Association of antenatal evaluations with postmortem and genetic findings in the series of fetal osteogenesis imperfecta.

INTRODUCTION: Counseling Osteogenesis Imperfecta (OI) pregnancies is challenging due to the wide range of onsets and clinical severities, from perinatal lethality to milder forms detected later in life. METHODS: Thirty-eight individuals from 36 families were diagnosed with OI through prenatal ultrasonography and/or postmortem clinical and radiographic findings. Genetic analysis was conducted on 26 genes associated with OI in these subjects that emerged over the past 20 years, while some genes were examined progressively, all 26 genes were examined in the group where no pathogenic variations were detected. RESULTS: Prenatal and postnatal observations both consistently showed short limbs in 97%, followed by bowing of the long bones in 89%. Among 32 evaluated cases, all exhibited cranial hypomineralization. Fractures were found in 29 (76%) cases, with multiple bones involved in 18 of them. Genetic associations were disclosed in 27 families with 22 (81%) autosomal dominant and five (19%) autosomal recessive forms, revealing 25 variants in six genes (COL1A1, COL1A2, CREB3L1, P3H1, FKBP10, and IFITM5), including nine novels. Postmortem radiological examination showed variability in intra-family expression of CREBL3 and P3H1-related OI. CONCLUSION: Prenatal diagnosis for distinguishing OI and its subtypes relies on factors such as family history, timing, ultrasound, genetic and postmortem evaluation.

Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Predictive value of ultrasound in prenatal diagnosis of hypospadias: hints for accurate diagnosis.

OBJECTIVES: This study aims to assess the diagnostic accuracy of targeted ultrasound examination in prenatal diagnosis of hypospadias and to evaluate the predictive values of defined ultrasonographic findings of hypospadias. METHODS: The cases diagnosed with hypospadias in our fetal medicine center were identified on an electronic database. The ultrasound reports, images and hospital records were reviewed retrospectively. The predictive value of prenatal ultrasound diagnosis and the predictive values of each sonographic finding were assessed according to the postnatal clinical examinations. RESULTS: Thirty-nine cases were diagnosed with hypospadias on ultrasound during the 6 years. Nine fetuses with missing postnatal examination records were excluded. Twentytwo of the remaining fetuses had their prenatal diagnosis of hypospadias confirmed in postnatal examinations, indicating a 73.3 % positive predictive value. Normal external genitalia was detected in postnatal examinations of three fetuses. Five fetuses were diagnosed with other external genital abnormalities, including micropenis (n=2), clitoromegaly (n=2), and buried penis with bifid scrotum (n=1) in postnatal examinations. The positive predictive value of prenatal ultrasound for any external genital abnormality was 90 %. CONCLUSIONS: Although the positive predictive value of ultrasound for genital anomalies is satisfying, it is slightly lower for the specific diagnosis of hypospadias. This reflects overlapping ultrasound findings of different external genitalia anomalies. Standardized, systematic evaluation of the internal and external genital organs, karyotyping and genetic sex determination are essential to achieve a precise prenatal diagnosis of hypospadias.

Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome.

Introduction: GDF5-BMPR1B signaling pathway-associated chondrodysplasias are a genetically heterogeneous group of conditions with significant phenotypic and genotypic overlap, consisting of Hunter-Thompson-type acromesomelic dysplasia, Grebe dysplasia, and Du Pan syndrome. Constituting a spectrum of clinical severity, these disorders are characterized by disproportionate short stature mainly involving middle and distal segments of the extremities. Du Pan syndrome represents the mildest end of this spectrum with less marked shortened limbs, fibular agenesis or hypoplasia, absence of frequent joint dislocations, and carpotarsal fusions with deformed phalangeal bones. Case Presentation: Here, we report the first prenatal diagnosis of Du Pan syndrome based on the sonographic findings of bilateral fibular agenesis and ball-shaped toes mimicking preaxial polydactyly accompanying subtle brachydactyly in the family. GDF5 (NM_000557.5) sequencing identified a homozygous pathogenic variant c.1322T>C, p.(Leu441Pro) in the fetus and confirmed the carrier status in the mother. Discussion: We suggest that the presence of bilateral fibular agenesis and the apparent image of preaxial polydactyly of the feet on prenatal ultrasound should alert suspicion to Du Pan syndrome, with the latter possibly being a sonographic pitfall. Alongside the fetal imaging, a detailed clinical examination of the expectant parents is also of great importance in establishing a preliminary diagnosis of Du Pan syndrome, as well as the other GDF5-BMPR1B-associated chondrodysplasias.

Clinical, Cytogenetic and Molecular Cytogenetic Outcomes of Cell-Free DNA Testing for Rare Chromosomal Anomalies.

The scope of cell-free DNA (cfDNA) testing was expanded to the genome, which allowed screening for rare chromosome anomalies (RCAs). Since the efficiency of the test for RCAs remains below the common aneuploidies, there is a debate on the usage of expanded tests. This study focuses on the confirmatory and follow-up data of cases with positive cfDNA testing for RCAs and cases with screen-negative results in a series of 912 consecutive cases that underwent invasive testing following cfDNA testing. Chorion villus sampling (CVS), amniocentesis (AS), fetal blood sampling, and term placenta samples were investigated using classical cytogenetic and molecular cytogenetic techniques. Out of 593 screen-positive results, 504 (85%) were for common aneuploidies, 40 (6.7%) for rare autosomal trisomies (RATs), and 49 (8.3%) for structural chromosome anomalies (SAs). Of the screen-positives for RATs, 20 cases were evaluated only in fetal tissue, and confined placental mosaicism (CPM) could not be excluded. Among cases with definitive results (n = 20), the rates of true positives, placental mosaics, and false positives were 35%, 45%, and 10%, respectively. Among screen-positives for SAs, 32.7% were true positives. The confirmation rate was higher for duplications than deletions (58.3% vs. 29.4%). The rate of chromosomal abnormality was 10.9% in the group of 256 screen-negatives with pathological ultrasound findings. This study provides further data to assess the efficiency of expanded cfDNA testing for RATs and SAs. The test efficiency for cfDNA seems to be higher for duplications than for deletions, which is evidence of the role of expert ultrasound in identifying pregnancies at increased risk for chromosome anomalies, even in pregnancies with screen-negatives. Furthermore, we discussed the efficiency of CVS vs. AC in screen-positives for RATs.

Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis.

OBJECTIVE: Blomstrand osteochondrodysplasia (BOCD, MIM #215045) is an ultrarare lethal skeletal dysplasia (LSD) perinatally, characterized by extremely advanced bone maturation, generalized osteosclerosis, and severe tetramicromelia caused by biallelic loss-of-function mutations in the parathyroid hormone receptor-1 gene (PTHR1). We aim to describe prenatal ultrasonographic features in a retrospective fetal case series of BOCD and emphasize the importance of multidisciplinary antenatal evaluation of LSDs to improve the differential diagnosis. METHOD: Prenatal ultrasound findings of five fetal cases diagnosed with BOCD between 2000 and 2019 in the Prenatal Diagnosis Unit and Medical Genetics were reviewed, along with postmortem examination results and confirmatory molecular results. RESULTS: All fetuses presented with severe sonographic findings of LSDs comprising tetramicromelia, thoracic hypoplasia, and retro-micrognathia. Marked cervical hyperextension was present in three fetuses. Flared metaphyses were prenatally identified in only one fetus. X-rays of four fetuses evaluated postmortem showed advanced bone maturation, generalized osteosclerosis, and dumbbell-like appearance of long bones due to metaphyseal enlargement. CONCLUSION: The presence of retro-micrognathia along with a protruding tongue and severe metaphyseal flaring can suggest a diagnosis of BOCD, when prenatal ultrasound findings are indicative for LSD. The diagnosis can be ascertained through postmortem clinical and radiological evaluation and/or molecular testing.

The effects of early or late multifetal reduction procedure on perinatal outcomes in multiple pregnancies reduced to twins or singletons: A single tertiary center experience.

OBJECTIVE: The aim of the study was to compare the effect of early or late fetal reduction (FR) procedures on perinatal outcomes in multiple pregnancies reduced to twins or singletons. STUDY DESIGN: This retrospective cohort study consisted of data from a single tertiary center between January 2013 and December 2020 and included 103 women with multiple pregnancies between 8 and 14 gestational weeks and who underwent FR by transabdominal approach. Late FR was defined as 11-13 6/7 gestational weeks (Group L) and early FR was defined as 8-10 6/7 gestational weeks (Group E) in the study. All pregnancies with FR were named Group S (Single) if reduced to singletons and Group T (Twin) if reduced to twin pregnancies. RESULTS: Thirty four percent (n = 35) were reduced to single pregnancy, the remaining 66% of these cases (n = 68) were reduced to twin pregnancy. The overall survival rate was 90%.When the cases were examined in terms of pregnancy complications, it was observed that the PPROM rate and preterm labor rate in the Group T were statistically significantly higher than the Group S (p = 0.015 and p < 0.001, respectively). When comparing the overall survival results between Group S and Group T, it was found that the overall survival of Group S was statistically significantly better (p < 0.001). When Group E and Group L were compared in terms of their pregnancy course and neonatal outcomes, no statistically significant difference was found between them. No statistically significant difference was found between the complication rates in the first week after the procedure (p < 0.05). Neonatal intensive care need was found at a rate of 31% in those with Group E, while this rate was found as 39% in Group L, and this difference was also not statistically significant (p = 0.480). When the preterm labor rate was compared between these two groups, there was no statistically significant difference in all three subgroups (<32nd, <34th, and <37th gestational weeks). CONCLUSION: When FR to singleton is required for fetal or maternal reasons, it should be discussed with the parents that the risk of fetal loss is similar to FR to twins, but the effect on perinatal survival is more favorable than expected.

The Giant Infantile Fibrosarcoma of Fetal Oropharynx and Anterior Neck.

Introduction: Infantile fibrosarcoma (IFS) usually arises in the extremities during the first 12 months of life and responds well to surgery. It is unusual in the oropharynx or the prenatal period. Case report: A giant solid mass was first detected in the oropharynx and anterior neck at 24 weeks of gestation by ultrasound and fetal MRI. An EXIT procedure with intrapartum intubation with appropriate supportive therapy was successful. The diagnosis of IFS was made postpartum, and the lesion responded to neoadjuvant chemotherapy. Conclusion: IFS may arise as early as 24 weeks of gestation. In this case, an EXIT procedure allowed postpartum diagnosis with subsequent treatment.

Prenatal sonographic and cytogenetic/molecular findings of 22q11.2 microdeletion syndrome in 48 confirmed cases in a single tertiary center.

PURPOSE: We aimed to present the fetal ultrasound, cytogenetic/molecular testing and postmortem or postnatal clinical findings of cases with 22q11.2DS diagnosed prenatally. MATERIALS AND METHODS: A retrospective medical record review of 48 prenatal cases diagnosed with 22q11.2DS were evaluated in our institution. Detailed ultrasound examination was performed on all fetuses. Postmortem and postnatal examinations were evaluated. The microdeletions were detected by karyotyping or microarray, then confirmed by FISH. Descriptive statistical analysis was performed. RESULTS: Demographic data of 48 prenatal cases including 46 singletons and 1 dichorionic diamniotic twin pregnancy were evaluated. The most common extracardiac anomaly was skeletal system anomalies (25%), in which PEV was the most frequent one (20.8%). Polyhydramnios rate was detected as 31%, in 6.6% as an isolated finding. Microdeletion has been detected by karyotyping in 13 cases (13/47, 27.7%) (including 2 unbalanced translocations), by FISH in 28 cases (28/48, 58.3%), by microarray/a-CGH testing in 7 cases. Microarray analysis showed that in one case with unbalanced translocation had two consecutive deletions; one was proximal and other one distal to critical region and not encompassing TBX1 gene but CRKL and LZTR1 genes. CONCLUSION: The current study demonstrates the whole spectrum of atypical phenotypic and genotypic variations of 22q11.2DS in the largest prenatal case series reported to date. Therefore, differential diagnosis should be considered not solely in CHD, but also in the presence of isolated clubfeet and polyhydramnios. Establishing the diagnosis in the prenatal period may allow a postnatal multidisciplinary approach, as well as affect the actual prevalence of the disease.

Follow-Up Studies of cf-DNA Testing from 101 Consecutive Fetuses and Related Ultrasound Findings.

PURPOSE: To determine the true- and false-positive rates of cf-DNA testing in a cohort of patients from tertiary care centers and assess the impact of ultrasound examinations in pregnancy management. MATERIALS AND METHODS: Clinical, cytogenetic and ultrasound data of 101 consecutive fetuses were collected retrospectively. Cases were classified into five groups according to the ultrasound findings. Karyotyping, interphase FISH and microarray techniques were used for follow-up studies. RESULTS: The overall false-positive rate was low for trisomy 21 (T21, 8.2 %), but significantly higher for trisomy 18 (T18, 40 %), monosomy X (MX, 50 %), X/Y trisomies (57.1 %), trisomy 13 (T13, 71.4 %). While single cases of trisomy 16, trisomy 22 and 8q duplication positive in cf-DNA were confirmed, 3 microdeletions (1p36 and two 22q11.2) were not. About 75 % of confirmed T21's and all confirmed T18 and T13 had major markers and/or malformations. While false-negative cases (two T21, one T18 and one T13) were identified due to abnormal ultrasound findings, all false-positive cases were normal sonographically. Ultrasound findings of confirmed trisomy 16, 22, dup8q, monosomy X and other X/Y aneuploidies were unspecific. Term placenta studies were helpful to assess the role of confined mosaicism in unconfirmed cf-DNA test results. A vanishing twin has been observed as the likely cause of one false-positive T18. CONCLUSION: Our study contributes clinical data on discrepant cf-DNA testing results, corroborates the need for confirmational invasive testing and underscores the benefit of expert ultrasound in the prevention of fatal diagnostic errors.

Prenatal Incidence and Clinical Value of the Absence of 12th Ribs in a Population in a Setting of Detailed Second-Trimester Sonography.

OBJECTIVES: We aimed to determine the incidence of the absence of the (last) 12th ribs in a population in a setting of detailed 2nd-trimester sonography using three-dimensional (3D) ultrasound and to assess whether or not this may be related to chromosomal aneuploidies. METHODS: Prospectively, we counted fetal ribs for the absence of the (last) 12th ribs in singleton pregnancies of women who presented to our clinic for detailed 2nd-trimester sonography. The assessment was carried out using 3D ultrasound. Volume data sets were acquired with the 3D skeleton mode using the maximum intensity with X-ray-weighted rendering. If the 3D skeleton mode was not sufficient, volume contrast imaging with the OmniView bone mode was used. RESULTS: The fetal ribs could be visualized in 97.01% of the 1,943 fetuses examined between 20 and 23 weeks' gestation. Timing the examination at 21, 22, or 23 weeks was found to be more successful than conducting it at 20 weeks. Twelfth ribs were found to be absent in 33 fetuses; 16 fetuses had 11 ribs unilaterally and 17 had so bilaterally. None of them had chromosomal abnormalities. Associated anomalies were present in 6 fetuses (18.2%); 2 of the anomalies were major and 4 minor. CONCLUSION: The incidence of absent 12th ribs in this mixed population was 1.75%. In the absence of additional anomalies, the prognosis is favorable.

Prenatal Diagnosis and Management of Ectopia Cordis: Varied Presentation Spectrum.

BACKGROUND: Ectopia cordis (EC) is a congenital anomaly associated with heart defects and extracardiac malformations. OBJECTIVES: We determined the various presentations of EC diagnosed in our center between 2010 and 2017. RESULTS: Seven fetuses from six pregnancies with EC were detected, five during the first trimester. Three were from multiple pregnancies, and both twins had EC in one monochorionic-monoamniotic pregnancy. Abdominal wall defects were detected in six fetuses. Kyphoscoliosis, cephalocele, clubfoot and short umbilical cord were other abnormalities. Five fetuses were terminated, one fetus died in utero, and one baby died on day two of life. Postnatal evaluation performed in all cases additionally detected cleft lips/palates in two fetuses and tetralogy of Fallot in one. CONCLUSION: Outcome is poor for these fetuses, EC can occur in a multiple pregnancy, most of the abnormalities can be identified in the first trimester and fetopsy continues to add information to the intrauterine diagnosis.

Incidence of an Aberrant Right Subclavian Artery on Second-Trimester Sonography in an Unselected Population.

OBJECTIVES: The aim of this study was to assess the incidence of an aberrant right subclavian artery (ARSA) among an unselected population during second-trimester sonography and to review the importance of this conotruncal variant as a marker of Down syndrome. METHODS: The presence or absence of an ARSA was assessed in an unselected population of 1913 second-trimester fetuses. RESULTS: Among the 1913 patients, an ARSA was detected in 20 fetuses (1.04%), all with a normal karyotype. Thirteen of 20 fetuses had an isolated ARSA, and 7 of them were nonisolated. Associated abnormal sonographic findings were an intracardiac echogenic focus (n = 3), a choroid plexus cyst (n = 1), pyelectasis (n = 1) and tetralogy of Fallot (n = 2). One of the cases of tetralogy of Fallot was also associated with a persistent left superior vena cava, a persistent right umbilical vein, hydrocephalus, rhombencephalosynapsis, and unilateral renal agenesis. There were only 2 fetuses with Down syndrome in this group, and both of them had a normal origin of the right subclavian artery. CONCLUSIONS: In an unselected population, an ARSA may be seen less frequently than in a high-risk population and may not be related to Down syndrome. An isolated ARSA is not a sufficient indication for karyotype analysis; it can be managed with noninvasive prenatal testing rather than invasive testing.

Intrapericardial diaphragmatic hernia: report of 2 cases with prenatal diagnosis.

An intrapericardial diaphragmatic hernia is a very rare congenital abnormality, with only a few cases reported in the English literature. The triad includes a massive pericardial effusion, bilateral pulmonary compression with or without pulmonary hypoplasia, and herniation of part of the liver into the pericardium. We report 2 cases of intrapericardial diaphragmatic hernias diagnosed prenatally in our obstetrics and gynecology unit.