A Novel Form of Familial Vasopressin Deficient Diabetes Insipidus Transmitted in an X-linked Recessive Manner

Abstract

Context: Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance.

Objective: This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner.

Methods: Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced.

Results: This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range.

Conclusion: X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.

Keywords: X-linked transmission; diabetes insipidus; vasopressin deficiency.

Figure 1.

Pedigree of kindred with familial X-linked diabetes insipidus. Black squares indicate affected males. Gray circles indicate obligate female carriers. Asterisks indicate individuals tested to define their vasopressin function.

Figure 2.

The relation of plasma vasopressin to plasma osmolality in members of kindred with familial X-linked recessive diabetes insipidus. The values in the affected males (N = 4) were obtained during fluid deprivation and/or 3% saline infusion. Those in the obligate female carriers (N = 4) and unaffected males and females (N = 5) were obtained during a water load followed by 3% saline infusion. The broken horizontal line labeled LD indicates the level of detection of the vasopressin assay. The area enclosed by the dotted line indicates the range of the relationship in 44 healthy, unrelated adults and children tested similarly.

Figure 3.

Relation of urine osmolarity to plasma vasopressin in members of kindred with familial X-linked recessive diabetes insipidus. The values in the 4 affected males were obtained before and during fluid deprivation. The values in the 4 obligate female carriers and 5 unaffected males and females were obtained before and during a water load. The vertical dashed line labeled LD indicates the limit of detection of the vasopressin assay (0.5 pg/mL). Lower values are plotted as 0.25 pg/mL. The area enclosed by the dotted line indicates the range of the relationship in 44 healthy adults and children under similar conditions.

Figure 4.

Effect of an emetic stimulus on plasma vasopressin in 2 boys with familial X-linked recessive diabetes insipidus. Ipecac was ingested at time zero. Nausea and vomiting occurred several times over 30 minutes in both. Plasma vasopressin was measured immediately before and at intervals of 10 minutes after ingestion. Area enclosed by the broken line indicates the range of plasma vasopressin levels observed in healthy participants in response to an emetic stimulus. Plasma vasopressin is plotted on a log scale.

Figure 5.

Homozygosity mapping based on exome variants for participant IV-1. Homozygosity mapping was performed by mapping profiles of nonparametric Iod (NPL): genome based on whole-exome sequencing variant data using Homozygosity Mapper. There were 5344.5 kb in total.