OP38.04: New aids to the prenatal diagnosis of thanatophoric dysplasia

Accurate diagnosis of skeletal dysplasias before birth is challenging. Targeted molecular diagnosis is the most reliable approach but, until the discovery of cell free fetal DNA (cffDNA) in maternal plasma, required invasive testing and a high index of suspicion of the underlying pathology following detailed ultrasound examination. Our primary objective was to improve the prenatal diagnosis of thanatophoric dysplasia (TD) by constructing charts of fetal size, defining frequency of sonographic features and exploring the role of non-invasive molecular diagnosis based on cffDNA. All cases with a confirmed diagnosis of TD seen in our Units since 1995 were identified, and records reviewed to ascertain ultrasound findings and measurements. Charts of fetal size were constructed using the LMS model and compared with those used in normal pregnancies and other skeletal dysplasias. Since 2007, the Genetics Laboratory at GOSH has offered cffDNA testing for selected single gene disorders; cases referred because of suspected TD were ascertained and cffDNA results compared with postnatal diagnoses. Fetal size charts derived from 39 cases demonstrated long bone length ⩽ 3rd centile from 12 weeks' gestation, with minimal growth in the 3rd trimester. Commonly reported sonographic features included bowed femora, frontal bossing, short fingers, cloverleaf skull, a small chest and polyhydramnios. Analysis of cffDNA in six cases confirmed the presence of 1948 A > G mutation in four, and 742 C > T mutation in a fifth. In the 6th case, no result could be issued because of the low concentration of cffDNA. A combination of ultrasound features with reference to disease-specific fetal size charts and molecular analysis of cffDNA permits accurate, non-invasive prenatal diagnosis of TD. For cases diagnosed in early pregnancy this approach may facilitate surgical intervention without compromising acquisition of the definitive diagnosis needed for genetic counselling.