Antenatal diagnostic dilemma in a pseudodominant pedigree with lamin-B receptor (LBR)-related regressive spondylometaphyseal dysplasia

Abstract

The lamin-B receptor (LBR) encodes a dual-functioning inner nuclear membrane pro-tein essential for cholesterol biosynthesis and chromatin organization. LBR patho-genic variants cause distinct phenotypes due to the dual function of LBR, includingPelger–Huët anomaly (PHA), PHA with mild skeletal anomalies (PHASK; MIM#618019), LBR-related regressive type of spondylometaphyseal dysplasia (LBR-R-SMD), Greenberg dysplasia (MIM# 215140). We here report the first case with radio-logical manifestations of LBR-R-SMD in the fetal period, and milder skeletal findingsin the similarly affected father. Direct sequencing ofLBRrevealed homozygousc.1534C>T (p.Arg512Trp) in exon 12 in both affected individuals. Our report furtherrefines the early phenotype in LBR-R-SMD, and demonstrates that the p.Arg512Trpmutation is associated with PHA. We propose that LBR-R-SMD should be consideredas a differential diagnosis in pregnancies with sonographic evidence of short andbowed tubular bones with narrow thorax. Evaluating peripheral blood smears ofexpectant parents for the presence of PHA may lead to a clinical diagnosis, allowingfor comprehensive prenatal genetic counseling.