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Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort.
J Clin Endocrinol Metab. 2013 Feb; 98(2):E346-54.JC

Abstract

CONTEXT

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking.

OBJECTIVE

The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH.

RESEARCH DESIGN AND METHODS

We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort.

RESULTS

CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups.

CONCLUSIONS

In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

Authors+Show Affiliations

Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23337727

Citation

Krone, Nils, et al. "Genotype-phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort." The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 2, 2013, pp. E346-54.
Krone N, Rose IT, Willis DS, et al. Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. J Clin Endocrinol Metab. 2013;98(2):E346-54.
Krone, N., Rose, I. T., Willis, D. S., Hodson, J., Wild, S. H., Doherty, E. J., Hahner, S., Parajes, S., Stimson, R. H., Han, T. S., Carroll, P. V., Conway, G. S., Walker, B. R., MacDonald, F., Ross, R. J., & Arlt, W. (2013). Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. The Journal of Clinical Endocrinology and Metabolism, 98(2), E346-54. https://doi.org/10.1210/jc.2012-3343
Krone N, et al. Genotype-phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort. J Clin Endocrinol Metab. 2013;98(2):E346-54. PubMed PMID: 23337727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. AU - Krone,Nils, AU - Rose,Ian T, AU - Willis,Debbie S, AU - Hodson,James, AU - Wild,Sarah H, AU - Doherty,Emma J, AU - Hahner,Stefanie, AU - Parajes,Silvia, AU - Stimson,Roland H, AU - Han,Thang S, AU - Carroll,Paul V, AU - Conway,Gerry S, AU - Walker,Brian R, AU - MacDonald,Fiona, AU - Ross,Richard J, AU - Arlt,Wiebke, AU - ,, Y1 - 2013/01/21/ PY - 2013/1/23/entrez PY - 2013/1/23/pubmed PY - 2013/4/11/medline SP - E346 EP - 54 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 98 IS - 2 N2 - CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/23337727/Genotype_phenotype_correlation_in_153_adult_patients_with_congenital_adrenal_hyperplasia_due_to_21_hydroxylase_deficiency:_analysis_of_the_United_Kingdom_Congenital_adrenal_Hyperplasia_Adult_Study_Executive__CaHASE__cohort_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2012-3343 DB - PRIME DP - Unbound Medicine ER -