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Bilateral Laparoscopic Adrenalectomy for Congenital Adrenal Hyperplasia with Severe Hypertension, Resulting from Two Novel Mutations in Splice Donor Sites of CYP11B1

Service d’Endocrinologie (O.C., J.V.), Chirurgie Générale et Thoracique (P.C.), and Laboratoire de Pathologie Cellulaire (F.L.-M.), Centre Hospitalier Universitaire, 38043 Grenoble, France; INSERM U-329, Hôpital Debrousse (S.P.-D., Y.M.), 69322 Lyon, France; INSERM U-244, Biochimie des Regulations Cellulaires Endocrines, Département de Biologie Moléculaire et Structurale, Commissariat à l’Energie Atomique (P.L., E.C., G.D.), 38054 Grenoble, France

Address all correspondence and requests for reprints to: Dr. Olivier Chabre, Service d’Endocrinologie, Centre Hospitalier Universitaire, 38043 Grenoble, France. E-mail: olivier.chabre{at}ujf-grenoble.fr

We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11ß-hydroxylase deficiency. Sequencing of the CYP11B1 gene showed two new base substitutions, a conservative 954 GC transversion at the last base of exon 5 (T318T), and a IVS8 + 4AG transition in intron 8. In addition, two polymorphisms were found in exons 1 and 2. The genetically female patient was raised as a male because of severe pseudohermaphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension with 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 was followed by normalization of blood pressure and good compliance with glucocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low 11ß-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 polymorphisms. This suggested that one CYP11B1 allele carried the intron 8 mutation, 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, consistent with truncation of exon 8. Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understanding the mechanisms and physiopathological consequences of two novel mutations of CYP11B1.

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