There are two forms of diabetes insipidus, central (neurohypophyseal), and nephrogenic, caused by pathogenic variants in the AVP gene and the AVPR2 or AQP2 genes, respectively. We report on a four-generation family, seven individuals had central diabetes insipidus (CDI) and the female index patient seen from age 16 to 26 years had (mild) nephrogenic diabetes insipidus. In her father with CDI, a known pathogenic heterozygous AVP variant c.232_234del p.(Glu78del) was identified, confirming the diagnosis of CDI in him and the other affected family members. In the proband, molecular analysis disclosed a novel heterozygous AVPR2 gene variant, c.962A > T p.(Asn321Ile) and an extremely skewed X-inactivation, confirming X-linked nephrogenic diabetes insipidus (XL-NDI). Whole exome sequencing showed no further causative mutation. This is the first report on the co-existence of CDI and NDI in one family. Our review of symptomatic female AVPR2 heterozygotes includes 23 families with at least one affected female (including this study). There were 21 different causative mutations. Mutation types in females did not differ from those in males. Both severe XL-NDI and mild forms were reported in females. All six females with severe XL-NDI had complete loss-of-function (null) mutations. The remaining 17 female probands had milder XL-NDI caused by 14 missense variants and three null variants of the AVPR2 gene. X-inactivation was studied in nine of these females; all showed extreme or slight skewing. The review underlines that XL-NDI in female AVPR2 heterozygotes is always accompanied by skewed X-inactivation, emphasizing a need for X-inactivation studies in these females.

中文翻译：

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一位患有遗传性中枢性尿崩症的X连锁性肾病性尿崩症的女性：病例报告和文献复习。

尿崩症有两种形式，分别是中枢性（神经下垂体性）和肾源性，分别由AVP基因和AVPR2或AQP2基因的致病变异引起。我们报告了一个四代家庭，其中7个人患有中枢性尿崩症（CDI），而16岁至26岁的女性指数患者患有（轻度）肾性尿崩症。在其父亲患有CDI的过程中，发现了一个已知的病原性杂合性AVP变体c.232_234del p。（Glu78del），从而证实了他和其他受影响家庭成员的CDI诊断。在先证者中，分子分析揭示了一种新的杂合性AVPR2基因变异，即c.962A> T p。（Asn321Ile）和极度偏斜的X灭活，证实了X连锁性肾病性尿崩症（XL-NDI）。整个外显子组测序未显示进一步的致病突变。这是关于一个家庭中CDI和NDI并存的第一份报告。我们对有症状女性AVPR2杂合子的综述包括23个家庭，其中至少有1位受影响的女性（包括本研究）。有21种不同的致病突变。女性的突变类型与男性没有差异。女性中既有严重的XL-NDI也有轻度的形式。患有严重XL-NDI的所有六名女性均具有完全的功能丧失（无效）突变。其余17位女性先证者的轻度XL-NDI是由AVPR2基因的14个错义变体和3个无效变体引起的。在其中的9位女性中研究了X失活。都显示出极端或轻微的倾斜。该评论强调，女性AVPR2杂合子中的XL-NDI总是伴有偏斜的X灭活现象，强调需要对这些雌性进行X灭活研究。