ResearchPad - sex-determination-and-reproductive-axis-development https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-034 Combined CNV, Haplotyping and Whole Exome Sequencing Implicates Inherited Novel SRY Mutations Not Account for Familial 46,XY Sex Reversal]]> https://www.researchpad.co/article/elastic_article_7135 SRY is one of the important genes involved in the process of human sex determination. The disturbed sex determination caused by SRY mutation accounts for 10-15% cases with complete gonadal dysplasia (CGD), also known as 46, XY sex reversal. Recently, three distal enhancers are disclosed in the upstream of SOX9 gene. In an inherited 46, XY sex reversal pedigree with 5 patients, p.Arg76Leu mutation of SRY and p.G212S mutation of NR5A1were identified from the proband who present with primary amenorrhea and lack of puberty development. The missense mutation of NR5A1was found to be derived from the mother. Interestingly, the paternal inherited p.Arg76Leu mutation of SRY was revealed from other 2 CGD patients, as well as from apparent normal male family members with fertility. P.Arg76Leu variation was found have no effect to the transcriptional activity of target gene SOX9, neither alteration of the nuclear translocation of SRY. Whole exome sequencing also found SRY mutation, FGF10 mutation, GJB4 gene mutation, etc. with no segregation in the family, which suggested SNVs are not main cause of the disease in this pedigree. By copy number variation and SNP haplotype analysis, SOX9 gene far upstream deletion of 68kb was disclosed from the 3 patients in this family, containing one of the enhancers of SOX9. Real-time PCR confirmed that the heterozygous deletion of the region result in loss of SR-XY, but not eSR-B and eALDI. Therefore, single nucleotide variation (SNV) of SRY and NR5A1 are not main causes of severe phenotype of CGD, the enhancers of SOX9 should be investigated carefully in such patients.

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<![CDATA[SUN-037 Discordant Serum 17-hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-oxygenated Androgens Useful?]]> https://www.researchpad.co/article/elastic_article_6698 Background 21-hydroxylase-deficiency (21OHD) accounts for more than 95% of CAH cases. Serum 17-hydroxyprogesteron (17OHP) and androstenedione (A4) are traditional biomarkers for monitoring therapy. While generally there is good linear correlation between 17OHP and A4, physicians are likely to encounter scenarios where 17OHP is within “acceptable range” while A4 is elevated and vice versa. Mildly elevated 17OHP is considered acceptable, as normalization of 17OHP is likely to result in overtreatment. 11-ketotestosterone (11KT) is a potent agonist of the androgen receptor with androgenic activity equivalent to testosterone. We hypothesized that patients with high 17OHP would be more likely than those with high A4 to be in good disease control. We speculated that A4 would correlate more strongly with 11-oxygenated C19 steroids (11oxyandrogens) than 17OHP and that patients in poor clinical control would have higher median fold-elevation of 11oxyandrogens, especially 11-KT, compared to controls. Methods We performed retrospective analysis of patients seen at NIH from 2006 to 2019 and identified discordant 17OHP and A4 (17-OHP ≥1200 ng/dL with A4 normal for age/sex or tanner stage and vice-versa). Good or poor clinical control was based on abnormal growth, precocious puberty, irregular menses, hypogonadotrophic hypogonadism and A4/T. Quantitation of 15 steroids in stored peripheral sera was performed by LC-MS/ MS and compared to age- and sex-matched controls. Data between groups were compared using t-tests or non-parametric Wilcoxon rank sum tests. Correlation analyses utilized the Pearson and Spearman’s rho. Results We identified 122 of 789 (15%) discordant laboratory assessments among adults [84 with high 17OHP (69%)] and 347 of 1,949 (18%) among children [319 with high 17OHP (92%)]. Of these, 50 patients with available serum samples were identified (44 with high 17OHP). Twenty-five patients (50%) appeared to have good disease control. There was no difference in the frequency of patients in good or poor control between patients with high 17OHP or those with high A4 (p=0.7). Median fold elevation of 11KT relative to controls was higher in patients in poor control (2.87 fold, IQR 1.87-5.42, range 0.31-10.69) but with wide ranges and substantial overlap compared to those in good control (1.71 fold, IQR 1.06-2.92, range 0.35-16.59, p=0.068). 17OHP correlated with 21-deoxycortisol (rs=0.67, p<.001) while A4 correlated strongly with 11oxyandrogens (rs range 0.42-0.71, p<.003 for all). However, we did not find any substantial difference in the level of 11oxyandrogens between patients with high 17OHP and those with high A4. Conclusion: Discordance between 17OHP and A4 is common in the management of CAH and patients with elevation of either of these biomarkers are equally likely to have poor disease control. Limited evidence suggests a role for 11KT, as a discriminator for disease control.

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<![CDATA[SUN-038 Social and Psychological Aspects of Partial Androgen Insensitivity Syndrome, Therapeutic Challenges]]> https://www.researchpad.co/article/N9d16195c-7dd6-41d0-8bc5-75aedb5a8362 <![CDATA[SUN-036 Evaluation of Gender Experience Among Individuals with Isolated GnRH Deficiency Compared to Controls]]> https://www.researchpad.co/article/N47f24a27-42e0-4cf9-a106-4a79c9fee391 <![CDATA[SUN-035 A Role for GNRH-II in the Control of Puberty?]]> https://www.researchpad.co/article/N5c0e4a75-284b-4494-ba9b-3623f698eeed