Background: Central diabetes insipidus may result from mutations in the preproAVP gene, most often heterozygous and occurring de novo or inherited in an autosomal dominant mode; in these cases, intracellular accumulation of the misfolded product of the mutated allele slowly destroys the AVP-producing neurons, so that the onset of symptoms may be delayed for up to 28 years by which time the posterior pituitary hyperintense signal is no longer visible on magnetic resonance imaging (MRI). Very few cases of autosomal recessive inheritance have been described.
Case presentation: A 4-year-old boy was referred for longstanding polyuria and polydipsia. The mother is French-Canadian and the father Lebanese. When seen for failure to thrive at 7 months, a serum sodium had been recorded at 145 mmol/l with a urine specific gravity <1005. At age 4 years, after 4 h of water deprivation, serum sodium was 144 mmol/l, serum osmolality 314 mmol/kg and urinary osmolality 111 mmol/kg. 2 h after 2.5 μg of DDAVP intranasally, urinary osmolarity was 442 mOsm/kg. Chronic treatment with DDAVP resulted in the disappearance of polyuria/polydipsia and in catch-up growth to target. MRI showed a normal posterior pituitary hyperintense signal. preproAVP was sequenced in the proband and in his asymptomatic parents. The patient was a compound heterozygote, having inherited a novel A to G transition in the splice acceptor site of intron 1 (IVS1-2A>G) from his mother and the known P26L mutation from his father; the latter has been reported in the homozygous state in two inbred Middle-Eastern pedigrees.
Conclusion: Consistent with bi-allelic inactivation of preproAVP, our patient had onset of symptoms in the first year of life. The presence of the posterior pituitary hyperintense signal suggests preservation of the AVP neurons. Making a genetic diagnosis avoided repeated MRI studies and allowed for family counseling.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology