Abstract
The autosomal dominant familial form of neurohypophyseal diabetes insipidus (adFNDI) is a rare inherited endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, also known as arginine vasopressin (AVP). To date, adFNDI has been linked to more than 70 different heterozygous point mutations of the 2.5 kb AVP gene, encoding the composite precursor protein of AVP. A minority of disease-causing mutations, such as the common c.55G>A variant, are predicted to affect amino acid residues close to the signal peptide (SP) cleavage site, and result in abnormal post-translational processing and intracellular trafficking of AVP precursors exerting neurotoxic activity on vasopressinergic magnocellular neurons. Generally, SP variants cause a gradual decline in the neurohypophyseal secretion of AVP in small children, although a wide variability in clinical onset and severity of manifestations has been reported. For the first time, we describe a kindred from Calabria (Southern Italy) with adFNDI and document a partial clinical phenotype in one female young adult member of the family. Methods: A young adult woman was subjected to clinical, neuroradiological and genetic assessments for a mild, adolescent-onset, polyuric state at our Endocrinology Unit. Her family medical history revealed an early-onset (<12 years of age) occurrence of polyuria and polydipsia, which was successfully managed with high doses of oral desmopressin, and a typical adFNDI inheritance pattern that was seen over three generations. Results: In the index patient, the extensive hypertonic dehydration during fluid deprivation test elicited a prompt elevation of urine osmolality and diuresis contraction, indicative of a partial adFNDI phenotype. Diagnosis was confirmed by concordant hormonal tests and magnetic resonance imaging (MRI) evidence of a reduced hyperintense signal of the neurohypophysis, which was regarded as compatible with the depletion of the vasopressinergic magnocellular neurons. Direct DNA sequencing and restriction enzyme cleavage analysis revealed that a heterozygous c.55G>A transition, predicting a p.Ala19Thr replacement in the C-terminal region of SP, was the cause of adFNDI in the investigated kindred. Conclusions: The identification of the genetic cause of aFNDI in this Calabrian kindred provides further information and confirms the wide variability of disease onset and severity of manifestations related to SP variants of the AVP gene, supporting the need for genetic testing in all patients with familial occurrence of polyuria, regardless of their clinical and radiological phenotype. Even though sexual differences in the antidiuretic responses are documented, it is unclear whether female gender would attenuate clinical disease progression in the presence of a pathogenic c.55G>A mutation.
Highlights
Neurohypophyseal diabetes insipidus (NDI) is a rare and heterogeneous endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, known as arginine vasopressin (AVP)
The extensive hypertonic dehydration elicited a prompt elevation of urine osmolality and diuresis contraction, without achieving a loss ≥5% of the initial body weight at the end of fluid deprivation testing, indicative of a partial clinical adFNDI phenotype [10,13]
It has been ascertained that the clinical symptoms of adFNDI derive from a gradual dItehcraesabseeeinn atshceernteauinreodhythpaotpthhyescelainl isceaclrseytimonptoofmms aotfuardeFANVDPI, daenrdivceofnrsoemquaegnrtalyd,udaol dneoctremaaseniifnestthuenntielutrhoehayfpfeocpthedyscehailldseicsresteivoenraolfmmoantuthrse tAoVsePv, earnadl yceoanrsseoqfueangtely[1, 4d]o
Summary
Neurohypophyseal diabetes insipidus (NDI) is a rare and heterogeneous endocrine disorder characterized by hypotonic polyuria, severe thirst and polydipsia, which results from a deficient neurosecretion of the antidiuretic hormone, known as arginine vasopressin (AVP). A minority of AVP gene variants causing adFNDI, such as the common G to A transition in position 55 of the coding DNA reference sequence (c.55G>A), known as g.279G>A, according to previous nomenclature based on genomic location, are predicted to affect amino acid residues close to the SP cleavage site [8,9], resulting in abnormal post-translational processing and intracellular trafficking of preproAVP and proAVP [10] These SP mutations cause a gradual decline in neurohypophyseal secretion of AVP during the first years of life, wide variations in the age of onset and severity of symptoms have been reported [10], and are speculated to be consequences of environmental factors and individual abilities of scavenging the retained pathogenic aggregates of AVP precursors [6,11,12]
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