Congenital Adrenal Hyperplasia

Research projects

Prenatal treatment of Congenital Adrenal Hyperplasia

- evaluation of treatment efficiency and outcome with emphasis on metabolic, cognitive and epigenetic markers.

Since the mid-1980s many children in the world at risk of congenital adrenal hyperplasia (CAH) have been treated with prenatal dexamethasone (DEX) to reduce congenital malformations, but the treatment is controversial.

Current knowledge indicates that prenatal DEX therapy for CAH is efficient in reducing virilization in affected girls. It was during decades considered safe, but recent data show that it may involve somatic and cognitive risks.

The current treatment protocol holds an ethical dilemma, since treatment has to be initiated before conventional prenatal diagnosis with chorionic villous sampling can be performed. Due to autosomal recessive inheritance, 7 out of 8 treated fetuses are thus subjected to glucocorticoids during early embryogenesis without benefit. Negative side-effects cannot therefore be tolerated and long-term data on treatment safety and health outcome are still very limited. There are also different opinions in the world whether DEX treatment should be part of the current clinical management of CAH or not. There is therefore an absolute necessity for evaluation of patients with respect to treatment related risk and benefit in this unique paediatric cohort.

The aim of the present study is to identify the metabolic, neuro-structural and neuro-functional effects of prenatal DEX in treated individuals from childhood to adult age. The neural and metabolic effects of postnatally administered glucocorticoids (GC) in CAH patients are also studied. In addition, we aim to explore the DEX effects on whole genome methylation and to correlate these changes to cognitive and neuro-structural outcome as a plausible mechanism of long-lasting foetal programming effects of DEX.

The data will give completely new knowledge on long lasting glucocorticoid effects on the human brain both in individuals with and without CAH. It will help the paediatric medical society in the decision whether DEX therapy in the context of CAH still can be used in the future by weighing risk versus benefit. The present study design provides a unique opportunity to study whether the mal effects of GC exposure really has long term effects on the human brain, if such effects are restricted to certain periods of the foetal life, and how such effects may via epigenetic processes be transmitted to future generations. Gender differences observed in reactions to stress, both somatic and psychiatric illness, may be explained by differences in the epigenetic as well as neurobiological mechanisms involved. Ultimately, pathophysiological changes as a link between environmental factors and inheritance can be identified.

Functional analysis of novel CYP21A2 mutations identified in patients with CAH

We study the functional and structural effects of novel and rare CYP21A2 mutations in vitro and in silico. Detailed functional analysis of novel CYP21A2 mutations improves the genotype-phenotype correlation and genetic counselling in affected families and increases the knowledge on CYP structure and function in general

Group members

Marius Zimmermann, Research engineer/post-doc
Leif Karlsson, MSc, PhD student
Lena Wallensteen, MD, PhD student
Malin Thomsen Sandberg, MD, PhD student
Anton Gezelius, student