ESPE Abstracts

Background: Central diabetes insipidus (CDI) in the neonatal age is usually a result of intracranial insult, either congenital or acquired. Familial CDI is usually an autosomal dominant disorder, presenting later in childhood (1-6 y) with polyuria and mostly caused by mutations in the Neurophysin II moiety of the AVP-NPII prohormone gene; these interfere with prohormone processing leading to gradual destruction of AVP secreting cells and result in arginine vasopressin (AVP) deficiency.

Objective: To assess the clinical, biochemical, and the genetic etiology of an unusual clinical presentation with neonatal CDI.

Clinical course: A 5 days old girl born to asymptomatic parents presented with severe dehydration, polyuria of 6-8 ml/kg/h, polydipsia, hypernatremia of 161 mmol/l, serum hyperosmolality of 322 mOsm/kg with concomitant low urine osmolality of 200 mOsm/kg. Normal serum sodium levels and osmolarity were achieved by 8 mg/d/Kg of desmopressin administered orally. Pituitary hormones levels and Magnetic resonance imaging (MRI) were normal.

Sequencing pf the AVP-NPII gene performed given the neonatal presentation and the possibility of consanguinity between parents revealed no mutations. Whole exome next generation sequencing revealed a homozygous splicing exon12:c.955-9C>A mutation in the neuroblastoma-amplified sequence - NBAS gene which is highly expressed in the pituitary gland and so far known to be associated with Short Stature, Optic Nerve Atrophy, and Pelger-Huet Anomaly. The mutation is predicted to alter significantly the splicing and is not present in a population cohort from the relevant ethnic background.

As ER-associated degradation has been recently reported to be required for vasopressin prohormone processing it is not surprising that a mutation in NBAS gene causes CDI as NBAS mainly functions as a component of an endoplasmic reticulum (ER) tethering complex.

Conclusion: The novel c.955-9C>A mutation in the ER tethering complex gene NBAS is probably a new genetic etiology for CDI. The unique neonatal clinical presentation suggests a special and early role for NBAS protein in the neonatal synthesis of AVP. Splicing and functional studies are currently underway.

Reference: Guojun Shi, Martin Spiess, Ling Qi; ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis; J Clin Invest. 2017;127(10):3897-3912.