Bilateral laparoscopic adrenalectomy for congenital adrenal hyperplasia with severe hypertension, resulting from two novel mutations in splice donor sites of CYP11B1

We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11 beta -hydroxylase deficiency. Sequencing of the CYP11B 1 gene showed two new base substitutions, a conservative 954 G-->C transver sion at the last base of exon 5 (T318T), and a IVS8 + 4A-->G transition in intron 8. In addition, two polymorphisms were found in exons 1 and 2. The g enetically female patient was raised as a male because of severe pseudoherm aphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension wit h pronounced hypertrophic cardiomyopathy. At 42 yr of age the occurrence of central retinal vein occlusion with permanent loss of left eye vision led to the decision to perform bilateral laparoscopic adrenalectomy. Surgery wa s followed by normalization of blood pressure and good compliance with gluc ocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low 11 beta -hydroxylase activity. Analysis of adrenal CYP11B1 messenger ribonucleic acid (mRNA) by RT-PCR and sequencing showed the expression of a shorter mRNA that lacked exon 8 and did not contain either the exon 5 mutation or the exon 1 and 2 p olymorphisms. This suggested that one CYP11B1 allele carried the intron 8 m utation, responsible for skipping exon 8. The other allele carried the exon 5 mutation, and its mRNA was not detectable. Western blot analysis showed weak expression of a shorter CYP11B immunoreactive band of 43 kDa, consiste nt with truncation of exon 8. Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understan ding the mechanisms and physiopathological consequences of two novel mutati ons of CYP11B1.