(Vienna, 28 September 2020) The recently presented European Best Practice Guidelines for the complex molecular genetic diagnosis of adrenogenital syndrome (21-OHD) are not only important for prenatal diagnosis and newborn screening and for patients with clinical symptoms but also for clinically healthy family members. The Guidelines have now been published in the European Journal of Human Genetics and are also referenced on the EMQN (European Molecular Genetics Quality Network) website. Sabina Baumgartner-Parzer from the Division of Endocrinology and Metabolism within MedUni Vienna's Department of Medicine III played a leading role in the drafting process.
Adrenogenital syndrome (AGS) is the name for a group of genetic disorders with autosomal recessive inheritance, in which production of certain endogenous steroid hormones in the adrenal cortex is disrupted. Both men and women can suffer from AGS but they manifest different gender-specific symptoms. More than 95% of cases are caused by genetic defects on the 21-hydroxylase gene (CYP21A2).
The clinically severe form is known as "classical AGS". This form of the disease can produce life-threatening symptoms right from birth, which could cause a salt wasting crisis in both genders or masculinisation of the external sexual characteristics in girls. The latter ranges from enlargement of the clitoris right through to formation of a pseudo-penis, despite the presence of internal female genitalia. A newborn screening programme also conducted in Austria includes checking for AGS, so as to prevent life-threatening salt wasting crises and initiate substitution therapy as soon as possible.
A milder form is "non-classical AGS", where symptoms do not occur until later on, often not being diagnosed until after puberty. These patients have a genetic defect that causes milder impairment of the function of the corresponding enzyme, so that the adrenal cortex can still produce a certain amount of cortisol and aldosterone. "Non-classical AGS" can even be so minimal that, although there is a biochemically detectable hormone imbalance, no marked clinical symptoms are exhibited, so that often AGS is only diagnosed when sufferers are unable to have children.
"In all forms, but particularly in the milder form with less marked symptoms, molecular genetic diagnosis is extremely important in making a diagnosis. In more severe forms, molecular genetic diagnosis is essential in order to provide reliable genetic counselling with regard to having children or family planning. Heterozygous carriers can only be reliably identified by molecular genetic diagnosis, since they are clinically normal," explains Baumgartner-Parzer.
Since the 21-OH gene is extremely complex (pseudogene, gene conversions, potentially multiple gene copies) with a broad range of different mutations, molecular genetic analysis is complex. Moreover, interpretation of the analysis results requires a deep understanding of the genetic constellations, since this diagnosis is not only important for newborn screening and the investigation of patients with clinical symptoms but also for clinically normal partners and family members.