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SRY Positive 46,XX: A Unique Family with Fertile Female Mother and Male Children Challenging the Dogma of Sex Determination

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
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.ish der(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.



 

Treatment and Management
Physical and speech therapy and regular growth monitoring were recommended for the proband and his sibling. Endocrinology consultations for growth hormone and testosterone therapy were also recommended.



 

Outcome and Follow-Up
Family and individual counseling and psychological support were recommended. A DSD next generation sequencing (NGS) panel and X-chromosome inactivation test were recommended for the mother, as well as genetic testing for other family members, including the older brother and maternal grandfather.

Discussion
Chromosome and FISH testing was essential for clarifying the diagnosis for this family. Although the management of KS and 46,XX DSD are largely similar, the genetic mechanisms, phenotypes, and recurrence risks differ. Of note, while some patients with KS may have treatment options to address infertility, 46,XX, SRY+ males are typically infertile.

The mother’s case is particularly novel. To the best of our knowledge, only one family with healthy 46,XX, SRY+ females has been reported previously (PMID: 38254992). 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 whole 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.



 

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