Abstract
Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.
Highlights
The congenital form of nephrogenic diabetes insipidus (NDI), a rare inherited disorder, is characterized by insensitivity of the distal nephron to the antidiuretic action of arginine-vasopressin (AVP) and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance [1]
We reported eight cases from seven families presented with X-linked NDI (AVPR2); one case presented with autosomal recessive NDI (AQP2) and one case presented with autosomal dominant NDI (AQP2)
It has been wellestablished that the heterozygous loss-of-function variants of vasopressin type 2 receptor (AVPR2) or aquaporin 2 (AQP2) are common disease-causing genes that result in congenital NDI [2, 3, 20]
Summary
The congenital form of nephrogenic diabetes insipidus (NDI), a rare inherited disorder, is characterized by insensitivity of the distal nephron to the antidiuretic action of arginine-vasopressin (AVP) and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia) [1]. In 90% of patients, inheritance of NDI arises from mutations in the X-linked gene coding for the vasopressin type 2 receptor (AVPR2) (OMIM #304800) [1, 2]. The remaining patients display autosomal recessive or dominant forms of inheritance due to mutations in the gene coding for the aquaporin 2 (AQP2) water channel (OMIM #222000; OMIM #125800, respectively) [1, 3]. Establishing the genetic diagnosis is important for NDI in order to enable early detection and a more efficient differential diagnosis in view of its unique associated features and long-term complications
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