Clinical Endocrinology (2008) 69, 926–930 doi: 10.1111/j.1365-2265.2008.03303.x © 2008 The Authors 926 Journal compilation © 2008 Blackwell Publishing Ltd ORIGINAL ARTICLE Blackwell Publishing Ltd Utility of AVP gene testing in familial neurohypophyseal diabetes insipidus Sridhar Chitturi*, Mark Harris*, Michael J. Thomsett*, Francis Bowling†, Ivan McGown‡, David Cowley‡, Gary M. Leong*, Jennifer Batch§ and Andrew M. Cotterill* *Paediatric Endocrinology and Diabetes, †Metabolic Medicine, ‡Clinical Chemistry, Mater Children’s Hospital and §Paediatric Endocrinology, Royal Children’s Hospital, Brisbane, Australia Summary Context Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder resulting from arginine vasopressin (AVP) gene muta- tions. A partial defect in AVP secretion occurs early in the course of FNDI and may not be detected by a water deprivation test (WDT). Testing for AVP gene mutations may confirm a diagnosis of FNDI when a WDT is inconclusive and may also predict individuals who will later develop FNDI. Objective To test the utility of AVP gene analysis in confirming the diagnosis of FNDI. Patients Five families (20 subjects, 14 symptomatic and six asymptomatic) with FNDI and nine children with idiopathic neurohypophyseal diabetes insipidus (INDI). Measurements Genomic DNA was analysed for AVP gene mutations using polymerase chain reaction (PCR) amplification and sequencing. Results Heterozygous AVP gene mutations were found in all subjects with FNDI but none of the ICDI patients. Each family had their own distinct mutation. We identified two novel mutations (C44W and C105S). One asymptomatic subject developed diabetes insipidus (DI) 4 months after detection of an AVP gene mutation. The WDT suggested partial DI in 4/6 but was normal in 2/6 children with FNDI. Conclusion AVP gene testing allowed diagnostic confirmation of FNDI when the WDT was inconclusive in symptomatic children, therefore obviating the need for a repeat WDT and enabling earlier initiation of appropriate treatment. AVP gene testing also has the potential to identify which asymptomatic children will later develop FNDI. (Received 3 October 2007; returned for revision 23 October 2007; finally revised 29 February 2008; accepted 15 May 2008) Introduction Neurohypophyseal diabetes insipidus (DI) is a disorder of free water homeostasis resulting from a deficiency of the posterior pituitary hormone arginine vasopressin (AVP). In children, the common causes include intracranial tumours (13–20%), Langerhans’ cell histiocytosis (7–15%), head injury (3–20%) and inherited mutations (6–20%); however, 18–50% of children have idiopathic neurohypo- physeal diabetes insipidus (INDI). 1,2 The diagnosis of DI is clinical and often relies on indirect evidence of AVP deficiency during water deprivation. In cases of partial DI the results of a water deprivation test (WDT) can be difficult to interpret. Patients with the most common form of familial neurohypophyseal diabetes insipidus (FNDI), autosomal dominant FNDI, have heterozygous mutations in the AVP gene. 3–10 This gene is located on the distal short arm of chromosome 20 (20p13) and consists of three exons encoding a signal peptide, AVP, neurophysin II (NPII), and copeptin. 11 The AVP mutations so far described in FNDI involve the coding regions of the gene and can be located in the signal peptide, the AVP moiety or the NPII domain. Although the pathophysiology of FNDI is not completely understood, it is thought that abnormal NPII folding or dimerization is the common consequence of all the AVP gene mutations so far described. 12 The retention and progressive accumulation of misfolded protein within the AVP secreting magnocellular neurones of the hypothalamus is thought to result in neurotoxicity and cell death. 6 This misfolding-neurotoxicity hypothesis would be consistent with the progressive postnatal development of AVP deficiency in FNDI. The age of onset of DI does vary between kindreds but autosomal dominant FNDI appears to be almost 100% penetrant. 12,13 In this study we describe the results of AVP gene testing in five families with neurohypophyseal DI, to highlight the role of genetic testing in confirming the diagnosis of FNDI in symptomatic children, especially when the results of the WDT are inconclusive. Subjects and methods Children with a clinical diagnosis of DI were identified from the endocrine databases held at the Mater Children’s Hospital and the Royal Children’s Hospital, Brisbane and from the private practice of one of the authors (M.J.T.) also located in Brisbane. Patients were Correspondence: Dr Andrew Cotterill, Level 2 Administration, Mater Children’s Hospital, Raymond Terrace, South Brisbane, Australia 4101. E-mail: Andrew.cotterill@mater.org.au Presented in part at the Endocrine Society’s 88th Annual Meeting, 24 June 2006.