This study reported the genetic spectrum and treatment approaches in a cohort of children with NDI registered on the Chinese multicenter database. We reported eight cases of seven families presented with X-linked NDI (AVPR2), one presented with autosomal recessive NDI (AQP2) and one autosomal dominant NDI (AQP2).
Although the pathophysiology and molecular diagnosis of congenital polyuric states has been well established19, we still encounter cases where the diagnosis is late and where inappropriate diagnostic testing and treatments are done. Optimizing the diagnostic strategy including genetic analysis is one of our top priorities. As is known disease-causing genes for NDI, it has been well established the heterozygous loss of function variants of AVPR2 or AQP2 result in congenital NDI 2, 3, 20. In order to try to elucidate the pathogenicity of variants of AVPR2 or AQP2, we compared population SNPs with pathogenic mutations from HGMD. Although in principle the existence of a single population variant dose not rule out pathogenicity, it is unlikely that the observed population variants of AVPR2 or AQP2 are pathogenic, since severe early-onset childhood disorders have specifically been excluded from gnomAD. We evaluated the variants in the 3D domain structure encoded by AVPR2 or AQP2 to find the positional correlation with pathogenicity. There is notable clustering in AVPR2 3D structure, with pathogenic mutations more likely to be within transmembrane region. Such clustering in transmembrane region was not shown for AQP2. An enrichment of diagnostic mutations by autosomal dominant inherited (AD) was found in the C terminal region of AQP2. Nonetheless, the pathogenic missense mutations of AVPR2 or AQP2 were significantly more likely to be buried within the domain. Systemic analysis of the protein structure and variants allowed us to make strong predictions about likely pathogenic variations both in AVPR2 and in AQP2. One of the limits of our study is the lack of functional studies, especially in case of the novel variants detected in the NDI cohort. So, the mutations identified in our study were considered as presumably disease causative post the protein structural analysis and in silico prediction.
As next generation sequencing is increasing applied in both research and clinical settings, more and more variants will be discovered in known disease genes as well as in novel disease genes. Although in silico predictions alone should not be relied on as the sole basis to determine the clinical significance of variants in proteins, we hope that the analysis used in this study provide useful structural evidence for variants interpretation. Moreover, combing clinical and population genetics with protein structural analysis offers widely applicable in silico method for improving the clinical interpretation of novel missense variation.
Massive free water losses cause significant morbidity, even in treated patients 6. High fluid intake is necessary to avoid hypernatremic dehydration, which can result in permanent neurologic complications. Most emergency protocol suggests initial treatment with 0.9% saline21. While the situation in different in NDI, because of the ongoing loses of essentially pure water with the urine. Infusion of 0.9% saline will result in excess sodium chloride administration and thus worsen the hypernatremia as observed in our case treating with 0.19% saline. Thus, children with NDI should be treated with hypotonic fluids, either enterally (water/milk) or, if need be, intravenously (5% dextrose in water)6, 22. Of course, hypotonic fluids must never be administered as an intravenous bolus. Emphasis on the infusion rate which only slightly exceed the urine output is to safely normalize plasma sodium concentration at a rate of less than 0.5 mmol/l/h (10–12 mmol/l/day). The main risk of a rapid decrease in plasma sodium is cerebral edema and potentially death. Yet, the concern of this complication and misunderstanding of NDI would lead to administration of excess salt with a risk of rapid increase in plasma Na, leading to osmotic demyelination6. The diagnosis of congenital NDI can either be missed or misunderstood, leading to dangerous mistreatment. It is quite important to early identify NDI with phenotype and genotype, and consequently optimize the treatment.
Hypernatremia in children with NDI will induce a strong thirst behavior and, when asked, the parents of patients with NDI often provide the typical history of an extremely thirsty child, who so avidly drinks large amounts of water, that it often vomits afterward. Older babies will typically want to preferentially drink water and avoid food. Patients are also at risk for nocturnal enuresis, hydronephrosis, and poor growth, presumably due to the need for high water consumption that interferes with adequate caloric intake. In our cohort, five neonates were diagnosed early with symptoms including fever, vomiting and anorexia. Even five families had multiple affects, only one family applied for early genetic screening for the newborn baby because of his affected sibling with NDI. Beside the indexes, we identified the three more males diagnosed of NDI by sequencing of AVPR2 and AQP2, and another four female individuals presented partial or subclinical NDI. Confirming the clinical diagnosis with genetic screening allows the early diagnosis and management of at-risk members of families with identified mutations6, 19, 23.
Our study had several limitations. The data were collected retrospectively from the registry system and we were not able to obtain complete data on all of the patients. We described the complications and treatment approaches during a median follow-up period of 5 years. Urological complications were noted such hydronephrosis and urinary incontinence (4/10). Unfortunately, there was no more details on nutrition, growth and mental development in our registry. It has been reported the long-term morbidities caused by NDI including primary nocturnal enuresis (44%), persistent small stature (38%), urologic complications (37%), persistent failure to thrive (29%), and CKD stage 2 or greater (30%)23. Here we reported only on case with delayed diagnosis who developed into CKD 3 stage.