A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)
Abstract
We report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (< 37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris had enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom…
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Biologically significant estrogen synthesis derives entirely from P450aro.
“Studies of patients with aromatase deficiency show that biologically significant estrogen synthesis derives entirely from P450aro (326, 327), although dietary phytoestrogens can provide some estrogen action in mice with targeted deletion of Cyp19a1 (543).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [326]
In the absence of placental aromatase activity, androgenic C19 steroids derived from the fetal adrenal are passed into the maternal circulation, causing marked virilization of the mother.
“However, in the absence of placental aromatase activity, androgenic C 19 steroids derived from the fetal adrenal are passed into the maternal circulation, causing marked virilization of the mother (326).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [326]
In fetuses homozygous for aromatase deficiency, the principal manifestation results from its deficiency in the placenta because ovarian steroidogenesis is quiescent during fetal life.
“In fetuses homozygous for aromatase deficiency, the principal manifestation results from its deficiency in the placenta (326) because ovarian steroidogenesis is quiescent during fetal life (106).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [326]
Fetoplacental estrogen is not needed for normal fetal development.
“Although it has traditionally been thought that aromatase activity is needed for embryonic and fetal development, infants and adults with aromatase deficiency have been described, showing that fetoplacental estrogen is not needed for normal fetal development (326, 542).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [326]
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- Authors
- Conte, F. A., Grumbach, M. M., Ito, Y., Fisher, C. R., & Simpson, E. R.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Ito, Y
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1994-06
- Volume
- 78
- Issue
- 6
- Pages
- 1287-1292
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2138838458
- Cited by
- 379
- References
- 3
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 7 · 2017: 3 · 2016: 12 · 2015: 5 · 2014: 8 · 2013: 10 · 2012: 8
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag008174-02, 5r01hd002335-26)
- National Institute on Aging (NICHHD RO1-AG-08174 ER8)
- National Center for Research Resources (M01RR001271, NCRR M01-RR-01271)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHHD RO1-HD-02335)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- aromatase deficiency, aromatase, P450arom, female pseudohermaphroditism, hypergonadotropic hypogonadism, multicystic ovaries, 46,XX disorders, missense mutations, compound heterozygosity, clitoral enlargement, hyperandrogenism, estrogen replacement therapy
- MeSH terms
- Adolescent, Adrenocorticotropic Hormone, Androgens, Aromatase, Cortodoxone, Estradiol, Female, Follicle Stimulating Hormone, Humans, 17-alpha-Hydroxypregnenolone, Hydroxyprogesterones, Hypogonadism, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Ovary, Polycystic Ovary Syndrome, Disorders of Sex Development, Syndrome, Point Mutation, 17-alpha-Hydroxyprogesterone
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