Cornelia de Lange syndrome: specific features for prenatal diagnosis

We present here a series of seven fetuses with ultrasound characteristics and abnormalities associated with Cornelia de Lange syndrome (CdLS) that were referred to our tertiary center between 2006 and 2012. CdLS was confirmed by examination after medical termination of pregnancy (TOP) in five cases and was confirmed clinically after birth in two. The characteristics and ultrasound findings of each case are summarized in Table 1. Amniocentesis revealed normal fetal karyotype in all cases. All seven fetuses had moderate to severe fetal growth restriction (FGR) and displayed upper limb abnormalities. Of the five fetuses that had developed hands, two (Cases 3 and 4) had a short first metacarpal bone (Figure 1) that was identified on x-ray after birth or TOP. Retrospective analysis of the prenatal ultrasound images of the other cases identified short first metacarpal bone in two of them (Cases 5 and 6). Facial features characteristic of CdLS were observed in all fetuses. All cases had a long, smooth and convex philtrum (Figure 2a), four (Cases 2 and 5–7) had a small upturned nose (Figure 2b) and six (Cases 1, 2 and 4–7) had retrognathia. Hypertrichosis was present in all fetuses, two of which had unusually long scalp hair (Cases 3 and 4) (Figure 2c), four had long eyelashes (Cases 2, 4, 5 and 7) (Figure 2e,f) and two had arched eyebrows (Cases 1 and 6) (Figure 2d). A mandibular spur was found in six fetuses (Cases 2–7) (Figure 2g). Prenatal features of CdLS have been described previously in the medical literature, with FGR, limb abnormalities and characteristic facial features being the most common1. Limb abnormalities, including micromelia, tend to be asymmetric and affect the distal upper extremities in the majority of cases, including syndactyly, clinodactyly of the fifth finger and oligodactyly3. More severe anomalies have also been detected, such as ulnar aplasia and flexed elbow4. In our series, all cases displayed limb anomalies, and in particular, upper limb anomalies, while only one had an anomaly of the foot (Case 1). A short, almost round, first metacarpal bone is one of the diagnostic criteria for CdLS3. The thumb is easily recognizable because it has only two phalanges. Assessment of the first metacarpal bone is possible by two-dimensional ultrasound in most cases, but three-dimensional (3D) acquisition can be helpful in difficult cases (Figure 1). Craniofacial features are well described postnatally and can be visualized in the prenatal period. Ultrasound examination in a midsagittal view can show a smooth and convex philtrum (Figure 2a), an upturned nose and anteverted nostrils (Figure 2b). A thin upper lip (Figure 2b) and low-set ears can also be identified3. 3D image reconstruction can be helpful in discerning the nature and extent of facial abnormalities. Micrognathia is also a common sign that can be assessed subjectively or objectively by measuring the inferior facial angle on the midsagittal fetal profile6, 7. A mandibular spur was detected by 3D ultrasound in six of the cases reported here. It was not looked for in our first case because we were not aware of this sign in 2006. A mandibular spur associated with CdLS was first described by postmortem x-ray of fetuses with CdLS9. This spur, located below the mandible, has a triangular shape with a sharp inferior tip (Figure 2g). Hypertrichosis is typical of CdLS; long eyelashes can be seen in the coronal plane but probably more easily in an axial plane8. Arched eyebrows and synophrys can be seen with 3D surface rendering (Figure 2d). Other malformations can be found with ultrasound that are not necessarily specific to CdLS. Congenital heart and genitourinary malformations are associated with CdLS in 13–70% and 12–41% of cases reported in the literature, respectively5. Cases of congenital diaphragmatic hernia have also been described. CdLS is a heterogeneous clinical and genetic condition. Most cases that result from de-novo mutations are diagnosed prenatally from their ultrasound findings. It is therefore essential to describe fetal anomalies objectively, as such descriptions can aid in a diagnosis, especially in cases with isolated FGR that cannot be explained by chromosomal abnormalities or vascular etiology. The characteristic features of CdLS described here can contribute to its diagnosis and help inform parents of the particular significance of this pathology.