From the Guidelines
Neonatal diabetes insipidus is primarily caused by genetic mutations, brain abnormalities, and perinatal complications, with the most common cause being mutations in genes involved in water regulation, particularly the AVP gene or the AVPR2 gene. The causes of neonatal diabetes insipidus (DI) can be broken down into several key factors:
- Genetic mutations: Mutations in genes involved in water regulation, such as the AVP gene (arginine vasopressin) or the AVPR2 gene (vasopressin receptor), are the most common cause of neonatal DI, as noted in the international expert consensus statement on the diagnosis and management of congenital nephrogenic diabetes insipidus 1.
- Brain abnormalities: Structural defects in the hypothalamus or pituitary gland can disrupt the production or release of antidiuretic hormone (ADH), leading to central DI, which can be distinguished from nephrogenic DI by its response to DDAVP 1.
- Perinatal complications: Severe hypoxia, intracranial hemorrhage, or infections affecting the central nervous system during or shortly after birth can damage the hypothalamus or pituitary, resulting in transient or permanent DI. In rare cases, neonatal diabetes insipidus can be transient, resulting from maternal lithium use during pregnancy or excessive fluid administration to the newborn, as seen in acquired NDI, which is characterized by adult onset and induction by lithium intake 1. To diagnose and manage neonatal diabetes insipidus, physicians should monitor urine output, serum sodium levels, and urine osmolality, and treatment typically involves replacing ADH with desmopressin (DDAVP), available as intranasal spray or oral tablets, with the dosage individualized based on the infant's response and fluid balance, as recommended by the European Reference Network on Rare Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology 1. Understanding these causes is crucial for early detection and appropriate management, as untreated diabetes insipidus in neonates can lead to severe dehydration and electrolyte imbalances, potentially causing long-term neurological complications, highlighting the importance of prompt diagnosis and treatment to improve morbidity, mortality, and quality of life outcomes.
From the Research
Causes of Neonatal Diabetes Insipidus (DI)
The causes of neonatal diabetes insipidus (DI) can be attributed to several factors, including:
- Genetic mutations in the AVPR2 or AQP2 genes, which are responsible for the proper functioning of the kidneys and the regulation of water balance in the body 2, 3, 4, 5, 6
- Mutations in the AVPR2 gene, which codes for the vasopressin V2 receptor, are the most common cause of congenital nephrogenic DI, accounting for approximately 90% of cases 5
- Mutations in the AQP2 gene, which codes for the vasopressin-sensitive water channel, can also cause autosomal recessive or dominant nephrogenic DI, although this is less common, accounting for approximately 10% of cases 5, 6
- Other genetic disorders, such as Bartter syndrome and cystinosis, can also lead to polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium 5
Genetic Mutations
Genetic mutations in the AVPR2 and AQP2 genes can lead to:
- Impaired renal concentrating ability, resulting in massive polyuria 3
- Failure to thrive, chronic fever, polydipsia, and polyuria in infancy 4
- Paradoxical hyponatremia and severe dehydration in response to medical treatment 4
- Challenges in diagnosis and management, particularly during infancy 4, 6
Diagnosis and Management
Diagnosis and management of neonatal DI can be challenging, and may involve:
- Genetic testing to confirm the presence of a mutation in the AVPR2 or AQP2 gene 2, 4, 6
- Water deprivation tests to assess renal concentrating ability 4
- Treatment with thiazide diuretics, potassium-sparing diuretics, and non-steroidal anti-inflammatory drugs to manage polyuria and electrolyte imbalances 3, 4
- Close monitoring of fluid status and electrolytes to prevent complications such as dehydration and electrolyte disturbances 4