCI
3.44
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk042154-09)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, DK 42154, 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
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
congenital lipoid adrenal hyperplasia, steroidogenic acute regulatory protein, 46,XX disorders of sex development, two-hit model, cholesteryl ester accumulation, ovarian steroidogenesis, adolescent girls
MeSH terms
Steroidogenic Acute Regulatory Protein, Adolescent, Adrenal Hyperplasia, Congenital, Base Sequence, DNA, Female, Humans, Phosphoproteins, Steroids, Frameshift Mutation, Gene Deletion

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