INTRODUCTION	Section 2 of 11
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Background: The word diabetes is derived from the Greek verb diabainein, which means to stand with legs apart, as in urination, or to go through. Insipidus comes from a Latin word meaning without taste. In contrast to diabetes mellitus (DM), which describes the excretion of sweet urine, diabetes insipidus (DI) describes the passing of tasteless urine because of its relatively low sodium content.

Nephrogenic DI (NDI) reached North America in 1761, carried by Ulster Scots who arrived in Nova Scotia, Canada, on a ship named Hopewell. Scottish folklore reports the existence of the disease in Scotland before 1761. According to legend, a gypsy woman traveling with her thirsty son is denied water by a housewife. The gypsy woman curses the housewife, causing the housewife's sons to crave water while condemning her daughters to pass the curse on to future generations.

Pathophysiology: The basis of water loss in DI is distinct from water loss caused by DM. The renal tubular collecting ducts are unable to concentrate urine secondary to vasopressin deficiency or resistance. The collecting duct concentrates urine by reabsorbing water, a function controlled by the posterior pituitary gland via secretion of vasopressin or antidiuretic hormone (ADH). Reabsorption of sugars, amino acids, and virtually all electrolytes is completed by the time the urine has reached this segment of the nephron. Consequently, the inability to conserve water by reabsorption in the collecting duct depletes body water, but leaves sodium unaffected. The net result is an extremely diluted, increased urine output resulting in hypernatremia. Polydipsia follows as the thirst mechanism urges replenishment of body water.

Secretion of vasopressin occurs in the posterior pituitary gland and is regulated at the paraventricular and supraoptic nuclei, which sense changes in osmolality. Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary by tumor, pressure, or surgical ablation results in decreased vasopressin secretion and central diabetes insipidus (CDI). Alternatively, DI may be idiopathic or inherited either as an autosomal dominant or as an autosomal recessive trait (locus 20p13).

NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X-linked, vasopressin V2 receptor deficiency, locus Xq28) or defective or absent aquaporin, the protein that transports water at the collecting duct (autosomal recessive, locus 12q13). The X-linked variety of NDI accounts for about 90% of all such cases.

As a consequence of one of these defects, the ducts do not respond appropriately to vasopressin. Normally, vasopressin is transported in the blood to receptor sites on the basolateral surface of the collecting duct membrane. Through a G protein–adenylate cyclase coupling, activation of the vasopressin receptor increases cyclic adenosine monophosphate (AMP) production and stimulates protein kinase A, leading to increased recycling of the protein aquaporin in the plasma membrane.

In the presence of vasopressin stimulus, exocytic insertion of aquaporin into the apical, or luminal, surface of the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen. Absence of the vasopressin receptor does not allow this process to take place, causing inhibition of water uptake and polyuria. Alternatively, defective or absent aquaporin impairs the process in the presence of normal V2 receptors.

Frequency:

• In the US: Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common causes of CDI. Of the genetic etiologies, the overall incidence in the general population is estimated to be 3 cases per 100,000 population (0.003%.) The male-to-female ratio is 60:40. X-linked NDI is very rare, although it exceeds the recessive variety by a ratio of 9:1. The mutation for males is 4 cases per million population.

Mortality/Morbidity:

• Dehydration results from an inability to reabsorb free water at a site distal to electrolyte reabsorption. Any patient unable to continuously replace water loss is vulnerable to dehydration, especially in warm weather when insensible water loss through perspiration and respiration substantially increases risk. Electrolyte abnormalities are caused by the loss of urinary free water, which produces hyperosmolar dehydration, leading to hypernatremia, hyperchloremia, and prerenal azotemia. Diminished blood volume increases blood viscosity and the risk of sludging and thrombosis.

• Failure to thrive occurs because of the patient's constant thirst conferring a sense of fullness that offsets the sense of hunger. The affected individual eats less than necessary for normal growth.
  
  
• Seizures are a consequence of the electrolyte abnormalities introduced in the central nervous system (CNS) by severe hypernatremia and hyperosmolar dehydration.

• Mental retardation results from the damage to the CNS caused by severe hyperosmolarity, seizures, and potential hypoxia, all of which are thought to account for the frequent occurrence of mental retardation.
  
  
• Death can occur from a hypovolemic shock or a hypernatremic seizure.

Sex:

• CDI secondary to hypothalamic-pituitary lesions occurs at random and should, therefore, be evenly distributed between the sexes.

• Autosomal dominant and autosomal recessive CDI occur equally in both sexes.

• NDI caused by an X-linked mutation affects males only. Autosomal dominant and autosomal recessive forms of NDI affect both sexes equally.

Age:

• DI occurs in people of a wide age range.

• Children who present with autosomal recessive CDI are generally younger than 1 year. Children who present with autosomal dominant CDI are often older than 1 year.

• NDI forms (including X-linked, autosomal dominant, and autosomal recessive forms) develop in early infancy, often in neonates younger than 1 week.

	CLINICAL	Section 3 of 11
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History:

• Diagnosis may be difficult in infants and children because of nonspecific presenting features (eg, poor feeding, failure to thrive, irritability). Therefore, a high index of suspicion is necessary.

• The earliest signs of diabetes insipidus (DI) include a vigorous suck with vomiting, fever without apparent cause, constipation, and excessively wet diapers from urination.

• In older infants and young children, irritability is generally due to a borderline state of dehydration coupled with hypernatremia and, sometimes, fever.

• Nocturia is common and expected because of increased urine production.

• CDI tends to develop suddenly.

Physical:

• The typical examination shows an irritable infant with a dripping wet diaper, along with detectable signs of dehydration (eg, dry mucous membranes, diminished skin turgor, decreased tearing, tachycardia). Often, skin turgor is not diminished in individuals with hypernatremic dehydration despite significant dehydration.

• In severely dehydrated patients, the pulse may be thready and rapid. Hypotension may be present because of hypovolemic shock.

• Mobile fecaliths may be palpable in the abdomen.

Causes: DI is due either to (1) deficiency of vasopressin secretion by the pituitary gland (CDI or neurogenic DI) or to (2) renal tubular unresponsiveness to vasopressin (NDI).

• Nongenetic causes

• Typical injuries include head trauma, tumor, and neurosurgical procedures.

• At all ages, destructive lesions of the pituitary and/or hypothalamus are the most common cause of DI.

• Genetic causes

• CDI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13.

• CDI with diabetes mellitus, optic atrophy, and mental retardation (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.

• X-linked NDI occurs from mutations in the antidiuretic arginine vasopressin V2 receptor (AVPR2) gene, mapped to Xq28.

• NDI with an autosomal dominant or recessive pattern is due to mutations in the gene designated AQP2; this gene directs water channel formation in the distal membrane and has not yet been mapped.