Fetal Skeletal Dysplasia Research Articles

Accuracy of prenatal diagnosis and prediction of lethality for fetal skeletal dysplasias

We reviewed all cases with fetal skeletal dysplasia and correlated the accuracy of prenatal diagnoses with the final post-mortem, radiological, or molecular diagnoses. The accuracy of prenatal prediction of lethality was also reviewed. All cases of fetal skeletal dysplasia referred between October 2002 and August 2010 were reviewed. Perinatal outcome, the accuracy of prenatal diagnosis, and prediction of lethality were ascertained. Lethality was suspected when significant thoracic narrowing, severe micromelia, multiple fractures, or long bone bowing was present. There were 40 cases of skeletal dysplasia. Thirty-nine (97.5%) were singletons and one (2.5%) was a dichorionic twin pregnancy. Twenty-eight (70%) pregnancies were terminated, five (12.5%) were stillborn, and only seven (17.5%) cases were live born. A final diagnosis was established in 28 (70%) cases. In 29 cases with a presumptive prenatal diagnosis, this was confirmed in 23 (79.3%) cases postnatally. Lethality was predicted with 100% certainty. We report higher prenatal/postnatal concordance rates in this series. A precise prenatal diagnosis is frequently difficult and often inaccurate. Prediction of lethality is much easier and often possible with accuracy. Parents need to be aware that the outcome of many skeletal dysplasias is poor.

Ellis-Van Creveld Syndrome: Prenatal Diagnosis, Molecular Analysis and Genetic Counseling

To present the perinatal findings and molecular genetic analysis of two siblings with Ellis-van Creveld (EvC) syndrome. A 33-year-old woman, gravida 3, para 1, was referred for genetic counseling at 18 gestational weeks because of recurrent fetal skeletal dysplasia. Two years previously, she had delivered a 1,316-g dead male baby at 28 gestational weeks with a karyotype of 46,XY, postaxial polydactyly of the hands, thoracic narrowness, endocardial cushion defects, transposition of the great arteries, shortening of the long bones, malposition of the toes, and hypoplastic nails. During this pregnancy, prenatal ultrasound at 18 gestational weeks revealed shortening of the long bones (equivalent to 15 weeks), postaxial polydactyly of both hands, thoracic narrowness, and endocardial cushion defects. The pregnancy was subsequently terminated, and a 236-g female fetus was delivered with a karyotype of 46,XX, postaxial polydactyly of the hands, thoracic dysplasia, endocardial cushion defects, shortening of the long bones, and malposition of the toes and hypoplastic nails. The phenotype of each of the two siblings was consistent with EVC syndrome. Molecular analysis of the EVC and EVC2 genes revealed heterozygous mutations in the EVC2 gene. A heterozygous deletion mutation of a 26-bp deletion of c.871-2_894del26 encompassing the junction between intron 7 and exon 8 of the EVC2 gene was found in the mother and two siblings, and a heterozygous nonsense mutation of c.1195C >T, p.R399X in exon 10 of the EVC2 gene was found in the father and two siblings. Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects.

OP31.04: Incidence and outcome of antenatally diagnosed skeletal dysplasia

To investigate the incidence and outcome of antenatally diagnosed skeletal dysplasia We investigated all cases of fetal skeletal dysplasia referred to a tertiary Fetal Medicine unit between 2002 and 2008. The ultrasound findings, concordance between antenatal and final diagnosis as well as pregnancy outcome were analyzed. Data were collected from the Fetal Medicine database and computerized records supplemented by individual chart reviews. Thirty three cases of skeletal dysplasia were identified. The median maternal age was 30 years (range 18–40) and the median gestational age at referral was 21 weeks (range 11–35 weeks). A provisional ultrasound diagnosis was possible in 21/33 (65%) cases. This diagnosis was however confirmed postnatally or after molecular testing in only half of the cases. The commonest skeletal dysplasia were thanatophoric dysplasia (n = 7) and osteogenesis imperfecta (n = 4). The perinatal outcome in this series was very poor with 64% pregnancies terminated (21/33), 9% (3/33) stillborn, 9% (3/33) died in early neonatal period and only 18% (6/33) alive after the neonatal period. Making a precise prenatal diagnosis of skeletal dysplasia is frequently difficult and often inaccurate. Prediction of lethality is however much easier and is often possible depending on thoracic circumference, degree of limb shortening or the presence of other abnormalities. Parents need to be aware that the outcome of many skeletal dysplasias is poor. Although a precise diagnosis is frequently not possible antenatally, the ultrasound findings usually allow an assessment of perinatal outcome. Decisions about termination of pregnancy can therefore be made with some confidence.

OC14.02: Three dimensional imaging of fetal skeletal dysplasia: comparison of 2D, 3D ultrasound and helical computed tomography

genitourinary malformations (7%); 15 gastrointestinal anomalies (6%) and 71 miscellaneous (26%). In 244 (89%) both ultrasound and MRI findings were in agreement with postnatal diagnoses. MRI changed the US diagnosis in 16 (5,8%) cases. Relevant additional information were provided in 7 (2,5%) cases: 3 central nervous system anomalies; 3 thoracic defects; 1 abdominal malformations. Ultrasound was more accurate than MRI in 4 (1,4%) cases: 1 case of placenta previa; 1 exomphalos; 1 CCAM in a twin pregnancy; 1 hypoplasia of corpus callosum. In 9 (3,2%) cases, the diagnoses at both US and MR imaging were not correlated with postnatal outcome. Conclusions: Prenatal US remains the primary fetal imaging modality. Prenatal diagnosis of even complex malformations was accurate in over 90% of cases. In a few selected patients in our experience, particularly in late pregnancy, MRI may however add relevant information.

Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases

Skeletal dysplasias are a heterogeneous group of conditions associated with various abnormalities of the skeleton. These conditions are caused by widespread disturbance of bone growth, beginning during the early stages of fetal development and evolving throughout life. Despite recent advances in imaging, fetal skeletal dysplasias are difficult to diagnose in utero due to a number of factors, including the large number of skeletal dysplasias and their phenotypic variability with overlapping features, lack of precise molecular diagnosis for many disorders, lack of a systematic approach, the inability of ultrasonography (US) to provide an integrated view, and variability in the time at which findings manifest in some skeletal dysplasias. US of suspected skeletal dysplasia involves systematic imaging of the long bones, thorax, hands and feet, skull, spine, and pelvis. Assessment of the fetus with three-dimensional US has been shown to improve diagnostic accuracy, since additional phenotypic features not detectable at two-dimensional US may be identified. The radiologist plays a major role in making an accurate diagnosis; however, representatives of other disciplines, including clinicians, molecular biologists, and pathologists, can also provide important diagnostic information.

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.

P33.09: 3D ultrasound, MRI and molecular diagnosis of thanatophoric dysplasia type I

Skeletal dysplasias are a heterogeneous group of bone growth disorders with different fetal outcomes. Prenatal sonographic examination is an excellent method for discovering fetal skeletal dysplasias. However, it is not always possible to differentiate TD from others skeletal dysplasias by ultrasonography alone and molecular genetic analysis of the fibroblast growth factor receptor 3 (fgfr3) gene is useful for prenatal diagnosis of TD. Therefore definitive diagnosis should always be accomplished by a comprehensive postnatal evaluation, including clinical, radiological, pathological, biochemical and molecular genetic examination. Thanatophoric dysplasia (TD) is the most common form of platyspondylic lethal skeletal dysplasias and TD 1 is characterized by short limbs, a narrow thoracic cage, straight femora, with or without a cloverleaf skull. In this report, one fetus with TD 1 was diagnosed by 3D ultrasound and MRI in the second trimester, and molecular analyses of the fgfr3 gene confirmed the postnatal diagnosis.

Contribution of three‐dimensional computed tomography in the assessment of fetal skeletal dysplasia

To compare the diagnostic accuracy of two-dimensional (2D) ultrasound and three-dimensional (3D) computed tomography (CT) for the diagnosis of fetal skeletal anomalies. Eleven pregnant women underwent 2D ultrasound and 3D-CT. Ten fetuses presented skeletal anomalies on 2D ultrasound and one fetus had a normal ultrasound exam but a familial history of osteopetrosis. We compared retrospectively the diagnoses established on 2D ultrasound and 3D-CT with the neonatal and/or postmortem work-up, which were used as the gold standard. 2D ultrasound provided the correct diagnosis in only two of the 11 cases. CT yielded the correct diagnosis in eight; in six of these, 2D ultrasound had been inconclusive. 3D-CT was more accurate than was 2D ultrasound in visualizing vertebral anomalies (abnormal shape of the vertebral bodies, abnormal interpedicular distance), pelvic bone malformations (delayed ossification of the pubic bones, abnormal acetabular shape) and enlarged metaphysis or synostoses in long bones. In three cases, neither 2D ultrasound nor CT provided the correct diagnosis. In this series, which included a variety of skeletal dysplasias, 3D-CT had a better diagnostic yield than did 2D ultrasound. Both imaging techniques are useful in the management of fetal dysplasia; 2D ultrasound is a useful screening test and 3D-CT is a valuable complementary diagnostic tool.

Case series: Combined spinal epidural anesthesia for Cesarean delivery andex utero intrapartum treatment procedure

To report the use of regional anesthesia and iv nitroglycerin to provide anesthesia and uterine relaxation for three Cesarean deliveries (CD) involving ex utero intrapartum treatment (EXIT) of potentially life-threatening airway obstruction in the newborn. Case 1--a 36-yr-old woman at 38 weeks' gestation was scheduled for an elective CD for fetal skeletal dysplasia and micrognathia. Case 2--a 34-yr-old woman at 35 weeks gestation had a fetal ultrasound revealing fixed neck flexion and micrognathia consistent with fetal arthrogryposis. Case 3--a 27-yr-old woman presented at 38 weeks gestation for CD for severe fetal micrognathia, with mandibular growth below the fifth percentile. For each case, a combined spinal epidural anesthetic was performed with 0.75% bupivacaine, fentanyl and morphine intrathecally followed by placement of a multiorifice epidural catheter. Prior to uterine incision patients received a loading dose followed by an iv infusion of nitroglycerin. Uterine relaxation was sufficient in all cases for delivery of the fetus, and allowed for evaluation by direct laryngoscopy and intubation while maintaining fetal-placental circulation. The surgical procedures were completed without incident. Anesthesia and uterine relaxation for CD and EXIT procedures can be safely provided with regional anesthesia and iv nitroglycerin.

First‐trimester fetal limb biometry in Chinese population

To establish reference ranges for fetal limb biometry obtained by transabdominal ultrasound examination at 12-14 weeks of gestation in Chinese women. A total of 1489 normal singleton fetuses between 12(+0) and 14(+6) weeks of gestation were examined transabdominally by two experienced observers. The gestation was ascertained by measurement of fetal crown-rump length (CRL) or biparietal diameter (BPD) and head circumference (HC). The lengths of the humerus and femur were prospectively worked out. Gestation-specific reference ranges for limb measurements were calculated. The femur length (FL) (mean +/- SD) was 9.15 +/- 1.44 mm at 12-12(+6) weeks, 11.45 +/- 1.35 mm at 13-13(+6) weeks, and 13.64 +/- 1.60 mm at 14-14(+6) weeks; the corresponding humerus length (HL) (mean +/- SD) was 9.63 +/- 1.44 mm, 12.01 +/- 1.41 mm, 14.29 +/- 1.48 mm, respectively. There was a general increase in fetal limb biometry with gestation. Fetal limb length can be an early marker of early growth restriction as well as fetal skeletal dysplasia among women in the local population.

Fetal Anomalies. Ultrasound Diagnosis and Postnatal Management

Maizels M, Cuneo BF, Sabbagha RE, eds. Fetal Anomalies. Ultrasound Diagnosis and Postnatal Management. 281 pages. New York: Wiley-Liss Inc., 2002. Hardback: ISBN 0 471 38052 0, price GBP 118.00/Euro 188.20. According to the preface, the purpose of this book is to illustrate, in a concise manner, the latest developments in the field of diagnostic ultrasound and the emerging necessity of a multidisciplinary approach to optimize fetal and infant care. All three editors and seven out of eight contributors are from North-Western University or University of Illinois, Chicago, IL, USA. It is stated that the idea of the publication grew out of meetings held by ‘The Institute for the Unborn Baby’ (http://www.iub.org), a consortium of obstetric, genetic and pediatric specialists who have regular meetings to discuss the diagnosis and management of fetuses and newborns with various abnormalities diagnosed in the institutions within the Chicago area. They have dedicated their book to ‘the families who will come to learn of an ultrasound finding in their unborn baby’. Reader target groups are colleagues − doctors and sonographers working with prenatal ultrasound diagnosis and postnatal management of congenital anomalies. The book consists of 12 chapters on the first trimester of pregnancy, the 10–14-week scan, detection of trisomies 21 and 18, the fetal face and neck, the fetal central nervous system, the fetal chest and abdomen, the fetal urinary tract, diagnosis of fetal structural genital anomalies, polycystic kidney disease and renal transplantation, the fetal heart, skeletal dysplasias and musculo-skeletal abnormalities and pediatric anesthesia. The chapters, except three, are each followed by a list of suggested reading, in which the most recent references are from 1998 and 1999. The book is well illustrated with many ultrasound pictures, of which some are a bit old, and eight pages with color illustrations. The two largest chapters of the book are on the fetal urinary tract and on the fetal heart – both on 70 pages. The chapter on the fetal heart is especially well illustrated regarding postnatal treatment, with many excellent drawings showing how pediatric cardiothoracic surgeons try to correct the different anomalies. In summary, even though the book is not a ‘must’, it might be a useful supplement in the handbook library in fetal medicine units and at centers counselling parents on congenital malformations.

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.

A molecular analysis of matrix remodeling and angiogenesis during long bone development.

The replacement of cartilage by bone is the net result of genetic programs that control chondrocyte differentiation, matrix degradation, and bone formation. Disruptions in the rate, timing, or duration of chondrocyte proliferation and differentiation result in shortened, misshapen skeletal elements. In the majority of these skeletal disruptions, vascular invasion of the elements is also perturbed. Our hypothesis is that the processes involved in endochondral ossification are synchronized via the vasculature. The purpose of this study was to examine carefully the events of vascular invasion and matrix degradation in the context of chondrocyte differentiation and bone formation. Here, we have produced a 'molecular map' of the initial vascularization of the developing skeleton that provides a framework in which to interpret a wide range of fetal skeletal malformations, disruptions, and dysplasias.

The association of early-onset fetal growth restriction, elevated maternal serum alpha-fetoprotein, and the development of severe pre-eclampsia.

From Antenatal Diagnostic Center referrals over 22 months, consultations for early-onset fetal growth restriction versus skeletal dysplasia were retrospectively identified. Those with elevated maternal serum alpha-fetoprotein (MSAFP) levels are the focus of this report. All had an early ultrasound confirming menstrual dates and subsequent sonography at < 28 weeks with at least two fetal biometric measures delayed by > or = 2 standard deviations from mean values. Of the five patients identified, the mean gestational age at the time of diagnosis of fetal growth restriction was 23.3 +/- 2.9 weeks. All had normal karyotypes and normal amniotic fluid AFP. None of the patients had evidence of hypertension or pre-eclampsia at diagnosis of fetal growth restriction. All five gravidas subsequently developed severe pre-eclampsia from 5.5 to 12.5 weeks after documentation of fetal growth delay. Three developed HELLP syndrome. Pregnancies were continued a mean duration of 10-2 weeks, with all five delivering at preterm gestations (mean = 33.5 +/- 1.7 weeks) for maternal indications of severe pre-eclampsia. Unexplained early-onset fetal growth restriction in conjunction with unexplained elevations of MSAFP together consistently heralded the subsequent development of severe pre-eclampsia.

Prenatal ultrasonographic fetal rib length measurement: correlation with gestational age.

The availability of normal data on fetal rib bone length would be of value in a variety of circumstances under which ultrasound examinations are performed. Fetal rib length measurements were obtained in 257 singleton fetuses in a prospective cross-sectional study. The study population consisted of pregnancies between 14 and 40 weeks with no evidence of growth disturbances, or structural or karyotypic abnormalities. Fetal rib length, as a function of gestational age, was expressed by the regression equation: RL = -0.5834 + 0.2030 (GA), where RL is the rib length in centimeters and GA the gestational age in weeks. The correlation was R = 0.94 (p < 0.0001). The normal limits of fetal rib length are defined, and a high correlation between fetal rib length, gestational age, and other standard determinants of fetal growth is demonstrated. Our results indicate that fetal rib length can be a useful adjunct in determining normal fetal growth and in the management of the pregnancy with fetal skeletal dysplasia.

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.

Ratios between growth parameters for the prenatal ultrasonographic diagnosis of skeletal dysplasias

The clinical applicability and usefulness of nine ratios that express the relation between particular fetal growth parameters were tested in ten fetuses affected by skeletal dysplasia. The results were compared with the ratios calculated from five growth-retarded fetuses without structural anomalies. Femur/foot, femur/head circumference, head circumference/thoracic circumference and abdominal circumference/thoracic circumference ratios are useful additional parameters for the prenatal ultrasonographic diagnosis of skeletal dysplasias. They reduce the problem of an unknown gestational age and help to distinguish between fetal skeletal dysplasia and intra-uterine growth-retardation caused by other factors.

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.