21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study
Abstract
Objective Our aim was to determine whether the clinical features of 21-hydroxylase-deficient nonclassic adrenal hyperplasia are correlated with either age at symptom onset or age at presentation, or both, and with the degree of adrenocortical abnormality.Study design In a multicenter cohort design 220 women with nonclassic adrenal hyperplasia, with a basal or adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level >30.3 nmol/L, were studied, either prospectively (n = 39) or retrospectively (n = 181). Patients were stratified by age of presentation into 5 groups: (1) <10 years (n = 25), (2) 10 to 19 years (n = 64), (3) 20 to 29 years (n = 83), (4) 30 to 39 years (n = 30), and (5) 40 to 49 years (n = 16). Two patients >50 years old were excluded from the analysis because of age.Results Ninety-two percent of patients <10 years old had premature pubarche at presentation, whereas clitoromegaly and acne were each present in only 20% of these younger subjects. With only patients > or =10 years old considered, presenting clinical features included hirsutism (59%), oligomenorrhea (54%), acne (33%), infertility (13%), clitoromegaly (10%), alopecia (8%), primary amenorrhea (4%), and premature pubarche (4%). Among the patients >/=10 years old, the prevalence but not the degree of hirsutism increased significantly with age. Basal levels of 17-hydroxyprogesterone in adolescents were significantly higher than the levels found either in children (<10 years old) or women 40 to 49 years old (P <.01 and P <.03, respectively), although no difference was noted in the stimulated 17-hydroxyprogesterone levels between age groups. The adrenocorticotropic hormone-stimulated levels but not the basal levels of 17-hydroxyprogesterone were significantly higher in patients with clitoromegaly than in women without clitoromegaly. Alternatively, there were no differences in either basal or stimulated 17-hydroxyprogesterone levels between patients with and those without hirsutism, acne, or alopecia.Conclusion In children <10 years old the most common presenting complaint was premature pubarche, whereas hirsutism and oligomenorrhea were more common in older patients. The prevalence of hirsutism increased with age, suggesting the progressive nature of nonclassic adrenal hyperplasia. Furthermore, the adrenocorticotropic hormone-stimulated levels of 17-hydroxyprogesterone were higher in patients with clitoromegaly, which suggests that the degree of adrenocortical dysfunction in nonclassic adrenal hyperplasia determines, at least in part, the clinical presentation.
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Most studies describe nearly normal adult height in NC CAH patients.
“However, most studies describe nearly normal adult height in NC CAH patients (417,423-425).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [425]
The most frequent CYP21A2 mutation in the 55 NCCAH children was V281L.
“The CYP21A2 genotyping of the 55 children affected by NCCAH showed that, as in other series, the most frequently observed mutation is V281L (23,29,30).”
From Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche (2011) · cites this paper as [23]
The 52.7% homozygosity for mild mutations is higher than in French adult and Brazilian adult series but similar to pediatric Spanish and Jewish series.
“a percentage strikingly higher than that recently reported in a large series of French adult patients (26) and in previous studies in adult Brazilian patients (23), but similar to the one detected in pediatric Spanish (29) and Jewish patients (30), mostly comprised of children with PP.”
From Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche (2011) · cites this paper as [23]
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- Authors
- Moran, C., Azziz, R., Carmina, E., Dewailly, D., Fruzzetti, F., Ibañez, L., Knochenhauer, E. S., Marcondes, J. A. M., Mendonca, B. B., Pignatelli, D., Pugeat, M., Rohmer, V., Speiser, P. W., & Witchel, S. F.
- Affiliations
- Mexican Social Security Institute (MX)
- ORCID
- Venue
- American Journal of Obstetrics and Gynecology
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 183
- Issue
- 6
- Pages
- 1468-1474
- ISSN
- 0002-9378 (ISSN-L)
- OpenAlex
- W1972639473
- Cited by
- 185
- References
- 20
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 10 · 2023: 17 · 2022: 12 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 8 · 2015: 8 · 2014: 8 · 2013: 3 · 2012: 10
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Obstetrics and Gynecology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD029364, R01-HD29364)
- 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
- 21-hydroxylase deficiency, age at presentation, age at symptom onset, 17-hydroxyprogesterone, adrenocorticotropic hormone stimulation, clitoromegaly, hirsutism, premature pubarche, adrenal insufficiency, adrenal hyperplasia
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Adult, Aging, Child, Child, Preschool, Clitoris, Female, Hirsutism, Humans, Middle Aged, Oligomenorrhea, Prospective Studies, Puberty, Precocious, Retrospective Studies, Vulvar Diseases, Cohort Studies, Disease Progression, 17-alpha-Hydroxyprogesterone
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