MON-078 WFS1 Related Disorder in A 4-Month Old Girl

Background: Idiopathic early-onset central diabetes insipidus (CDI) may be due to mutations of arginine vasopressin-neurophysin II (AVP-NPII (AVP)) or wolframin (WFS1/2) genes (1). Clinical Case: A 4-month old girl presented to our pediatric endocrinology clinic due to severe polydipsia-polyphagia and polyuria. Plasma and urine glucose and HbA1c were normal and 24h monitoring of urinary output was elevated (4.2ml/kg/h). We proceeded to a modified 5-h water deprivation test followed by 0.1 mcg DDAVP IM. Results were compatible with partial central DI: at 5-hrs weight loss 5%, urine osmolality 155 from 111 at 0΄and 355 mOsm/kg 2hrs after DDAVP administration. Pituitary MRI was normal with presence of posterior pituitary bright spot and normal pituitary stalk. We initiated therapy with oral desmopressin acetate titrated at the dose of 70mcg x 3/day under close clinical and biochemical surveillance. Hyponatremia, with high natriuresis >100 mmol/L and elevated BNP occurred the 3rd day. Fludrocortisone 100 mcg x 2/day controlled natriuresis and supplemental oral NaCl 15% 15ml/day was needed to restore normal electrolytes (2). Marked catch-up growth was observed already at 1 month for height, weight and head circumference. Methods: Whole exome sequencing was performed targeted to a gene panel related to DI, containing AVP gene, WFS1/2 genes and AVPR2/AQP2 genes. Result: Two heterozygous variants were revealed: WFS1:NM_001145853:exon8:c. G997A:p.V333I,WFS1:NM_006005:exon8:c.G997A:p.V333I and WFS1:NM_00114585 3:exon8:c.G1832A:p.R611H,WFS1:NM_006005:exon8:c.G1832A:p.R611H reported as possibly damaging in 1/6 and 4/6 prediction programs respectively. These variants will be checked in both parents to confirm the presumed compound heterozygosity pattern in the child. Conclusion: We present a 4-month old girl with two heterozygous variants of WFS1 gene which may cause early-onset central diabetes insipidus and possibly a WFS1 related disorder (1). Reference: (1) Perrotta S et al. Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations. Eur J Endocrinol. 2015 Apr;172(4):461-72 (2) Papadimitriou DT, Spiteri A, Attilakos A, Papadimitriou A. Cerebral Salt Wasting Complicated by Central Diabetes Insipidus and Growth Hormone Deficiency. Indian J Pediatr. 2018 Jul;85(7):580-581

SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene

Central diabetes insipidus (CDI) is a disorder of water balance characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although non-hereditary causes are the most frequent, Familial CDI forms, due to heterozygous mutations in the AVP gene, have also long been recognized. Inheritance occurs mostly in an autosomal dominant manner with almost complete penetrance. The AVP gene encodes for a 164 aminoacids preprotein: the AVP preprohormone which consists of a signal peptide, AVP hormone (9 amino acidpeptide), Neurophysin II (AVP carrier), and a glycoprotein, Copeptin. The AVP preprohormone, is produced in the hypothalamus sand is targeted to the endoplasmic reticulum (ER) by the signal peptide. After cleavage and processing, the AVP hormone is packaged within protein carrier NPII and are transported by axonal trafficking to the neurohypophysis where they can be stored and secreted. Structural changes in NPII have been associated with intracellular accumulation of mutant AVP precursors that have been postulated to be cytotoxic and decreased cell viability of vasopressin-producing neuronsin the neurohypophysis. In this study we describe two index cases from two families of four-generation kindred suspected to have Familial neurohypophyseal diabetes insipidus (FNDI), with absent or barely visibleposterior pituitary by MRI. A water deprivation test was performed in both cases, resulting confirmatory for DI in case 1 while it was inconclusive in case 2. In both cases, molecular studies revealed a pathogenic variant in heterozygous state in the NPII region of the AVP gene, in case 1 we found a previously reported and well characterized variant p.Cys116Gly, cysteine at codon 116 is involved in disulfide bridge important for the secondary structure of NPII. While in case 2 we found a novel variant, p.Gly45Val, in which all in silico tools predict deletereous, whereas there are a previously reported patogenic variant at the same amino acid residueand in 3D modeling it can be observed that structural and conformational changes occur in binding bridge of NPII. We are reporting two novel non related familial CDI cases, even though lack of functional studies, the clinical phenotype in each pedigree suggest this diagnosis, and support the genetic counseling.

Forty-One Individuals With Mutations in the AVP-NPII Gene Associated With Familial Neurohypophyseal Diabetes Insipidus

Context Familial neurohypophyseal diabetes insipidus is a rare disease produced by a deficiency in the secretion of antidiuretic hormone and is caused by mutations in the arginine vasopressin gene. Objective Clinical, biochemical, and genetic characterization of a group of patients clinically diagnosed with familial neurohypophyseal diabetes insipidus, 1 of the largest cohorts of patients with protein neurophysin II (AVP-NPII) gene alterations studied so far. Design The AVP-NPII gene was screened for mutations by PCR followed by direct Sanger sequencing in 15 different unrelated families from Spain. Results The 15 probands presented with polyuria and polydipsia as the most important symptoms at the time of diagnosis. In these patients, the disease was diagnosed at a median of 6 years of age. We observed 11 likely pathogenic variants. Importantly, 4 of the AVP-NPII variants were novel (p.(Tyr21Cys), p.(Gly45Ser), p.(Cys75Tyr), p.(Gly88Cys)). Conclusions Cytotoxicity seems to be due to consequences common to all the variants found in our cohort, which are not able to fold correctly and pass the quality control of the ER. In concordance, we found autosomal dominant familial neurohypophyseal diabetes insipidus in the 15 families studied.

Vasopressin and oxytocin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [92]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [67].

Early-onset central diabetes insipidus is associated with de novo arginine vasopressin–neurophysin II or Wolfram syndrome 1 gene mutations

ObjectiveIdiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin–neurophysin II (AVP–NPII (AVP)) or wolframin (WFS1) genes.Design and methodsSequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.ResultsTwo patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome.ConclusionsEarly-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.