Knowledge on rare diseases and orphan drugs

CDI is a rare disease with a reported prevalence of 1/25,000.

Idiopathic CDI onset can occur at any age but most often in 10-20 year olds. In the familial form, disease onset can be as early as the neonatal period. The symptoms characteristic of CDI are polyuria and polydipsia, usually associated with weight loss. Nocturia is common and in children often presents as enuresis. Polyuria is characterized by a urine volume in excess of 150 ml/kg/24h at birth, 100-110 ml/kg/24h until the age of 2 years, and 40-50 ml/kg/24h in older children and adults. Water deprivation leads to rapid dehydration. In children, additional symptoms of CDI can include lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In secondary CDI, further manifestations may be present resulting from the secondary cause.

Acquired CDI, especially in children and young adults, is caused by destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. The known causes of these lesions include germinoma, craniopharyngioma, Langerhans cell histiocytosis, sarcoidosis, local inflammatory, autoimmune or vascular diseases and trauma from surgery or accident. Midline cerebral and cranial malformations are another possible cause of CDI. Between 20 and 50 % of cases are considered idiopathic. Autoimmunity may play a role in the pathogenesis of CDI. Genetic defects in AVP synthesis inherited as autosomal dominant, autosomal recessive or X-linked recessive traits are the underlying cause in less than 10% of CDI.

Diagnosis of CDI is based on the demonstration of plasma hyperosmolality (> 300 mosm/l) associated with urine hypoosmolality (< 300 mosm/l or urine/plasma osmolality ratio < 1) and polyuria. A water deprivation test and blood test is needed to differentiate CDI from nephrogenic diabetes insipidus (NDI). The administration of desmopressin will help to make a differential diagnosis between CDI and NDI. Once the diagnosis of CDI has been established, other investigations are mandatory, including tumor markers, skeletal survey and especially brain neuroimaging.

The main differential diagnosis is NDI as the disorders share the same manifestations. Recently, the dosage of aquaporin 2 (AQP2) has been used in the differential diagnosis of CDI as the failure to increase AQP2 excretion after desmopressin administration indicates a nephrogenic form of diabetes insipidus. Wolfram syndrome is another differential diagnosis.

Genetic counseling is required in the very rare cases of familial CDI.

Immediate water intake and drug therapy is the course of treatment for CDI to correct water and electrolyte levels. Desmopressin is the most commonly used antidiuretic drug and can be given parenterally, orally or intranasally. Daily requirements are 100-1200 micrograms in 3 divided doses given orally, approximately 2-40 micrograms intranasally or 0.1-1 micrograms parenterally with maximum plasma concentrations being reached in 40-55 minutes. Follow-up is necessary to monitor electrolyte levels and determine the success of a chosen treatment. In early infancy, fluids alone can be a management strategy. Acquired CDI can be transient if the underlying causes of CDI are removed and the pituitary stalk is intact.

There is no cure for idiopathic CDI but it is a manageable disease with no effect on life expectancy. In cases of secondary CDI, inadequate treatment of the underlying disease can lead to death.

Last update: July 2012 - Expert reviewer(s): Dr Stefano GHIRARDELLO