BackgroundAutosomal dominant inheritance of congenital nephrogenic diabetes insipidus (CNDI) is rare and usually caused by variations in the AQP2 gene. We have investigated the genetic and molecular background underlying symptoms of diabetes insipidus (DI) in a Swedish family with autosomal dominant inheritance of the condition.MethodsThe proband and her father were subjected to water deprivation testing and direct DNA sequencing of the coding regions of the AQP2 and AVP genes. Madin-Darby canine kidney (MDCK) cells stably expressing AQP2 variant proteins were generated by lentiviral gene delivery. Localization of AQP2 variant proteins in the cells under stimulated and unstimulated conditions was analyzed by means of immunostaining and confocal laser scanning microscopy. Intracellular trafficking of AQP2 variant proteins was studied using transient expression of mutant dynamin2-K44A-GFP protein and AQP2 variant protein phosphorylation levels were assessed by Western blotting analysis.ResultsClinical and genetic data suggest that the proband and her father suffer from partial nephrogenic DI due to a variation (g.4807C > T) in the AQP2 gene. The variation results in substitution of arginine-254 to tryptophan (p.R254W) in AQP2. Analysis of MDCK cells stably expressing AQP2 variant proteins revealed disabled phosphorylation, impaired trafficking and intracellular accumulation of AQP2-R254W protein. Notably, blocking of the endocytic pathway demonstrated impairment of AQP2-R254W to reach the cell surface.ConclusionsPartial CNDI in the Swedish family is caused by an AQP2 variation that seems to disable the encoded AQP2-R254W protein to reach the subapical vesicle population as well as impairing its phosphorylation at S256. The AQP2-R254W protein is thus unable to reach the plasma membrane to facilitate AVP mediated urine concentration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0213-3) contains supplementary material, which is available to authorized users.

Background: Early onset of breast development in a young girl is usually a benign and isolated prepubertal condition, i.e., premature thelarche (PT), but can sometimes be progressive and the first sign of pubertal precocity (PP). Serum 17β-estradiol (17β-E2) level is a possible marker to differentiate between benign and pathological forms of breast development. We defined an upper serum 17β-E2 level for benign, “classic” PT for girls aged 9–48 months. Methods: Serum 17β-E2 was analysed with a highly sensitive extraction radioimmunoassay (RIA). Gonadotropins, Tanner breast stage, growth, other investigations, and clinical outcome were assessed in 125 girls with breast development, in a population-based study in West Sweden. Results: A total of 125 of 128 girls had a benign form of breast development with a mean serum 17β-E2 level of 15.2 pmol/L and a mean + 2 SD of 31 pmol/L, which was regarded as the upper limit for benign PT; 3 girls with PP had 17β-E2 levels above 70 pmol/L. Conclusion: This is the first study to define an upper serum 17β-E2 level associated with benign PT. Girls aged 9–48 months with PT and Tanner breast stage 2 have 17β-E2 levels below 32 pmol/L using extraction RIA. LH below the detection limit (0.1 IU/L) and measurable FSH support benign PT.

ContextThe use of testosterone enanthate (TE), 50–75 mg intramuscularly (i.m.)/month, for the treatment of boys with delayed puberty or slow progression to induce puberty is the standard of care (SoC) in Sweden. This treatment is empirical and has not been scientifically evaluated. Replacement therapy in hypogonadal boys/young men in Sweden after induction is mainly performed with testosterone undecanoate (TU), 1,000 mg/3 months. TE is only available on license. TE was deregistered in Sweden in 2006. Therefore, this study was initiated to compare the two products.ObjectiveTo clinically evaluate pubertal progression with six injections of TE, 75 mg i.m./month (1/3–1/5 of adult dose), compared with two injections of TU, 250 mg i.m./3 months (1/4 of adult dose).Trial designIn the Pubertal Replacement in Boys Study (PRIBS), boys aged 14–16 years in West Sweden with pubertal delay were randomized in a parallel study to TE or TU for pubertal progression. Inclusion criteria were morning testosterone levels of 0.5–3 nmol/L and testicular volume ≤6 ml. Between June 2014 and Nov 2019, 27 boys were included.MethodsThe primary outcome was testicular enlargement ≥8 ml after 12 months. TU treatment was considered clinically similar if the number of boys with testicular enlargement ≥8 ml was 80%–125% of the number of boys with TE. Fisher’s exact chi-square test was used for this analysis.ResultsBoth treatments were well tolerated. Twelve of 14 (86%) TU-treated boys reached the primary outcome and 12/12 in the TE group. Fisher’s exact chi-square testing indicated a one-sided p-value of 0.28 (the two-sided p-value was 0.483). The TU treatment was considered not clinically different from SoC. A post-hoc study showed 25% power. Therefore, no evidence-based conclusion can be drawn from the results even if the clinical data support a similar effect of the treatments.ConclusionThe present small-scale study supports that both TE and TU had similar effects in terms of pubertal progression.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/home, identifier NCT05417035; https://www.clinicaltrialsregister.eu/ctrsearch/search, identifier EUDRACTEudraCT nr 2012-002337-11.