Rauch-Steindl syndrome: intrauterine phenotype and diagnostic utility of prenatal exome sequencing.

Abstract

Rauch-Steindl syndrome (RAUST) is a rare developmental disorder caused by pathogenic variants in the NSD2 gene, typically characterised postnatally by microcephaly, growth restriction and developmental delay. We report the case of a fetus presenting at 24 weeks of gestation with severe microcephaly (head circumference<1 st centile), a transverse cerebellar diameter in the 20th centile, cystic changes in the temporal poles and fetal growth restriction. While quantitative fluorescent PCR and microarray analysis were normal, trio whole-exome sequencing (WES) identified a heterozygous de novo splice-site variant (NM_133330.3:c.760+1G>C) in NSD2, classified as pathogenic. Prenatal MRI revealed brain biometry below the first centile and cystic changes in the temporal poles. The pregnancy resulted in a live birth at 38 weeks; the neonate was small-for-gestational-age with microcephaly but lacked major facial dysmorphisms. This report expands the known phenotypic spectrum of RAUST to the prenatal period, characterised by early-onset microcephaly, growth restriction and temporal polar cysts.