Recurrent Male Hydrops Fetalis Reveals Hidden Incontinentia Pigmenti: Lessons From Pseudogene-Interfered Genomic Diagnosis.

OBJECTIVE

To report incontinentia pigmenti (IP) as an overlooked genetic etiology in three families with recurrent non-immune hydrops fetalis (NIHF), and to highlight the necessity of phenotype-driven targeted prenatal testing and multidisciplinary care in the next-generation sequencing (NGS) era.

METHODS

Three unrelated families with recurrent male NIHF and negative chromosomal microarray analysis/NGS results were investigated. Genetic counselors conducted detailed maternal history-taking and physical examinations to identify subtle ectodermal features suggestive of IP. Targeted long-range PCR and multiplex ligation-dependent probe amplification (MLPA) were employed to bypass interference from the pseudogene IKBKGP1 and detect IKBKG exon 4-10 deletions.

RESULTS

All three mothers displayed subtle ectodermal features, including hypopigmented streaks, patchy alopecia, and dental anomalies. Genetic testing revealed heterozygous IKBKG exon 4-10 deletions in all 3 mothers, and a hemizygous deletion in the third affected male fetus of Family 3-both missed by conventional short-read NGS. Prenatal ultrasound consistently demonstrated increased nuchal translucency, cervical cystic hygroma, and generalized edema, serving as early indicators of IP-related NIHF.

CONCLUSION

Pseudogene-aware molecular tools combined with maternal phenotyping are essential for uncovering hidden IP and reducing unexplained fetal loss in the NGS era.