Synoptic Reporting in Clinical Placental Pathology: A Preliminary Investigation Into Report Findings and Interobserver Agreement.

INTRODUCTION: Placental pathology is key for investigating adverse pregnancy outcomes, however, lack of standardization in reporting has limited clinical utility. We evaluated a novel placental pathology synoptic report, comparing its robustness to narrative reports, and assessed interobserver agreement. METHODS: 100 singleton placentas were included. Histology slides were examined by 2 senior perinatal pathologists and 2 pathology residents using a synoptic report (32 lesions). Historical narrative reports were compared to synoptic reports. Kappa scores were calculated for interobserver agreement between senior, resident, and senior vs resident pathologists. RESULTS: Synoptic reporting detected 169 (51.4%) lesion instances initially not included in historical reports. Amongst senior pathologists, 64% of all lesions examined demonstrated fair-to-excellent agreement (Kappa ≥0.41), with only 26% of Kappas ≥0.41 amongst those examined by resident pathologists. Well-characterized lesions (e.g., chorioamnionitis) demonstrated higher agreement, with lower agreement for uncommon lesions and those previously shown to have poor consensus. DISCUSSION: Synoptic reporting is one proposed method to address issues in placenta pathology reporting. The synoptic report generally identifies more lesions compared to the narrative report, however clinical significance remains unclear. Interobserver agreement is likely related to differential in experience. Further efforts to improve overall standardization of placenta pathology reporting are needed.

Thrombospondin-1 Plays a Major Pathogenic Role in Experimental and Human Bronchopulmonary Dysplasia.

Rationale: Extremely preterm infants develop bronchopulmonary dysplasia (BPD), a chronic lung injury that lacks effective treatment. TSP-1 (thrombospondin-1) is an antiangiogenic protein that activates TGF-ß1 (transforming growth factor-ß1), a cytokine strongly linked to both experimental and human BPD. Objectives:1) To examine effects of inhibiting TSP-1-mediated TGF-ß1 activation (LSKL [leucine-serine-lysine-leucine]) in neonatal rats with bleomycin-induced lung injury; 2) to examine effects of a TSP-1 mimic (ABT-510) on lung morphology; and 3) to determine whether TSP-1 and related signaling peptides are increased in lungs of human preterm infants at risk for BPD. Methods: From Postnatal Days 1 to 14, rat pups received daily intraperitoneal bleomycin (1 mg/kg) or vehicle and were treated with daily subcutaneous LSKL (20 mg/kg) or vehicle alone. Separate animals were treated with vehicle or ABT-510 (30 mg/kg/d). Paraffin-embedded lung tissues from 47 autopsies (controls; death <28 d, n = 30 and BPD at risk; death ⩾28 d, n = 17) performed on infants born <29 completed weeks' gestation were semiquantified for injury markers (collagen, macrophages, and 3-nitrotyrosine), TSP-1, and TGF-ß1. Measurements and Main Results: Bleomycin or ABT-510 increased lung TGF-ß1 activity and macrophage influx, caused pulmonary hypertension, and led to alveolar and microvascular hypoplasia. Treatment with LSKL partially prevented abnormal lung morphology secondary to bleomycin. Lungs from human infants at risk for BPD had increased contents of TSP-1 and TGF-ß1 when compared with controls. TGF-ß1 content correlated with markers of lung injury. Conclusions: TSP-1 inhibits alveologenesis in neonatal rats, in part via the upregulated activity of TGF-ß1. Observations in human lungs suggest a similar pathogenic role for TSP-1 in infants at risk for BPD.

Lipocalin-2 and calprotectin as stool biomarkers for predicting necrotizing enterocolitis in premature neonates.

BACKGROUND: Necrotizing enterocolitis (NEC) is a major challenge for premature infants in neonatal intensive care units and efforts toward the search for indicators that could be used to predict the development of the disease have given limited results until now. METHODS: In this study, stools from 132 very low birth weight infants were collected daily in the context of a multi-center prospective study aimed at investigating the potential of fecal biomarkers for NEC prediction. Eight infants (~6%) received a stage 3 NEC diagnosis. Their stools collected up to 10 days before diagnosis were included and matched with 14 non-NEC controls and tested by ELISA for the quantitation of eight biomarkers. RESULTS: Biomarkers were evaluated in all available stool samples leading to the identification of lipocalin-2 and calprotectin as the two most reliable predicting markers over the 10-day period prior to NEC development. Pooling the data for each infant confirmed the significance of lipocalin-2 and calprotectin, individually and in combination 1 week in advance of the NEC clinical diagnosis. CONCLUSIONS: The lipocalin-2 and calprotectin tandem represents a significant biomarker signature for predicting NEC development. Although not yet fulfilling the "perfect biomarker" criteria, it represents a first step toward it. IMPACT: Stool biomarkers can be used to predict NEC development in very low birth weight infants more than a week before the diagnosis. LCN2 was identified as a new robust biomarker for predicting NEC development, which used in conjunction with CALPRO, allows the identification of more than half of the cases that will develop NEC in very low birth weight infants. Combining more stool markers with the LCN2/CALPRO tandem such as PGE2 can further improve the algorithm for the prediction of NEC development.

Proteomics Profiling of Stool Samples from Preterm Neonates with SWATH/DIA Mass Spectrometry for Predicting Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a life-threatening condition for premature infants in neonatal intensive care units. Finding indicators that can predict NEC development before symptoms appear would provide more time to apply targeted interventions. In this study, stools from 132 very-low-birth-weight (VLBW) infants were collected daily in the context of a multi-center prospective study aimed at investigating the potential of fecal biomarkers for NEC prediction using proteomics technology. Eight of the VLBW infants received a stage-3 NEC diagnosis. Stools collected from the NEC infants up to 10 days before their diagnosis were available for seven of them. Their samples were matched with those from seven pairs of non-NEC controls. The samples were processed for liquid chromatography-tandem mass spectrometry analysis using SWATH/DIA acquisition and cross-compatible proteomic software to perform label-free quantification. ROC curve and principal component analyses were used to explore discriminating information and to evaluate candidate protein markers. A series of 36 proteins showed the most efficient capacity with a signature that predicted all seven NEC infants at least a week in advance. Overall, our study demonstrates that multiplexed proteomic signature detection constitutes a promising approach for the early detection of NEC development in premature infants.

Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects.

Primary defects in motile cilia result in dysfunction of the apparatus responsible for generating fluid flows. Defects in these mechanisms underlie disorders characterized by poor mucus clearance, resulting in susceptibility to chronic recurrent respiratory infections, often associated with infertility; laterality defects occur in about 50% of such individuals. Here we report biallelic variants in LRRC56 (known as oda8 in Chlamydomonas) identified in three unrelated families. The phenotype comprises laterality defects and chronic pulmonary infections. High-speed video microscopy of cultured epithelial cells from an affected individual showed severely dyskinetic cilia but no obvious ultra-structural abnormalities on routine transmission electron microscopy (TEM). Further investigation revealed that LRRC56 interacts with the intraflagellar transport (IFT) protein IFT88. The link with IFT was interrogated in Trypanosoma brucei. In this protist, LRRC56 is recruited to the cilium during axoneme construction, where it co-localizes with IFT trains and is required for the addition of dynein arms to the distal end of the flagellum. In T. brucei carrying LRRC56-null mutations, or a variant resulting in the p.Leu259Pro substitution corresponding to the p.Leu140Pro variant seen in one of the affected families, we observed abnormal ciliary beat patterns and an absence of outer dynein arms restricted to the distal portion of the axoneme. Together, our findings confirm that deleterious variants in LRRC56 result in a human disease and suggest that this protein has a likely role in dynein transport during cilia assembly that is evolutionarily important for cilia motility.

Gastroschisis Is Associated With Placental Delayed Villous Maturation.

Gastroschisis is a congenital abnormality characterized by visceral herniation through an abdominal wall defect. While the cause of gastroschisis is unknown, it has been linked to risk factors including young maternal age, smoking, and alcohol use during pregnancy. To date, the only established placental correlate is amniocyte vacuolization. Based on our clinical experience, we hypothesized that delayed villous maturation (DVM) is also associated with gastroschisis. We conducted a retrospective slide review of 23 placentas of neonates with gastroschisis. Additionally, we selected 2 control groups of placentas: 1 with a previous diagnosis of DVM and 1 with normal villous morphology. All placentas were randomized and reviewed by 2 perinatal pathologists, who were blinded to the group; DVM and amniocyte vacuolization were assessed. Gastroschisis was associated with increased placental DVM in 65.2% of cases (vs 13.6% of controls; P = .0007) and increased amniocyte vacuolization in 52.2% of cases (vs 9.1% of controls; P = .003) compared to the control group. Based on the normal and DVM groups, kappa agreement between current slide review and initial pathology diagnosis was 0.419, indicating moderate agreement. Our study shows that gastroschisis is associated with placental DVM. This association may be due to (1) a common upstream factor contributing to both gastroschisis and DVM or (2) DVM may be a consequence of the altered placental and amniotic environment in the context of gastroschisis.

Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis.

Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.

Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia.

BACKGROUND: Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified. OBJECTIVE: The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes. STUDY DESIGN: A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight <10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small-for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small-for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters. RESULTS: Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth-restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles. CONCLUSION: Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted.

A Case of Fulminant Bacillus cereus Lung Necrosis in a Preterm Neonate.

Bacillus cereus is a ubiquitous Gram-positive rod seldom considered pathogenic in clinical isolates. However, it possesses multiple virulence factors explaining why it has been linked to fulminant and pyogenic infections in vulnerable hosts. Its recovery from sterile samples in immunocompromised patients cannot be disregarded. Premature infants would fall into this category. We describe the case of a neonate born at 26 weeks of gestational age, who died of a rapidly progressive B. cereus necrotizing pneumonia following suspected nosocomial acquisition. The rapidity of his course and the autopsy findings of necrosis with minimal inflammation suggest a toxin-mediated process. Pathologists should be aware of this pathogen and obtain proper microbiological samples in the presence of such autopsy findings, as the diagnosis may have infection-prevention implications in health-care settings.

Recurrent Placental Transcriptional Profile With a Different Histological and Clinical Presentation: A Case Report.

Statistically, patients with severe pregnancy complications are at risk of recurrent complications, but it is less understood if patients present with similar or different placental pathologies in subsequent pregnancies. In this case report, we describe 2 consecutive adverse pregnancies in the same woman 4 years apart. The first pregnancy was diagnosed as early-onset preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, with placental maternal vascular malperfusion features, such as syncytial knots and accelerated villous maturity. In contrast, the second pregnancy was associated with normotensive fetal growth restriction and placental "immunological" lesions, such as massive perivillous fibrin deposition and chronic intervillositis. However, based on the expression of FLT1, LIMCH1, and TAP1 by quantitative polymerase chain reaction, the placentas from both pregnancies were found to exhibit an "immunological" transcriptional signature. This suggests that this small panel of gene expression markers may be able to predict the future reoccurrence of an immunological placental pathology despite no histological evidence within the first pregnancy. These results call for more studies looking at paired pregnancies of individuals with recurrent obstetric complications and confirm the importance of assessing matched transcriptional and histopathological placental information.

The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology.

BACKGROUND: Preeclampsia is a life-threatening disorder of pregnancy, demonstrating a high degree of heterogeneity in clinical features such as presentation, disease severity, and outcomes. This heterogeneity suggests distinct pathophysiological mechanisms may be driving the placental disease underlying this disorder. Our group recently reported distinct clusters of placental gene expression in preeclampsia and control pregnancies, allowing for the identification of at least 3 clinically relevant gene expression-based subtypes of preeclampsia. Histopathological examination of a small number of samples from 2 of the gene expression-based subtypes revealed placental lesions consistent with their gene expression phenotype, suggesting that detailed placental histopathology may provide further insight into the pathophysiology underlying these distinct gene expression-based subtypes. OBJECTIVES: The objective of the study was to assess histopathological lesions in the placentas of patients belonging to each identified gene expression-based subtype of preeclampsia, characterized in our previous study. Our goal was to further understand the pathophysiologies defining these gene expression-based subtypes by integrating gene expression with histopathological findings, possibly identifying additional subgroups of preeclampsia patients. STUDY DESIGN: Paraffin-embedded placental biopsies from patients included in the gene expression profiling study (n = 142 of 157, 90.4%) were sectioned, hematoxylin and eosin stained, and imaged. An experienced perinatal pathologist, blinded to gene expression findings and clinical information, assessed the presence and severity of histological lesions using a comprehensive, standardized data collection form. The frequency and severity scores of observed histopathological lesions were compared among gene expression-based subtypes as well as within each subtype using using Fisher exact tests, Kruskal-Wallis tests, and hierarchical clustering. The histological findings of the placental samples were visualized using t-distributed stochastic neighbor embedding and phylogenetic trees. Concordance and discordance between gene expression findings and histopathology were also investigated and visualized using principal component analysis. RESULTS: Several histological lesions were found to be characteristic of each gene expression-based preeclampsia subtype. The overall concordance between gene expression and histopathology for all samples was 65% (93 of 142), with characteristic placental lesions for each gene expression-based subtype complementing prior gene enrichment findings (ie, placentas with enrichment of hypoxia-associated genes showed severe lesions of maternal vascular malperfusion). Concordant samples were located in the central area of each gene expression-based cluster when viewed on a principal component analysis plot. Interestingly, discordant samples (gene expression and histopathology not reflective of one another) were generally found to lie at the periphery of the gene expression-based clusters and tended to border the group of patients with phenotypically similar histopathology. CONCLUSION: Our findings demonstrates a high degree of concordance between placental lesions and gene expression across subtypes of preeclampsia. Additionally, novel integrative analysis of scored placental histopathology severity and gene expression findings allowed for the identification of patients with intermediate phenotypes of preeclampsia not apparent through gene expression profiling alone. Future investigations should examine the temporal relationship between these 2 modalities as well as consider the maternal and fetal contributions to these subtypes of disease.

Impaired antimicrobial response and mucosal protection induced by ibuprofen in the immature human intestine.

BACKGROUND: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (INDO) and ibuprofen (IBU) has been shown to be an effective therapy for the closure of patent ductus arteriosus (PDA). However, this treatment has been associated with an increased risk of developing enteropathies in neonates. Whether the use of IBU is safer than INDO for the immature intestine remains to be elucidated. METHODS: The direct impact of IBU on the human immature intestinal transcriptome was investigated using serum-free organ culture. Differentially expressed genes were analyzed with Ingenuity Pathway Analysis software and compared with those previously reported with INDO. Validation of differentially expressed genes was confirmed by qPCR. RESULTS: We identified several biological processes that were significantly modulated by IBU at similar levels to what had previously been observed with INDO, while the expression of genes involved in "antimicrobial response" and "mucus production" was significantly decreased exclusively by IBU in the immature intestine. CONCLUSIONS: Our findings indicate that IBU has a harmful influence on the immature intestine. In addition to exerting many of the INDO observed deleterious effects, IBU alters pathways regulating microbial colonization and intestinal epithelial defense.

Prenatally Diagnosed Infant AML.

We report the first case of a fetus with acute myeloid leukemia, without Down syndrome, diagnosed in utero. A cordocentesis sample prepared to investigate hepatomegaly led to further evaluations revealing acute myeloid leukemia, monocytic type, in the fetus. Cytogenetic analysis showed mixed lineage leukemia duplication, no gene disruption or trisomy. Planned treatment included intrauterine exchange transfusion to extend gestation, low-dose chemotherapy at birth, and full chemotherapy once stable. Before any intervention, the child was delivered emergently for maternal condition and died 2 hours later. Although it is now possible to diagnose hematologic malignancy in a fetus, there is little information to direct management.

Apparent Diffusion Coefficient of the Placenta in Twin versus Singleton Pregnancies.

Previous studies in singleton pregnancies reported conflicting trends in apparent diffusion coefficient (ADC) values with gestational age (GA) and stable relative ADC (rADC; ADC placenta divided by ADC globe) throughout pregnancy. The purpose of our study was to compare the ADC and rADC of placentas of twin and singleton pregnancies. MATERIALS AND METHODS: Fetal MRI of 11 twin and 23 singleton pregnancies were retrospectively analyzed. Each group was further divided by GA (≤24 and >24 weeks). On ADC, 3 regions of interest were selected in the placenta and 1 in the globe. ADC and rADC measurements were compared between different GA and between singleton and twin placentas. RESULTS: No significant difference was shown between ADC and rADC values of singleton and twin placentas as well as between ADC and rADC values of singleton and twin placentas at different GA. No significant difference was shown when accounting for both GA and number of fetuses. CONCLUSION: The diffusion characteristics of twin placentas are similar to those of singleton placentas. ADC and rADC remain stable throughout pregnancy in twin and singleton placentas, reflecting stable extracellular water diffusion, despite changes associated with placental maturation.

The nitric oxide synthase 2 pathway is targeted by both pro- and anti-inflammatory treatments in the immature human intestine.

BACKGROUND AND AIM: NO synthase 2 (NOS2) was recently identified as one the most overexpressed genes in intestinal samples of premature infants with necrotizing enterocolitis (NEC). NOS2 is widely implicated in the processes of epithelial cell injury/apoptosis and host immune defense but its specific role in inflammation of the immature human intestinal mucosa remains unclear. Interestingly, factors that prevent NEC such as epidermal growth factor (EGF) attenuate the inflammatory response in the mid-gestation human small intestine using serum-free organ culture while drugs that are associated with NEC occurrence such as the non-steroidal anti-inflammatory drug, indomethacin (INDO), exert multiple detrimental effects on the immature human intestine. In this study we investigate the potential role of NOS2 in modulating the gut inflammatory response under protective and stressful conditions by determining the expression profile of NOS2 and its downstream pathways in the immature intestine. METHODS: Gene expression profiles of cultured mid-gestation human intestinal explants were investigated in the absence or presence of a physiological concentration of EGF (50 ng/ml) or 1 µM INDO for 48 h using Illumina whole genome microarrays, Ingenuity Pathway Analysis software and quantitative PCR to investigate the expression of NOS2 and NOS2-pathway related genes. RESULTS: In the immature intestine, NOS2 expression was found to be increased by EGF and repressed by INDO. Bioinformatic analysis identified differentially regulated pathways where NOS2 is known to play an important role including citrulline/arginine metabolism, epithelial cell junctions and oxidative stress. At the individual gene level, we identified many differentially expressed genes of the citrulline/arginine metabolism pathway such as ARG1, ARG2, GLS, OAT and OTC in response to EGF and INDO. Gene expression of tight junction components such as CLDN1, CLDN2, CLDN7 and OCN and of antioxidant markers such as DUOX2, GPX2, SOD2 were also found to be differentially modulated by EGF and INDO. CONCLUSION: These results suggest that the protective effect of EGF and the deleterious influence of INDO on the immature intestine could be mediated via regulation of NOS2. Pathways downstream of NOS2 involved with these effects include metabolism linked to NO production, epithelial barrier permeability and antioxidant expression. These results suggest that NOS2 is a likely regulator of the inflammatory response in the immature human gut and may provide a mechanistic basis for the protective effect of EGF and the deleterious effects of INDO.

H3.1 K36M mutation in a congenital-onset soft tissue neoplasm.

We describe a patient who presented with a congenital soft tissue lesion initially diagnosed as infantile fibromatosis at 15 days of age. Unusually, the mass demonstrated malignant progression leading to death at 20 months of age. Biological progression to malignancy is not known to occur in fibromatosis, and fibrosarcoma is not known to progress from a benign lesion. Whole-exome sequencing of the tumor identified a driver mutation in histone H3.1 at lysine (K)36. Our findings support the link between oncohistones and infantile soft tissue tumors and provide additional evidence for the oncogenic effects of p.K36M in H3 variants.

Recurrent Massive Perivillous Fibrin Deposition and Chronic Intervillositis Treated With Heparin and Intravenous Immunoglobulin: A Case Report.

BACKGROUND: Massive perivillous fibrin deposition (MPVFD) and chronic intervillositis (CI) are related rare pathological correlates of severe intrauterine growth restriction (IUGR) and fetal loss with high recurrence rates. No standard management has been established. CASE: A patient underwent termination of pregnancy at 21 weeks for severe early onset IUGR. Placental histology showed mixed CI with MPVFD. Several months later, the patient became pregnant and was managed with prednisone and aspirin (ASA) but miscarried at 16 weeks. Placental pathology showed MPVFD and focal CI. For two subsequent pregnancies, she was treated with intravenous immunoglobulin (IVIG), heparin, and ASA. Both pregnancies resulted in healthy near-term deliveries with normal placentas. CONCLUSION: IVIG, heparin, and ASA can be an option in patients with recurrent pregnancy loss due to MPVFD and CI.

Atypical fibrodysplasia ossificans progressiva diagnosed by whole-exome sequencing.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissue that begins during the first decade of life. Our patient presented with intrauterine growth retardation, respiratory distress, neonatal onset soft tissue masses, bilateral hallux valgus, and congenital anomalies of the thyroid and uterus. She was initially diagnosed with atypical infantile myofibromatosis based on clinical and pathological findings. She underwent whole-exome sequencing (WES) as part of the FORGE study to identify the gene for infantile myofibromatosis; however a de novo dominant mutation in ACVR1 (NM_001105.4:c.617G>A) revised the diagnosis to FOP. This patient highlights the utility of WES as an early diagnostic tool in the investigation of patients with unusual presentations of rare diseases, thereby providing clinicians with accurate molecular diagnoses and the opportunity to tailor clinical management to improve patient care.

Leukemia cutis and facial nerve palsy as presenting symptoms of acute lymphoblastic leukemia.

Leukemia cutis and facial nerve palsy are rare presenting symptoms of leukemia. This report describes a case of acute T-cell lymphoblastic leukemia (ALL) presenting with only these two symptoms, a presentation of ALL that, to our knowledge, has not been previously described. It serves to alert physicians to look for underlying malignancy in the setting of cutaneous findings associated with facial nerve palsy.