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

Abstract

ObjectiveTo 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.MethodsFetuses 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.ResultsForty-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.ConclusionThese 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.

Short and tall stature: a new paradigm emerges

“…In some cases, this difference may be due to the severity of the growth plate abnormality. For example, severe activating mutations in FGFR3 associated with thanaphoric dysplasia and achondroplasia cause growth failure of prenatal onset, 126,127 whereas a milder mutation causing hypochondroplasia often produces a birth length within the normal range with short stature developing later. However, in other cases, the temporal onset, pre- vs. postnatal, may depend on whether the gene is important in the fetal growth plate, which is morphologically and functionally somewhat different from the growth plate in childhood.…”

Droplet digital PCR combined with minisequencing, a new approach to analyze fetal DNA from maternal blood: application to the non-invasive prenatal diagnosis of achondroplasia

“…Digital PCR has already been proposed as an alternative technique to other quantitative techniques for non‐invasive prenatal testing of aneuploidies as well as monogenic disorders . Several groups have reported on the diagnosis of achondroplastic fetuses using different analytical techniques such as MALDI‐TOF, restriction analysis, QF‐PCR, quantitative real time PCR, and more recently NGS . The early PCR‐based methods appear to be suitable in diseases for which there is a single hotspot mutation.…”

A sonographic approach to the prenatal diagnosis of skeletal dysplasias

“…Thus, the long bones in achondroplasia are of normal length at the time of the 20‐week anomaly scan with growth only dropping off after around 24 to 25 weeks' gestation (Figure A). This together with the other features such as relative macrocephaly (Figures J and B), short fingers (Figures B and G), and polyhydramios significantly aids the sonographic diagnosis of the most common skeletal dysplasias . Additional features and normal Doppler investigations also help distinguish achondroplasia from IUGR.…”