P780: Uniparental isodisomy of chromosome 8 in a one-year-old boy: A rare case report

The mother's case is particularly novel.Only one family with healthy 46,XX, SRY + females has been reported previously.In that family, the Xq/Yp translocation deleted critical genes on the X chromosome, leading to male lethality and preferential inactivation of the Xq/Yp derivative chromosome in females, allowing for normal female development.In our family's case, the shared genotype of 46,XX, SRY + was viable in a fertile female and her male offspring.This unique occurrence suggests a previously undescribed molecular mechanism and challenges the current understanding of sex determination.Our diagnostic dilemma involves exploring, in the context of this families' shared 46,XX, SRY + genotype, how the mother's SRY could be silenced while her sons' SRY remained active.Skewed X-activation testing as well as a DSD NGS Panel or exome/genome sequencing are indicated to identify potential genetic modifiers of the SRY gene, within a fertile female phenotype.Conclusion: We report a unique case of a 46,XX, SRY + healthy female without infertility and sexual ambiguity.Further investigation is needed to uncover the genetic mystery of sex determination in this family.Introduction: Pseudoautosomal regions of sex chromosomes involving translocation of X chromosome and Yp with SRY can cause a rare 46,XX testicular disorder of sex development (DSD).Individuals with the derivative X containing the SRY gene are phenotypically male with infertility.Here, we report two 46,XX DSD male siblings who inherited the SRY-positive X chromosome from their mother, a fertile female with 46, XX, SRY + .Case Presentation: A male proband was referred at 7 months of age for suspected Klinefelter Syndrome (KS).He presented with abnormal head shape, failure to thrive, and developmental delay.By age two, he developed gross/fine motor delays, dysphagia, hypotonia, bilateral ankle pronation, frequent falls, and speech delay.At the time of diagnosis, the proband's family included an older brother with developmental delay and a healthy mother with a history of one miscarriage (10 weeks male).Diagnostic Workup: Prenatal microarray of the male proband from an outside institution revealed an X chromosome gain, consistent with KS.Confirmatory postnatal testing, including chromosome analysis and fluorescence in situ hybridization (FISH) was performed at VUMC cytogenetics lab and showed 46,XX.ishder(X)t(X;Y)(p22.3;p11.3)(SRY+ ) results.Approximately two years later, this proband's newborn maternal half-brother was seen in the genetics clinic after an over-the-counter test showed XX chromosomes.Subsequent chromosome and FISH testing of the healthy half-sibling and mother showed 46,XX, SRY + .Microarray analysis of the mother's peripheral blood indicated a derivative X with an Xp terminal deletion and a gain of Yp material, including the SRY gene.