Diabetes insipidus (DI) is a disease characterized by polyuria and polydipsia due to inadequate release of vasopressin from the posterior pituitary gland (neurohypophyseal diabetes insipidus NHP-DI) or due to vasopressin insensitivity by the renal distal tubule, leading to a deficiency in tubular water reabsorption (nephrogenic diabetes insipidus or NDI).
It is remarkable how much more we know today about the genetic causes vasopressin defects, and yet there are still patients that get misdiagnosed or worse remain undiagnosed and suffer horrible consequences of dehydration and its complications.
Why is that so? Because many of the milder forms of DI have “non-classic” presentation and their clinical picture can be intermediate between NDI and NHP-DI. To make things worse, some patients with DI may be so partial that they can even be confused with patients that simply drink too much (such as patients that have various forms of polydipsia). However, making the diagnosis of DI and further more the type of DI (NHP-DI vs. NDI) is essential as the right treatment very much depends on confirming the right diagnosis and the specific type of DI.
The knowledge that a number of conditions for which there is genetic testing may be associated with DI is extraordinarily important as these patients if genetically conformed they may be followed for the development of DI. In addition, genetic testing can specifically lead to confirmation of NHP-DI vs. NDI helping out the clinician in identifying the proper therapy.
As part of our presentation, we discussed patients that were referred to the National Institutes of Health Clinical Center (NIH-CC). These were two male siblings that carried an uncertain diagnosis of DI. Genetic testing using next generation sequencing led to the proper diagnosis of NDI for the two brothers who previously had struggled to receive the proper therapy and as other children with DI that are not treated properly were failing in their growth and overall development. The finding of a novel mutation in the vasopressin receptor (the AVPR2 gene) confirmed the diagnosis of NDI, and with their proper treatment they are now thriving.
Consequently, we emphasized the need for genetic testing of cases of patients with suspected genetic forms of DI, since it is obvious from the information presented above that the correct diagnosis has implications for therapy and even survival for the youngest among our patients. Genetic testing should be done at expert laboratories and may be prioritized such as that the cost may not be excessive. For example, patients with NDI may be first tested for mutations of the vasopressin receptor (the AVPR2 gene). If the results are negative, then one may follow with mutations of the aquaporin-2 (AQP2) gene, and so on.
One disease I talked quite a bit about is Wolfram syndrome, a disease that causes DI along with diabetes mellitus, optic atrophy and deafness and is also known by the initials of these conditions as DIDMOAD. The disorder is autosomal recessive and is caused by mutations in the wolframin gene (WFS1). However, increasingly “milder” mutations of the WFS1 gene are found to cause partial or incomplete manifestations of the syndrome raising the possibility that even single (heterozygote) mutations of the WFS1 gene can cause, for example, diabetes mellitus.
Clearly, now we know that WFS1 mutations in the autosomal recessive state may cause DI (specifically NHP-DI) without causing any of the other symptoms of the Wolfram syndrome. Recently, a new gene causing wolfram syndrome was described, called CISD2. CISD2 mutations therefore may also cause isolated NHP-DI, although no such cases have been described so far.
I also discussed disorders that cause DI and are neither genetic nor endocrine such as Erdheim-Chester disease and where genetic discoveries, including BRAF mutations in the lesions of these patients, have led to significant improvements in their treatment. Patients with Erdheim-Chester disease, a hematologic disease, may present with DI, NHP-DI specifically, and the knowledge of this manifestation can lead to early application of medical therapy with tyrosine kinase inhibitors (TKI) which can save the lives of these patients and reverse DI. Treatment with TKIs was only made possible in this disease after BRAF (and other) mutations were identified, a powerful demonstration of the importance of genetics in battling disease and leading to effective new treatments.
Finally, I presented the ongoing efforts to identify molecules that can work with as vasopressin analogs or bypass the defect in the vasopressin receptor gene (AVPR2) for patients with the respective defects. These studies could not be made possible without discoveries in genetics and their concurrent translation into structural biology and pharmacogenetics. It is anticipated that in the next few years, a variety of small molecules will become available for better therapeutical options of our patients with DI and related disorders.
Dr. Constantine A. Stratakis is the scientific director of the NICHD Division of Intramural Research.