Prenatal Characterization of Houge-Janssens Syndrome Type 2: A Case Report and Systematic Review of Fetal Phenotypes Associated With PPP2R1A Mutations.

Background: Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally by hypotonia, developmental delay, intellectual disability, and distinctive craniofacial features.

Methods: We describe a 28-year-old pregnant woman referred for increased nuchal translucency (4.4 mm) and high risk on first trimester screening. Noninvasive prenatal testing showed no common aneuploidies. At 23 weeks of gestation, fetal ultrasound revealed ventriculomegaly and suspected partial agenesis of the corpus callosum. Genetic testing included karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES).

Results: Karyotype and CMA were normal. WES identified a de novo heterozygous missense variant in PPP2R1A, NM_014225.6: c.548G>A (p.R183Q), classified as pathogenic. Following genetic counseling, the couple elected to terminate the pregnancy. Integrating our findings with 12 previously reported prenatal cases, we conducted a systematic review of fetal phenotypes associated with PPP2R1A variants. The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%).

Conclusion: We present the most comprehensive synthesis to date of prenatal phenotypes associated with PPP2R1A-related neurodevelopmental disorders. These findings provide crucial insights into the prenatal spectrum of HJS2 and highlight key sonographic indicators to support early diagnosis and genetic counseling.