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Prenatally diagnosed 45,X/46,XY mosaicism with a male phenotype

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction
The 45,X/46,XY genotype can present on a spectrum of phenotypes due to tissue mosaicism. The occurrence of mosaics is 1.5 to 1.7 out of 10,000. Male phenotypes can have structural changes to the Y chromosome. One finding is the isodicentric Y chromosome (idic[Y]); a duplication of one chromosome arm with subsequent repair, leading to a chromosome with identical arms on both sides–with instability from double centromeres.

Case Presentation
A 30-year-old Gravida 1 Para 0 at 14 weeks gestation, presented for evaluation of Tay-Sachs disease carrier status. Initial ultrasound demonstrated a female phenotype in fetus. Prior prenatal cell-free DNA screening determined fetal sex to be female (46,XX). At her 20-week anatomy ultrasound, male external genitalia were noted. No other structural abnormalities were noted. Repeat cfDNA noted chromosome findings of 45,X.

Diagnostic Workup
Amniocentesis at 28 weeks demonstrated 45,X. Subsequent FISH analysis reported: 45,X, XYY or X with dicentric Y, and XY. Further studies highlighted a 16.9 Mb block of Y chromosome material in single copy from Yp11.2 to Yq11.221 with 9.2 Mb copy number loss from Yq11.221q11.23, showing loss of protein-coding genes for DAZ1, DAZ2, DAZ3, and DAZ4. Infant cord blood noted chromosome findings of 46, X psu idic(Y)(q11.2)/45, X/46, XX, Placental chromosome analysis noted two cell lines: 45,X, and 46,X and idic(Y). Infant peripheral blood noted two cell lines: 45,X and 46,X psu idic(Y).

Treatment and Management
Diagnostic amniocentesis was performed at 28 weeks. Antenatal surveillance was performed twice weekly until delivery. At 38 weeks gestation, the patient delivered a phenotypic male infant.

Outcome and Follow-Up
Infant evaluated by pediatric genetics. Notable physical exam findings included normal phallus and scrotum with bilateral descended testes.

Discussion
Presence of instability in the idic(Y) produces numerous phenotypes due to mosaicism, dictated by variable percentages of cell lines in each tissue type. Gonadal development is dependent on the percentage of the predominant cell line, which dictates phenotype. SRY on the distal portion of Yp is required for testicular development. Various amounts of SRY and Y-bearing cells in the gonads have been described in the literature with differing phenotypes. Breakpoints in Yq for idic(Y) can result in two copies of SRY, like this patient. Even with multiple copies of SRY, a male phenotype may not be expressed. Despite this, 95% of 45,X/46,XY fetuses present with normal male genitalia. Unfortunately, the gonads were not biopsied for assessment of cell line composition. Infertility can be seen in 45,X mosaics. The Y chromosome contains the azoospermia factor (AZF) regions. This includes AZFa, AZFb, and AZFc on the proximal portion of Yq. The DAZ gene family is located within AZFc, producing a protein component for spermatozoa tails. Deletion of DAZ is linked to infertility. For this patient, the copy number loss resulted in loss of the DAZ gene family, with disruption of AZFc, likely resulting in future infertility. Page 3 of 3 Anatomic findings at 14 and 20 weeks were incongruous in terms of fetal sex, yet fetal genitalia, itself, appeared structurally normal. Discrepancies in ultrasound could be attributed to user error or inaccuracy. However, ultrasonography in pregnant women at 11-14 weeks gestation shows high sensitivity and specificity in detecting sex, with sensitivity higher in female sex determination. It is possible, but unlikely the early ultrasound was incorrectly read.

Conclusion
Here is presented a case of prenatal diagnosis of 45,X/46,X idic(Y)/46,XY via amniocentesis where initial findings on ultrasound at 14 weeks contrasted ultrasound findings noted at 20 weeks. This is likely the first reported case of a dramatic phenotypic change between two gestational ages that resulted in further testing. The case highlights the importance of counseling patients throughout all stages of their prenatal care, particularly as new information arises. 

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