SNOMEDCT: 723440000; ORPHA: 93606; DO: 0112121;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Nephrogenic syndrome of inappropriate antidiuresis | 300539 | X-linked recessive | 3 | AVPR2 | 300538 |
A number sign (#) is used with this entry because of evidence that nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is caused by gain-of-function mutations in the gene encoding the vasopressin V2 receptor (AVPR2; 300538) on chromosome Xq28. Constitutive activation of the receptor results in antidiuresis.
Loss-of-function mutations in the AVPR2 gene result in X-linked nephrogenic diabetes insipidus (NDI; 304800).
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. When the cardinal features of SIADH were defined by Bartter and Schwartz (1967), levels of AVP could not be measured. Subsequently, radioimmunoassays revealed that SIADH is usually associated with measurably elevated serum levels of AVP. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterized by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP (Feldman et al., 2005).
Feldman et al. (2005) described 2 unrelated male infants whose clinical presentations were consistent with the presence of chronic SIADH, but who had undetectable AVP levels. The first patient presented at age 3 months with irritability, and the second patient presented at age 2.5 months with 2 generalized seizures. Both patients had normal early neonatal courses. Physical and laboratory examination showed mild systolic hypertension and hyponatremia with normal serum potassium and bicarbonate. There was decreased serum osmolality with inappropriately increased urinary osmolality and urinary sodium levels. Other findings included low blood urea nitrogen, low or suppressed renin activity, and normal aldosterone levels, indicating euvolemia. Feldman et al. (2005) hypothesized that these infants had gain-of-function mutations in the V2R gene.
In 2 unrelated patients with NSIAD, Feldman et al. (2005) identified 2 different mutations in the AVPR2 gene (R137C, 300538.0021 and R137L, 300538.0022). Feldman et al. (2005) concluded that the R137C and R137L mutations caused constitutive activation of the receptor and were the likely cause of the patients' SIADH-like clinical picture, which they termed 'nephrogenic syndrome of inappropriate antidiuresis.' The mother of one of the patients also carried the mutation; she had normal serum sodium levels and normal serum and urine osmolality.
Bartter, F. C., Schwartz, W. B. The syndrome of inappropriate secretion of antidiuretic hormone. Am. J. Med. 42: 790-806, 1967. [PubMed: 5337379] [Full Text: https://doi.org/10.1016/0002-9343(67)90096-4]
Feldman, B. J., Rosenthal, S. M., Vargas, G. A., Fenwick, R. G., Huang, E. A., Matsuda-Abedini, M., Lustig, R. H., Mathias, R. S., Portale, A. A., Miller, W. L., Gitelman, S. E. Nephrogenic syndrome of inappropriate antidiuresis. New Eng. J. Med. 352: 1884-1890, 2005. [PubMed: 15872203] [Full Text: https://doi.org/10.1056/NEJMoa042743]