Umbilical Cord Diseases Affecting Obstetric and Perinatal Outcomes.

BACKGROUND: (1) The aim of this article is to describe the physiopathology underlying umbilical cord diseases and their relationship with obstetric and perinatal outcomes. (2) Methods: Multicenter case series of umbilical cord diseases with illustrations from contributing institutions are presented. (3) Results: Clinical presentations of prenatal ultrasound findings, clinical prenatal features and postnatal outcomes are described. (4) Conclusions: Analysis of our series presents and discusses how umbilical cord diseases are associated with a wide variety of obstetric complications leading to a higher risk of poor perinatal outcomes in pregnancies. Knowing the physiopathology, prenatal clinical presentations and outcomes related to umbilical diseases allow for better prenatal counseling and management to potentially avoid severe obstetric and perinatal complications.

Clinical Presentations and Diagnostic Imaging of VACTERL Association.

Background: VACTERL association consists of Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal, and Limb defects. The diagnosis depends on the presence of at least three of these structural abnormalities. Methods: The clinical presentation and diagnostic prenatal imaging of VACTERL association are comprehensively reviewed. Results: The most common feature is a vertebral anomaly, found in 60-80% of cases. Tracheo-esophageal fistula is seen in 50-80% of cases and renal malformations in 30% of patients. Limb defects including thumb aplasia/hypoplasia, polydactyly, and radial agenesis/hypoplasia are present in 40-50% of cases. Anorectal defects, like imperforate anus/anal atresia, are challenging to detect prenatally. Conclusion: The diagnosis of VACTERL association mostly relies on imaging techniques such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis should exclude similar diseases such as CHARGE and Townes-Brocks syndromes and Fanconi anemia. New insights into genetic etiology have led to recommendations of chromosomal breakage investigation for optimal diagnosis and counseling.

Placental and Umbilical Cord Anomalies Diagnosed by Two- and Three-Dimensional Ultrasound.

The aim of this review is to present a wide spectrum of placental and umbilical cord pathologies affecting the pregnancy. Placental and umbilical cord anomalies are highly associated with high-risk pregnancies and may jeopardize fetal well-being in utero as well as causing a predisposition towards poor perinatal outcome with increased fetal and neonatal mortality and morbidity. The permanent, computerized perinatology databases of different international centers have been searched and investigated to fulfil the aim of this manuscript. An extended gallery of prenatal imaging with autopsy correlation in specific cases will help to provide readers with a useful iconographic tool and will assist with the understanding and definition of this critical obstetrical and perinatological issue.

Three-dimensional ultrasonography by means of HDlive rendering in the first trimester of pregnancy: A pictorial review.

Our objective was to describe early embryo/fetus anatomy and abnormalities provided by three and four-dimensional (3D/4D) ultrasound using HDlive rendering technology in the first trimester of pregnancy. Normal and pathologic embryonic and fetal volume data set with postprocessing using HDlive rendering mode. Virtual fetoscopic imaging of the normal and pathologic fetus even at early stage of development with increasing maternal-fetal bonding process. HDlive represents a novel and valuable lightening system for 3D/4D ultrasound application that may aid the prenatal interpretation of early congenital malformations although limitations and cautions are still needed for inclusion in obstetric clinical practice.

Skeletal dysplasia with bowing long bones: Proposed flowchart for prenatal diagnosis with case demonstration.

OBJECTIVE: Skeletal dysplasia with bowing long bones is a rare group of multiple characterized congenital anomalies. MATERIALS AND METHODS: We introduce a simple, practical diagnostic flowchart that may be helpful in identifying the appropriate pathway of obstetrical management. RESULTS: Herein, we describe four fetal cases of bent bony dysplasia that focus on ultrasound findings, phenotype, molecular tests, distinctive X-ray features, and chondral growth plate histology. The first case was a typical campomelic dysplasia resulting from a de novo mutation in the SOX9 gene. The second fetus was affected by osteogenesis imperfecta Type II carrying a mutation in the COLA1 gene. The third case was a rare presentation of campomelic dysplasia, Cumming type, in which SOX9 examination was normal. Subsequently, a femoral hypoplasia unusual facies syndrome is also discussed. CONCLUSION: Targeted molecular tests and genetic counseling are required for supplementing ultrasound imaging in order to diagnose the correct skeletal disorders.

First trimester diagnosis of cervico-thoracic diastematomyelia and diplomyelia using three-dimensional ultrasound.

BACKGROUND: Diastematomyelia and diplomyelia are rare form of spinal cord malformations (SCM) characterized by sagittal cleft in the spinal cord, conus medullaris, and/or filum terminale with splaying of the posterior vertebral elements and duplication of the spinal cord into two twin cords. Prenatal diagnosis of these diseases by two-dimensional ultrasound has been reported usually late in pregnancy and only recently in the first trimester. OBJECTIVE: We describe the first case of cervico-thoracic diastematomyelia and diplomyelia diagnosed early in pregnancy using three-dimensional ultrasound.

Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 of 11 families (82 %). We sequenced C5orf42 in 313 JS probands and identified mutations in 28 (8.9 %), most with a phenotype of pure JS. Only 2 out of 17 OFDVI patients (11.7 %) were mutated. A comparison of mutated vs. non-mutated OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects may predict C5orf42 mutations, while tongue hamartomas are more common in negative patients.

Complete trisomy 9 with unusual phenotypic associations: Dandy-Walker malformation, cleft lip and cleft palate, cardiovascular abnormalities.

OBJECTIVE: Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality. CASE REPORT: The first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch. CONCLUSION: Complete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy.

Bifid uvula and familial Stickler syndrome diagnosed prenatally before the sonographic "equals sign" landmark.

PURPOSE: The prenatal ultrasound visualization of the soft palate and especially the uvula may be technically difficult due to its anatomy and presence of surrounding structures. A cleft involving the soft palate and the uvula is one of the clinical features of Stickler syndrome, a rare connective tissue disorder. MATERIALS AND METHODS: Third trimester scan performed at 30 weeks' gestation in a pregnant woman with a familial history of Stickler syndrome using conventional 2D ultrasound. RESULTS: Transabdominal scan performed with the fetal head in oblique plane and following fetal swallowing movements enabled a previously unrecognized median cleft at the level of the uvula. Molecular biology analysis allowed a precise prenatal diagnosis of Stickler syndrome and excluded overlapping syndrome. CONCLUSIONS: The prenatal ultrasound diagnosis was achieved time before the "equals signs" was proposed as a useful sonographic marker of a normal uvula. The identification of a bifid uvula by conventional 2D ultrasound led to a prenatal diagnosis of Stickler syndrome in this affected Family and allowed the neonatologist team to be available at the time of birth. Moreover, postnatal multispecialist follow up could be timely planned for targeted organ examination and appropriate management.

Bifid choroid plexus: always a normal fetal brain structure variant?

Choroid plexus, a fetal organ developing approximately from the sixth week of gestation, plays a fundamental role in developing fetal brain organization. As relatively little is known about the relationship between anomalies of choroid plexuses structure and their role in brain function, we examined cases of bifid choroid plexus (BCP) and discussed their potential association with lateral ventriculomegaly, other abnormal ultrasound findings, and their potential role as markers of fetal chromosomal abnormalities. In the present study, we described 23 cases of fetal BCP found in 2145 routine second trimester ultrasounds. For each patient 2D and 3D ultrasound volumes were acquired. BCP was defined as a choroid plexus whose body was divided into two portions (arms) differently located and oriented on the three spatial axes in correspondence to the lateral ventricle, in one or both sides. The entity of the separation and reciprocal orientation of the two arms was examined. The presence of BCP in a low-risk population of pregnant women undergoing routine second trimester ultrasound was showed. Lateral ventricles significantly increased in the presence of BCP. Malformations were found in four of 23 fetuses with BCP. Pregnancy outcome was favorable only in one of these four cases. We suggest that in the presence of mono or bilateral BCP without associated abnormal ultrasound findings, a closer look at fetal brain or extra-cranial structures is recommended. If no related abnormalities are found, serial prenatal and postnatal sonographic follow-up should be considered. In the presence of concomitant abnormal findings, genetic counseling, fetal karyotyping and magnetic resonance imaging, if possible by gestational age, are strongly advised.

Arthrogryposis multiplex congenita-like syndrome associated with median cleft lip and palates: first prenatally detected case.

An early second-trimester prenatal ultrasound diagnosis of an arthrogryposis multiplex congenita-like syndrome associated with median clefts is reported. A molecular biological work-up was performed to search for a potentially overlapping syndrome and dysostosis. Autopsy and postmortem radiogram were performed to confirm the ultrasound diagnosis. Prenatal diagnosis enabled early detection of multiple fetal malformations, thus allowing early termination of pregnancy. Moreover, three-dimensional ultrasound with volume rendering in the maximum surface mode demonstrated its value in diagnosing oro-facial clefts, even at an early stage of fetal development.

Craniosynostosis with wormian bone, bowing of the long bones, unilateral short femur, and focal fibula deficiency: a prenatal diagnostic dilemma.

The prenatal detection in the second trimester of pregnancy of a fetus with craniosynostosis, wide metopic suture, and wormian bone associated with bowing of the long bones, unilateral short femur, and focal fibula deficiency is reported. These ultrasonographic findings when not supported by a diagnostic molecular biology result represent a prenatal dilemma in term of both parent's counseling and management of potential overlapping skeletal diseases.

OmniView algorithm: a novel 3-dimensional sonographic technique in the study of the fetal hard and soft palates.

The purpose of this pictorial essay is to report on the application of OmniView (GE Healthcare, Zipf, Austria), new 3-dimensional sonographic software, and its application in the prenatal sonographic study of the fetal hard and soft palates. We will show that this novel technique is easy and feasible, requires a limited learning curve, and provides correct volume interrogation of the region of interest. The OmniView algorithm may be useful in training programs, and volume data sets can be interpreted by experts in remote sites. Future prospective studies with consecutive patients will be necessary to evaluate whether the routine application of OmniView will increase the prenatal diagnosis of facial clefting, especially those with isolated palate defects.

Recruitment of host's progenitor cells to sites of human amniotic fluid stem cells implantation.

The amniotic fluid is a new source of multipotent stem cells with a therapeutic potential for human diseases. Cultured at low cell density, human amniotic fluid stem cells (hAFSCs) were still able to generate colony-forming unit-fibroblast (CFU-F) after 60 doublings, thus confirming their staminal nature. Moreover, after extensive in vitro cell expansion hAFSCs maintained a stable karyotype. The expression of genes, such as SSEA-4, SOX2 and OCT3/4 was confirmed at early and later culture stage. Also, hAFSCs showed bright expression of mesenchymal lineage markers and immunoregulatory properties. hAFSCs, seeded onto hydroxyapatite scaffolds and subcutaneously implanted in nude mice, played a pivotal role in mounting a response resulting in the recruitment of host's progenitor cells forming tissues of mesodermal origin such as fat, muscle, fibrous tissue and immature bone. Implanted hAFSCs migrated from the scaffold to the skin overlying implant site but not to other organs. Given their in vivo: (i) recruitment of host progenitor cells, (ii) homing towards injured sites and (iii) multipotentiality in tissue repair, hAFSCs are a very appealing reserve of stem cells potentially useful for clinical application in regenerative medicine.

Prenatal ultrasound and histological diagnosis of fetal nasal glioma (heterotopic central nervous system tissue): report of a new case and review of the literature.

INTRODUCTION: Nasal glioma is a rare, benign congenital midline facial lesion. MATERIALS AND METHODS: Prenatal ultrasound diagnosis performed at 2nd trimester of pregnancy revealed a right-sided mass at the level of the fetal face extending from the right internal canthus to the nasal bridge. CONCLUSION: Differential diagnosis of facial mass in the fetus represents a critical issue because is essential in guiding the prenatal counselling of the couple and in guiding the prenatal and/or postnatal management. Alternative diagnoses such as dacryocystocele, dermoid cyst, retinoblastoma or teratoma, hemangioma, and encephalocele that can not completely be excluded prenatally are discussed. Embryology, pathology, prenatal ultrasound diagnostic clusters of the lesion as well as MR imaging findings are discussed together with review of the literature.

Craniosynostosis: prenatal diagnosis by means of ultrasound and SSSE-MRI. Family series with report of neurodevelopmental outcome and review of the literature.

INTRODUCTION: Craniosynostosis is a condition characterized by a premature closure of one or more skull sutures and refers to a wide spectrum of cranial malformation with an estimated birth of 1:2,000-1:4,000 live births. Four receptors (FGFR 1, FGFR 2, FGFR 3, FGFR 4) involving mutation in the fibroblast growth factor have been identified. MATERIALS AND METHODS: Two cases occurred in the same family and diagnosed prenatally by means of ultrasound, and antenatal and postnatal MR imaging are reported. Molecular biology regarding identification of craniosynostosis type has been analyzed. A revision of the medical literature is also provided. CONCLUSION: The premature closure of sagittal suture is characterized by a disproportionately large occipito-frontal and short biparietal diameter (scaphocephaly). The prenatal ultrasound diagnosis of craniosynostosis in utero may be difficult and be suspected when the cephalic index, the cranial shape or the fetal face shape are abnormal. Fetal karyotype is recommended and DNA testing plays a critical role in achieving an appropriate diagnosis, when possible. The prognosis of craniosynostosis is primarily dependent on the presence of associated anomalies as craniosynostosis are correlated with three to fivefold increased risk for cognitive disabilities.

Regression of fetal cerebral abnormalities by primary cytomegalovirus infection following hyperimmunoglobulin therapy.

OBJECTIVE: To assess the effects of maternal and intra-amniotic hyperimmunoglobulin (HIG) infusions among cytomegalovirus (CMV) infected fetuses with ultrasound abnormalities following a primary CMV infection. PATIENTS AND METHODS: The subjects were fetuses with CMV-associated cerebral and other ultrasound abnormalities. Three mothers were treated with HIG infusions during pregnancy and two were untreated. Fetal ventricle size, organ echodensity and placental thickness were measured by ultrasound before and after HIG infusions. The children were evaluated between 3 and 7 years of age. RESULTS: The ventriculomegaly of all three fetuses of HIG-treated mothers regressed and the ascites, hepatic echodensities, periventricular echodensities, and intestinal echodensities disappeared. Their sensorial, mental and motor development was normal at 4, 4.7, and 7 years of age. In contrast, both infants born of untreated mothers had signs and symptoms of severe CMV cerebropathy. CONCLUSION: The outcomes of the infants born to HIG-treated mothers support the efficacy of HIG as a treatment for CMV-infected fetuses with ultrasound cerebral abnormalities.

Multipotent mesenchymal stromal cells from amniotic fluid: solid perspectives for clinical application.

BACKGROUND: Mesenchymal stromal cells are multipotent cells considered to be of great promise for use in regenerative medicine. However, the cell dose may be a critical factor in many clinical conditions and the yield resulting from the ex vivo expansion of mesenchymal stromal cells derived from bone marrow may be insufficient. Thus, alternative sources of mesenchymal stromal cells need to be explored. In this study, mesenchymal stromal cells were successfully isolated from second trimester amniotic fluid and analyzed for chromosomal stability to validate their safety for potential utilization as a cell therapy product. DESIGN AND METHODS: Mesenchymal stromal cells were expanded up to the sixth passage starting from amniotic fluid using different culture conditions to optimize large-scale production. RESULTS: The highest number of mesenchymal stromal cells derived from amniotic fluid was reached at a low plating density; in these conditions the expansion of mesenchymal stromal cells from amniotic fluid was significantly greater than that of adult bone marrow-derived mesenchymal stromal cells. Mesenchymal stromal cells from amniotic fluid represent a relatively homogeneous population of immature cells with immunosuppressive properties and extensive proliferative potential. Despite their high proliferative capacity in culture, we did not observe any karyotypic abnormalities or transformation potential in vitro nor any tumorigenic effect in vivo. CONCLUSIONS: Fetal mesenchymal stromal cells can be extensively expanded from amniotic fluid, showing no karyotypic abnormalities or transformation potential in vitro and no tumorigenic effect in vivo. They represent a relatively homogeneous population of immature mesenchymal stromal cells with long telomeres, immunosuppressive properties and extensive proliferative potential. Our results indicate that amniotic fluid represents a rich source of mesenchymal stromal cells suitable for banking to be used when large amounts of cells are required.

Fetal aortic root dilation: a prenatal feature of the Loeys-Dietz syndrome.

Loeys-Dietz syndrome is a recently described autosomal dominant disorder with cardinal manifestations in cardiovascular, craniofacial and skeletal systems. Although the disease has some phenotypic overlap with Marfan syndrome, the disease, that is caused by mutations in the transforming growth factor beta-receptor 1 (TGFBR1) or transforming growth factor beta-receptor 2 (TGFBR2) genes, presents many distinctive features and a particularly aggressive cardiovascular course. We describe prenatal identification of an aortic root aneurysm in a fetus of 19 week of gestation as an early marker of Loeys-Dietz syndrome.