Alternative titles; symbols
SNOMEDCT: 45369008; ORPHA: 178029, 30925; DO: 12388;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Diabetes insipidus, neurohypophyseal | 125700 | Autosomal dominant | 3 | AVP | 192340 |
A number sign (#) is used with this entry because neurohypophyseal diabetes insipidus is caused by heterozygous mutation in the arginine vasopressin gene (AVP; 192340) on chromosome 20p13. An X-linked form of neurohypophyseal diabetes insipidus (304900) has been suggested, but the evidence is weak.
Neurohypophyseal diabetes insipidus is an autosomal dominant disorder of free water conservation characterized by childhood onset of polyuria and polydipsia. Affected individuals are apparently normal at birth, but characteristically develop symptoms of vasopressin deficiency during childhood (summary by Wahlstrom et al., 2004).
Normally the posterior pituitary hormones, antidiuretic hormone and oxytocin, are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and transported within axons, possibly in a biologically inactive, bound form, to the posterior lobe of the pituitary where they are stored. One of the most dramatic examples of familial diabetes insipidus is that reported by Adolph Weil (1884) of Heidelberg and his son Alfred Weil (1908). Seven generations were affected. Dolle (1950-52) reported a follow-up on this family, which contained numerous instances of male-to-male transmission.
Braverman et al. (1965) reported the postmortem findings in a case of pitressin-responsive diabetes insipidus. As in 5 previously reported cases, a striking decrease in the nerve cells of the supraoptic and paraventricular nuclei of the hypothalamus with associated mild gliosis was found. In this family the father and paternal grandmother were thought to have had diabetes insipidus. In the sibship of the male proband, 2 sisters had definite diabetes insipidus and a brother may have been affected. One child of each of 3 of the sibs was also thought to have the disorder. Dominant pedigrees of pitressin-responsive diabetes insipidus had been reported also by Pender and Fraser (1953), Moehlig and Schultz (1955) and Martin (1959). One would scarcely expect a defect in synthesis of antidiuretic hormone to behave as a dominant. Isolated deficiencies of other pituitary hormones (e.g., 'sexual ateliosis,' or isolated growth hormone deficiency; see 262400) usually behave as recessives.
From studies of 5 affected members of a family with a 'dominant' form of central diabetes insipidus, Blackett et al. (1983) concluded that the disorder is predominantly a deficiency of arginine vasopressin (AVP; 192340) and its carrier protein, nicotine-stimulated neurophysin (NSN) but that significant partial deficiency of oxytocin (OT; 167050) and its carrier protein, estrogen-stimulated neurophysin (ESN), exists.
Toth et al. (1984) reported an extensively affected Canadian kindred. Of 121 persons in 7 generations, 34 were affected. The disorder showed variability in age of onset and in severity and apparently spontaneous abatement in old age. Plasma ADH levels were very low in spite of adequate osmotic stimulation, e.g., with infusion of hypertonic saline. The level rose when furosemide was given, suggesting an osmoreceptor defect and a normal ADH response to volume change. The osmoreceptors are in the hypothalamus; volume receptors are mainly in the atria, aortic arch, and carotid arteries.
Pedersen et al. (1985) studied 5 families. In 4, autosomal dominant inheritance was unquestionable. In the fifth (family C), the pattern was consistent with X-linked dominance. No linkage was found in 1 extensively affected kindred. Because of availability of a radioimmunoassay for plasma arginine vasopressin, it was possible to corroborate the diagnosis by such assays before and after water deprivation. An arginine vasopressin level lower than 2 pg/ml strongly suggested the diagnosis of what they termed cranial diabetes insipidus if at the same time serum osmolality was higher than 295 mosmol/kg.
Laing et al. (1991) described a family with affected individuals in 4 generations. Autosomal dominant cranial diabetes insipidus was associated with a characteristic facial appearance, namely hypertelorism, broad and short nose, and long philtrum.
Pivonello et al. (1998) evaluated biochemical parameters of bone metabolism and the bone mineral density (BMD) in patients with central diabetes insipidus, either treated or not treated with endonasal desmopressin. The patients were divided into 2 groups: patients who did not receive treatment with desmopressin for at least 1 year (group 1), and patients chronically treated with desmopressin since the diagnosis of diabetes insipidus (group 2). Serum osteocalcin concentrations were significantly lower in patients of both groups compared with healthy subjects. BMD was significantly decreased in patients of groups 1 and 2 compared with controls, both at lumbar spine and femoral neck. A significant inverse correlation was found between disease duration and BMD values. The authors concluded that patients with central diabetes insipidus had a significant bone impairment compared with healthy subjects, and that replacement with endonasal desmopressin at standard doses did not prevent or reverse the bone impairment. These findings suggested that in patients with central diabetes insipidus, bone status analysis is mandatory, and a bone-loss preventing treatment might be beneficial.
Pivonello et al. (1999) presented evidence showing that a 6-month treatment with alendronate in patients with central diabetes insipidus was effective in significantly improving BMD at the lumbar spine, which was significantly worsened in untreated patients. They advocated alendronate treatment in patients with central diabetes insipidus with documented osteopenia or osteoporosis.
Magnetic resonance imaging (MRI) had revealed isolated pituitary stalk (PS) thickening (PST) in certain cases of idiopathic or secondary central diabetes insipidus (CDI) due to infiltrative processes. Leger et al. (1999) studied 26 children with CDI and PST who underwent cerebral MRI at the age of 8 +/- 4 years and were followed (24 patients) by clinical and MRI evaluation, respectively, for 5.5 +/- 3.6 and 3.0 +/- 2 years in the absence of any treatment other than hormonal substitutive therapy. Complete anterior pituitary evaluation for 24 of the 26 patients revealed those suffering from associated growth hormone deficiency (see 262400) (14 patients: 1 with germinoma, 3 with histiocytosis, and 10 with idiopathic) and from multiple hormone deficiencies (7 patients: 3 with germinoma, 1 with histiocytosis, and 3 with idiopathic). At the first MRI evaluation, PS enlargement varied from 2.2 to 9.0 mm at a proximal (10 patients), distal (2 patients), or middle (6 patients) PS level, or along the entire PS (8 patients). The intrasellar content, which usually reflects the anterior pituitary gland, was normal (12 patients), small (8 patients), or enlarged (6 patients). At the last evaluation, a change in MRI features was found in 16 patients; morphologic and/or signal changes in the PST (16 patients, of whom 6 showed an increase in PST) and changes in anterior pituitary gland size (8 patients: 3 with increased, and 5 with decreased) were noted. The authors concluded that the natural history of idiopathic isolated CDI with PST is unpredictable, and, although germinoma should always be considered during the first 3 years of follow-up in patients showing CDI with PST requiring repeated investigations every 3 to 6 months, it remains a less frequent etiology for 15% of the cases.
In a large cohort of patients with apparently idiopathic CDI or CDI of known etiology, Pivonello et al. (2003) evaluated the occurrence of circulating autoantibodies to AVP (192340)-secreting cells and correlated it to clinical, immunologic, and radiologic features. AVP-secreting cells were measured by an indirect immunofluorescence method. AVP-secreting cells were found in 23.3% of CDI patients: 21 idiopathic (32.8%) and 14 nonidiopathic (16.3%; chi square = 13.1; P less than 0.001). AVP-secreting cells were independently associated with age less than 30 years at disease onset (P = 0.001) in patients with idiopathic CDI and with history of autoimmune diseases (P = 0.006 and P = 0.02, respectively) and radiologic evidence of pituitary stalk thickening (P = 0.02 and P = 0.003, respectively) in both idiopathic and nonidiopathic CDI. The likelihood of autoimmunity in one patient with apparently idiopathic CDI with age of onset less than 30 years was 53%; it increased to 91% when history of autoimmune diseases was associated and to 99% when pituitary stalk thickening was further associated. The authors concluded that autoimmunity is associated with 1/3 of patients with apparently idiopathic CDI. Also, autoimmune CDI is highly likely in young patients with a clinical history of autoimmune diseases and radiologic evidence of pituitary stalk thickening. Conversely, autoimmunity probably represents an epiphenomenon in patients with nonidiopathic CDI.
Wahlstrom et al. (2004) reported an American kindred with autosomal dominant neurohypophyseal diabetes insipidus. The index patient was a 78-year-old man noted to have hypotonic polyuria after a surgical procedure. He had experienced polyuria and polydipsia since childhood but had avoided medical attention by assiduously maintaining access to water at all times. His family had recognized that some members required large volumes of water, and to accommodate these individuals (known in the family as 'water dogs'), a number of extra wells had been dug on the family farm. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations supported the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of neurohypophyseal diabetes insipidus. Affected family members were found to have a mutation in the AVP gene (192340.0020), demonstrating that mutations affecting the AVP moiety can result in initiation of these pathologic processes.
Phillips et al. (1986) and Repaske et al. (1990) used RFLPs of the contiguous vasopressin-neurophysin II gene (192340) and oxytocin-neurophysin I gene (OT; 167050) on chromosome 20 for linkage studies in 3 families with autosomal dominant neurohypophyseal diabetes insipidus. Cosegregation of the disease phenotype and RFLP haplotypes were informative with 12 members of 2 families yielding a maximum lod score of 2.71 at theta = 0.0. There was no failure of cosegregation, which, if found, would exclude this region as the site of the mutation. No large deletions, insertions, or rearrangements in the vasopressin gene were found. The work of Repaske et al. (1990) appeared to make it quite certain that the mutation in this disorder resides in the AVP gene. That mutation in other genes can lead to the same phenotype is, of course, possible.
In a consanguineous Palestinian family with neurohypophyseal diabetes insipidus, Willcutts et al. (1999) identified a 301C-T mutation in exon 1 of the AVP gene (192340.0016), replacing proline-7 of mature AVP with leucine (Leu-AVP). All 3 affected children were homozygous for the mutation, and the parents were heterozygous, suggesting autosomal recessive inheritance. Serum Leu-AVP levels were elevated in all 3 children and further increased during water deprivation to as high as 30 times normal, as measured by radioimmunoassay. The youngest child (2 years old) was only mildly affected, but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting to the authors that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children.
Christensen et al. (2004) screened for mutations in the AVP gene in 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In each of 6 kindreds, they identified a unique novel mutation, and in the other 9 kindreds, 7 different previously described mutations. All of the mutations occurred in heterozygous state. In an Asian American family, Christensen et al. (2004) identified a 1797T-C transition predicting a val67-to-ala substitution (V67A; 192340.0019). The authors noted that this mutation affects a region of the molecule unaffected by other identified mutations and produces only a minor change. The inheritance pattern in this family was atypical and suggested incomplete penetrance. The proband apparently inherited the disease through his affected mother, although allegedly neither of his maternal grandparents had a history of polyuria, but a brother of the maternal grandmother was affected.
An apparent defect in synthesis of vasopressin in the rat results in diabetes insipidus only in the homozygote, although the heterozygote shows reduced vasopressin. Oxytocin synthesis is not impaired (Valtin et al., 1965). Morphologic features suggest excessive activity of the hypothalamoneurohypophyseal system which controls secretion of vasopressin (Sokol and Valtin, 1965). Autosomal dominant diabetes insipidus is associated with oligosyndactyly in the mouse (Falconer et al., 1964). Majzoub et al. (1984), who referred to diabetes insipidus in the Brattleboro rat as semirecessive, demonstrated that the vasopressin gene is expressed but at a reduced level. They found that the hypothalamus of these rats contains detectable, although markedly reduced, levels of an mRNA indistinguishable in size from and similar in sequence to authentic vasopressin mRNA. Levels of oxytocin mRNA were the same in Brattleboro and normal rat hypothalami. Schmale et al. (1984) compared the vasopressin gene from normal and diabetes insipidus (Brattleboro) rats. Except for a single deletion of a G residue in the second exon (the region coding for the neurophysin carrier protein), the genes were identical. Blot analysis of hypothalamic RNA as well as transfection and microinjection experiments indicated that the mutant gene is correctly transcribed and spliced, but the resulting mRNA is not efficiently translated. Jirikowski et al. (1992) found that injection into the hypothalamus of purified mRNA from normal rat hypothalami or of synthetic copies of the vasopressin mRNA led to selective uptake, retrograde transport, and expression of vasopressin exclusively in the magnocellular neurons which are known to secrete oxytocin and vasopressin. Reversal of the diabetes insipidus for up to 5 days was observed within hours of the injection.
Russell et al. (2003) established murine knockin models of 2 different naturally occurring human mutations that cause autosomal dominant neurohypophyseal diabetes insipidus. A mutation in the signal sequence of the AVP gene, ala-1 to thr (A-1T; 192340.0003), is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor, cys67 to ter (C67X; 192340.0005), exhibited polyuria and polydipsia by 2 months of age; these features of diabetes insipidus progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP (138120) and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of wildtype and mutant AVP precursors within the cell bodies. This murine model recapitulated many features of the human disorder and demonstrated that expression of the mutant AVP precursor leads to progressive neuronal cell loss, presumably through a dominant-negative effect. Phillips (2003) tabulated 21 disorders caused by mutations in 18 genes which demonstrated the dominant-negative phenomenon and were instances of hormone deficiency.
The cosegregation of diabetes insipidus of the autosomal dominant neurohypophyseal type with Huntington disease (Frontali et al., 1986) is compatible with linkage of the 2 loci. Pedersen et al. (1985) found a lod score of 1.172 for linkage of this form of diabetes insipidus and MN blood group (111300).
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