Late‐onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene

Abstract

Familial neurohypophyseal diabetes insipidus (FNDI) is mainly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria in early childhood. In this study, we aimed to determine the molecular genetics and clinical characteristics of a large Swedish-Norwegian family presenting with very late-onset autosomal dominant FNDI. Six probands with a history of developing polyuria and polydipsia during adolescence were studied. Information on family demography was collected by personal interview with family members. The genetic cause of FNDI was identified by DNA sequencing analysis of the coding regions of the AVP gene. The clinical characteristics were determined by the measurement of basal urine production and osmolality as well as by measurements of concurrent levels of plasma AVP, plasma osmolality, and urine osmolality during fluid deprivation and bolus injection of DDAVP. The integrity of the neurohypophysis was evaluated by magnetic resonance imaging. The mean age of encountering the first clinical symptoms in the family was 14·8 years (range 3-30 years) (n = 17). All six affected subjects investigated were heterozygous for a novel mutation in the AVP gene (g.1848C>T) predicting a p.Pro84Leu substitution in the AVP precursor protein. We found partial deficiency in evoked AVP secretion during fluid deprivation in one subject and complete deficiency in another. The pituitary bright spot was absent in all six affected subjects studied. A novel mutation in the AVP gene predicted to cause a neurophysin II dimerization defect is causing surprisingly late onset of FNDI in a large, six generation, Swedish-Norwegian family. The mutation is associated with both complete and partial deficiency in evoked AVP secretion during fluid deprivation in patients who have suffered from FNDI for decades.