Aldosterone synthase deficiency type I with no documented homozygous mutations in the CYP11B2 gene.

This case report concerns a girl born from non-consanguineous parents and hospitalized in another hospital at the age of 14 days because of a severe salt-losing syndrome (Na=125, K=8.6 mEq/l). In spite of normal genitalia, diagnosis of 21-hydroxylase deficiency was assessed on the basis of a slightly increased 17-OH-progesterone serum level (6.4 ng/ml). The onset of both hydrocortisone and 9alpha-fluorohydrocortisone therapy was followed by a resolution of the clinical picture. At the age of 60 days she was admitted to our clinic for a re-evaluation of the diagnosis. Steroid hormone serum levels were measured after withdrawal of therapy and diagnosis of corticosterone methyl oxidase (CMO) deficiency type I was definitely established in the light of the biochemical results: i.e. very low 18-hydroxycorticosterone (18-OH-B) serum levels (20 pg/ml), an abnormally high corticosterone/18-OH-B serum ratio (306.5) and an abnormally low 18-OH-B/aldosterone serum ratio (2.1). This autosomal recessively inherited disorder can be differentiated from CMO type II and other salt-wasting syndromes only on the basis of the serum steroid hormone pattern. After establishing the diagnosis of CMO I deficiency, hydrocortisone therapy was withdrawn whilst treatment with 9alpha-fluorohydrocortisone was begun again, with a satisfactory clinical and metabolic impact. Direct sequences of the patient's DNA were able to identify only a (heterozygous) amino acid substitution in exon 7 of that gene, which is known to have only a small effect on enzyme activity and cannot be the only cause of the patient's phenotype: valine-386-alanine (V386A) GTG-->GcG. No homozygous mutations in the CYP11B2 gene were observed. This is the first report of a patient with CMO type I who does not carry any homozygous mutation in the entire CYP11B2 alleles, whereas some cases with no mutations in this gene have already been reported in CMO II. The present study seems to be inconsistent with the previously reported correlation of the phenotype and genotype in CMO type I. A reasonable question that might be raised on the basis of our findings in this case report is whether other genes, apart from CYP11B2, are involved in the regulation of terminal aldosterone synthesis.