Osteogenesis Imperfecta: Multidisciplinary and Goal-Centered Care.

We describe a case of osteogenesis imperfecta (OI) in a late preterm female of 35-week gestation. The mother did have a history of substance abuse, poor prenatal care, and hypertension. On the day of delivery, an ultrasound revealed skeletal dysplasia and breech with nonreassuring fetal tracing, leading to an emergency cesarean. The clinical exam was concerning for OI, and postnatal care was focused on optimizing respiratory status and minimizing pain and discomfort during routine care. Genetics, endocrine, orthopaedics, and palliative care were all involved to diagnose and educate the family. Support and education were needed for bedside staff to minimize angst at performing routine care, given the high risk of fractures. While initially stable on minimal oxygen, once the diagnosis of type III OI was made, a progressively deforming condition with respiratory status decompensation, the family wished to minimize suffering, limited aggressive medical care, and focused on comfort. The infant eventually died from respiratory failure in the neonatal intensive care unit. We present this case to demonstrate the need for an interdisciplinary team approach to support both family and staff in cases of OI.

Osteogenesis Imperfecta: Multidisciplinary and Goal-Centered Care.

We describe a case of osteogenesis imperfecta (OI) in a late preterm female of 35-week gestation. The mother did have a history of substance abuse, poor prenatal care, and hypertension. On the day of delivery, an ultrasound revealed skeletal dysplasia and breech with nonreassuring fetal tracing, leading to an emergency cesarean. The clinical exam was concerning for OI, and postnatal care was focused on optimizing respiratory status and minimizing pain and discomfort during routine care. Genetics, endocrine, orthopaedics, and palliative care were all involved to diagnose and educate the family. Support and education were needed for bedside staff to minimize angst at performing routine care, given the high risk of fractures. While initially stable on minimal oxygen, once the diagnosis of type III OI was made, a progressively deforming condition with respiratory status decompensation, the family wished to minimize suffering, limited aggressive medical care, and focused on comfort. The infant eventually died from respiratory failure in the neonatal intensive care unit. We present this case to demonstrate the need for an interdisciplinary team approach to support both family and staff in cases of OI.

cellmlmanip and chaste_codegen: automatic CellML to C++ code generation with fixes for singularities and automatically generated Jacobians.

Hundreds of different mathematical models have been proposed for describing electrophysiology of various cell types. These models are quite complex (nonlinear systems of typically tens of ODEs and sometimes hundreds of parameters) and software packages such as the Cancer, Heart and Soft Tissue Environment (Chaste) C++ library have been designed to run simulations with these models in isolation or coupled to form a tissue simulation. The complexity of many of these models makes sharing and translating them to new simulation environments difficult. CellML is an XML format that offers a widely-adopted solution to this problem. This paper specifically describes the capabilities of two new Python tools: the cellmlmanip library for reading and manipulating CellML models; and chaste_codegen, a CellML to C++ converter. These tools provide a Python 3 replacement for a previous Python 2 tool (called PyCML) and they also provide additional new features that this paper describes. Most notably, they can generate analytic Jacobians without the use of proprietary software, and also find singularities occurring in equations and automatically generate and apply linear approximations to prevent numerical problems at these points.

Placental mesenchymal dysplasia: An underdiagnosed placental pathology with various clinical outcomes.

BACKGROUND: Placental mesenchymal dysplasia (PMD) is a rare vascular and connective placental anomaly, which is often associated with severe fetal and/or maternal complications. The diversity of presentation of PMD challenges diagnosis and effective pregnancy management. OBJECTIVE: We aimed to review cases presenting at 7 tertiary centers worldwide over the last decade and to study the occurrence of obstetric and neonatal complications. STUDY DESIGN: Pathology databases from 7 tertiary hospitals were screened for cases of PMD (between 2007-2017). Pregnancy history, outcomes and ultrasound images were then reviewed for each case. RESULTS: Twenty-two cases of PMD were identified. Mean gestational age at diagnosis was 23 weeks (16-39 weeks). Prenatal biochemical screening was abnormal in 8 cases (36%). Of the 12 cases that underwent invasive genetic testing, 4 were abnormal. Six patients (27%) developed maternal complications (preeclampsia/gestational hypertension). Fetal growth restriction was identified in 11 cases (50%) and fetal death in 4 (18%). Four (18%) pregnancies were terminated, 9/14 (64%) delivered preterm and only three (14%) progressed normally. Fourteen babies were born alive; 5 (35%) died in the first sixty-one days after birth, 5 (35%) had transient thrombopenia and 1 (7%) had developmental delay at last follow-up. Our series identified four potential new associations with PMD: placental triploidy mosaicism, CHARGE syndrome, fetal pleuropulmonary blastoma and fetal skeletal dysplasia. CONCLUSIONS: PMD was substantially under-diagnosed before delivery in this cohort. Sonographers, fetal medicine specialists, obstetricians and pathologists should all suspect PMD in cases of an enlarged placenta and should look for fetal abnormalities. Diagnostic genetic testing should be discussed to exclude partial molar pregnancy. Close pregnancy follow-up is indicated due to the high risk of associated fetal or maternal adverse outcomes.

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy.

Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56+CD16- dNK among the total CD45+ leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. Furthermore, the degranulation capacity of dNK cells, as assessed by CD107a, was decreased in the second trimester. We suggest that in the first trimester, trophoblast-dNK interactions generate a population of dNK cells with a suppressed activating phenotype. In the second trimester, the loss of trophoblast-dNK interactions led to the inhibition of dNK cell function, although their activating receptor expression was increased. We speculate that during pregnancy, two mechanisms operate to modulate the dNK cell activation:suppression of activating receptor levels in the first trimester by trophoblasts and disengagement of receptor-ligand coupling in the second trimester.

The Placental Distal Villous Hypoplasia Pattern: Interobserver Agreement and Automated Fractal Dimension as an Objective Metric.

The distal villous hypoplasia (DVH) pattern is a placental correlate of fetal growth restriction. Because the pattern seems to involve less complexity than do appropriately developed placental villi, we postulated that it may be associated with lower fractal dimension-a mathematical measure of complexity. Our study objectives were to evaluate interobserver agreement related to the DVH pattern among expert pathologists and to determine whether pathologist classification of DVH correlates with fractal dimension. A study set of 30 images of placental parenchyma at ×4 magnification was created by a single pathologist from a digital slide archive. The images were graded for the DVH pattern according to pre-specified definitions and included 10 images graded as "no DVH" (grade  =  0), 10 with mild to moderate DVH (grade  =  1), and 10 with severe DVH (grade  =  2). The images were randomly sorted and shown to a panel of 4 international experts who similarly graded the images for DVH. Weighted kappas were calculated. For each image, fractal dimension was calculated by the Box Counting method. The correlation coefficient between (1) the averaged DVH scores obtained by the 5 pathologists and (2) fractal dimension was calculated. The mean weighted kappa score among the observers was 0.59 (range: 0.42-0.70). The correlation coefficient between fractal dimension and the averaged DVH score was -0.915 (P < 0.001). Expert pathologists achieve fair to substantial agreement in grading DVH, indicating consensus on the definition of DVH. Distal villous hypoplasia correlates extremely well with fractal dimension and represents an objective measure for DVH.

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.

SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools.

BACKGROUND: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. RESULTS: We present the Systems Biology Markup Language (SBML) Qualitative Models Package ("qual"), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. CONCLUSIONS: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks.

Dyssegmental dysplasia, Silverman-Handmaker type: prenatal ultrasound findings and molecular analysis.

OBJECTIVES: The objective of this study is to describe the prenatal sonographic features and the results of DNA analysis on three fetuses with dyssegmental dysplasia, Silverman-Handmaker type (DD-SH). METHODS: A retrospective review of three fetuses with confirmed DD-SH was conducted. The fetal ultrasound findings, the radiological characteristics, and the results of the mutation analysis of the heparan sulphate perlecan gene 2 (HSPG2) were reviewed. RESULTS: There were three cases in two families with DD-SH diagnosed prenatally. The main prenatal ultrasound and the radiological features of DD-SH were severe limb shortening and vertebral segmentation and fusion defects (anisospondyly). The DNA analysis of the HSPG2 gene showed that the two affected fetuses in a nonconsanguineous family had a compound heterozygote for the c.646G > T transversion in exon 7 and a c.5788C > T transition in exon 46. The fetus born to the consanguineous couple had a homozygous mutation c.1356-27_1507 + 59del. CONCLUSION: DD-SH can be diagnosed prenatally using fetal ultrasound as early as 13 weeks. Xrays and DNA analysis of the HSPG2 gene are important for the confirmation of the diagnosis and for the preimplantation and prenatal diagnosis in pregnancies at risk.

Multidisciplinary management of invasive placenta previa.

OBJECTIVE: To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. METHODS: We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). RESULTS: All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). CONCLUSION: Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.

Objectif : Évaluer l'efficacité d'une approche d'équipe multidisciplinaire visant l'atténuation de la morbidité maternelle grave chez les femmes qui présentent un placenta prævia invasif. Méthodes : Nous avons mené une étude prospective auprès de 33 femmes qui présentaient un placenta prævia et increta-percreta (diagnostiqué par échographie et/ou imagerie par résonance magnétique) et qui accouchaient au Mount Sinai Hospital de Toronto, à la suite du lancement (en janvier 2008) d'une approche d'équipe visant les femmes qui présentaient une telle placentation. Nous avons inclus les accouchements chez les femmes visées jusqu'en juin 2012. Nous avons analysé les dossiers prénataux (services externes et services hospitaliers) en vue d'y repérer l'utilisation par l'obstétricien titulaire de six composantes d'équipe prédéfinies : (1) consultation prénatale en médecine fœto-maternelle; (2) consultation en chirurgie gynécologique; (3) IRM prénatale; (4) consultation en radiologie interventionnelle et mise en place préopératoire de sondes à ballonnet dans les divisions antérieures des artères iliaques internes; (5) planification à l'avance de la date de chirurgie; et (6) chirurgie menée par des membres de l'équipe chirurgicale vouée aux cas de placenta invasif. Les détails de l'évolution prénatale, de l'accouchement et de la période postpartum ont été consignés afin d'établir un score composite de morbidité maternelle grave en cinq points fondé sur la présence ou l'absence de ce qui suit : (1) admission à l'USI à la suite de l'accouchement; (2) transfusion de plus de deux unités de sang; (3) anesthésie générale (administration ou conversion); (4) temps opératoire se situant dans le quartile le plus élevé (> 125 minutes); et (5) complications postopératoires significatives (réhospitalisation, hospitalisation postpartum prolongée et/ou embolie pulmonaire). Résultats : Les 33 participantes ont survécu au cours de cette période. Les deux tiers (22/33) d'entre elles présentaient cinq ou six des six composantes des soins multidisciplinaires. L'utilisation croissante des composantes des soins multidisciplinaires a été associée à une baisse significative de la morbidité composite (R2 = 0,228, P = 0,005). Conclusion : L'évaluation et la prise en charge en équipe des femmes qui présentent un placenta prævia invasif sont susceptibles d'améliorer les issues maternelles et devraient être favorisées sur une base régionale.

Broadening the ciliopathy spectrum: motile cilia dyskinesia, and nephronophthisis associated with a previously unreported homozygous mutation in the INVS/NPHP2 gene.

Nephronophthisis associated ciliopathies (NPHP-AC) are a group of phenotypically related conditions that include Joubert syndrome, Meckel syndrome, nephronophthisis (NPHP), and Senior-Loken syndrome. We report on a male fetus with prenatal ultrasound findings at 24 weeks of gestation of anhydramnios, large and echogenic kidneys and situs inversus totalis. Histopathology revealed nephronophthisis and tracheal mucosa electron microscopy revealed ciliary dysgenesis. DNA analysis of the NPHP genes showed a previously unreported homozygous mutation, p.Arg603* (c.1078+1G>A), in the INVS/NPHP2 gene. This mutation is thought to abolish the splice donor site for exon 8, which likely disrupts the normal splicing of the INVS/NPHP2 gene.

Neuropathology of fetal stage Seckel syndrome: a case report providing a morphological correlate for the emerging molecular mechanisms.

Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Pathological descriptions of fetal stage Seckel syndrome are rare and pre-date the evolving understanding of the genetic and molecular mechanisms involved. The autopsy findings in a case of fetal Seckel syndrome at 30 weeks gestation are presented, with detailed description of the neuropathological findings. Severe neurological abnormalities in a male fetus were observed that included microencephaly, cortical neuronal migration disorder, white matter tract hypoplasia/aplasia, premature depletion of the germinal matrix with cystic transformation and patchy absence of the external granular cell layer of the cerebellum. The striking neuropathological finding in this case was evidence of failure of the developing brain's germinal elements, providing rare morphological insight into the abnormal development of the Seckel syndrome fetal brain. The selective failure of this proliferating cell population correlates with the emerging molecular evidence that Seckel syndrome is caused by defects in ATR-dependent DNA damage signaling with resultant premature death of proliferating cells.

WNT2 promoter methylation in human placenta is associated with low birthweight percentile in the neonate.

Neonates with birthweights below the tenth percentile for gestational age are considered small for gestational age (SGA). Such infants have an increased risk for perinatal mortality and morbidity as well as an increased lifetime risk for adult onset disorders. Low birth weight percentile is etiologically heterogeneous and may result from maternal, fetal, placental and environmental factors. However, the molecular determinants of human SGA are not well elucidated. We proposed that fetal growth potential could be negatively impacted by the epigenetic dysregulation of specific genes in the placenta. Using methyl DNA immunoprecipitation coupled with Agilent CpG island microarrays, we analyzed the differences in DNA methylation between placentas of eight SGA neonates and eight controls with birthweight percentiles above the tenth percentile. We identified several candidate genomic regions with differential DNA methylation between the two groups. The DNA methylation differences identified in the promoter of the WNT2 gene were prioritized for further study in an extended cohort of 170 samples given the important function of this gene in mouse placental development and its high expression in human placenta. High WNT2 promoter methylation (WNT2PrMe) was found only in placental tissue and not in the cord blood of the fetus. It was significantly associated with reduced WNT2 expression in placenta and with low birthweight percentile in the neonate. Our results show that WNT2 expression can be epigenetically downregulated in the placenta by DNA methylation of its promoter and that high WNT2PrMe is an epigenetic variant that is associated with reduced fetal growth potential. Note: All of the array data in the manuscript can be accessed from the Gene Expression Omnibus (GEO) NCBI database under GEO accession number GSE22326.

PTPN11 gene mutation associated with abnormal gonadal determination.

Germline mutations in the PTPN11 gene have been associated with Noonan syndrome (NS) and LEOPARD syndrome. Both germline and somatic mutations in this gene have been reported in association with malignancies. However, the T507K mutation in the PTPN11 gene, has only been reported in malignancies and in a fetus with hydrops fetalis but not in a live patient with NS. We report the autopsy findings in a fetus with the T507K mutation who presented prenatally with hydrops fetalis, cystic hygroma and 46, XX karyotype. On autopsy, the patient was found to have testes, male external genitalia, but absent Wolffian ducts.

Third-trimester stillbirths: correlative neuropathology and placental pathology.

Although in recent years placental pathology has been the subject of a wealth of detailed descriptions and diagnostic categorization, systematic correlation of these conditions with the pathology of stillbirth has not been attempted. We examine the relationship between specific inflammatory, maternal, and fetal vascular pathologies and the central nervous system pathology and histological indicators of fetal compromise. Our design was a retrospective case series of 37 3rd-trimester intrauterine fetal deaths. In general, mixed placental pathologies were the rule, with three quarters of the placentas demonstrating combinations of maternal vascular pathology, fetal vascular pathologies, umbilical cord abnormalities, or inflammatory lesions. The range of brain pathology was limited to acute, severe congestion, white matter edema, and neuronal karyorrhexis (pontosubicular necrosis with or without neuronal karyorrhexis at other sites). Established periventricular leukomalacia was present in only 2 cases. The presence of neuronal karyorrhexis or white matter gliosis was correlated with the presence of a high-grade inflammatory lesion and with fetal thymic involution. Neuronal karyorrhexis, but not white matter gliosis, correlated as well with histologically established fetal vascular lesions in the placenta, even once the effect of inflammation was accounted for. Gliosis also correlated with inflammation, meconium staining, and thymic involution. Central nervous system injury may be the end result of complex placental pathologies, and neuronal injury may be a consequence of the fetal inflammatory response. The correspondence between the time courses of histological features of chorioamnionitis, neuronal karyorrhexis, and thymic involution points to irreversible central nervous system injury being common 12-48 hours prior to in utero demise.

Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases.

Chondrodysplasia punctata (CDP) is etiologically a heterogeneous condition and has been associated with single gene disorders, chromosome abnormalities and teratogenic exposures. The first publication of the association between CDP and maternal autoimmune connective tissue disorder was by Curry et al. 1993]. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and subsequently, other cases have been reported. We report on eight cases of maternal collagen vascular disease associated with fetal CDP and included the cases reported by Curry et al. 1993. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and Costa et al. [1993]. Maternal systemic lupus erythematosis (SLE) and chondrodysplasia punctata in two infants. Coincidence or association? 1st Meeting of Bone Dysplasia Society, Chicago, June 1993] which were reported in an abstract form. We suggest that maternal autoimmune diseases should be part of the differential diagnosis and investigation in newborns/fetuses with CDP. Thus, in addition to cardiac evaluation, fetuses/newborn to mothers with autoimmune diseases should have fetal ultrasound/newborn examination and if indicated, X-rays, looking for absent/hypoplastic nasal bone, brachydactyly, shortened long bones and epiphyseal stippling.

Fetal MR imaging of atelosteogenesis type II (AO-II).

The diastrophic dysplasia family of osteochondrodysplasias comprises a spectrum of skeletal diseases characterized by abnormal growth and remodelling of cartilage and bone. They are caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene. Different defects in this gene product give rise to the variety of phenotypes based on the level of residual transport capacity. We reported a case of a fetus with this spectrum, evaluated and diagnosed with fetal MRI.

Raine syndrome: a rare lethal osteosclerotic bone dysplasia. Prenatal diagnosis, autopsy, and neuropathological findings.

Raine syndrome is an autosomal recessive condition with generalized osteosclerosis, characteristic facial dysmorphism and brain abnormalities including intracerebral calcifications. We report on a case with Raine syndrome born to nonconsanguineous couple and report the prenatal sonogram/MRI, the fetopathology, and neuropathology findings.

Misoprostol associated refractile material in fetal and placental tissues after medical termination of pregnancy.

Misoprostol is a synthetic prostaglandin analog administered vaginally to induce labor for intrauterine death or termination of pregnancy for congenital abnormalities. We encountered a case of misoprostol induction of labor at 14 weeks of gestation for fetal acrania associated with amniotic bands. Histology demonstrated abundant deposits of refractile material appearing to be of vegetable fiber origin on the maternal surface of the fetal membranes. Misoprostol tablet scrapings had a similar microscopic appearance. Ten additional placentas from cases of misoprostol induction of labor between 16 and 18 weeks of gestation were examined and half were found to contain such deposits. No deposits were seen in cases between 15 and 18 weeks of gestation where misoprostol was not used. We attribute the refractile material to a nonmedicinal ingredient, microcrystalline cellulose, in the misoprostol tablet preparation. This study demonstrates that vaginal administration of misoprostol tablets can be detected microscopically in at least half of cases and may have a florid appearance simulating a potential causative factor of fetal malformation. Despite the large amounts of microcrystalline cellulose and its apparent embedding in placental tissue, the misoprostol in our index case was unlikely to have caused the amniotic bands and the resulting cranial abnormality.