Hindawi Publishing Corporation International Journal of Pediatrics Volume 2012, Article ID 937175, 4 pages doi:10.1155/2012/937175 Review Article Nephrogenic Syndrome of Inappropriate Antidiuresis D. Morin,1, 2 J. Tenenbaum,1 B. Ranchin,3 and T. Durroux2 1 Centre de R´ef´erence des Maladies R´enales Rares du Sud-Ouest, N´ephrologie P´ediatrique, CHU Montpellier, Universit´e Montpellier 1, 34295 Montpellier, France 2 CNRS, UMR 5203, Inserm U661, IGF, Universit´e Montpellier 1-2, 34094 Montpellier, France 3 Service de N´ephrologie P´ediatrique, Centre de R´ef´erence des Maladies R´enales Rares, Hoˆpital Femme-M`ere-Enfant, Hospices Civils de Lyon, UFR de M´edecine Lyon-Est et Inserm U499, Universit´e Claude Bernard Lyon I, 69500 Lyon, France Correspondence should be addressed to D. Morin, d-morin@chu-montpellier.fr Received 30 July 2011; Accepted 21 December 2011 Academic Editor: Raymond Quigley Copyright © 2012 D. Morin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mutations in the vasopressin V2 receptor gene are responsible for two human tubular disorders: X-linked congenital nephrogenic diabetes insipidus, due to a loss of function of the mutant V2 receptor, and the nephrogenic syndrome of inappropriate antidiuresis, due to a constitutive activation of the mutant V2 receptor. This latter recently described disease may be diagnosed from infancy to adulthood, as some carriers remain asymptomatic for many years. Symptomatic children, however, typically present with clinical and biological features suggesting inappropriate antidiuretic hormone secretion with severe hyponatremia and high urine osmolality, but a low plasma arginine vasopressin level. To date, only two missense mutations in the vasopressin V2 receptor gene have been found in the reported patients. The pathophysiology of the disease requires fuller elucidation as the phenotypic variability observed in patients bearing the same mutations remains unexplained. The treatment is mainly preventive with ﬂuid restriction, but urea may also be proposed. 1. Introduction Since 1992, when the vasopressin V2 receptor gene (AVPR2) sequence that codes for the V2 receptor (V2R) was ﬁrst described [1], more than 200 mutations in the AVPR2 have been found in patients presenting with X-linked congenital nephrogenic diabetes insipidus (cNDI) [2, 3]. Functional studies of these mutant receptors have demonstrated a loss of function in the mutated protein that results in the insensitivity of the renal collecting duct to the action of the arginine vasopressin hormone (AVP). This in turn leads to a defect in water reabsorption with polyuria, polydipsia, and hypernatremic dehydration. Recently, it was demonstrated that the V2R may be aﬀected by gain of function mutations that cause a new syndrome: the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) [4]. This phenomenon has been ob- served for other G-protein-coupled receptors, for example, TSH (thyrotoxicosis), LH (familial male-limited precocious puberty), PTH-rp (Bloom syndrome), and the calcium sensing receptors (hypercalciuric hypocalcemia). NSIAD was subsequently described in two infant boys presenting with seizures due to severe hyponatremia and high urinary osmolality, but low plasma AVP levels. AVPR2 sequencing demonstrated that these two children harbored the arginine- 137-cysteine (R137C) and arginine-137-leucine (R137L) mutations in their respective V2 receptors. Since 2005, when the disease was ﬁrst described, all the NSAID patients presented in the literature have had one of these two AVPR2 mutations [4–10]. Functional studies have shown that both mutations are responsible for a constitutive activation of the mutant V2R, leading to inadequate water reabsorption in spite of low AVP levels [4, 11]. Nevertheless, the clinical presentations of these NSIAD patients have been highly variable, with one of them showing severe neurological consequences, while others were fully asymptomatic with only a urine dilution defect revealed during water-load testing [5, 6]. Thus, patients may be diagnosed early in life or in adulthood, or they may remain asymptomatic. The diagnosis of NSIAD thus should be systematically considered in cases of childhood hyponatremia, especially when associated with high urine osmolality.