Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA

ABSTRACT Objective To improve the prenatal diagnosis of thanatophoric dysplasia by defining the change in fetal size across gestation and the frequency of sonographic features, and developing non‐invasive molecular genetic diagnosis based on cell‐free fetal DNA (cffDNA) in maternal plasma. Methods Fetuses with a confirmed diagnosis of thanatophoric dysplasia were ascertained, records reviewed, sonographic features and measurements determined. Charts of fetal size were then constructed using the LMS (lambda‐mu‐sigma) method and compared with charts used in normal pregnancies and those complicated by achondroplasia. Cases in this cohort referred to our Regional Genetics Laboratory for molecular diagnosis using cffDNA were identified and results reviewed. Results Forty‐two cases were scanned in our units. Commonly reported sonographic features were very short and sometimes bowed femora, frontal bossing, cloverleaf skull, short fingers, a small chest and polyhydramnios. Limb shortening was obvious from as early as 13 weeks' gestation, with minimal growth after 20 weeks. Analysis of cffDNA in three of these pregnancies confirmed the presence of the c.742C>CT (p.Arg248Cys) or the c.1948A>AG (p.Lys650Glu) mutation in the fibroblast growth factor receptor 3 gene. Conclusion These data should improve the accuracy of the sonographic diagnosis of thanatophoric dysplasia and have implications for reliable and safe targeted molecular confirmation using cffDNA. © 2013 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd. What's already known about this topic? Thanatophoric dysplasia is a lethal skeletal dysplasia amenable to prenatal diagnosis using fetal ultrasound with molecular confirmation following an invasive procedure. What does this study add? This study provides data to help distinguish thanatophoric dysplasia from other skeletal dysplasias and demonstrates the potential for safe, definitive molecular confirmation using cell‐free fetal DNA in maternal plasma.