Prenatal Screening for Fetal X-Linked Ichthyosis: A Large Cohort Study Combining Non-Invasive Prenatal Testing and Maternal Serum Unconjugated Estriol Analysis.

OBJECTIVE

This study aimed to evaluated the clinical utility of an integrated prenatal screening strategy combining non-invasive prenatal testing (NIPT) and maternal serum unconjugated estriol (uE3) quantification for detecting X-linked ichthyosis (XLI) in male fetuses.

METHODS

Within a retrospective cohort of 95,485 screened pregnancies, 147 cases exhibiting low second-trimester uE3 levels (Multiple of the Median, MoM ≤ 0.3) were identified. Participants were stratified based on uE3 MoM values into Group 1 (uE3 ≤ 0.1) and Group 2 (0.1 < uE3 ≤ 0.3). NIPT was performed in 41 cases to detect maternal Xp22.31 microdeletions encompassing the STS gene. Fetal genotypes were verified via chromosomal microarray analysis (CMA) of amniotic fluid in cases opting for invasive prenatal diagnosis. For those without prenatal diagnosis, verification was conducted by STS-specific PCR using newborn heel blood samples.

RESULTS

The incidence of confirmed XLI was significantly higher in Group 1 (49.3%, 35/71) than in Group 2 (1.3%, 1/76). Among the 41 cases that underwent NIPT, maternal Xp22.31 deletions were detected in 28 cases. When this deletion combined with an extremely low maternal serum uE3 level (MoM ≤ 0.3), the positive predictive value for XLI reached 100%, which was markedly higher than that of NIPT alone (theoretical ∼50% PPV) or uE3 screening alone (49.3% PPV).

CONCLUSION

Integrating NIPT-based maternal CNV detection with maternal serum uE3 quantification significantly improves the accuracy of prenatal XLI screening. This combined approach is most clinically actionable in a specific scenario: a male fetus presenting with normal ultrasound findings, extremely low maternal uE3, and a positive family history of isolated XLI without comorbidities.