AVPR2基因激活变异致儿童肾性抗利尿不适当综合征二例并文献复习

Diagnosis and follow-up of 2 cases of pediatric nephrogenic syndrome of inappropriate antidiuresis resulting from activating mutation in AVPR2 and literature review

目的探讨AVPR2基因激活变异致儿童肾性抗利尿不适当综合征(NSIAD)的临床表现、基因变异特点及治疗方法。方法回顾性分析2019年4月首都医科大学附属北京儿童医院确诊的2例NSIAD的临床诊疗和随访资料。以“肾性抗利尿不适当综合征”“AVPR2基因”“nephrogenic syndrome of inappropriate antidiuresis”“AVPR2 gene”为检索词分别在中国知网、万方数据库及PubMed、Springer Link中检索建库至2020年5月的相关文献,并进行复习。结果2例患儿均为男孩,就诊时年龄分别为5岁3月龄和2月龄,均存在慢性重度低钠血症,伴低血渗透压、高尿渗透压和高尿钠。基因检测均为AVPR2基因母源半合子变异(c.409C>T,p.R137C)。例1患儿自主限水、静脉滴注和口服补钠,血钠升高不明显,予口服呋塞米片,血钠上升至正常。随访1年,患儿一直呋塞米片口服治疗,血电解质维持正常。例2患儿予以限水同时口服及静脉补盐,血钠可升至正常;呼吸道感染后血钠再次下降,经抗感染和呋塞米片口服治疗,血钠维持正常。4个月后自行停药,每天补盐并限水,现1岁,生长发育良好,血电解质正常。文献检索到英文文献50篇,无相关中文文献,共30例先证者病例,其中16例(53%)为婴幼儿及儿童期发病,多以惊厥起病。9例婴幼儿NSIAD的AVPR2基因变异为R137C,5例为R137L,提示第409碱基变异为热点变异位点。治疗主要为限水和口服尿素,未见呋塞米口服治疗的报道。结论NSIAD除不明原因低钠血症外,无特异性表现。AVPR2基因测序有助于早期诊断及时治疗。2例患儿限水治疗及补钠效果有限,口服呋塞米治疗后,血钠可维持正常。

Objective To analyze the clinical and genetic features,as well as the treatment outcomes of two boys with nephrogenic syndrome of inappropriate antidiuresis(NSIAD)caused by gain-of-function mutations in the V2 vasopressin receptor gene(AVPR2).Methods The clinical manifestations,genetic testing,therapeutic interventions and the outcomes of two boys with NSIAD hospitalized in the Department of Endocrinology,Beijing Children′s Hospital in April 2019 were reported.A literature search with"Nephrogenic syndrome of inappropriate antidiuresis"and"AVPR2 gene"as keywords was conducted at the China national knowledge infrastructure(CNKI),the Wanfang Data Knowledge Service Platform,PubMed and Springer Link up to May 2020.Relevant published articles were reviewed.Results The two cases presented with chronic and severe hyponatremia with hypo-osmolality,inappropriately elevated urinary osmolality and urinary sodium levels.The onset age was 5.25-years and 2 months respectively.AVPR2 sequencing revealed a previously described hemizygous activating mutation(c.409C>T,p.R137C)in both of boys,each inherited the variant from their mother.Patient 1 limited fluid intake by himself in his daily life,intravenous and oral sodium supplementations showed no significant increase of serum sodium level.Oral furosemide increased the serum sodium level and maintained it within normal range.The serum sodium and potassium levels were in the normal range during the 1-year follow-up period with oral furosemide.The serum sodium level of Patient 2 increased with restricting fluid intake and with salt supplementation.However,after he experienced respiratory infection,the plasma sodium level decreased.Subsequently,oral anti-infection medicine and furosemide were applied.The serum sodium level increased two days later and remained at a normal range afterwards.The boy was 1 year old with normal growth.He stopped taking furosemide after 4 months while taking 1 gram of salt per day,the blood sodium level maintained at normal range.Literature search identified no reports in Chinese journals,whereas 50 publications were found in English journals.A total of 30 NSIAD probands were reported and 16 of those(53%)had childhood onset,most presented with seizures.The majority had a hotspot change at the nucleotide position of 409 in AVPR2.Nine cases had an amino acid change as R137C and five cases as R137L.Fluid restriction and oral urea intake were main treatment options,no report so far was found with oral furosemide treatment.Conclusions NSIAD presented with hyponatremia without any other specific presentations.Genetic testing for variants in AVPR2 is helpful for early diagnosis and timely treatment.The first two cases of oral furosemide treatment were reported by the article which helped to maintain a normal serum sodium level after limiting fluid intake and supplementing sodium which showed limited effect.