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In Vitro Expression Studies of a Novel Mutation 299 in a Patient Affected with Apparent Mineralocorticoid Excess

Department of Pediatrics, New York Presbyterian Hospital-Weill Medical College of Cornell University (K.L.-S., N.A., B.P.B., M.I.N., R.C.W.), and Department of Pediatrics, New York University School of Medicine (P.Z.), New York, New York 10021

Address all correspondence and requests for reprints to: Maria I. New, M.D., Department of Pediatric Endocrinology, New York Presbyterian Hospital, Weill Medical College of Cornell University, Room M-630, Box 103, 525 East 68th Street, New York, New York 10021. E-mail: minew{at}med.cornell.edu.

Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive disorder that results in low renin hypertension and other characteristic clinical features. Typical patients present with severe hypertension, hypokalemia, and undetectable aldosterone. Most patients also have low birth weight, failure to thrive, and nephrocalcinosis. The 11ßhydroxysteroid dehydrogenase type 2 (11ßHSD2) defect is documented by demonstrating a failure to convert cortisol to cortisone. Here, we report a patient with typical phenotypic features of AME who does not carry any of the previously described mutations in the HSD11B2 gene. This female patient from a consanguineous Pakistani family presented at age 9 yr. She had a low birth weight compared with her siblings and presented with hypertension (225/120 mm Hg), low plasma renin activity, hypokalemic metabolic alkalosis, suppressed aldosterone, and bilateral nephrocalcinosis. Echocardiogram did not reveal left ventricular hypertrophy, and baseline ophthalmological evaluation did not demonstrate hypertensive retinopathy. However, at age 12 yr, she developed mild to moderate hypertensive retinopathy. Biochemical analysis showed an elevated urinary cortisol to cortisone metabolites ratio (tetrahydrocortisol and 5-tetrahydrocortisol/tetrahydrocortisone) of 28 (normal, 0.66–2.44). She had a cortisol secretion rate of 0.43 mg/d (normal, 5–25 mg/d). Sequence analysis of the HSD11B2 gene revealed a novel homozygous 299 mutation in exon 5. In vitro expression in Chinese hamster ovary cells revealed that this mutation resulted in no activity.

This work was supported by United States Public Health Service Grant HD-00072 and Children’s Clinical Research Center Grant RR-06020.

Abbreviations: AME, Apparent mineralocorticoid excess syndrome; CHO, Chinese hamster ovary; 11ßHSD2, 11ß-hydroxysteroid dehydrogenase type 2; MR, mineralocorticoid receptor; PRA, plasma renin activity; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

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