{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T22:03:12Z","timestamp":1784757792367,"version":"3.55.0"},"reference-count":22,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by renal resistance to arginine vasopressin (AVP), resulting in the kidneys\u2019 inability to concentrate urine. Approximately 90% of NDI cases follow an X-linked inheritance pattern and are associated with pathogenic variants in the AVPR2 gene, which encodes the vasopressin receptor type 2. The remaining 10% are attributed to mutations in the AQP2 gene, which encodes aquaporin-2, and may follow either autosomal dominant or recessive inheritance patterns. We present the case of a male infant, younger than nine months of age, who was clinically diagnosed with NDI at six months. The patient presented recurrent episodes of polydipsia, polyuria, dehydration, hypernatremia, and persistently low urine osmolality. Despite adjustments in pharmacologic treatment and strict monitoring of urinary output, the clinical response remained suboptimal. Given the lack of improvement and the radiological finding of an absent posterior pituitary (neurohypophysis), the possibility of coexistent central diabetes insipidus (CDI) was raised, prompting a therapeutic trial with desmopressin. Nevertheless, in the absence of clinical improvement, desmopressin was discontinued. The patient\u2019s management was continued with hydrochlorothiazide, ibuprofen, and a high-calorie diet restricted in sodium and protein, resulting in progressive clinical stabilization. Whole-exome sequencing identified a novel homozygous missense variant in the AQP2 gene (c.398T &gt; A; p.Val133Glu), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria: PM2 (absent from population databases), PP2 (missense variant in a gene with a low rate of benign missense variation), and PP3 (multiple lines of computational evidence supporting a deleterious effect)]. NDI is typically diagnosed during early infancy due to the early onset of symptoms and the potential for severe complications if left untreated. In this case, although initial clinical suspicion included concomitant CDI, the timely initiation of supportive management and the subsequent incorporation of molecular diagnostics facilitated a definitive diagnosis. The identification of a previously unreported homozygous variant in AQP2 contributed to diagnostic confirmation and therapeutic decision-making. The diagnosis and comprehensive management of NDI within the context of polyuria-polydipsia syndrome necessitates a multidisciplinary approach, integrating clinical evaluation with advanced molecular diagnostics. The novel AQP2 c.398T &gt; A (p.Val133Glu) variant described herein was associated with early and severe clinical manifestations, underscoring the importance of genetic testing in atypical or treatment-refractory presentations of diabetes insipidus.<\/jats:p>","DOI":"10.3390\/ijms26157415","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report of Nephrogenic Diabetes Insipidus with a Novel Mutation in the AQP2 Gene"],"prefix":"10.3390","volume":"26","author":[{"given":"Alejandro","family":"Padilla-Guzm\u00e1n","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Cl\u00ednicas, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"},{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Amparo","family":"Ochoa-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"},{"name":"Department of Maternal and Child Health, Pediatric Nephrology Service, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-757X","authenticated-orcid":false,"given":"Jessica Mar\u00eda","family":"Forero-Delgadillo","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"},{"name":"Department of Maternal and Child Health, Pediatric Nephrology Service, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Apraez-Murillo","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-0439","authenticated-orcid":false,"given":"Harry","family":"Pachajoa","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"},{"name":"Medical Genetics Service, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime M.","family":"Restrepo","sequence":"additional","affiliation":[{"name":"Health Sciences Faculty, Universidad Icesi, Cali 760031, Colombia"},{"name":"Department of Maternal and Child Health, Pediatric Nephrology Service, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1530\/EJE-20-0114","article-title":"Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus","volume":"183","author":"Bichet","year":"2020","journal-title":"Eur. J. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1159\/000505548","article-title":"Diabetes Insipidus: New Concepts for Diagnosis","volume":"110","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_4","first-page":"e13523","article-title":"Diabetes Insipidus: Pathogenesis, Diagnosis, and Clinical Management","volume":"13","author":"Mutter","year":"2021","journal-title":"Cureus"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"The Working Group for Renaming Diabetes Insipidus, Arima, H., Cheetham, T., Christ-Crain, M., Cooper, D., Gurnell, M., Drummond, J.B., Levy, M., I McCormack, A., and Verbalis, J. (2022). Changing the name of diabetes insipidus: A position statement of The Working Group for Renaming Diabetes Insipidus. Endocrinol. Metab., 69, 1281\u20131284.","DOI":"10.1507\/endocrj.EJ20220831"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gao, C., Higgins, P.J., and Zhang, W. (2020). AQP2: Mutations Associated with Congenital Nephrogenic Diabetes Insipidus and Regulation by Post-Translational Modifications and Protein-Protein Interactions. Cells, 9.","DOI":"10.3390\/cells9102172"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10178","DOI":"10.3892\/etm.2021.10178","article-title":"Nephrogenic diabetes insipidus in children (Review)","volume":"22","author":"Duicu","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"111825","DOI":"10.1016\/j.mce.2022.111825","article-title":"Genetic basis of nephrogenic diabetes insipidus","volume":"560","author":"Hureaux","year":"2023","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1007\/s00467-010-1598-7","article-title":"Validation of the revised Schwartz estimating equation in a predominantly non-CKD population","volume":"25","author":"Amy","year":"2010","journal-title":"Pediatr. Nephrol."},{"key":"ref_10","unstructured":"Knoers, N., and Lemmink, H. (2020). Hereditary Nephrogenic Diabetes Insipidu. GeneReviews\u00ae, University of Washington."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pcl.2018.09.006","article-title":"Nephrogenic Diabetes Insipidus","volume":"66","author":"Kavanagh","year":"2019","journal-title":"Pediatr. Clin. North. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1515\/jpem-2019-0529","article-title":"From infancy to adulthood: Challenges in congenital nephrogenic diabetes insipidus","volume":"33","author":"Atmis","year":"2020","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e402","DOI":"10.1097\/PEC.0000000000001438","article-title":"Nephrogenic Diabetes Insipidus in Childhood Assessment of Volume Status and Appropriate Fluid Replenishment","volume":"36","author":"Guarino","year":"2020","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"LLiao, P., Xiang, T., Li, H., Fang, Y., Fang, X., Zhang, Z., Cao, Q., Zhai, Y., Chen, J., and Xu, L. (2021). Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.566524"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, Q., Tian, D., Cen, J., Duan, L., and Xia, W. (2021). Novel AQP2 Mutations and Clinical Characteristics in Seven Chinese Families With Congenital Nephrogenic Diabetes Insipidus. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.686818"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1007\/s12020-012-9704-1","article-title":"Mutations in the AVPR2, AVP-NPII, and AQP2 genes in Turkish patients with diabetes insipidus","volume":"42","author":"Duzenli","year":"2012","journal-title":"Endocrine"},{"key":"ref_17","first-page":"85","article-title":"Clinical Overview of Nephrogenic Diabetes Insipidus Based on a Nationwide Survey in Japan","volume":"57","author":"Fujimoto","year":"2014","journal-title":"Yonago Acta Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hagstr\u00f6mer, C.J., Steffen, J.H., Kreida, S., Al-Jubair, T., Frick, A., Gourdon, P., and T\u00f6rnroth-Horsefield, S. (2023). Structural and functional analysis of aquaporin-2 mutants involved in nephrogenic diabetes insipidus. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-41616-1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, Q., Lu, B., Yang, J., Li, C., Li, Y., Chen, H., Li, N., Duan, L., Gu, F., and Zhang, J. (2021). Molecular Characterization of an Aquaporin\u22122 Mutation Causing Nephrogenic Diabetes Insipidus. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.665145"},{"key":"ref_20","first-page":"1273","article-title":"Use of T1-weighted MR imaging to differentiate between primary polydipsia and central diabetes insipidus","volume":"13","author":"Moses","year":"1992","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_21","first-page":"510","article-title":"Lack of MRI neurohypophyseal bright signal in a child with congenital nephrogenic diabetes insipidus","volume":"3","author":"Chehade","year":"2010","journal-title":"NDT Plus"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Milano, S., Carmosino, M., Gerbino, A., Svelto, M., and Procino, G. (2017). Hereditary nephrogenic diabetes insipidus: Pathophysiology and possible treatment. An update. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112385"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7415\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:20:39Z","timestamp":1760034039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7415"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":22,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157415"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157415","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,1]]}}}