Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients

Author:

Riedl Stefan12,Röhl Friedrich-Wilhelm3,Bonfig Walter4,Brämswig Jürgen5,Richter-Unruh Annette5,Fricke-Otto Susanne6,Bettendorf Markus7,Riepe Felix8,Kriegshäuser Gernot9,Schönau Eckhard10,Even Gertrud10,Hauffa Berthold11,Dörr Helmuth-Günther12,Holl Reinhard W13,Mohnike Klaus14,_ _

Affiliation:

1. 1Division of Pediatric Pulmology, Allergology and Endocrinology, Department of Pediatrics, Medical University of Vienna, Vienna, Austria

2. 2Department of Pediatrics, St. Anna Kinderspital, Medical University of Vienna, Vienna, Austria

3. 3Department of Biometrics, Otto von Guericke Universität Magdeburg, Magdeburg, Germany

4. 4Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria

5. 5Department of Pediatrics, Pediatric Endocrinology, Westfälische Wilhelmsuniversität Münster, Münster, Germany

6. 6Department of Pediatrics, Pediatric Endocrinology, Helios Klinikum Krefeld, Krefeld, Germany

7. 7Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany

8. 8Pediatric Endocrinology, Kronshagen, Kiel, Germany

9. 9Institute of Clinical Chemistry and Laboratory Medicine, General Hospital Steyr, Steyr, Austria

10. 10Department of Pediatrics, Pediatric Endocrinology, Universität zu Köln, Cologne, Germany

11. 11Department of Pediatric Endocrinology, University of Duisburg-Essen, Essen, Germany

12. 12Department of Pediatrics, Pediatric Endocrinology, Friedrich Alexander Universität Erlangen, Erlangen, Germany

13. 13Institute of Epidemiology and Medical Biometry (ZIBMT), University of Ulm, Ulm, Germany

14. 14Department of Pediatrics, Pediatric Endocrinology, Otto von Guericke Universität Magdeburg, Magdeburg, Germany

Abstract

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80–90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine

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