Akari Nakamura-Utsunomiya1,2, Satoshi Goda1, Seiichi Hayakawa3, Sakata Sonoko1, Ewout J Hoorn4, Anne Blanchard5, Akiko Saito-Hakoda6, Haruna Kakimoto7, Rumi Hachiya8, Miki Kamimura6, Rie Kawakita9, Shinji Higuchi9, Rika Fujimaru10, Yoko Shirai11, Daichi Miyaoka12, Yuki Nagata13,14, Yutaro Kishi15, Aya Wada16, Akari Mitsuboshi17, Kayo Ozaki17, Nagisa Komatsu18, Hidetaka Niizuma6, Junko Kanno6, Ikuma Fujiwara6, Yukihiro Hasegawa8, Tohru Yorifuji9, Wendy Brickman19,20, Marie-Christine Vantyghem21, Kei Yamaguchi22,23, Naoki Goshima22,23, Takeshi Y Hiyama24. 1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. 2. Department of Pediatrics, Hiroshima Prefectural Hospital, Hiroshima, Japan. 3. Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan. 4. Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 5. Center of Clinical investigation, Faculty of Medicine, Hospital European George Pompidou Paris, Paris, France. 6. Department of Pediatrics, Tohoku University Hospital, Sendai, Japan. 7. Department of Pediatrics, Kagoshima University Hospital, Kagoshima, Japan. 8. Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan. 9. Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan. 10. Department of Pediatrics, Osaka City General Hospital, Osaka, Japan. 11. Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan. 12. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. 13. Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. 14. Department of vascular medicine, Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan. 15. Department of Endocrinology and Metabolism, Niigata University Medical and Dentist Hospital, Niigata, Japan. 16. Department of Pediatrics, Gunma University Hospital, Tochigi, Japan. 17. Division of Endocrinology and Metabolism, Hyogo Prefectural Kobe children's Hospital, Kobe, Japan. 18. Department of Pediatrics, Kumamoto Chuo Hospital, Kumamoto, Japan. 19. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 20. Division of Endocrinology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA. 21. Department of Endocrinology, Diabetology, Metabolism and Nutrition, Lille University Hospital, Lille, France. 22. Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan. 23. ProteoBridge Corporation, Tokyo, Japan. 24. Department of Cellular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Abstract
OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.
OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.