Characterization of Bardet–Biedl syndrome by postmortem microfocus computed tomography (micro‐CT)

Confirmation of fetal anomalies detected antenatally is important for informing future management, particularly following termination of pregnancy. Despite significant imaging advances, antenatal ultrasonography identifies only 68% of autopsy-confirmed findings1. As parental consent for invasive autopsy is declining, important phenotypic information to help guide genetic testing and counseling is being lost. Postmortem imaging using microfocus computed tomography (micro-CT) provides a feasible alternative or complementary tool to autopsy in small early-gestation fetuses2. It provides high-resolution, three-dimensional digital images that rival light microscopy in enabling accurate diagnosis with high sensitivity3. We describe here how micro-CT changed clinical management by confirming a cardiac anomaly detected antenatally and suggesting a complex multisystem syndrome with subsequent genetic confirmation. A 33-year-old primigravida attended for routine antenatal sonography at 12 + 5 weeks' gestation. The singleton fetus had increased nuchal translucency thickness of 8 mm and blood flow across only the right atrioventricular valve. The patient underwent chorionic villus sampling for fetal array comparative genomic hybridization testing, with a resolution of 3 Mb, returning a normal result (arr(1-22, X) × 2). The parents were counseled that the imaging features could be part of a syndromic genetic condition, such as Smith-Lemli–Opitz, or a ciliopathy, and opted to terminate the pregnancy by medical induction at 15 + 6 weeks' gestation. The terminated fetus weighed 69 g, with crown–rump length of 12 cm and crown–heel length of 17.5 cm. Due to small fetal size and potential difficulty of cardiac dissection, whole-body micro-CT was performed (XTH225 micro-CT scanner; 70 μm resolution; Nikon Metrology, Tring, UK) following written parental consent. Images were reconstructed (CTPro3D software; Nikon Metrology, Tring, UK) and postprocessed (Volume Graphics GmbH, Heidelberg, Germany). Image analysis revealed an atrioventricular septal defect of 0.2 cm in diameter, with hypoplastic left heart syndrome, including mitral valve stenosis, left ventricular hypoplasia, aortic atresia and ascending and aortic arch hypoplasia. The ascending aortic arch measured only 0.05 cm in diameter (Figure 1). There were bilateral multiple renal cortical cysts (Figure 2) and bilateral upper- and lower-limb postaxial polydactyly (Figure 3), which were not identified antenatally. Following imaging results, consent was obtained for examination of the heart and kidneys at autopsy with further genetic testing. Autopsy corroborated imaging findings, with renal histology showing extensive cystic dilatation of the renal tubules. Two compound heterozygous mutations in the BBS7 gene were found (NM_176824.2:c.187G > A/p.(Gly63Arg)mat and NM_176824.2:c.973G > T/p.(Glu325Ter)pat) by whole-genome sequencing, using a trio analysis methodology, consistent with Bardet–Biedl syndrome4. Given a recurrence risk for future pregnancies of 25% in this autosomal recessive syndrome5, the parents received counseling regarding future preimplantation or antenatal genetic testing. In conclusion, micro-CT is a non-invasive highly detailed method for assessing early-gestation fetal anatomy, and provides an alternative or adjunctive tool to the standard autopsy technique. In this case, micro-CT imaging was able to better characterize the antenatal cardiac anomalies and provide additional useful information regarding renal and musculoskeletal anomalies, leading to change in future pregnancy management and genetic counseling. S.C.S. is supported by a RCUK/UKRI Innovation Fellowship and Medical Research Council (MRC) Clinical Research Training Fellowship (Grant Ref: MR/R00218/1). This award is jointly funded by the Royal College of Radiologists (RCR). I.C.S. is funded by a National Institute for Health Research (NIHR) Clinical Doctoral Research Fellowship. O.J.A. is funded by a NIHR Career Development Fellowship (NIHR-CDF-2017-10-037), and N.J.S. is funded by a NIHR Senior Investigator award. The authors receive funding from the Great Ormond Street Children's Charity and the Great Ormond Street Hospital NIHR Biomedical Research Centre. This article presents independent research funded by the MRC, RCR, NIHR, and the views expressed are those of the author(s) and not necessarily those of the NHS, MRC, RCR, NIHR or the Department of Health.