medwireNews: The genotype of patients with congenital adrenal hyperplasia (CAH) closely matches patients’ symptoms, say researchers.

“Genotyping is a useful complementary tool for confirming or excluding CAH diagnosis and predicting the clinical manifestations in patients who are diagnosed before the symptomatic phase”, write Daniel Carvalho (Universidade de São Paulo, Brazil) and study co-authors.

The type and frequency of mutations they identified in their cohort of 480 Brazilian patients were similar to those reported for patients of other ethnicities, they report in the European Journal of Endocrinology.

Sequencing of the CYP21A2 gene proved vital for maximising genotype diagnosis, says the team, with a diagnostic approach based on site-directed mutation analysis falling short “more often than expected”. Although it identified mutations in both alleles in 88.6% of patients with salt-wasting CAH and 86.3% of those with simple virilising CAH, sequencing of the CYP21A2 gene brought the rate up to 100% in classical CAH patients and also improved the detection of mutations in patients with nonclassical CAH.

Overall, genotype predicted CAH phenotype in 97.3% of patients. It was 88.2% accurate for patients whose genotype predicted no residual enzymatic activity and 70.0% accurate for those with less than 2% activity. Most patients in these two groups had salt-wasting CAH, but the proportion was highest in the group with no residual activity, which the researchers say is “important for clinical decisions in asymptomatic patients during the neonatal period”.

However, if patients in the less severe group (<2% activity) carried the most common mutation for these two groups – IVS2-13A/C>G – it conferred a 1.71-fold increased risk of having a salt-wasting phenotype.

“Its presence in some simple virilizing patients can be explained by alternative splicing, which leads to a minimal residual enzyme activity, thus avoiding salt loss”, say Carvalho and team.

Genotype predicted phenotype with 98% accuracy in patients with 3–7% residual enzymatic activity, who comprised patients with simple virilising CAH plus one with nonclassical, and 100% accurate for those with more than 20% activity, who all had nonclassical CAH.

The team also found stimulated 17-hydroxyprogesterone (17-OHP) levels to be a useful guide in nonclassical CAH patients. In this group, a stimulated-17-OHP level of 44.3 ng/mL was 67.4% sensitive and 70.2% specific for predicting severe mutations, which Carvalho et al note is helpful information for genetic counselling.

By Eleanor McDermid, Senior medwireNews Reporter

Eur J Endocrinol 2016; Advance online publication

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