Beyond Classical Diabetes Insipidus: A Retrospective Case Series Illustrating the Diagnostic Complexity and Diverse Etiologies of Polyuria-Polydipsia Syndrome.

Background Polyuria-polydipsia syndrome encompasses a heterogeneous group of disorders, including central diabetes insipidus (CDI), nephrogenic diabetes insipidus (NDI), and primary polydipsia. Despite presenting with similar clinical manifestations, these conditions differ markedly in their underlying pathophysiology, prognosis, and management. Distinguishing between them remains clinically challenging, particularly in patients with partial disease and in resource-limited settings where newer diagnostic biomarkers such as copeptin are not routinely available. This study highlights the diagnostic complexity and diverse etiologies of polyuria-polydipsia syndrome through a retrospective case series. Methods We conducted a retrospective observational study of patients presenting with polyuria-polydipsia syndrome at a tertiary care center over a five-year period. Clinical, biochemical, and radiological data were retrieved from medical records. Patients underwent diagnostic evaluation based on clinical indication, including assessment of serum and urine osmolality and a supervised water deprivation test with or without a desmopressin challenge, as appropriate. Additional imaging and genetic investigations were performed where clinically indicated. Patients were classified as having CDI, NDI, or primary polydipsia based on the available clinical, biochemical, radiological, and, where applicable, genetic findings in accordance with standard diagnostic criteria. Results A total of seven patients were included, demonstrating diverse etiologies: complete CDI (n = 1), CDI associated with pituitary stalk interruption syndrome (n = 1), partial CDI (n = 1), NDI with a possible CLCN5 gene variant (n = 1), primary polydipsia (n = 1), pheochromocytoma presenting as a diabetes insipidus mimic (n = 1), and CDI secondary to postoperative and post-radiotherapy craniopharyngioma with panhypopituitarism (n = 1). Despite similar presenting complaints, each case exhibited distinct biochemical and radiological profiles. The water deprivation test followed by a desmopressin challenge enabled definitive diagnosis. Etiology-specific management resulted in significant clinical improvement across the cohort. Conclusion Polyuria-polydipsia syndrome represents a diagnostically challenging entity with diverse underlying etiologies. A structured approach integrating clinical evaluation, biochemical testing, dynamic assessment, and imaging remains effective for accurate diagnosis, even in the absence of advanced biomarkers. Recognition of atypical and reversible causes is essential to avoid misdiagnosis and ensure appropriate, targeted management.