Adipsic Hypernatremia without Hypothalamic Lesions Accompanied by Autoantibodies to Subfornical Organ

Adipsic (or essential) hypernatremiais a rare hypernatremiacaused by a deficiency in thirstregulation and vasopressinrelease. In 2010, we reported a case in which autoantibodies targeting the sensory circumventricular organs(sCVOs) caused adipsic hypernatremiawithout hypothalamic structurallesions demonstrable by magnetic resonance imaging (MRI); sCVOs include the subfornical organ(SFO) and organumvasculosum of the lamina terminalis(OVLT), which are centers for the monitoring of body-fluid conditions and the control of water and salt intakes, and harbor neurons innervating hypothalamic nuclei for vasopressinrelease. We herein report three newly identified patients (3- to 8-year-old girls on the first visit) with similar symptoms. The common features of the patients were extensive hypernatremiawithout any sensation of thirstand defects in vasopressinresponse to serum hypertonicity. Despite these features, we could not detect any hypothalamic structurallesions by MRI. Immunohistochemical analyses using the sera of the three patients revealed that antibodies specifically reactive to the mouse SFO were present in the sera of all cases; in one case, the antibodies also reacted with the mouse OVLT. The immunoglobulin (Ig) fraction of serum obtained from one patient was intravenously injected into wild-type mice to determine whether the mice developed similar symptoms. Mice injected with a patient's Ig showed abnormalities in water/salt intake, vasopressinrelease, and diuresis, which resultantly developed hypernatremia. Prominent cell death and infiltration of reactive microglia was observed in the SFO of these mice. Thus, autoimmune destruction of the SFO may be the cause of the adipsic hypernatremia. This study provides a possible explanation for the pathogenesis of adipsic hypernatremiawithout demonstrable hypothalamus-pituitary lesions.