Diagnosis Of Fetal Skeletal Dysplasia Research Articles

Diagnosing Fetal Skeletal Dysplasia Using Three-Dimensional Computed Tomography: A Study Protocol for an Interventional Study

Background: Fetal skeletal dysplasias are a group of skeletal dysplasias occurring during the fetal stage. As the use of fetal ultrasonography has become widespread, the rate of prenatal diagnosis of skeletal dysplasias has increased. However, many fetal skeletal dysplasia phenotypes have indistinct definitions, making definitive prenatal diagnosis difficult. Fetal imaging methods that are the basis of diagnosing fetal skeletal dysplasias include ultrasonography and three-dimensional computed tomography. The use of three-dimensional computed tomography requires specific imaging techniques and cannot easily be performed at all facilities. In the present study, we propose to conduct a survey for the preparation of a protocol with a low risk, and a high diagnostic accuracy. Methods: In total, 50 pregnant women who undergo three-dimensional computed tomography for the diagnosis of fetal skeletal dysplasias will be included. The primary outcome is prenatal diagnostic accuracy for fetuses with skeletal dysplasias. The secondary outcome is the safety from radiation exposure. Results and conclusion: Three-dimensional computed tomography should be considered for the prenatal diagnosis of fetal skeletal dysplasias, as it is important to judge whether the prognosis is favorable or lethal. When considering the risk of radiation exposure, high quality images that are adequate for a diagnosis have been obtained using low-dose three-dimensional computed tomography scans. This approach reduces the level of radiation to which the pregnant woman and fetus are exposed. Trial registration: University hospital Medical Information Network (UMIN) Center: Trial registration number is UMIN000034744. Data of registration is October 01, 2018. (URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039610)

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

BackgroundFetal skeletal dysplasia (FSD) comprises a complex group of systemic bone and cartilage disorders. Many FSD phenotypes have indistinct definitions, making definitive prenatal diagnosis difficult. The condition is typically diagnosed using sonography; however, three-dimensional computed tomography (3D-CT) also aids in making a prenatal diagnosis. This study aimed to examine the efficacy of 3D-CT in the prenatal diagnosis of FSD by comparing the diagnostic accuracy of fetal sonography and 3D-CT.MethodsOn suspicion of FSD based on ultrasound examination, we performed 3D-CT prenatally to obtain detailed skeletal information on FSD. To minimize exposure of the fetuses to radiation without compromising image quality, we used predetermined 3D-CT settings for volume acquisition.ResultsNineteen fetuses were suspected of having skeletal dysplasia based on ultrasonography findings. Of these, 17 were diagnosed with FSD using 3D-CT. All 17 fetuses diagnosed with FSD prenatally were confirmed postnatally to have the condition. The postnatal diagnosis (campomelic dysplasia) differed from the prenatal diagnosis (osteogenesis imperfecta) in only one infant. Sixteen cases (94.1%) were diagnosed both prenatally and postnatally with FSD. Five infants had lethal skeletal dysplasia; one died in utero, and four died as neonates. We determined the appropriate delivery method for each infant based on the prenatal diagnosis.Conclusions3D-CT is a valuable tool for augmenting ultrasound examinations in the diagnosis of FSD. While improving the diagnostic tool of sonography is essential in cases of suspected FSD, 3D-CT imaging is indispensable for diagnosis and classification, enabling better planning for resuscitation of the infant after birth.Trial registrationUniversity Hospital Medical Information Network (UMIN) Center trial registration number is UMIN000034744. Registered 1 October, 2018 – Retrospectively registered.

Prenatal diagnosis of fetal skeletal dysplasias in a tertiary Hospital in Spain

ObjectiveTo assess the diagnostic accuracy of prenatal ultrasound for detecting fetal skeletal dysplasias and to describe its role in orienting genetic studies. Study designObservational study of pregnant women surveyed in our hospital, between 2011 and 2018, with fetal long bones below the 3rd centile (shortened long bones), either as an isolated finding or associated to other skeletal anomalies. We used a systematic protocol for the ultrasound evaluation and selection of those fetuses suspected of having a skeletal dysplasia.We report the demographics of these patients along with the sonographic follow-up of their fetuses, the genetic results and the outcome of the pregnancies and the newborn in the entire group and also compare data between the two sub-groups (isolated shortened long bones vs shortened long bones associated to other anomalies). ResultsA total of 81 pregnancies with a suspected fetal skeletal dysplasia were included, with a complete follow-up available in 75 cases, 22 with isolated shortened long bones and 53 cases that presented shortened long bones with other skeletal anomalies. In the shortened long bones sub-group, a total of five (23 %) were born healthy neonates, 10 (45 %) were small for gestational age or intrauterine growth restricted (one of them of genetic origin) and seven (32 %) had a skeletal dysplasia (6 of them with genetic diagnosis). Whilst among the 53 cases that presented with shortened long bones + other skeletal anomalies, three (6%) were healthy neonates, five (9%) were small for gestational age/intrauterine growth restricted (two of genetic origin) and 45 (85 %) had a skeletal dysplasia (19 genetically confirmed and 26 with a clinical diagnosis). These differences in frequencies between the two sub-groups were determined to be statistically significant (χ2: p = 0.02). ConclusionAround one third of fetuses with isolated shortened long bones will have a skeletal dysplasia. If abnormal skeletal ultrasound findings are associated with shortened long bones, the risk for skeletal dysplasia is significantly increased (85 %). Prenatal systematic approach in a multidisciplinary unit is useful in the orientation of genetic studies.

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

BackgroundThis study aims to provide genetic diagnoses for 30 cases of fetal skeletal dysplasia, and a molecular basis for the future prenatal diagnosis of fetal skeletal dysplasia.MethodsA total of 30 cases of fetal skeletal dysplasia detected with ultrasound between January 2014 and June 2017 were analyzed. Among these fetuses, 15 fetuses had local skeletal malformations, while 15 fetuses had short limb malformations. Samples of fetal umbilical cord blood, amniotic fluid, and/or aborted tissue were collected from all cases. Karyotyping, whole genome sequencing, and targeted next-generation sequencing of skeletal disease-related pathogenic genes were performed, as needed. Blood samples were taken from the parents for verification using Sanger sequencing.ResultsAmong the 30 cases of fetal skeletal dysplasia, two cases were diagnosed with trisomy 18. However, none of these cases were identified with any microdeletions or microreplications associated with skeletal dysplasia. Among the 28 chromosomally normal cases with fetal skeletal dysplasia, 21 cases were detected with mutations in genes related to skeletal diseases. Furthermore, collagen gene mutations were detected in six fetuses with short limb malformations, while heterozygous disease-causing mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were detected in seven fetuses. The remaining fetuses carried mutations in other various genes, including tumor protein p63 (TP63), cholestenol delta-isomerase (EBP), cholinergic receptor nicotinic gamma subunit (CHRNG), filamin B (FLNB), and SRY-box 9 (SOX9). Three compound heterozygous mutations in CHRNG, COL11A2 and SOX9 were carried by phenotypically healthy parents.ConclusionTargeted next-generation sequencing can significantly improve the prenatal diagnoses of fetal skeletal dysplasia, providing parents with more precision medicine, and improved genetic counseling.

Prenatal US Findings of Musculoskeletal Anomalies

Fetal musculoskeletal malformations take a number of pathologic forms, among which a variety of lethal dysplasias and several anomalies have a poor perinatal and postnatal outcome. Precise antenatal ultrasonographic diagnosis of bone dysplasia may be very difficult, but differentiation between a lethal and a nonlethal variety is very important in terms of antenatal care and the prediction of fetal outcome. Variety of lethal skeletal dysplasias commonly show very short long bones and narrow thorax. For the differential diagnosis of fetal skeletal dysplasia, comprehensive evaluation of fetal bones including cranium, face, ribs, and spine is very important. Genetic counseling is critical and individualized multidisplinary prenatal and postnatal care is important for the management of fetal skeletal dysplasias. Several anomalies leading to limb loss or contracture as the expression of other pathologic entities have a poor outcome, and their early detection is also very important for the management of a pregnancy. Focal musculoskeletal anomalies can occur in isolation or in association with a large variety of syndromes, malformations and disorders. Thus, the early and accurate prenatal diagnosis of anomalies is important not only for detecting the anomaly itself, but is also helpful with regard to these other, associated, anomalies.

Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII

Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders.

Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

A 26-year-old woman with a past history of fetal skeletal dysplasia was referred to our institution at 24weeks of gestation following a routine sonographic diagnosis of short limbs in the fetus. A fetal ultrasound showed short limbs, a narrow thorax, short ribs with marginal spurs, and polydactyly. Conventional cytogenetics analysis of cultured amniocytes demonstrated that the fetal karyotype was normal. Using targeted exome sequencing of 226 known genes implicated in inherited skeletal dysplasia, we identified compound heterozygous mutations in the DYNC2H1 gene in the fetus with short rib-polydactyly syndrome, type III (SRPS III), c.1151 C>T(p.Ala384Val) and c.4351 C>T (p.Gln1451*), which were inherited from paternally and maternally, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. To our knowledge, this is the first report of DYNC2H1 mutations causing SRPS III, in the Chinese population. Our findings expand the number of reported cases of this rare disease, and indicate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia.

Three‐dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia

(1) To study the use and diagnostic value, as a complement to ultrasound, of helical computed tomography (helical CT) to differentiate normal fetuses from cases of skeletal dysplasia; (2) to define the most relevant indications for helical CT; and (3) to evaluate its diagnostic performance with respect to radiological criteria considered discriminatory. This was a retrospective study from 2005 to 2008 in 67 pregnant women who underwent helical CT after 26 weeks of gestation for suspected fetal skeletal dysplasia due to fetal shortened long bones on ultrasound (≤ 10(th) percentile), either alone or associated with other bone abnormalities. The results were compared with pediatric examinations in 41 cases and with fetal autopsy findings after elective termination of pregnancy in the others. Helical CT had a sensitivity of 82%, specificity of 91% and positive and negative predictive values of 90% and 83%, respectively, for diagnosis of fetal skeletal dysplasia. An etiological diagnosis that had not been suspected at ultrasound was specified in 15% of cases and diagnoses suspected at ultrasound were confirmed in 24% and discounted in 43% of cases. The prevalence of skeletal dysplasia was increased in cases of micromelia < 3(rd) percentile or if there was a combination of bone signs. Helical CT showed 69% sensitivity in identifying individual predefined pathological bone signs which were confirmed on fetal autopsy findings. Helical CT is a key examination, in combination with ultrasound, in the diagnosis of fetal skeletal dysplasia from 26 weeks of gestation. It should be reserved for cases with severe micromelia below the 3(rd) percentile and for those with micromelia ≤ 10(th) percentile associated with another bone sign. A checklist of discriminatory signs is proposed.

Prenatal diagnosis of osteogenesis imperfecta type II by three‐dimensional computed tomography: The current state of fetal computed tomography

We report a case of osteogenesis imperfecta (OI) (OMIM166210) type II, in which a prenatal diagnosis was made by three-dimensional computed tomography (3D-CT). Subsequent molecular analysis revealed a recurrent, heterozygous mutation in COL1A2. Fetal CT is a powerful tool for visualizing the fetal skeleton and can provide a definitive diagnosis of fetal skeletal dysplasias; however, whether or not its employment for prenatal diagnosis is warranted in terms of fetal radiation risks remains controversial, both medically and ethically. Based on our experience, we review the current state of fetal CT for the diagnosis of skeletal dysplasias, with a discussion of the relevant literature.

Prenatal diagnosis of fetal skeletal dysplasia with 3D CT

Clinical use of 3D CT for fetal skeletal malformations is controversial. The purpose of this study was to evaluate the efficacy of fetal 3D CT using three protocols with different radiation doses and through comparing findings between fetal CT and conventional postnatal radiographic skeletal survey. Seventeen fetuses underwent CT for suspected skeletal dysplasia. A relay of three CT protocols with stepwise dose-reduction were used over the study period. The concordance between the CT diagnosis and the final diagnosis was assessed. Ninety-three radiological findings identifiable on radiographs were compared with CT. Fetal CT provided the correct diagnosis in all 17 fetuses, the detectability rate of cardinal findings was 93.5 %. In 59 % of the fetuses an US-based diagnosis was changed prenatally due to CT findings. The estimated fetal radiation dose in the final protocol was 3.4 mSv (50 %) of the initial protocol, and this dose reduction did not result in degraded image quality. The capability of fetal CT to delineate the skeleton was almost the same as that of postnatal skeletal survey. The perinatal management was altered due to these more specific CT findings, which aided in counseling and in the management of the pregnancy.

PRENATAL DIAGNOSIS OF SKELETAL DYSPLASIAS

Skeletal anomalies occur with a frequency of around 1:500 and can present a diagnostic challenge when detected prenatally. Increasingly more sophisticated imaging such as MRI or CT may elucidate features more easily interpreted by postnatal radiologists. The aetiology of these anomalies is varied and includes aneuploidy, genetic syndromes, skeletal dysplasias, teratogens, disruption and maternal disease, making a multidisciplinary approach to the diagnosis essential. The estimated prevalence of skeletal dysplasias varies from 2–3/10,000 to 4–7/10,000 and diagnosis may require biochemical, cytogenetic, molecular genetic or haematological investigation. Clinical genetic input is often required as the family history or parental examination may yield valuable clues to the diagnosis. This review will briefly describe the normal embryology and sonographic appearances of fetal limb development and go on to suggest a systematic approach to the diagnosis of fetal skeletal dysplasias.

Reference values for fetal limb biometry at 10-14 weeks of gestation.

To calculate reference ranges for fetal limb measurements obtained by transabdominal ultrasound at 10-14 weeks of gestation. Six hundred and six normal fetuses were examined transabdominally in a cross-sectional study by a single observer. The crown-rump length of the fetuses ranged from 31 to 78 mm. Measurement of the length of the humerus, ulna, femur, tibia and foot was attempted from the longest section of each structure. To assess intraobserver repeatability, three sets of repeated measurements were obtained in 26 fetuses. An appropriate ultrasound measurement was obtained in a percentage of cases ranging from 93.2% to 97.9%. A significant correlation was found between crown-rump length measurements and humerus length (r = 0.74, P < 0.001), ulna length (r = 0.70, P < 0.001), femur length (r = 0.77, P < 0.001), tibia length (r = 0.69, P < 0.001) and foot length (r = 0.58, P < 0.001). Crown-rump length-specific reference ranges for each measurement were calculated with the method of scaled absolute residuals. The study of intraobserver variability showed coefficients of variation ranging from 7.9 to 10.0% and intraclass correlation coefficients ranging from 0.89 to 0.94. Fetal limb size is strongly correlated with crown-rump length. Despite a significant biological variability of the measurements, the availability of reference ranges could be of help in the early diagnosis of fetal skeletal dysplasias.

Fetal Imaging in the Skeletal Dysplasias

Second-trimester diagnosis of fetal skeletal dysplasia is becoming increasingly common. By careful examination of the fetus for skeletal mineralization, shape and size of long bones and cranium, and abnormalities of other organ systems, a definitive diagnosis can often be achieved by ultrasound. Fetal radiography is very helpful in giving more information about bone shape and mineralization as well as in confirming the diagnosis. Subsequent obstetric management should be dictated by the natural history of the disease, the parents' wishes, and the gestational age at diagnosis. Because many of these disorders have a high recurrence risk, genetic counseling and follow-up are an important part of the management of these patients.

Second Trimester Diagnosis of Fetal Skeletal Dysplasias

Second Trimester Diagnosis of Fetal Skeletal Dysplasias

Second Trimester Diagnosis of Fetal Skeletal Dysplasias

Second Trimester Diagnosis of Fetal Skeletal Dysplasias

Diagnosis of fetal skeletal dysplasias with ultrasound

In 1977 we reported the in utero diagnosis of a skeletal dysplasia, chondroectodermal dysplasia. Since then we have used ultrasound to examine 66 pregnant women who were at risk for fetal skeletal dysplasia. In an effort to establish a normal curve for long bone length, the femurs and, in some cases, humeri, of 57 normal second-trimester fetuses were measured by real-time ultrasound. In addition, femur and humerus measurements were obtained in 50 abortuses by means of ultrasound in a waterbath and were compared with blindly obtained extemal measurements of the same long bones. Mean in vivo ultrasound measurements of fetal femur and humerus were consistently less than mean ultrasound waterbath measurements by 16%. External measurements of the femur and humerus of abortuses were in concordance with water-bath ultrasound measurements in the same abortuses until 18 weeks, after which the means progrssively diverged to a difference of 17% at 25 weeks, with the ultrasound measurements being smaller. Based on the above in vivo normative ultrasound data, a positive diagnosis was made in five of seven second-trimester fetuses at risk for a skeletal dysplasia (camptomelic dysplasia, two fetuses with Roberts syndrome, diastrophic dysplasia, and thrombocytopenia with absent radii syndrome). In two others (chondroectodermal dysplasia and osteogenesis imperfecta) long bone measurements were diminished, but not outside 95% confidence levels, and the diagnosis was based on fetoscopy findings and identification of a femoral fracture. All other fetuses were normal at birth following negative ultrasound evaluation. The study demonstrates the feasibility of diagnosing various skeletal dysplasias with ultrasound. Further study will be required before the accuracy of diagnosis in all dysplasias can be fully assessed.