2 2. Pathophysiology of NSIAD AVP is synthesized in the supraoptic and paraventricular nuclei and acts through three types of AVP receptors: the V1a receptor (vasopressive eﬀects of AVP), the V1b receptor found in the adenohypophysis (ACTH secretion), and the V2 receptor (V2R) localized in the distal renal collecting duct [12]. At the cellular level, AVP-V2R binding initiates a cascade of events, with adenosine 3 : 5-cyclic phosphate (cAMP) production through stimulated V2R coupling with the Gαs protein and the activation of adenylyl cyclase. Intra- cytoplasmic protein phosphorylation by cAMP-dependent protein kinase A therefore occurs, which leads to the exocytic insertion of aquaporin 2 (AQP2), a speciﬁc water channel, into the luminal membrane of the principal cells of the renal collecting duct, thereby increasing its water permeability. Under normal conditions, AVP activation of the V2R also leads to phosphorylation of serine residues located in the C-terminal receptor tail with, secondarily, β-arrestin recruitment and V2R internalization [13]. This negative regulation of the V2R after stimulation by AVP prevents prolonged and excessive tubular reabsorption of water. In NSIAD, the constitutively active mutant V2R appears to lose this important property, at least partly, but by a mechanism that remains not fully understood. Functional studies of the R137C- and R137L-V2R mutants have shown that both mutants have increased basal cAMP production compared with the Wt-V2R, conﬁrming their constitutive activity [4, 11]. It has also been shown that their relatively low amplitude constitutive activities are only weakly sensitive to the action of a V2R-inverse agonist like the SR121463 compound [11]. These data suggest that these mutant receptors are mainly in an almost blocked conformation and are consistent with Decaux’s observation that NSIAD patients are insensitive to nonpeptide V2R inverse agonists [6]. Nevertheless, it has also been shown that the relatively low AVP-induced stimulation of both mutants is completely inhibited by V2R inverse agonists. Therefore, this latter ﬁnding suggests that, although these mutant receptors are more often in a blocked conformation, they can also adopt a more ﬂexible conformation capable of a desensitization/internalization process [11]. 3. Clinical Presentation All patients diagnosed with NSIAD to date have been boys and most diagnoses were made during the ﬁrst two years of life. Most patients appeared to have a relatively clear phenotype with biological features initially suggesting a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia, low serum osmolality, and unexpectedly high urine osmolality, but low plasma AVP levels. The main clinical features, seizure or irritability, appeared to be linked to the severe hyponatremia. During the neonatal period, boys bearing the mutated receptor seem able to enough dilute their urine and there- fore avoid the risk of severe hyponatremia. Indeed, unless peculiar clinical conditions such as neonatal asphyxia, the physiological limitation in concentration capacity during the International Journal of Pediatrics ﬁrst weeks of life may protect them from excessive water reabsorption during this period. Two large kindreds of patients with NSIAD have also been reported. Decaux et al. reported the ﬁrst kindred and showed that the male patients in this family had been diagnosed in adulthood and were doing well, suggesting that NSIAD conditions may sometimes remain unrecognized until advanced age [6]. The late diagnosis in such patients may also be explained by the drop in water excretion naturally observed in the elderly [14]. The female carriers of this X-linked disorder were also clinically asymptomatic, but some of them demonstrated an impaired ability to dilute urine during a water-load test performed with 20 mL/kg of water. More recently, we reported another four-generation family with NSIAD bearing the R137C-V2R mutation [5]. In this family, the clinical presentation was highly variable in the male carriers. Indeed, one of the children had two episodes of seizures related to hyponatremia with low plasma AVP level, when he was 10 months and 34 months. Both episodes occurred during the summertime when large amounts of water were given to this young boy to prevent dehydration. His older brother, also bearing the mutated V2R, lived in the same city and, as far as we know, had the same diet but remained fully asymptomatic. Unfortunately, a ﬁrst cousin, also having the same AVPR2 mutation, experienced several seizure episodes due to recurrent hyponatremia between 27 months and 5 years of age and eventually developed permanent mental retardation. A water-load test was performed in the asymptomatic male carrier (10 mL/kg water load) and the heterozygous females (20 mL/kg water load). The results showed that water loading in the hemizygous male carrier was characterized by persistent AQP2 urine excretion independently of concomi- tant vasopressin excretion. This ﬁnding is consistent with a constitutive activation of the V2R. Slow and incomplete water elimination with slight hyponatremia was also found. The female carriers displayed variable biological ﬁndings after water loading that can be explained by random X inactivation [5]. Among all the family members explored, only the symp- tomatic hemizygous male exhibited all the expected signs under basal conditions: persistent AQP2 urine excretion, low output of highly concentrated urine, and low plasma and urine AVP levels. His asymptomatic brother, bearing the same mutation, had low AQP2 excretion and normal urine output under basal conditions but displayed a total absence of downregulation of AQP2 excretion after a cautious 10 mL/kg water load. Concerning the plasma AVP levels measured in these NSIAD patients, most levels appeared to be low or unde- tectable in spite of hyponatremia and high urine osmolality. Nevertheless, in at least one case, it was shown that AVP pro- duction can persist despite low plasma sodium and plasma osmolality [8]. Thus, of the four SIADH categories described, NSIAD most often belongs to the D group with a low plasma AVP levels, although it can also be grouped in category B, which is characterized by a measurable plasma AVP level [8, 15]. The explanation for this persistent AVP secretion