Prenatal diagnosis of bone dysplasias

Abstract

Bone dysplasias are individually rare but collectively common. The prenatal diagnosis of bone dysplasias, especially perinatally lethal dysplasias, is of major interest to obstetric services. The current nosology of genetic skeletal disorders addresses over 400 disorders. However, in clinical practice, we encounter only a limited number of disorders, such as FGFR3-related dysplasias, osteogenesis imperfecta, and type II collagenopathies. The recent development of non-invasive prenatal genetic testing using cell-free fetal DNA in maternal blood samples has had a major impact on the prenatal diagnosis of genetic diseases. However, imaging examinations remain critical for the final diagnosis of bone dysplasias because molecular testing only shows genetic variants, and not their pathogenicity - most variants are clinically insignificant. Bone dysplasias are typically suspected when limb shortening is identified by screening ultrasound. Further assessment can be followed by more detailed ultrasound, magnetic resonance imaging (MRI), and CT. Based on these data, rational decision-making is feasible, even when the definitive prenatal diagnosis is not feasible. Here, we highlight key images of common bone dysplasias obtained by currently available modalities.

Figure 1.

Achondrogenesis Type 1B (ACG1B) and Thanatophoric dysplasia Type 1 (TD1). (a, b) Postmortem radiographs of a fetus with ACG1B at 14 weeks of gestation. The radiographic diagnosis is based on severely defective vertebral ossification, wider interpedicular distances in the cervical and lumbar spines than in the thoracic spine, crescent-shaped ilia, and extreme shortening and a stellate appearance of long bones. (c, d) Transvaginal 3D-US in a different fetus with ACG1B at 12 weeks. The maximum intensity projection (MIP) images recapitulate the characteristic skeletal changes seen in a and b. (e) Transabdominal 3D-US in a fetus with TD1 at 21 weeks. The image demonstrates thoracic narrowing, platyspondyly, interpedicular distance narrowing of the lower lumbar spine, iliac hypoplasia, and extremely short long bones. (f) MRI of a different fetus with TD1 at 34 weeks. It shows a body shape similar to that of 3D-US. (g) A postmortem radiograph of another fetus with TD1 at 31 weeks. This shows telephone receiver-like bowing of the femora and mild bowing of other long bones, as well as the other findings seen in 3D-US.

Figure 2.

Nager syndrome. a, b (right hand), c (left hand). 3D-US at 29 weeks (a, c) and 33 weeks (b). The surface rendering images reveal a distinctive facial gestalt resembling that of Treacher-Collins syndrome (severe micrognathia and downward slanting of the palpebral fissures), aplasia of the right thumb, and a proximally set, hypoplastic left thumb. d, e, f (right hand), g (left hand), h. Three-dimensional reconstructed CT images (3D-CT) at 31 weeks. The volume rendering images show micrognathia, right humeroradial synostosis, and aplasia of the right thumb. However, it is difficult to determine whether or not the left thumb is hypoplastic. i, j (right hand), k (left hand). Postnatal radiographs. Radiographs confirm the above abnormalities of the right elbow and thumb and hypoplasia of the left first metacarpal. (l) A clinical photograph of the left hand. It reveals a slim, long, proximally set left thumb with thenar hypoplasia. Hypoplasia of the left thumb may be better assessed on US than on CT.

Figure 3.

Thanatophoric dysplasia Type 1 (TD1) and Type 2 (TD2). (a, b) 3D-CT of TD1 at 18 and 31 weeks. The images were obtained with the same CTDIvol (1.5 mGy). The signal-to-noise ratio is much better in b than in a because of increased mineralization of bones in the late gestational age. (c) 3D-CT of TD2 at 29 weeks. The image was obtained with ultra-low CTDIvol (0.39 mGy) using model-based iterative reconstruction (MBIR). The image quality is identical to that of b.

Figure 4.

Prenatal lethal type of hypophosphatasia. (a) Postmortem 3D-CT at 19 weeks. The VR image shows defective calvarial ossification except for the frontal bones, thin ribs, defective spinal ossification in a random pattern, metaphyseal ossification defects of long bones, and sharp angulation of the femora. (b, c) Postmortem radiographs at 19 weeks. The manifestation on the frontal radiograph is identical to that of 3D-CT. The lateral radiograph reveals random ossification of the spine. (d) 2D-US at 18 weeks. The sagittal image shows defective vertebral ossification identical to that of the postmortem lateral radiograph. (e) 3D-US at 18 weeks. The image demonstrates random vertebral ossification. The ribs are deemed to be wavy in contour as a result of respiratory movement during the image acquisition, which masquerades as rib fractures. In fact, however, the ribs are not fractured. (f, g) 2D-US at 18 weeks. These images show bowing of the femora and “too well seen brain structures” with mild compression of the right frontal bone from normal pressure.

Figure 5.

Prenatal benign type of hypophosphatasia (a-d) and mild osteogenesis imperfecta (e-h). (a) A radiograph of a neonate with prenatal benign form of hypophosphatasia born at 31 weeks. It shows a normal width and mineralization of long bones and sharp bowing of the femora. (b) 3D-CT at 30 weeks. The image shows the same findings as the radiograph. (c, d) US at 30 weeks. The 2D-image show sharp angulation of the femora, and the 3D-image reveals Bowdler’s spur (a bone projection from the peak of the sharply bent femur). (e) A radiograph of a neonate with mild osteogenesis imperfecta born at 36 weeks. It shows slenderness and metaphyseal osteoporosis of long bones and obtuse bowing of the femora. The bowing is asymmetric. (f) 3D-CT at 34 weeks. The image recapitulates the radiographic findings, but it is not definitively determined whether there is metaphyseal osteoporosis. (g, h) US at 32 weeks. The 2D-US images reveal asymmetric bowing of the femora.

Figure 6.

Severe osteogenesis imperfecta. (a) A postmortem radiograph at 21 weeks shows a narrow thorax with a beaded appearance of the ribs due to multiple fractures. The long bones are thick and crumpled as a result of remodeling of fractures. (b) 3D-US at 20 weeks of gestation. The image shows a narrow thorax with beaded ribs and thickening of the humerus. (c, d) 2D-US at 20 weeks. These images demonstrate a bowed, crumpled femur and “too-well-seen” brain structures and compression of the calvarium from normal pressure.

Figure 7.

Campomelic dysplasia. (a, b) 3D-CT at 30 weeks. The images show widening of the ischiopubic junction, bowing of the femora, tibiae, and fibulae, and aplasia of the scapular wing (c) 3D-US at 28 weeks demonstrates aplasia of the scapular wing. (d) Postnatal radiograph at 38 weeks. The radiographic findings are identical to those of CT and US. (e) A magnified view of the upper thorax shows aplasia of the scapular wing.

Figure 8.

Achondroplasia. (a-e) US of a fetus with achondroplasia obtained between 32 and 36 weeks. (a) The 3D-US image shows trident hand. (b) The 2D-US image demonstrates frontal bossing and mid-face recession. (c) The 3D-US image displays mid-face flattening. Trident hand is not seen on this image. (d) The 2D-US image shows the “collar hoop” sign of the femoral neck (white arrow), which is a rounded contour of the distal segment of the femoral neck and bone projection at the junction between the femoral neck and shaft. (e) The 3D-US image demonstrates a pointed appearance of the femoral neck (arrow) and metaphyseal cupping of the distal femur (arrowhead). (f, g) The lateral and frontal radiographs of the femur from a different ACH neonate show findings identical to those in d and e, respectively.

Figure 9.

Achondroplasia and Hypochondroplasia. (a-e) Postnatal radiographs at 34 weeks and 3D-CT at 32 weeks from a patient with achondroplasia. The 3D-CT images display the key imaging findings seen on the radiographs, including mild platyspondyly, trident ilia, proximal femoral scooping, and metaphyseal cupping of long bones. (f-j) Postnatal radiographs at 30 weeks and 3D-CT at 28 weeks from a hypochondroplasia patient. The 3D-CT images and radiographs show trident ilia and mild femoral scooping. However, the vertebral bodies look normal, and metaphyseal cupping is very mild. Despite the mild metaphyseal deformity, shortening of long bones is identical to that of achondroplasia.

Figure 10.

Thanatophoric dysplasia Type 1. (a-f) US at 24 weeks and 3D-CT at 28 weeks from a fetus with thanatophoric dysplasia Type 1. (a) The 2D-US image shows a narrow thorax and protuberant abdomen. (b, c) The 3D-US image and 3D-CT image demonstrate proximal femoral constriction or scooping. (d) The 3D-US image demonstrate mid-face hypoplasia and trident hand. (e, f) The 3D-CT images provide diagnostic findings, including a narrow thorax, severe platyspondyly, interpedicular distance narrowing of the lower lumbar spine, iliac hypoplasia, and severe shortening of long bones. (g, h) 2D-US from different fetuses with thanatophoric dysplasia Type 1 at 19 weeks and 16 weeks. The images reveal deep sulci in the temporooccipital regions (arrows).

Figure 11.

Short rib polydactyly dysplasia Type 3. (a, b) Postmortem radiographs at 21 weeks show severely short ribs, thoracic narrowing, trident ilia, and severe shortening with metaphyseal cupping of long bones. The spine appears normal. (c, d) 3D-CT at 20 weeks. The images demonstrate findings identical to those of the postmortem radiographs. The fetus showed hyperextension of the neck (star-gazing posture), which often occurs in lethal bone dysplasias. (e, f) 3D-US at 20 weeks. The images show thoracic narrowing and iliac hypoplasia. (g) The 2D-US image displays metaphyseal cupping of the femur.

Figure 12.

Achondrogenesis Type 2. (a, b) Postmortem radiographs from an affected fetus at 21 weeks. These images show hallmarks of the disorder, including rudimentary ossification of the vertebral bodies, absent ossification of the ischia and pubic bones, and severe shortening with metaphyseal cupping of long bones. The abdomen is protuberant, and the thorax is short. (c, d, e) US at 18 weeks. The 2D-US images demonstrate ossification defects of the vertebral bodies and extreme shortening of long bones. The 3D-US image displays a short thorax and protuberant abdomen. (f, g) Postmortem radiographs from a different patient at 31 weeks. The skeletal changes are similar to but more severe than those of a and b. (h, i) 3D-CT at 25 weeks. The images recapitulate the findings on the postmortem radiographs.

Figure 13.

Chondrodysplasia punctata tibia-metacarpal type. (a, b) US at 26 weeks. The 2D image shows multiple echogenic foci in the epiphysis of the proximal femur (stippled calcifications), and the 3D image displays mid-face hypoplasia. (c, d) 3D-CT at 34 weeks. The images demonstrate epiphyseal stippling and tibial shortening. (e) A postnatal radiograph at 38 weeks. Epiphyseal stippling is seen in the proximal humeri and distal femora. The tibiae are shorter than the fibulae.

Figure 14.

Lethal metatropic dysplasia. (a, b) 3D-CT images from an affected fetus at 27 weeks. The images show a narrow thorax, severe platyspondyly, wide ilia, and severe dumbbell deformity of the femur. (c, d) US at 24 and 27 weeks. The 3D-US image shows platyspondyly and broad ilia. The 2D-US image displays a large epiphyseal cartilage of the proximal femur and severe metaphyseal splaying (dumbbell deformity). The dumbbell-shaped femur may be mistaken for bowing of the femur. (e, f) Postmortem radiographs from a different patient at 36 weeks. The fetus had congenital contractures (arthrogryposis). The radiographs show similar manifestations as a and b. The ribs are broad, and severe platyspondyly is evident. Lateral radiograph shows dumbbell-shaped long bones. (g, i, h) US at 24 and 31 weeks. The 3D-US images show defective vertebral ossification with broad posterior arches and dumbbell deformity of the femur. The 2D-US image reveals a large epiphyseal cartilage of the distal femur and severe metaphyseal splaying.

Figure 15.

Desbuquois dysplasia (a-f) and Osteopathia striata with cranial sclerosis (g-j). (a, b, c) 3D-CT at 27 weeks. The images show multiple coronal clefts of the spine, genu recurvatum, prominence of the lesser trochanter (arrow), and hypoplasia of the distal segment of the second metacarpal (arrowhead). The metacarpal abnormality represents hyperphalangy of the index finger (a supernumerary ossicle distal to the metacarpal. (d, e, f) Postnatal radiographs confirm the findings seen on CT. (g, h) 3D-CT at 31 weeks. The images show a large head, fibular aplasia, and possible generalized osteosclerosis. (i, j) Postnatal radiographs confirm the findings seen on CT.