Prenatal assessment of a suspected skeletal dysplasia using ultrasound presents great challenges, both in achieving an accurate diagnosis and then in assigning a correct prognosis. Although recognition of lethal skeletal dysplasias is fairly reliably accomplished using ultrasonography, differentiating between the different types to make a precise diagnosis remains difficult, with reported accuracy ranging from 31 to 65%[1-7]. Making a quick and accurate diagnosis is important for reducing parental anxiety, and is especially important in cases of genetic disorders, for which the recurrence risk can be up to 50%. Most of the benefit of making a precise diagnosis will lie in determining the likelihood of a recurrence and offering appropriate prenatal testing at an earlier stage in future pregnancies.
There has been a recent explosion of knowledge concerning the biochemical and molecular defects associated with skeletal dysplasias. However, the application of these findings in directing patient care is difficult, because a precise molecular diagnosis entails testing a large number of genes. To date, guidelines for the diagnosis of skeletal dysplasias advise using the constellation of abnormalities to determine the most likely differential diagnosis, and then proceeding sequentially. For each patient, a succession of genes is examined, one at a time. As an alternative to the focused sequential approach of assessment on a gene-by-gene basis, a more efficient strategy is based on parallel evaluation of the genes most frequently associated with skeletal dysplasia on a customized multiplex panel. Using a custom single nucleotide polymorphism (SNP) microarray (Arrays CGC®; CGC Genetics, Porto, Portugal), with 26 point mutations in the six genes (FGFR3, COL2A1, SLC26A2, CRTAP, LEPRE1 and SOX9) most frequently associated with achondroplasia, thanatophoric dysplasia, achondrogenesis Types IB and II, osteogenesis imperfecta (recessive type) and campomelic dysplasia, it is possible to identify the molecular basis of the most frequent and severe forms.
We report two cases of thanatophoric dysplasia diagnosed prenatally using microarray technology. The first case concerned a 32-year-old woman, gravida 2 para 1, and the second a 43-year old woman, gravida 4 para 3. Paternal age was 37 and 47 years, respectively. Both patients presented for second-trimester anomaly scans at 20 weeks' gestation. In both cases the scans revealed that the thorax was narrow and all long bones were well below the 3rd centile in length, with curved femurs (Figure 1). The ultrasound appearances were thought to be consistent with a lethal skeletal dysplasia. Microarray tests for the condition were performed, using DNA already extracted by chorionic villus sampling in the first case and from amniocytes in the second case. Mutation c.1138A>G on FGFR3 was detected in the first case and in the second case mutation c.742C>T was found on the same gene (Figure 2). This led to a diagnosis of thanatophoric dysplasia Type 1 within 7 days of the second-trimester anomaly scan. The results were confirmed by sequence analysis.
Compared with the traditional sequential testing using gene-by-gene genetic analysis, this new approach considerably reduces turnaround time and cost of diagnosis. This allows for more precise counseling of families regarding prognosis in current and future pregnancies. We therefore believe that SNP microarrays have huge potential for prenatal diagnosis.