Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Abstract
Context: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. Objective: This study sought to study mortality and causes of death in CAH. Design, Setting, and Participants: We studied patients with CAH (21-hydroxylase deficiency, n = 588; CYP21A2 mutations known, >80%), and compared them with controls (n = 58 800). Data were derived through linkage of national population-based registers. Main Outcome Measures: Mortality and causes of death. Results: Mean age of death was 41.2 ± 26.9 years in patients with CAH and 47.7 ± 27.7 years in controls (P < .001). Among patients with CAH, 23 (3.9%) had deceased compared with 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3 (1.2–4.3) in CAH males and 3.5 (2.0–6.0) in CAH females. Including only patients born 1952–2009, gave similar total results but only patients with salt wasting (SW) or with unclear phenotype had an increased mortality. The causes of death in patients with CAH were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter, all except one were deceased before the introduction of neonatal screening in 1986, and most of them in the first weeks of life, probably in an adrenal crisis. Conclusions: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The SW phenotype also seemed to have worse outcome in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.
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One study calculated the standardized mortality ratio (SMR) to be 3 times higher in children with congenital adrenal hyperplasia, and mortality was significantly higher in infancy and children up to 4 years old.
“One study calculated the standardized mortality ratio (SMR) to be 3 times higher in children with CAH, and the mortality was significantly higher in infancy and children up to 4 years old (45), especially in the salt-wasting phenotype (46, 47).”
From Hypoglycaemia in adrenal insufficiency (2023) · cites this paper as [47]
The Mortality section reports an overall hazard ratio of 2.8 for patients with CAH versus controls, approximately threefold higher, and says the excess mortality was concentrated in the first year of life. It does not report a standardized mortality ratio for children or establish significantly higher mortality throughout ages 0–4. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBilateral adrenalectomy has been successfully used to treat female infertility with uncontrolled hyperandrogenism in 21OH deficiency and uncontrolled hypertension in 11βOH deficiency.
“Bilateral adrenalectomy has been successfully used to treat female infertility with uncontrolled hyperandrogenism in 21OH deficiency 87 and uncontrolled hypertension in 11βOH deficiency.88”
From Congenital adrenal hyperplasia (2017) · cites this paper as [88]
In a Swedish population-based study, adrenal crisis was reported as the leading cause of death in 588 patients with CAH.
“In a Swedish population-based study, adrenal crisis was reported as the leading cause of death in 588 patients with CAH59.”
From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [59]
Adrenal crisis is estimated to be responsible for up to 42% of excess deaths in patients with CAH, and patients with the salt-wasting form are especially at risk.
“Adrenal crisis is estimated to be responsible for up to 42% of excess deaths in patients with CAH and patients with the salt-wasting form are especially at risk59.”
From Management challenges and therapeutic advances in congenital adrenal hyperplasia (2022) · cites this paper as [59]
A register of 588 individuals with CAH showed a hazard ratio for death of 2.3 (CI, 1.2 to 4.3), equating to a 6.5-year mean reduction in life expectancy, attributed to adrenal crises.
“A register of 588 individuals with CAH showed a hazard ratio for death of 2.3 (CI, 1.2 to 4.3), equating to a 6.5-year mean reduction in life expectancy (214) attributed to adrenal crises.”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [214]
Treating pediatricians are constantly faced with the risk of over- and under-dosing their patients, which may lead to complications of excess steroid therapy and adrenal crisis, respectively.
“Therefore, treating pediatricians are constantly faced with the risk of over- and under-dosing their patients, which may lead to complications of excess steroid therapy ( Falhammar et al., 2014 ) and adrenal crisis ( El-Maouche et al., 2018 ), respectively.”
From Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach (2023) · cites this paper as Falhammar et al., 2014
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References 41 · Cited by 196
Research works printed but not linked: 1
- New MI. Extensive clinical experience: Nonclassical 21-hydroxy- lase deficiency. J Clin Endocrinol Metab. 2006;91:4205-4214.
- Authors
- Falhammar, H., Frisén, L., Norrby, C., Hirschberg, A. L., Almqvist, C., Nordenskjöld, A., & Nordenström, A.
- Affiliations
- Department of Endocrinology, Metabolism and Diabetes (H.F.),171 76 Stockholm, Sweden;
- Department of Clinical Neuroscience (L.F.), 171 76 Stockholm, Sweden;
- Department of Medical Epidemiology and Biostatistics (C.N., C.A.), 171 76 Stockholm, Sweden;
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Corresponding author
- Falhammar, Henrik
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-12-01
- Volume
- 99
- Issue
- 12
- Pages
- E2715-E2721
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1991990426
- Cited by
- 196
- References
- 41
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 19 · 2023: 25 · 2022: 16 · 2021: 22 · 2020: 16 · 2019: 15 · 2018: 19 · 2017: 8 · 2016: 12 · 2015: 8 · 2014: 1
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion)
- Open Archive (Karolinska Institutet) (submittedVersion)
- Funders
- Karolinska Institutet
- Stockholms Läns Landsting
- Vetenskapsrådet
- 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
- congenital adrenal hyperplasia, 21-hydroxylase deficiency, mortality, causes of death, adrenal crisis, salt-wasting phenotype, CYP21A2 mutations, newborn screening, cardiovascular mortality, cancer mortality, suicide
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Adult, Aged, Aged, 80 and over, Cause of Death, Child, Child, Preschool, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Registries, Sweden, Cohort Studies, Survival Analysis, Young Adult
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