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Effects of Aging on Vasopressin Production in a Kindred with Autosomal Dominant Neurohypophyseal Diabetes Insipidus Due to the E47 Neurophysin Mutation

Divisions of Pediatric Endocrinology (C.P.M.) and Radiology (E.W., C.B.), Children’s Hospital and Regional Medical Center, Seattle, Washington 98105; and Division of Endocrinology, Metabolism and Molecular Medicine (Mi.I., J.L.J, Ma.I.), Northwestern University Medical School, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: C. Patrick Mahoney, M.D., Pediatric Endocrine Division, CH-92, Children’s Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, Washington 98105-0371. E-mail: pmahon{at}chmc.org

Abstract

Postmortem examinations of the hypothalamus of patients with autosomal dominant neurohypophyseal diabetes insipidus (adNDI), which have been reported only on persons dying between the ages of 37–87 yr, reveal the presence of the arginine vasopressin (AVP)-producing parvocellular neurons but the absence of 95% of the expected AVP-producing magnocellular neurons. To determine whether the clinical course of adNDI is compatible with the hypothesis that the neuropathologic findings are attributable to a progressive loss of magnocellular neurons beginning in early life, we performed posterior pituitary magnetic resonance imaging and water deprivation tests, including plasma ACTH measurements, on 17 affected members of a kindred with the E47 neurophysin mutation whose ages ranged from 3 months to 54 yr. Nine adult nonaffected members (ages, 20–56 yr) underwent these tests as controls.

All six children undergoing magnetic resonance imaging demonstrated a posterior pituitary hyperintense signal (PPHS). Eight of nine affected adults showed an absent or barely visible PPHS, whereas eight of nine age-matched nonaffected adults produced a normal size PPHS. During water deprivation tests, infants concentrated their urine normally, and a 3-month-old infant produced a high plasma AVP level of 15.7 pmol/liter. By school age, affected children were no longer able to concentrate their urine or prevent hypernatremia. Affected adults became dehydrated; their median plasma AVP level was less than 1.0 pmol/liter, but their median fasting plasma ACTH was 2-fold greater than the level of nonaffected adults (10.0 vs. 5.0 pmol/liter; P = 0.008).

These results suggest that adNDI is a progressive disease associated with chronic loss of the magnocellular neurons that supply AVP to the posterior pituitary but preservation of the parvocellular neurons that supply AVP and CRH to the median eminence and stimulate ACTH production during hypernatremia.

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