Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

Neonatal Abstinence Syndrome among Infants Born to Mothers with Sickle Cell Hemoglobinopathies.

OBJECTIVE: The objective of this study is to examine risk factors for neonatal abstinence syndrome (NAS) among infants born to mothers with sickle cell hemoglobinopathies (SCH). STUDY DESIGN: Retrospective cohort study of nonanomalous, singleton infants born to mothers with laboratory confirmed SCH. Infants were included if they were diagnosed with NAS prior to hospital discharge. The outcome of interest was the association of maternal variables with NAS. RESULTS: Of 131 infants born to mothers with SCH, 4% (n = 5) were diagnosed with NAS. Mothers of infants with NAS were more likely to have SC disease (80%) compared with other SCH (20%), p = 0.001. Fifteen women had antepartum (AP) admissions for pain and/or sickle crisis. Of these patients, four infants (29%) were diagnosed with NAS. The median (5th and 95th percentile) maternal AP length of stay for women with infants diagnosed with NAS to mothers with sickle cell disease was 132 (5, 180) days (p = 0.02). CONCLUSION: Incidence of NAS among mothers with SCH is low; severe disease characterized by AP sickle cell crisis requiring prolonged AP admission for pain control significantly increases the risk of NAS. Further studies are needed to investigate the association of maternal opioid dose and NAS.

Developmental considerations with regard to so-called absence of the leaflets of the arterial valves.

BACKGROUND: Absent arterial valve leaflets are rare anomalies. On the basis of our understanding of the normal development of the arterial valves, we draw inferences that might offer clues to their morphogenesis. METHODS: We describe the findings from four human fetal autopsies with so-called "absent" arterial valvar leaflets. We then make inferences relative to these finding on the basis of our current understanding of normal development, the latter obtained by analysis of episcopic data sets from a large series of mouse embryos. RESULTS: The fetuses had died between 12 and 15 weeks of gestation. In two cases, we found absence of the leaflets of the pulmonary valve, with patency of the arterial duct, but otherwise normal hearts. In a third case, there was absence of the leaflets of both arterial valves, along with a perimembranous ventricular septal defect and a "window-type" arterial duct. This fetus had a completely muscular subaortic infundibulum. The last fetus had a pulmonary dominant common arterial trunk, with absence of the truncal valvar leaflets, but again with a muscular subtruncal infundibulum. Findings from the analysis of the mouse embryos reveal that the arterial valvar leaflets are formed from the distal outflow cushions, but that the cushions have a separate function in septating the arterial roots and the proximal outflow tracts. CONCLUSIONS: When interpreting the fetal findings in the light of development, we conclude that there had been normal fusion of the major outflow cushions, but failure in excavation of their peripheral margins in three of the cases. In the fourth case, however, the cushions had not only failed to excavate but had also failed to separate the arterial roots.

Congenital coronary artery anomalies for the pathologist.

Congenital coronary artery anomalies are rare. Pathologists are exposed to those in mainly two settings; in association with sudden death and usually extreme exercise in young adults, and in association with complex congenital heart disease in the pediatric and perinatal population. Pediatric pathologists, other pathologists and pathologists' assistants performing pediatric or forensic autopsies therefore need to be familiar with coronary artery anomalies.

A Large Postmortem Database of COVID-19 Patients Can Inform Disease Research and Public Policy Decision Making.

CONTEXT.­: Autopsies performed on COVID-19 patients have provided critical information about SARS-CoV-2's tropism, mechanisms of tissue injury, and the spectrum of disease. OBJECTIVE.­: To provide an updated database of postmortem disease in COVID-19 patients, assess relationships among clinical and pathologic variables, evaluate the accuracy of death certification, and correlate disease variables to causes of death. DESIGN.­: The 272 postmortem examinations reported in this paper were submitted by 14 pathologists from 9 medical or forensic institutions across the United States. The study spans the eras of the 3 principal COVID-19 strains and incorporates surveyed demographic, clinical, and postmortem data from decedents infected with SARS-CoV-2, including primary and contributing causes of death. It is the largest database of its kind to date. RESULTS.­: Demographics of the decedents reported here correspond well to national statistics. Primary causes of death as determined by autopsy and official death certificates were significantly correlated. When specifically cited disease conditions found at autopsy were correlated with COVID-19 versus non-COVID-19 death, only lung findings characteristic of SARS-CoV-2 infection or the absence of lung findings were significantly associated. CONCLUSIONS.­: Changes in hospitalization and disease likely stem from longer lifespans after COVID-19 diagnosis and alteration in treatment approaches. Although Omicron variants preferentially replicate in the upper airways, autopsied patients who died of COVID-19 in that time period showed the same lung damage as earlier decedents. Most importantly, findings suggest that there are still unelucidated risk factors for death from COVID-19 including possibly genetic susceptibility.

Giant Placental Chorangioma and Severe Ductal Arch Constriction: A Case Report With a Favorable Outcome.

Giant chorangiomas are uncommon yet frequently associated with adverse pregnancy outcomes. A 37-year-old female was referred due to findings of a placental mass during a second-trimester ultrasound. A fetal survey at 26 weeks revealed a 69×97×75 mm heterogenous placental tumor with two prominent feeding vessels. Her prenatal course was complicated by worsening polyhydramnios requiring amnioreduction, gestational diabetes, and transient severe ductal arch (DA) constriction. Placental pathology confirmed the diagnosis of giant chorioangioma following delivery at 36 weeks. To our knowledge, this represents the first case of DA constriction in the setting of a giant chorangioma.

De novo translocation t(5;9)(q11.2;p22) associated with hydrops fetalis and cystic hygroma.

We report on a case of a prenatally diagnosed non-immune hydrops fetalis and cystic hygroma associated with the balanced translocation t(5;9)(q11.2;p22), an association that to our knowledge has not been reported previously. Both parents had normal karyotypes. The infant was born prematurely at 33 and 3/7 weeks gestation and expired 12 h after delivery.

Regulation of Proinflammatory Molecules and Tissue Factor by SARS-CoV-2 Spike Protein in Human Placental Cells: Implications for SARS-CoV-2 Pathogenesis in Pregnant Women.

SARS-CoV-2 infects cells via binding to ACE2 and TMPRSS2, which allows the virus to fuse with host cells. The viral RNA is detected in the placenta of SARS-CoV-2-infected pregnant women and infection is associated with adverse pregnancy complications. Therefore, we hypothesize that SARS-CoV-2 infection of placental cells induces pro-inflammatory cytokine release to contribute to placental dysfunction and impaired pregnancy outcomes. First, expression of ACE2 and TMPRSS2 was measured by qPCR in human primary cultured term cytotrophoblasts (CTBs), syncytiotrophoblast (STBs), term and first trimester decidual cells (TDCs and FTDCs, respectively), endometrial stromal cells (HESCs) as well as trophoblast cell lines HTR8, JEG3, placental microvascular endothelial cells (PMVECs) and endometrial endothelial cells (HEECs). Later, cultured HTR8, JEG3, PMVECs and HEECs were treated with 10, 100, 1000 ng/ml of recombinant (rh-) SARS-CoV-2 S-protein ± 10 ng/ml rh-IFNγ. Pro-inflammatory cytokines IL-1ß, 6 and 8, chemokines CCL2, CCL5, CXCL9 and CXCL10 as well as tissue factor (F3), the primary initiator of the extrinsic coagulation cascade, were measured by qPCR as well as secreted IL-6 and IL-8 levels were measured by ELISA. Immunohistochemical staining for SARS-CoV-2 spike protein was performed in placental specimens from SARS-CoV-2-positive and normal pregnancies. ACE2 levels were significantly higher in CTBs and STBs vs. TDCs, FTDCs and HESCs, while TMPRSS2 levels were not detected in TDCs, FTDCs and HESCs. HTR8 and JEG3 express ACE2 and TMPRSS2, while PMVECs and HEECs express only ACE2, but not TMPRSS2. rh-S-protein increased proinflammatory cytokines and chemokines levels in both trophoblast and endothelial cells, whereas rh-S-protein only elevated F3 levels in endothelial cells. rh-IFNγ ± rh-S-protein augments expression of cytokines and chemokines in trophoblast and endothelial cells. Elevated F3 expression by rh-IFNγ ± S-protein was observed only in PMVECs. In placental specimens from SARS-CoV-2-infected mothers, endothelial cells displayed higher immunoreactivity against spike protein. These findings indicated that SARS-CoV-2 infection in placental cells: 1) induces pro-inflammatory cytokine and chemokine release, which may contribute to the cytokine storm observed in severely infected pregnant women and related placental dysfunction; and 2) elevates F3 expression that may trigger systemic or placental thrombosis.

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.

Clinicopathologic conference: multiple fetal demises, lactic acidosis and hepatic iron accumulation.

A case of a premature infant with lactic acidosis and hepatic iron accumulation, born to a mother with multiple fetal demises, is presented and discussed by both clinician and pathologist, in this traditional clinico-pathologic conference. The discussion includes the differential diagnoses of lactic acidosis and hepatic iron accumulation in infants.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

CONTEXT.­: This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. OBJECTIVE.­: To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. DESIGN.­: Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. RESULTS.­: Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. CONCLUSIONS.­: Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

Spondyloepiphyseal dysplasia congenita.

We report a case of spondyloepiphyseal dysplasia congenita (SED congenita), diagnosed at autopsy of a term infant. Prenatal ultrasound at 20 weeks of gestation had shown shortening of all the fetal long bones, with bowing of the femora and humeri, clubfeet, and small thoracic cage. We discuss the diagnostic features of SED and the main differential diagnoses.

A Rare Presentation of Common Arterial Trunk with Intact Ventricular Septum.

Common arterial trunk is a rare anomaly on its own, but with an intact ventricular septum it is extremely rare. An unexpected finding at autopsy prompted a review of the literature and a review of the developmental considerations associated with the outflow tracts. The case presented was an intrauterine fetal death at 37 weeks gestation. At autopsy, the only anatomic abnormalities were pulmonary dominant common arterial trunk with an intact ventricular septum, ventriculo-arterial septal defect, coarctation and widely patent arterial duct. A review of the literature and the developmental concepts related to the outflow tracts of the developing heart demonstrate the rare nature of this particular variation of common arterial trunk.

Discordant omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex and cardiac malformations in monochorionic twins.

The omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex was first described by Carey et al. in 1978. It constitutes a specific combination of malformations. There are very few case reports of discordant OEIS in monozygotic twins and very few reports of OEIS in association with both hypoplastic left heart and ventricular septal defect. Our case represents the fifth reported case of cardiac malformations in a fetus with OEIS complex.

Congenital perineal hernia in a fetus with trisomy 18.

Perineal hernias are very rare and mostly reported in adults, with only 7 cases reported in children. We report a female fetus, terminated at 18 weeks of gestation due to trisomy 18. In addition to multiple typical findings of trisomy 18, this fetus had perineal hernia with defect of the perineal skin and prolapse of multiple bowel loops. To our knowledge there are no reported cases of perineal hernia presenting antenatally nor are there reported cases of perineal hernia associated with trisomy 18.

Massive pericardial effusion treated with in utero pericardioamniotic shunt in a fetus with intrapericardial teratoma.

Teratoma is the leading neoplasm diagnosed in neonates and infants. Although over 99% of teratomas found in the fetus and newborn are histologically benign, those tumors may cause death if vital structures are involved or if the airway is compromised. We review the literature on antenatal intrapericardial teratomas and report a case of intrapericardial teratoma, with massive pericardial effusion and fetal hydrops, diagnosed on antenatal ultrasound at 21 weeks of gestation. Pericardioamniotic shunt was placed at 22 weeks and 6 days gestational age. In spite of successful drainage of the pericardial effusion, fetal demise was documented 8 days later, likely due to tumor compression of the heart.

Aromatase may play a critical role in the pathogenesis of juvenile nasopharyngeal angiofibroma.

The pathophysiology of juvenile nasopharyngeal angiofibroma (JNA) has yet to be fully elucidated, but the influence of steroid hormones in their growth has been suggested. This neoplasm is known to afflict adolescent males. However, only a minority of the neoplastic cells express androgen receptors. The expression of estrogen receptor beta by the tumor cells recently has been demonstrated. Aromatase (P450) is an enzyme which is responsible for converting androgens to estrogens. However, the rule of aromatase in the pathogenesis of JNA is unknown. In this study we attempt to explain the hormone-induced growth theory by characterizing the aromatase (P450) in JNA. We examined five sinonasal JNA from adolescent males, all of which stained positive for aromatase. We propose that this enzyme is responsible for the local conversion of androgens into estrogens, which subsequently bind to the estrogen receptors leading to the growth of these tumors.

Thirteen-year-old child with a malignant chest tumor: clinicopathologic conference.

A case of pleuropulmonary blastoma in a 13-year-old child, exposed to the Chernobyl disaster while in-utero, is presented and discussed by both clinician and pathologist, in this traditional clinical-pathologic conference. The discussion includes the differential diagnoses of chest mass in children.