A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort.

PURPOSE: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. METHODS: Clinical data was collected through an extensive web-based survey. RESULTS: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). CONCLUSION: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.

Conservative management or cesarean hysterectomy for placenta accreta spectrum: the PACCRETA prospective study.

BACKGROUND: Placenta accreta spectrum is a life-threatening condition that has increased dramatically in recent decades along with cesarean rates worldwide. Cesarean hysterectomy is widely practiced in women with placenta accreta spectrum; however, the maternal outcomes after cesarean hysterectomy have not been thoroughly compared with the maternal outcomes after alternative approaches, such as conservative management. OBJECTIVE: This study aimed to compare the severe maternal outcomes between women with placenta accreta spectrum treated with cesarean hysterectomy and those treated with conservative management (leaving the placenta in situ). STUDY DESIGN: From a source population of 520,114 deliveries in 176 hospitals (PACCRETA study), we designed an observational cohort of women with placenta accreta spectrum who had either a cesarean hysterectomy or a conservative management (the placenta left in situ) during cesarean delivery. Clinicians prospectively identified women meeting the inclusion criteria and included them at delivery. Data collection started only after the women had received information and agreed to participate in the study in the immediate postpartum period. The primary outcome was the transfusion of >4 units of packed red blood cells within 6 months after delivery. Secondary outcomes were other maternal complications within 6 months. We used propensity score weighting to account for potential indication bias. RESULTS: Here, 86 women had conservative management and 62 women had cesarean hysterectomy for placenta accreta spectrum during cesarean delivery. The primary outcome occurred in 14 of 86 women in the conservative management group (16.3%) and 36 of 61 (59.0%) in the cesarean hysterectomy group (risk ratio in propensity score weighted model, 0.29; 95% confidence interval, 0.19-0.45). The rates of hysterectomy, total estimated blood loss exceeding 3000 mL, any blood product transfusion, adjacent organ injury, and nonpostpartum hemorrhage-related severe maternal morbidity were lower with conservative management than with cesarean hysterectomy (all adjusted, P≤.02); but, the rates of arterial embolization, endometritis, and readmission within 6 months of discharge were higher with conservative management than with cesarean hysterectomy. CONCLUSION: Among women with placenta accreta spectrum who underwent cesarean delivery, conservative management was associated with a lower risk of transfusion of >4 units of packed red blood cells within 6 months than cesarean hysterectomy.

Exome sequencing identifies the first genetic determinants of sirenomelia in humans.

Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene.

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.

Transcriptomic and immunohistochemical approaches identify HLA-G as a predictive biomarker of gestational choriocarcinoma resistance to monochemotherapy.

OBJECTIVE: Using a transcriptional approach on tissue samples, we sought to identify predictive biomarkers of post molar malignant transformation, and of choriocarcinoma chemosensitivity to mono- (methotrexate or actinomycin D) or polychemotherapy [EMA(Etoposide, Methotrexate, Actinomycin D)-CO(Cyclophosphamide, Vincristine) and EMA-EP(Etoposide, Cisplatine)] regimens. METHODS: We studied the expression of a 760-gene panel (PanCancer Pathway) related to oncogenesis and immune tolerance in tissue samples of complete hydatidiform moles and gestational choriocarcinoma. RESULTS: We did not identify any differentially expressed gene between moles with post molar malignant transformation in choriocarcinoma (n = 14) and moles with remission (n = 20). In monochemoresistant choriocarcinoma (n = 34), four genes (HLA-G, COL27A1, IL1R2 and GLI3) had a significantly reduced expression and one (THEM4) had an increased expression [FDR (false discovery rate) adjusted p-value ≤ 0.05] when compared to monochemosensitive choriocarcinoma (n = 9). The proportion of trophoblast cells and the intensity of immunohistochemical HLA-G expression were reduced in monochemoresistant choriocarcinoma (p < 0.05). In polychemoresistant choriocarcinoma (n = 20) we did not identify differentially expressed genes with an FDR adjusted p-value ≤ 0.05 when compared to polychemosensitive choriocarcinoma (n = 15). Gene pathway analysis revealed a predicted activation of IFN ᵞ in monochemoresistant choriocarcinoma and inhibited IL2 and TNF in polychemoresistant choriocarcinoma. The main biological functions predicted to be altered in chemoresistant choriocarcinoma were related to immunological homeostasis and leukopoiesis. CONCLUSION: HLA-G is a strong candidate gene to predict choriocarcinoma resistance to monochemotherapy and that further studies are required to implement its routine quantification in the decision process for the management of gestational choriocarcinoma.

Postmortem Diagnosis of Heart-hand Syndrome Associated With a 7p22.1p22.3 Deletion in a 16-week-old Fetus.

We report a male fetus with a 6.8 Mb deletion on chromosome 7p22.1p22.3 at 16 weeks of gestation. The fetus presented a heart-hand syndrome with great artery malposition, bilateral radial ray deficiency, a single pelvic kidney, and growth retardation. This deletion involves a minimal deleted region for cardiac malformation and the RAC1 gene, previously described in limb anomalies in mice. This fetus is the third human case with limb defects and RAC1 deletion.

First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive.

BACKGROUND: Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking. OBJECTIVES: To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients. STUDY DESIGN: Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy. RESULTS: First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8-90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5-6 (exact OR 8.961, 95%CI 1.60-64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78-138.13) were associated with the risk of requiring salvage chemotherapy. CONCLUSION: Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility.

Outcome of First-Line Hysterectomy for Gestational Trophoblastic Neoplasia in Patients No Longer Wishing to Conceive and Considered With Isolated Lung Metastases: A Series of 30 Patients.

OBJECTIVE: This study aimed to assess the outcome of first-line hysterectomy in patients diagnosed as having gestational trophoblastic neoplasia (GTN) whose postoperative imaging showed lung images considered as metastases. METHODS: From 1999 to 2016, patients no longer wishing to conceive, treated by their initial physician by hysterectomy, and whose postoperative imaging workup showed lung images considered as metastasis were identified in the French Trophoblastic Disease Reference Center database. We sought to identify significant predictive factors of requiring salvage chemotherapy. RESULTS: Thirty patients were identified with a maximum number of 2 visible lung nodules and a median largest size of 14 mm on chest x-ray. Nine of these patients had an International Federation of Gynecology and Obstetrics score of higher than 6, and there were no postterm GTN. Twenty-two patients (73.33%; 95% confidence interval, 54.11-87.72; P = 0.0053) normalized their human chorionic gonadotropin (hCG) without salvage chemotherapy, whereas 7 received 1 line of salvage monochemotherapy (8-day methotrexate) and 1 required 2 lines of monochemotherapy (5-day actinomycin D after failure of methotrexate). After a 12.45-month median follow-up (range, 3-48.4 months) since the first normalized hCG, none of these patients died. The median interval between successful hysterectomy and hCG normalization was 3.15 months (range, 1.6-8.7 months). Patients who required salvage chemotherapy had a median size of the largest lung metastasis on chest computed tomography of 4 mm larger than those cured by hysterectomy (P = 0.0455). CONCLUSIONS: For GTN patients no longer wishing to conceive with lung metastases discovered postoperatively, treated by hysterectomy, and whose hCG is decreasing, it is reasonable to expect and to inform patients that approximately 27% will require salvage chemotherapy. However, in patients with lung metastases discovered preoperatively, evidence to recommend first-line hysterectomy is insufficient and these patients should receive first-line chemotherapy.

Efficacy and Safety of Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for Gestational Trophoblastic Neoplasia.

OBJECTIVE: The objective of this study was to evaluate the characteristics and outcomes of patients treated for gestational trophoblastic neoplasia (GTN) with second-line 5-day dactinomycin after failed first-line 8-day methotrexate. METHODS: From 1999 to 2017, patients with methotrexate resistant GTN treated with second line dactinomycin were identified at the French Trophoblastic Disease Reference Center. Using univariate and multivariate analysis, we identified significant predictive factors of second line dactinomycin failure. RESULTS: A total of 877 GTN patients were treated with first-line 8-day methotrexate, of which 103 required second-line 5-day dactinomycin for methotrexate failure. Complete response was observed in 78 patients (75.7% [95% confidence interval, 66.3-83.6]; P < 0.0001), whereas 25 needed third-line treatment, 13 for dactinomycin resistance and 12 for post-dactinomycin relapse. Overall survival of patients treated with dactinomycin was 100%. An interval of greater than or equal to 7 months between antecedent pregnancy termination and methotrexate initiation was a predictive factor significantly associated with second-line dactinomycin failure in multivariate analysis (exact odds ratio, 9.17 [95% confidence interval, 1.98-50.70]; P = 0.0029). No grades 4 and 5 adverse effects were experienced and the most common toxicity being grade 1 nausea (14.6%). CONCLUSION: Given a 75.7% complete response rate in methotrexate failed low-risk GTN patients treated with second-line dactinomycin and an overall survival rate of 100% after third-line treatment, the use of dactinomycin should be favored as second-line, regardless of human chorionic gonadotropin level at the time of dactinomycin initiation. However, an interval between the termination of the antecedent pregnancy and methotrexate initiation longer than 6 months should encourage considering alternative therapeutic strategies.

PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes.

OBJECTIVE: Recently reported expression of programmed cell death 1 ligand 1 (PD-L1) in gestational trophoblastic diseases (GTDs) suggests that the immune tolerance of pregnancy might be hijacked during neoplastic process. We assessed PD-L1 protein expression in premalignant and malignant GTD lesions and analyzed associations with disease severity and chemotherapy outcomes. METHODS: We included 83 GTD whole-tissue sections from 76 patients in different treatment settings. PD-L1 protein expression was assessed with immunohistochemistry in each trophoblast subtype with the Allred total score (ATS), which combines intensity and proportion expression on a 0- to 8-point scale. Peritumoral immune infiltrate was scored on hematoxylin-eosin-safran-stained slides. RESULTS: PD-L1 expression was ubiquitous and strong in all GTD trophoblast subtypes. For invasive moles, ATS scores were maximal at 8 in 100%, 100%, and 75% of syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast specimens, respectively. For choriocarcinomas, ATS was 8 in 80% of specimens. Immune infiltrates were moderate to severe in 61%, 100%, and 100% of peritumoral zones of choriocarcinoma, epithelioid trophoblastic tumor, and invasive moles, respectively. Because of the homogeneous pathological findings, no significant differences in PD-L1 expression profiles or peritumoral immune infiltrates were found regarding FIGO (International Federation of Gynecology Obstetrics) prognostic score, fatal outcome, or chemosensitivity. CONCLUSIONS: We confirm that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independently from FIGO score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role for PD-L1 in the development and tolerance of GTD. Assessment of anti-PD-L1 drug in GTD patients has been activated.

Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases.

OBJECTIVE: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. METHOD: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. RESULTS: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). CONCLUSION: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.

Practical guidelines of the EOTTD for pathological and genetic diagnosis of hydatidiform moles.

Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts' group involved in its development.

Risk factors for placenta accreta spectrum disorders in women with any prior cesarean and a placenta previa or low lying: a prospective population-based study.

This study aimed to identify the risk factors for placenta accreta spectrum (PAS) in women who had at least one previous cesarean delivery and a placenta previa or low-lying. The PACCRETA prospective population-based study took place in 12 regional perinatal networks from 2013 through 2015. All women with one or more prior cesareans and a placenta previa or low lying were included. Placenta accreta spectrum (PAS) was diagnosed at delivery according to standardized clinical and histological criteria. Of the 520,114 deliveries, 396 fulfilled inclusion criteria; 108 were classified with PAS at delivery. Combining the number of prior cesareans and the placental location yielded a rate ranging from 5% for one prior cesarean combined with a posterior low-lying placenta to 63% for three or more prior cesareans combined with placenta previa. The factors independently associated with PAS disorders were BMI ≥ 30, previous uterine surgery, previous postpartum hemorrhage, a higher number of prior cesareans, and a placenta previa. Finally, in this high-risk population, the rate of PAS disorders varies greatly, not only with the number of prior cesareans but also with the exact placental location and some of the women's individual characteristics. Risk stratification is thus possible in this population.

Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).

[Giant teratoma of the umbilical cord associated with foetal malformations: a morphological and cytogenetic study]. / Tératome géant du cordon ombilical associé à des malformations fœtales: étude morphologique et cytogénétique.

We report on an unusually large teratoma of the umbilical cord associated with multiple fetal anomalies. At 18 WG, an umbilical cord tumour was discovered by ultrasonography in a 38 year-old woman. A 2680 g female neonate (46, XX) was delivered at 37 WG by caesarean section. During surgery for exomphalos, a complete bowel malrotation, ischemic jejunal stenoses and bowel duplication were discovered. The tumor (2515 g) was a teratoma supplied by collaterals of the umbilical vein. Proliferative index calculated by flow cytometry was less than 10%. Tumor karyotype revealed several numerical anomalies with no structural abnormalities using multi-FISH analysis. Immunostaining for CEA and AFP were observed in endodermic derivatives of the duplication and associated with transient high levels of AFP in the blood. To our knowledge, it is the first case to be reported in the literature where karyotype, multi-FISH and FCM studies were available.

Prenatal presentation of multiple anomalies associated with haploinsufficiency for ARID1A.

The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to characteristic craniofacial and digital findings. We present three fetuses and a male neonate with ventriculomegaly/hydrocephalus, absence of the corpus callosum (ACC), cerebellar hypoplasia, retinal dysplasia, lung lobulation defects, renal dysplasia, imperforate or anteriorly placed anus, thymus hypoplasia and a single umbilical artery. Facial anomalies included downslanting palpebral fissures, wide-spaced eyes, low-set and posteriorly rotated ears, a small jaw, widely spaced nipples and hypoplastic nails. All fetuses had heterozygous variants predicting premature protein truncation in ARID1A (c.4886dup:p.Val1630Cysfs*18; c.4860dup:p.Pro1621Thrfs*27; and c.175G>T:p.Glu59*) and the baby's microarray demonstrated mosaicism for a deletion at chromosome 1p36.11 (arr[GRCh37] 1p36.11(26,797,508_27,052,080)×1∼2), that contained the first exon of ARID1A. Although malformations, in particular ACC, have been described with CSS caused by pathogenic variants in ARID1A, prenatal presentations associated with this gene are rare. Retinal dysplasia, lung lobulation defects and absent thymus were novel findings in association with ARID1A variants. Studies in cancer have demonstrated that pathogenic ARID1A variants hamper nuclear import of the protein and/or affect interaction with the subunits of SWI/SNF complex, resulting in dysregulation of the PI3K/AKT pathway and perturbed PTEN and PIKC3A signaling. As haploinsufficiency for PTEN and PIKC3A can be associated with ventriculomegaly/hydrocephalus, aberrant expression of these genes is a putative mechanism for the brain malformations demonstrated in patients with ARID1A variants.