Knowledge on rare diseases and orphan drugs

To date, over 350 families have been reported with genetic mutations, for which over 90% involve the gene AVPR2.

The disease typically presents in the first year of life. Typical features of NDI are failure to thrive associated with, feeding difficulties, vomiting, constipation, fever, and irritability. Hypernatremia occurs where management is lacking for urinary water losses. Acquired NDI is more common in adulthood, presenting with polyuria/polydipsia. Affected adults typically drink and void between 10-12 litres per day. Polyuria may exceed 10 liters in children.

The disease results from the failure of the renal tubules to respond to antidiuretic hormone. In most cases, the disease is caused by mutations in the gene located on Xq28 coding for the V2 receptor of antidiuretic hormone. In cases of autosomal recessive or dominant transmission, NDI is caused by mutations in the AQP2 gene (12q13) that codes for aquaporin-2. Aquaporin-2 is involved in the transportation of water in the renal tubules. Acquired NDI is mainly caused by drugs with lithium therapy used in psychiatric diseases such as bipolar disorder.

A diagnosis of diabetes insipidus (DI) is easily established by the presence of inappropriately dilute urine in the context of hypernatraemic dehydration. If DI is suspected based on history, yet plasma sodium concentration and osmolality are normal, a water deprivation test can help confirm the diagnosis. Once the diagnosis of DI is established, a desmopressin test (DDAVP) can distinguish between central and nephrogenic DI. In congenital NDI, the diagnosis can be confirmed by genetic testing.

The main differential diagnosis is central diabetes insipidus. There are also forms of secondary inherited forms of NDI, associated with other inherited diseases, such as Bartter syndrome, cystinosis and distal Renal Tubular Acidosis (dRTA). These patients have a clinical phenotype of NDI, but associated with other features of the underlying disorder, such as hypokalaemic alkalosis (Bartter syndrome) or acidosis (cystinosis, dRTA).

Mutation analysis of amniotic cells or chorionic villi is possible in families with a known genetic cause of NDI, but is associated with a small risk of fetal injury or loss. As the osmotic load of breast milk or formulas is low, most cases of NDI present during the weaning period and genetic testing on a blood sample obtained from the umbilical cord at birth is usually sufficient to establish an early diagnosis and thus prevent dehydration episodes.

In most cases, the disease is X-linked recessive, but it can also be autosomal recessive or dominant. Genetic counseling should be offered to affected families.

Abnormal urine concentration does not respond to antidiuretic hormone treatment. Treatment is prophylactic with prevention of hypernatremic dehydration events by minimizing urinary losses. Patients should receive a low salt diet with limited potassium and protein intake. Thiazide diuretics (e.g. hydrochlorothiazide) and prostaglandin synthesis inhibitors (e.g. indomethacin, ibuprofen or celecoxib) can further help reduce urine output. Careful dietetic counselling is recommended to ensure adequate caloric and protein intake, as well as normal growth in children.

Mental impairment associated with intracranial calcifications has been previously reported, but is no longer seen in patients with adequate medical treatment. One report highlights an increased prevalence of attention deficit/hyperactivity disorder in patients with NDI, but it is unclear if this reflects an intrinsic aspect of the disorder, or the constant craving for water and the frequent need for voiding. Dilation of the urinary tract has been reported in patients with NDI, especially in those with voiding abnormalities and can lead to serious bladder and/or kidney function impairment.

Last update: April 2020 - Expert reviewer(s): Pr Detlef BÖCKENHAUER | ERKNet*

* European Reference Network