Prenatal diagnosis of fetal skeletal dysplasia using 3-dimensional computed tomography: a prospective study

Fetal skeletal dysplasia (FSD) is a group of systemic bone and cartilage disorders that develops prenatally and may be detected by fetal ultrasonography. Considering most cases of skeletal dysplasia involve the mutation of a single gene, a postnatal diagnosis can be reached if this mutation is identified. Although the widespread use of fetal ultrasound imaging has improved the detection of FSD, prenatal diagnosis remains relatively difficult because of the rarity of the condition (approximately one in every 5000 births) [1]. The diversity of the FSD phenotypes also contributes to the difficulty in diagnosing these disorders. FSDs comprise 436 diseases that are classified into 42 groups, according to the Nosology & Classification of Genetic Skeletal Disorders: 2015 Revision [2]; however, the phenotypic definition of each disease is often unclear. It is important to clarify whether it is a lethal or nonlethal disorder to plan the most effective delivery method and the best postnatal treatment [3].

Fetal ultrasonography is the most standard method to detect FSD; however, it is unsuitable for the analysis of the skeleton because supersonic waves reflect it with the bone cortex. It was reported that the rate of accurate prenatal diagnosis of skeletal dysplasia was approximately 65% [4]. Fetal magnetic resonance imaging (MRI) is useful for the analysis of the fetal spine and depiction of marrow and soft tissue; however, it is unsuitable for bone cortical depiction like fetal sonography. Three-dimensional computed tomography (3D-CT) is commonly used to diagnose cardiac atherosclerosis, cerebral aneurysms, and cerebral artery stenosis. This imaging technique creates better images of thromboses and vascular wall calcification in cerebral aneurysms compared to cerebral angiography. In 2004, Ruano et al. reported that fetal 3D-CT was a useful diagnostic method, complementary to ultrasonography, and may improve the diagnostic accuracy of skeletal disorders [5]. Considering the increased risk associated with the radiation introduced by this clinically beneficial method, we elected to use low-dose 3D-CT for prenatal diagnosis in this study. This study aimed to determine the efficacy of 3D-CT in the prenatal diagnosis of FSD by comparing the prenatal and postnatal diagnoses in patients with this condition.

A total of 2447 fetuses underwent prenatal sonography and were delivered in our institution between 2012 and 2019. Of the 2447 fetuses, sonography revealed that 19 were suspected of having FSD, and we performed 3D-CT for those 19 fetuses. Of the 19 fetuses that underwent 3D-CT, 17 were diagnosed with FSD prenatally; however, the other two cases were diagnosed as not being FSD (one of the normal fetus, and another case of suspected trisomy 21). FSD was confirmed postnatally in all 17 of these fetuses. Sonography had a sensitivity of 100%, a specificity 99%, and positive and negative predictive values of 89.5 and 100%, respectively. On the other hand, 3D-CT had 100% sensitivity and specificity, and additionally, positive and negative predictive values of 100%.

The first-line method for the prenatal diagnosis of skeletal dysplasia is typically sonographic imaging; however, it is difficult to perform a classification of FSD. Although 3D-CT may be a valuable imaging tool complementary to ultrasonography for the diagnosis and classification of FSD, it is necessary to select the appropriate sonography settings to minimize the degree of fetal irradiation without compromising image quality [6, 7]. Fetal radiation exposure should be concerned with fetal CT. The dose of 3D-CT was a mean CTDI_vol of 3.5 mGy (range: 1.9–4.9 mGy); this is “low-dose” fetal CT, which has been reported in 2013: a mean CTDI_vol of 2.2 mGy [4] and 4.2 mGy [8]. In 2008, the International Commission on Radiological Protection recommended that in utero exposure to less than 100 mGy would be of no practical significance and poses a lifetime cancer risk [9]. A mean CTDI_vol of 2.9 mGy is far below 100 mGy.

MRI may be useful to differentiate between FSD and other limb malformations [10, 11]. Spatial recognition is easy in fetal MRI, as the bone marrow and soft tissue are clearly identified. However, it may not be suitable for identifying the bone cortex. CT uses ionizing radiation to produce an X-ray image which is similar to that produced by plain radiography. Radiography has traditionally been used as a diagnostic imaging method for skeletal system diseases, and the experience can be reflected in diagnostic CT imaging using X-ray characteristics of skeletal system diseases. Observations from a 360° view are made possible by obtaining 3D images, and the diagnostic accuracy may be increased by observing from the direction with greatest visibility. Furthermore, fetuses in utero often have their limbs and spines flexed. Therefore, image reconstruction may be enabled by eliminating these limbs from view or selecting only the section to be observed by trimming, which then provides meaningful images for diagnosis [12]. Using low-dose 3D-CT imaging, we can create an MIP image of a point that we should focus on. The depiction of the details for abnormal points is made clearer by adding the MIP images; therefore, it helps in making a diagnosis of FSD.

Fetal bone 3D-CT (as an auxiliary test for ultrasound examinations) provides detailed information on systemic skeletal structure when performed at 26 weeks’ gestation onward. The detection of abnormal findings outside the skeletal system on sonography can greatly affect the diagnosis [8, 13]. For a diagnosis of FSD, both sonography and 3D-CT appear to be useful methods. In some cases, it can be difficult to differentiate skeletal dysplasia from a chromosomal abnormality. Of the 19 infants that underwent 3D-CT in our study, only one was suspected of having a chromosomal abnormality. In this case, skeletal dysplasia was suspected based on ultrasonography findings, but the results of 3D-CT suggested trisomy 21. Postnatal chromosomal testing was performed, resulting in a final diagnosis of trisomy 21 and the exclusion of this infant from the study. Some cases can be complicated, with concomitant skeletal dysplasia and a chromosome aberration. In particular, cases with combined ACH and trisomy 21 have been reported [14, 15]. ACH is included as a type of dysplasia in the group of FGFR3 abnormalities, where growing parts become hypoplastic due to endochondral ossification. This can be difficult to differentiate from trisomy 21 [14, 15]. In 2001 [16] and 2014 [17], it was reported that femoral shortening during the second trimester is associated with a high relative risk of chromosomal abnormalities, particularly trisomy 21. If fetal femoral shortening is observed, it is important to consider the possibility of conditions such as chromosomal abnormalities, fetal growth restriction, and various other anomalies. Attention should also be paid to the presence of abnormal findings outside of the skeletal system (e.g., abnormalities in cardiac structure, the nervous/gastrointestinal system, and facial features) to reach a differential diagnosis. When making a prenatal diagnosis, it is important to bear in mind that cases of concomitant skeletal dysplasia and chromosomal abnormalities are possible, albeit rare.

Desbuquois dysplasia is a severe autosomal recessive disorder that belongs to the multiple dislocation group [18]. It is characterized by shortened long bones, joint laxity, pre- and postnatal growth retardation, and progressive scoliosis. In the case of infant 12, the mother’s first child also had skeletal dysplasia (congenital dislocation of the knees), which was identified after birth. Although this child had been diagnosed with Larsen syndrome, it had neither been identified prenatally by sonography/3D-CT nor confirmed via postnatal genetic testing. The mother’s second child (infant 12), in contrast, underwent a prenatal ultrasound examination and 3D-CT and was diagnosed with Desbuquois dysplasia, rather than Larsen syndrome. Postnatal genetic testing led to a definitive diagnosis of Desbuquois dysplasia (type 1), which is due to a mutation in the CANT1 gene [19, 20]. It is difficult to distinguish Desbuquois dysplasia and Larsen syndrome based on clinical manifestations. In the case of infant 12, it was demonstrated that an accurate prenatal diagnosis using an ultrasound examination and 3D-CT imaging was important to achieve a definitive diagnosis via postnatal molecular evaluation.

HPP is a condition in which tissue non-specific ALP loss or decrease causes abnormal bone and tooth mineralization [21]. Many cases of HPP are inherited in an autosomal recessive, rather than an autosomal dominant manner. HPP can be classified into the following six clinical forms, which vary based on severity [22]: 1) perinatal severe, 2) perinatal benign, 3) infantile, 4) childhood, 5) adult, and 6) odontohypophosphatasia. If parents have a child with HPP, they should be given genetic counseling with respect to future pregnancies, and the couple can decide whether to undergo carrier detection testing. If both the mother and father are carriers, the child has a 25% probability of being homozygous. Our fatal perinatal case appeared to be a severe one. The symptoms of perinatal cases appear early, resulting in intrauterine fetal death [23], stillbirth, or neonatal death. If we have a diagnosis of HPP in the prenatal period, we are able to start the enzyme replacement therapy promptly.

Compared to normal fetuses, those with FSD are more likely to be in an abnormal fetal position owing to differences in physique, restricted posture, limited joint range of motion, and fractures [24]. In cases of OI, it can be difficult to prevent intrauterine fractures as they can be caused by fetal movement (Fig. 5). Studies have shown that, in cases of OI, performing a cesarean delivery does not increase the frequency of fetal bone fractures compared to vaginal delivery [25]. Moreover, in cases of the lethal type of OI, fetal survival does not appear to be affected by delivery mode (cesarean vs. vaginal delivery). For other types of skeletal dysplasias, the mode of delivery is often selected based on whether the condition is lethal. When the disease is diagnosed as lethal, vaginal delivery may be selected even if the fetus is breech. However, in cases with marked head enlargement, a cesarean section is required regardless of whether the case is fatal, owing to the potential difficulty in passing through the mother’s pelvis. Before delivery, the parents, obstetricians, pediatricians, and orthopedic surgeons need to discuss the plan for the resuscitation of the infant after birth. The classification by imaging of 3D-CT is imperative to decide on the delivery mode and treatment policy for the infant, for example, whether to perform endotracheal intubation, or to surgically treat the infants. Reliable prenatal diagnosis is required to determine whether the case is fetal and its degree of severity.

When considering the risk of radiation exposure, CT examination has not historically been the preferred method for pregnant women. However, in recent years, high-quality images adequate for diagnosis have been displayed by low-dose 3D-CT, reducing the level of radiation to which the mother and fetus are exposed. The limitation of this study is the relatively small sample size. Future studies should include a larger sample size to improve the power of the results. Continuation of this study is important to improve the diagnostic accuracy of fetal skeletal dysplasia.

3D-CT is a valuable tool for augmenting ultrasound examinations in the diagnosis of FSD. While improving the diagnostic tool of sonography is important in cases of suspected FSD, 3D-CT imaging is indispensable for a diagnosis and a classification, enabling better planning for resuscitation of the infant after birth.