Congenital Adrenal Hyperplasia – The Main Effect of 21-Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders resulting from enzymatic defects in steroidogenesis. More than 95% of CAH cases result from a deficiency of the 21-hydroxylase enzyme, which leads to cortisol deficiency, with or without aldosterone insufficiency, and also an excess of androgen. The clinical spectrum varies from milder symptoms to severe cases settled by the functional impairment of the corresponding pathogenic variant in the CYP21A2 gene. The two major forms of CAH caused by 21-hydroxylase deficiency are the classical form and the non-classic, or late onset form. There are two subtypes of the classic form: salt wasting and simple virilized. Diagnosis is clinically confirmed by 17OH-progesterone measurements, although genotyping is now progressively assuming an essential role for characterising patients. Genotyping is sometimes challenging, due to the existence of the highly homologous CYP21A1P pseudogene. The 21-hydroxylase enzyme is encoded by the CYP21A2 gene, where most of the pathogenic variants defects are due to meiotic recombination phenomena events between the CYP21A2 and CYP21A1P. Complete gene analysis is recommended to obtain a correct diagnosis and a better understanding of the underlying mechanisms of the disease in patients with CAH, and is relevant for prognosis and for prescribing the appropriate type of genetic counselling.