ESPE Abstracts

Background: Genetic diversity of mutations in the CYP21A2 gene is the main cause of the monogenic Congenital adrenal hyperplasia (CAH) disorder. On chromosome 6p23.1, the CYP21A2 gene is partially overlapped by the TNXB gene and reside in tandem with their highly homologous corresponding pseudogenes (CYP21A1P and TNXA), which leads to recurrent homologous recombination.

Methods and Results: The genetic status of a family of Cypriot origin is presented. The index case concerns the female (46, XX) neonate originally assigned as male as she presented with severe (Prader 5) virilization and subsequently diagnosed with the salt-wasting (SW) form of CAH based on biochemical and hormonal findings. Genetic defects in the CYP21A2 and TNXB genes were investigated by Sanger, multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR assay. The neonate carried in compound heterozygosity the TNXA/TNXB chimeric gene complex (termed CAH-X CH-1) that results in a contiguous CYP21A2 and TNXB deletion and in her second allele the severe IVS2-13A/C>G in CYP21A2.

Conclusions: The classic SW-CAH due to 21-hydroxylase deficiency may result from various complex etiological mechanisms and such can involve the formation of monoallelic TNXA/TNXB chimeras found in trans with other CYP21A2 pathogenic variants. By identifying the correct CAH genotypes for a given phenotype, should be able to assist clinicians in prenatal diagnosis, appropriate treatment and genetic counseling.