Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.
Open accessAbstract
Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.
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Lipoid CAH has been reported in most ethnic groups but is common among the Japanese, Korean, and Palestinian Arab populations.
“Lipoid CAH has been reported in most ethnic groups but is common among the Japanese, Korean, and Palestinian Arab populations1,3,4,10,11,13,29,30,31,32).”
From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [29]
The paper reports lipoid CAH in two unrelated Japanese kindreds (Abstract; page unavailable), supporting its occurrence among Japanese people. It does not establish that lipoid CAH is common in Japan, Korea, or Palestinian Arab populations, or that it has been reported in most ethnic groups; searches for those population terms found no such passage. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe 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 [110]
The Abstract and Case histories (pages not indexed) document spontaneous pubertal development in 46,XX patients treated in infancy. The Discussion proposes that ovarian tissue avoids the early cholesterol-related damage seen in adrenal and testicular tissue, which is consistent with the two-hit explanation. But it presents that mechanism as a possibility and offers an alternative, rather than establishing that the model explains the development. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMeasurements of estradiol, progesterone, and gonadotropins throughout the cycle in affected adult females with lipoid CAH confirmed the two-hit model.
“Measurements of estradiol, progesterone, and gonadotropins throughout the cycle in affected adult females with lipoid CAH confirmed this model (110).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [110]
The Case histories (page unavailable) report estradiol, progesterone, LH, and FSH profiles during menstrual cycles in two affected females. The Discussion (page unavailable) interprets the findings as consistent with ovarian steroidogenesis despite StAR mutations, but presents cholesterol-related damage as a possible explanation and offers an alternative mechanism. The measurements therefore support, rather than confirm, the two-hit model. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAlthough 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 [110]
The Case histories report breast development, measurable estradiol, and periodic or cyclic vaginal bleeding in two 46,XX patients with lipoid CAH. The Discussion says estrogen was sufficient for secondary sexual development and endometrial growth, but describes the bleeding as possibly anovulatory or due to severely deficient luteal phases. It does not establish monthly estrogen withdrawal as the mechanism. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLipoid CAH is common in Japan and Korea.
“Lipoid CAH is the most fatal form of CAH and is common in Japan and Korea.”
From Congenital lipoid adrenal hyperplasia (2014) · cites this paper as [29]
The paper reports two affected Japanese kindreds (Abstract; no page provided), but that does not establish how common lipoid CAH is in Japan. Searches for prevalence and for Korea found no passage addressing its frequency in either country. The Introduction calls it the most severe form of CAH, but that does not settle the geographic claim being audited. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- [13]13. Nakae, J., T. Tajima, T. Sugawara, K. Hanakai, T. Hotsubo, N. Igarashi, Y. Igarashi, T. Ishii, N. Koda, T. Kondo, et al. 1997. Analysis of the steri- odogenic acute regulatory protein (StAR) gene in Japanese patients with congeni- tal lipoid adrenal hyperplasia: functional implications. Hum. Mol. Genet. In press.
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- Authors
- Fujieda, K., Tajima, T., Nakae, J., Sageshima, S., Tachibana, K., Suwa, S., Sugawara, T., & Strauss, J. F.
- Affiliations
- Hokkaido University (JP)
- Obihiro Kosei General Hospital (JP)
- Kanagawa Children's Medical Center (JP)
- University of Pennsylvania (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1997-03-15
- Volume
- 99
- Issue
- 6
- Pages
- 1265-1271
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC507941
- OpenAlex
- W1998831344
- Semantic Scholar
- 89c07dac091b228e4d37510d92627177eda61494
- Cited by
- 162
- References
- 12
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 8
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Texas Tech University
- National Institutes of Health
- U.S. Public Health Service
- University of California, San Francisco
- Japan Society for the Promotion of Science
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-06274, HD-34449, P01HD006274, U54HD034449)
- 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, spontaneous puberty, 46,XX disorders of sex development, steroidogenic acute regulatory protein, ovarian steroidogenesis, polycystic ovary, 46,XX karyotype, adrenal steroidogenesis, testicular steroidogenesis, glucocorticoid therapy, menarche, thelarche
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adolescent, Adrenal Hyperplasia, Congenital, Adult, Amino Acid Sequence, Base Sequence, Child, Cholesterol Side-Chain Cleavage Enzyme, Female, Humans, Molecular Sequence Data, Mutation, Ovary, Pedigree, Phosphoproteins, Puberty, Frameshift Mutation, Sequence Analysis, DNA, Gene Expression Regulation, Developmental
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