A total of 2,447 fetuses underwent prenatal sonography and were delivered in our institution between 2012 and 2019. Of the 2,447 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%.
Patient characteristics
The mean maternal age was 32.2 (range: 20–41) years, and the mean gestational age at the first findings of FSD was 24.8 (range: 15–36) weeks. The mean 3D-CT imaging period was 31.1 (range: 24-38) weeks’ gestation, which is consistent with the period when CT testing is generally performed for prenatal diagnosis (approximately 30 weeks’ gestation). Patient characteristics are presented in Table 2.
Table 2: Characteristics of 17 infants with FSD
Infant
|
Maternal age (years)
|
GA at the first finding of FSD (weeks)
|
GA at
3D-CT
(weeks)
|
GA at delivery
(weeks)
|
Delivery
mode
|
Birth
weight (g)
|
Prognosis
|
1
|
33
|
36
|
36
|
38
|
CS
|
2599
|
alive
|
2
|
20
|
27
|
27
|
34
|
CS
|
2243
|
alive
|
3
|
30
|
30
|
30
|
36
|
BE
|
1587
|
1 day
|
4
|
38
|
15
|
28
|
37
|
CS (breech)
|
2169
|
3 days
|
5
|
27
|
24
|
24
|
37
|
VD
|
2233
|
2 days
|
6
|
30
|
24
|
28
|
37
|
CS
|
2924
|
alive
|
7
|
34
|
29
|
33
|
38
|
VD
|
3400
|
alive
|
8
|
40
|
25
|
33
|
38
|
VD
|
2621
|
alive
|
9
|
29
|
22
|
31
|
38
|
CS (repeat)
|
2250
|
alive
|
10
|
41
|
27
|
31
|
38
|
CS (NRFS)
|
2080
|
alive
|
11
|
29
|
33
|
35
|
38
|
VD
|
2496
|
alive
|
12
|
30
|
34
|
38
|
39
|
VD
|
2676
|
alive
|
13
|
39
|
17
|
35
|
37
|
CS
|
2569
|
alive
|
14
|
39
|
30
|
27
|
39
|
CS (repeat)
|
1843
|
alive
|
15
|
38
|
18
|
36
|
37
|
CS (breech)
|
2866
|
alive
|
16
|
25
|
16
|
27
|
27
|
VD
|
-
|
IUFD
|
17
|
26
|
15
|
28
|
38
|
CS (breech)
|
1710
|
1 day
|
BE: breech extraction, CS: cesarean section, GA: gestational age, IUFD: intrauterine fetal death, NRFS: non-reassuring fetal status, FSD: fetal skeletal dysplasia, VD: vaginal delivery
Classification of fetal skeletal dysplasia
Prenatal imaging data, postnatal findings, and pre- and postnatal diagnosis are presented in Table 3. The specific postnatal diagnoses were as follows: osteogenesis imperfecta (OI, n=3), thanatophoric dysplasia (TD, n=2), achondroplasia/hypochondroplasia (ACH/HCH, n=6), hypophosphatasia (HPP, n=2), campomelic dysplasia (CD, n=2), Desbuquois dysplasia (n=1), and Creveld syndrome (n=1). The two infants with HPP were siblings.
Table 3: Comparison between pre- and postnatal findings and diagnosis
Infant
|
Prenatal
|
Postnatal
|
findings
|
diagnosis
|
findings
|
diagnosis
|
1
|
Shortening and bowing of long bones,
Fractures of femur and ribs
|
OI
|
Shortening and bowing of long bones,
Fractures of femur and ribs
|
OI
|
2
|
Shortening and bowing of long bones, hydramnios
|
OI
|
Shortening and fractures of long bones
|
OI
|
3
|
Shortening and bowing of long bones, Narrow thorax, Megalencephaly
|
OI
|
Shortening and bowing of long bones, Rib fractures, Narrow thorax
Facial dysmorphy
|
OI
|
4
|
Shortening of long bones,
Narrow thorax, Megalencephaly
|
TD
|
Rhyzomelic shortening of long bones,
Bowing of long bones, Narrow thorax
Megalencephaly, Platyspondylia
|
TD
|
5
|
Shortening and bowing of long bones
Long bones fractures
Narrow thorax, Megalencephaly
Hydramnios
|
TD
|
Shortening and bowing of long bones
Megalencephaly, Frontal bossing
Narrow thorax, Platyspondylia
Trident hand
|
TD
|
6
|
Shortening of long bones, Narrow thorax
|
ACH or HCH
|
Shortening of long bones, Narrow thorax
|
ACH
|
7
|
Shortening of long bones, Narrow thorax
|
ACH
|
Shortening of long bones, Narrow thorax
|
ACH
|
8
|
Shortening of long bones, Narrow thorax
Trident hand
|
ACH
|
Shortening of long bones, Frontal bossing
Narrow thorax, Trident hand
|
ACH
|
9
|
Shortening of long bones, Narrow thorax
|
ACH
|
Shortening of long bones, Narrow thorax
|
ACH
|
10
|
Shortening of long bones, Narrow thorax, Trident hand
|
ACH
|
Shortening of long bones, Frontal bossing
Narrow thorax, Trident hand
Facial dysmorphy of Down syndrome
|
ACH
Trisomy 21
|
11
|
Shortening of long bones
|
ACH or HCH
|
Shortening of long bones, Frontal bossing
|
HCH
|
12
|
Shortening and bowing of long bones
Hypoplastic scapulae
|
CD
|
Shortening and bowing of long bones
Hypoplastic scapulae
|
CD
|
13
|
Shortening and bowing of long bones
Mild curvature with scapular hypoplasia
Club feet
|
OI
|
Bowing of long bones, Club feet
Hypoplastic scapulae, Rib fractures
Ambiguous genitalia, Facial dysmorphy
|
CD
|
14
|
Dislocation of elbow and knee, Club feet
Radioulnar synostosis
|
Desbuquois disorder
|
Dislocation of shoulder, elbow
Articulation coxae and knee
Facial dysmorphy, Scoliosis, brevicollis
|
Desbuquois disorder
|
15
|
Shortening of long bones
Hyperdactylia
CHD (AVSD, single atrium)
|
Elis-van Creveld syndrome
|
Shortening of long bones, Narrow thorax
Hyperdactylia
CHD (AVSD, single atrium)
|
Elis-van Creveld syndrome
|
16
|
Shortening of long bones, Narrow thorax
|
HPP
|
-
|
HPP
|
17
|
Shortening of long bones
Narrow thorax, hydramnios
|
HPP
|
Shortening of long bones, Narrow thorax, Hypoplasia of lung
Low levels of serum ALP
|
HPP
|
ACH: achondroplasia, AVSD: atrial ventricular septal defect, CD: campomelic dysplasia, CHD: congenital heart disease, HCH: hypochondroplasia, HPP: hypophosphatasia, OI: osteogenesis imperfecta, TD: thanatophoric dysplasia
Sixteen infants (94.1 %) were diagnosed both prenatally and postnatally with FSD. The pre- and post-natal diagnoses differed in one infant who was diagnosed with OI prenatally but with CD postnatally. In this case, prenatal findings by 3D-CT were long bone shortening and mild curvature with scapular hypoplasia (Figure 1), therefore, we diagnosed “OI” prenatally. However, we diagnosed “CD” in the postnatal period because we identified ambiguous genitalia and facial dysmorphia.
Lethality
Of the five fetuses with poor prognoses, one had OI, two had TD, and two had HPP. One of the fetuses with HPP suffered intrauterine fetal death at 27 weeks’ gestation, while the remaining four infants died within two days of birth. We identified lethality in the prenatal period in all five fetuses.
Trisomy 21 and achondroplasia
Infant 8 was diagnosed prenatally with ACH based on ultrasound findings of shortened long bones, a narrow thorax, and a trident hand (Figure 2). After birth, the characteristic trisomy 21 facial features were noted, and the results of chromosomal testing (G-band; 47, XY, +21) confirmed trisomy 21. FGFR3 genetic analysis also indicated a G1193A mutation in G380, indicating that the infant also had ACH.
Postnatal genetic testing
Genetic testing was performed in 11 infants (number; 1-2, 6-8, 10, 13-17).
In infant 12, we identified dislocation of the knee and elbow, as well as clubfeet, through sonography and 3D-CT, leading us to suspect Desbuquois dysplasia (Figure 3). Postnatal genetic testing confirmed our suspicion of Desbuquois dysplasia (type 1) due to a mutation of the 613165 calcium-activated nucleotidase 1 (CANT1) gene.
The two infants with HPP (infants 14 and 15) had the same parents. Ultrasonography at 18 weeks’ gestation in the first child revealed marked long bone shortening and a soft, deformed skull, which was suggestive of fetal HPP. Therefore, we measured maternal alkaline phosphatase (ALP) levels, which were low. At 27 weeks’ gestation, the child suffered an intrauterine fetal death. After the child was stillborn, autopsy imaging was performed. The CT images also indicated a likely diagnosis of HPP. Genetic testing of the placental tissue revealed a compound heterozygote with mutations in two tissue-nonspecific alkaline phosphatase genes (ALPL; p.K224E, c.1559delT), and confirmed our diagnosis of HPP. The parents’ second child exhibited severe shortening of all four limbs at 15 weeks’ gestation, with 3D-CT revealing findings typical of severe prenatal HPP (Figure 4), with hardly any ossification. At 38 weeks’ gestation, the infant was delivered via cesarean section but suffered neonatal death at 1 day of age.