Chimeric CYP11B2/CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia

CYP11B1 and CYP11B2 are highly homologous genes that can form chimera following unequal crossing-over during meiosis. A chimeric CYP11B1/CYP11B2 gene causes glucocorticoid-remediable aldosteronism (GRA), while the rare CYP11B2/CYP11B1 chimeric gene leads to 11β-hydroxylase deficiency (11-OHD). The aim of the study was to find the underlying genetic causes of three distinct Chinese pedigrees with 11-OHD. The family history, clinical data, laboratory findings and alterations in the CYP11B1 gene sequence were analyzed in all patients. We found that patient 1 and patient 2 harbored novel homozygotic chimeric CYP11B2/CYP11B1 genes consisting of the promoter, exons 1-6 of CYP11B2, and exons 7-9 of CYP11B1. Patient 3 had compound heterozygotic mutation with one allele containing the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1, and the other allele comprising novel, previously undescribed p.W56X (c.168G>A) mutation in exon 1 of CYP11B1. The breakpoints to form Chimeric CYP11B2/CYP11B1 were not the same for the three patients. Rare chimeric CYP11B2/CYP11B1 gene mutations are the underlying cause of disease in three patients with 11-OHD. We hypothesize that the lack expression of CYP11B1 under the control of the CYP11B2 promoter in zona fasciculata may contribute to a cortisol defect as well as the resultant 11-OHD.