Dilatative Uropathy as a Manifestation of Neurohypophyseal Diabetes Insipidus due to a Novel Mutation in the Arginine Vasopressin-Neurophysin-II Gene

Abstract

Polydypsia and polyuria are frequent symptoms in patients with sellar masses caused by neurohypophyseal diabetes insipidus. Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the arginine vasopressin (AVP) -neurophysin II (NPII) gene, should be considered as a rare differential diagnosis. A delayed diagnosis bears the risk of life-threatening electrolyte imbalances and permanent urinary tract damage, leading to impaired quality of life.We present a Caucasian kindred of at least 4 generations with FNDI.Clinical histories, endocrine para-meters, and results of molecular analyses of the AVP gene are presented with a review of the literature on diabetes insipidus (DI) related urinary tract dilatation.Polyuria and polydipsia were only reported based on explicit and thorough interrogation after more than 4 years of clinical follow-up. A novel heterozygous mutation in the AVP gene was found in all examined symptomatic subjects (c.1-33_c.4del37nt). A literature review revealed that non-obstructive hydronephrosis (NOH) is a rare but known complication of DI.Since increased fluid intake is often a typical familial pattern in adFNDI, it is frequently missed as being pathologic in affected patients, therefore a detailed clinical history of drinking volumes is of critical importance. AVP gene testing is an important component in the confirmation of the diagnosis. Otherwise unexplainable NOH should lead to further investigations and evaluation of rare diseases like FNDI.

Persistent severe polyuria after renal transplant

“…Long-standing severe polyuria with a high voiding load in DI can lead to bladder distension and high pressure with reflux, causing hydronephrosis and functional obstruction, especially if double micturition (voiding) is not taught and practised [ 11 – 13 ]. Voluntary retention of urine due to social embarrassment may also be an important contributory factor in children and young adults.…”

The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

“…We know from previous studies that the phenotype of adFNDI patients having SP variants in the AVP gene in rare cases can be partial and is often associated with highly variable and later-than-average age at onset [8,19,23,25]. In this study, we identified a novel, inherited SP variant in the AVP gene (Ser18del) in a large Danish kindred with predominant female occurrence of polyuria and polydipsia.…”

“…Variability in phenotype between patients with the same SP variant in the AVP gene as well as between patients with SP variants and those with variants affecting other parts of the AVP prohormone have been described before [8,19,23,25]. Furthermore, in a KI mouse model, the SP variant Ala19Thr caused no apparent DI phenotype at the age of 12 months, evaluated by variables such as water intake, urine output, and urine osmolality [12].…”

“…Among the more than 70 different adFNDI-causing variants identified in the AVP gene, 8 affect the region encoding the signal peptide (SP) of the AVP preprohormone [3,19,20], and 1 is located immediately upstream in the 5′ UTR [21]. Only 2 of these variants have previously been studied in cell lines (Ala19Thr and g.227delG) [5,8,[22][23][24], and 1 of these (Ala19Thr) has additionally been introduced into the mouse genome [12].…”

“…Although behavioural effects of AVP have been described [45], evidence that variants in the AVP gene causing FNDI should have any direct effect on behaviour is lacking. It has previously been reported using self-assessment tools that DI affects the quality of life [19]. In future studies, it would be interesting to focus not only on the clinical and molecular aspects of DI but definitely also on the neglected psychological aspects of this disease.…”