Micro-CT and high-field MRI for studying very early post-mortem human fetal anatomy at 8 weeks of gestation.

OBJECTIVE: This study involved very early post-mortem (PM) examination of human fetal anatomy at 8 weeks of gestation (WG) using whole-body multimodal micro-imaging: micro-CT and high-field MRI (HF-MRI). We discuss the potential place of this imaging in early first-trimester virtual autopsy. METHODS: We performed micro-CT after different contrast-bath protocols including diffusible iodine-based contrast-enhanced (dice) and HF-MRI with a 9.4 T machine with qualitative and quantitative evaluation and obtained histological sections. RESULTS: Nine fetuses were included: the crown-rump length was 10-24 mm and corresponded to 7 and 9 WG according to the Robinson formula. The Carnegie stages were 17-21. Dice micro-CT and HF-MRI presented high signal to noise ratio, >5, according to the Rose criterion, and for allowed anatomical phenotyping in these specimens. Imaging did not alter the histology, allowing immunostaining and pathological examination. CONCLUSION: PM non-destructive whole-body multimodal micro-imaging: dice micro-CT and HF-MRI allows for PM human fetal anatomy study as early as 8 WG. It paves the way to virtual autopsy in the very early first trimester. Obtaining a precision phenotype, even regarding miscarriage products, allows a reverse phenotyping to select variants of interest in genome-wide analysis, offering potential genetic counseling for bereaved parents.

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.

Less-invasive autopsy for early pregnancy loss.

Autopsy investigations provide valuable information regarding fetal death that can assist in the parental bereavement process, and influence future pregnancies, but conventional autopsy is often declined by parents because of its invasive approach. This has led to the development of less-invasive autopsy investigations based on imaging technology to provide a more accessible and acceptable choice for parents when investigating their loss. Whilst the development and use of more conventional clinical imaging techniques (radiographs, CT, MRI, US) are well described in the literature for fetuses over 20 weeks of gestational age, these investigations have limited diagnostic accuracy in imaging smaller fetuses. Techniques such as ultra-high-field MRI (>3T) and micro-focus computed tomography have been shown to have higher diagnostic accuracy whilst still being acceptable to parents. By further developing and increasing the availability of these more innovative imaging techniques, parents will be provided with a greater choice of acceptable options to investigate their loss, which may in turn increase their uptake. We provide a narrative review focussing on the development of high-resolution, non-invasive imaging techniques to evaluate early gestational pregnancy loss.

Extending the prenatal Noonan's phenotype by review of ultrasound and autopsy data.

OBJECTIVES: The antenatal phenotypic spectrum of Noonan Syndrome (NS) requires better characterization. METHODS: This multicenter retrospective observational included 16 fetuses with molecularly confirmed NS admitted for fetopathological examination between 2009 and 2016. RESULTS: Among 12 pathogenic variants (PV) in PTPN11 (80%), 5 (42%) fell between position c.179 and c.182. Ultrasound showed increased nuchal translucency (n = 13/16, 93%), increased nuchal fold after 15 weeks of gestation (n = 12/16, 75%), pleural effusions (n = 11/16, 69%), polyhydramnios (n = 9/16, 56%), hydrops (n = 7/16, 44%), cardiovascular (n = 6/16, 38%) and cerebral (n = 4/16, 25%) anomalies. Fetopathological examination found dysmorphic features in all cases, cardiovascular anomalies (n = 12/15, 80%), pulmonary hypoplasia (n = 10/15, 67%), effusions (n = 7/15, 47%) and neuropathological anomalies (n = 5/15, 33%). Hydrops was significantly (p = 0.02) more frequent in the four fetuses with RIT1, NRAS and RAF1 PV versus the 12 fetuses with PTPN11 PV. CONCLUSIONS: Increased nuchal translucency and nuchal fold is common in NS. Noonan Syndrome antenatal phenotype showed high in utero fetal death, hydrops, prenatal pleural effusion and pulmonary hypoplasia, although the inclusion of only deceased fetuses will have selected more severe phenotypes. Non-specific cardiovascular and neurological abnormalities should be added to NS antenatal phenotype. Next generation sequencing will help detect more genotypes, clarifying the prenatal phenotype and identifying genotype-phenotype correlations.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Evidence for and against vertical transmission for severe acute respiratory syndrome coronavirus 2.

COVID-19 can severely affect pregnant women Furthermore, issues regarding vertical transmission of severe acute respiratory syndrome coronavirus 2 are emerging. In patients and neonates who are showing symptoms of coronavirus disease 2019, real-time polymerase chain reaction of nasal and throat swabs, sputum, and feces is performed to detect the presence of severe acute respiratory syndrome coronavirus 2. In addition, real-time polymerase chain reaction of vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood, or breast milk for the detection of severe acute respiratory syndrome coronavirus 2 did not show substantial results. Viremia was present in 1% of adult patients who were showing symptoms of coronavirus disease 2019. Here, we reviewed 12 articles published between Feb. 10, 2020, and April 4, 2020, that reported on 68 deliveries and 71 neonates with maternal infection in the third trimester of pregnancy. To determine whether infection occurred congenitally or perinatally, perinatal exposure, mode of delivery, and time interval from delivery to the diagnosis of neonatal infection were considered. Neonates with severe acute respiratory syndrome coronavirus 2 infection are usually asymptomatic. In 4 cases, a diagnostic test for severe acute respiratory syndrome coronavirus 2 infection was performed within 48 hours of life. Furthermore, detection rates of real-time polymerase chain reaction and the interpretation of immunoglobulin M and immunoglobulin G antibodies levels in cord and neonatal blood were discussed in relation with the immaturity of the fetal and neonatal immune system.

Early needle aspiration of large infant cephalohematoma: a safe procedure to avoid esthetic complications.

Cephalohematoma is a common pathology in newborns. Observation is the primary treatment for most patients with small uncomplicated cephalohematoma. Conversely, a large cephalohematoma can lead to calcification with unesthetic local deformation or deformational plagiocephaly. The objective of the study was to evaluate the iatrogenic risk associated with early puncture under local anesthesia and oral sucrose. This is a retrospective study of 67 consecutive newborns followed at Montpellier University Hospital, France, between 2010 and 2017. Large cephalohematoma was defined on the basis of the bump projection. Due to the uncertainty of the spontaneous resorption and the risk of calcification after 4 weeks which render the needle aspiration ineffective, puncture was performed between 2 and 4 weeks of life after coagulation evaluation and ultrasound of the skull and scalp. Puncture was performed in 43 boys (64%) and 24 (36%) girls between day 15 and day 30 after birth. The cephalohematoma maximal projection measured by ultrasound ranged from 9 to 13 mm (Q1,Q4) with a median value of 12 mm. No puncture-related complication was recorded during the intervention and at the 1-month follow-up visit.Conclusion: In newborns with large and persistent unesthetic cephalohematoma, puncture under local anesthesia with oral sucrose can be safely proposed between day 15 and day 30 after birth.What is Known:• Infant cephalohematoma is a frequent pathology of newborns, consisting of a traumatic subperiosteal hematoma of the skull. Most cephalohematomas are small and require no treatment because they spontaneously disappear within the first month.• Large and non-resorptive cephalohematomas may have significant esthetic and functional consequences.What is New:• Early puncture under local anesthesia is a safe, effective, and rapid procedure, decreasing the risk of persistent skull deformities.• Puncture can be proposed for newborns with a large (high projection and/or high angle connection) persistent anesthetic cephalohematoma, between day 15 and day 30, before spontaneous calcification.