Anna Nordenström1,2, Johan Svensson1,2, Svetlana Lajic1,2, Louise Frisén3,4, Agneta Nordenskjöld1,5,6, Christina Norrby7, Catarina Almqvist7,8, Henrik Falhammar9,10. 1. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 2. Paediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. 3. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 4. Child and Adolescent Psychiatry Research Centre, Stockholm, Sweden. 5. Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. 6. Paediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. 7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 8. Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. 9. Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden. 10. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Abstract
CONTEXT: Congenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH. OBJECTIVE: We investigated whether the mortality was lower, and determined the cause of death in carriers and population controls. DESIGN: A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age. RESULTS: The overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls. CONCLUSION: Obligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.
CONTEXT: Congenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH. OBJECTIVE: We investigated whether the mortality was lower, and determined the cause of death in carriers and population controls. DESIGN: A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age. RESULTS: The overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls. CONCLUSION: Obligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.