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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2244-2254
Copyright © 1998 by The Endocrine Society

Special Articles

Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess1

Swati Dave-Sharma, Robert C. Wilson, Madeleine D. Harbison, Ron Newfield, Maryam Razzaghy Azar, Zygmunt S. Krozowski, John W. Funder, Cedric H. L. Shackleton, H. Leon Bradlow, Ji-Qing Wei, Jos Hertecant, Antoinette Moran, Richard E. Neiberger, J. Williamson Balfe, Abduhl Fattah, Denis Daneman, H. Ilker Akkurt, Carlo De Santis and Maria I. New

Department of Pediatrics, Division of Pediatric Endocrinology, New York Hospital-Cornell Medical Center, New York, New York 10021

Address all correspondence and requests for reprints to: Maria I. New, M.D., Department of Pediatrics, Division of Pediatric Endocrinology, New York Hospital-Cornell Medical Center, 525 East 68th Street, Room M-420, New York, New York 10021. E-mail: lavander{at}mail.med.cornell.edu

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11ß-hydroxysteroid dehydrogenase type 2 enzyme activity (11ßHSD2). The 11ßHSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME.

All of the patients had characteristic signs of a severe 11ßHSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2–13 yr of treatment in six patients demonstrated significant improvement in all patients.

The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5{alpha}-tetrahydrocortisol/tetrahydrocortisone was 6.7–33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone.

Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11ßHSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype.

In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.




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