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Full access; International audience; 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.

Minimal invasive surgery and reconstructive surgery tend to become the standard in France in the management of head and neck tumors. The use of endoscopic approaches (through endoscopic endonasal/transoral approaches±robot-assisted) instead of open surgery and the use of reconstructive surgery using autologous (flaps) or heterologous materials aim to reduce surgical morbidity by making-up for the loss of substance to restore the function. The impact of these substantial changes in surgical techniques has not been assessed with respect to postoperative radiotherapy practice. Endoscopic endonasal approaches result, however, in piecemeal resection, which, along the analysis of resection margins (a key prognostic factor), make the interpretation of the quality of resection more complex for radiation oncologists. The definition of tumour sub-volumes to be irradiated and doses to these sub-volumes then requires accurate histosurgical mapping and close multidisciplinary consultation between surgeons, pathologists, radiologists and radiation oncologists. Similarly, the increasing use of various types of flaps (of soft tissue or bone flaps), adapted to the patient and tumor anatomy, is associated with substantial modifications to the operating bed. The delineation of tumour volumes in postoperative radiotherapy is made more complex. Tremendous multidisciplinary efforts should now be initiated to fully take advantage of surgical advances and to further optimize the therapeutic index by making radiotherapy also less toxic, i.e. "mini-morbid".

Minimal invasive surgery and reconstructive surgery tend to become the standard in France in the management of head and neck tumors. The use of endoscopic approaches (through endoscopic endonasal/transoral approaches±robot-assisted) instead of open surgery and the use of reconstructive surgery using autologous (flaps) or heterologous materials aim to reduce surgical morbidity by making-up for the loss of substance to restore the function. The impact of these substantial changes in surgical techniques has not been assessed with respect to postoperative radiotherapy practice. Endoscopic endonasal approaches result, however, in piecemeal resection, which, along the analysis of resection margins (a key prognostic factor), make the interpretation of the quality of resection more complex for radiation oncologists. The definition of tumour sub-volumes to be irradiated and doses to these sub-volumes then requires accurate histosurgical mapping and close multidisciplinary consultation between surgeons, pathologists, radiologists and radiation oncologists. Similarly, the increasing use of various types of flaps (of soft tissue or bone flaps), adapted to the patient and tumor anatomy, is associated with substantial modifications to the operating bed. The delineation of tumour volumes in postoperative radiotherapy is made more complex. Tremendous multidisciplinary efforts should now be initiated to fully take advantage of surgical advances and to further optimize the therapeutic index by making radiotherapy also less toxic, i.e. "mini-morbid".

Pseudoamniotic band syndrome is a rare complication that occurs after invasive procedures for complicated monochorionic twins. We report 2 cases of intrauterine recipient fetal death after laser therapy for twin-twin transfusion syndrome due to umbilical cord constriction by the amniotic band.

International audience; Infantile hemangioma (IH) is the most common benign vascular tumor of infancy, occurring predominantly in the head and neck. It is characterized by specific endothelial expression of glucose transporter-1 (GLUT-1) and involution with time, spontaneous or on beta-blockers treatment. Although some predisposing factors are known, the exact pathogenesis remains unclear. We report a case of pulmonary IH GLUT-1 positive, initially suspected as a cystic pulmonary airway malformation, in a child presenting with both cardiac and renal malformations. The clinical, radiological, pathological, and genetics findings are discussed with a review of the literature. Although pulmonary IH is a rare lesion, it should be suspected when facing a pulmonary cystic mass in a child.

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.

TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.

International audience

Background Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. Methods We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Results Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were “poorly differentiated,” and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years. Conclusions Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling. Pediatr Blood Cancer 2015; 9999:XX–XX © 2015 Wiley Periodicals, Inc.

P57 protein is implicated in some human imprinting disorders such as hydatiform mole and Beckwith-Wiedemann syndrome (BWS), both characterized by mesenchymal and vascular placental abnormalities. We investigated p57 immunohistochemical expression in placental vascular proliferative disorders of preterm and term placentas, including chorangiosis (n = 5), chorangiomatosis (n = 2), chorangiomas (n = 7), umbilical cord angioma (n = 1), and placental mesenchymal dysplasia (PMD) (n = 7). P57 was expressed in decidua, cytotrophoblast, intermediate trophoblast and stromal cells of normal terminal, intermediate and stem villi, umbilical cord, chorangiosis, chorangiomatosis, and chorangiomas. In contrast, there was a loss of p57 expression in stromal cells of dysplastic stem villi in all cases of PMD regardless of whether associated with BWS or not. P57 seems to be involved in the pathogenesis of a subset of placental vascular proliferative disorders in preterm and term placentas, such as PMD. The loss of p57 expression in PMD could be of diagnostic value in helping to distinguish this rare placental lesion from its mimickers.

The 22q11 deletion syndrome is one of the most common human microdeletion syndromes, with a wide spectrum of abnormalities. The fetal phenotype associated with the 22q11 deletion is poorly described in the literature. A national retrospective study was performed from 74 feto-pathological examinations. The objectives were to evaluate the circumstances of the 22q11 deletion diagnosis and to describe fetal anomalies. Post mortem examinations were performed after 66 terminations of pregnancy and eight fetal deaths. The series included nine fetuses from the first trimester, 55 from the second trimester, and ten from the third trimester. A 22q11 FISH analysis was recommended for 57 fetuses after multidisciplinary prenatal diagnostic counseling and for 17 fetuses by a fetal pathologist. Conotruncal heart defects were the most common anomalies (65 fetuses), followed by thymus defects (62 fetuses), and malformations of the urinary tract (25 fetuses). This study identified several unusual and severe features rarely described in the literature. Neurological abnormalities were described in ten fetuses, with seven neural tube defects and five arhinencephalies. This series also included lethal malformations: two hypoplastic left heart syndromes, two bilateral renal agenesis, and one tracheal agenesis. Genetic analysis for a 22q11 deletion is usually indicated when a congenital conotruncal heart and/or thymus defect is detected, but might also be useful in case of other lethal or severe malformations that initially led to the termination of pregnancy.

Hyperimmunoglobulinemia D is the less severe form of mevalonate kinase deficiency (MKD) caused by recessive inherited mutation in the mevalonate kinase gene. Hyperimmunoglobulinemia D is characterized by febrile attacks, often associated with transient digestive manifestations, such as abdominal pain, diarrhea, and vomiting. Here we report for the first time 2 patients with MKD revealed by severe neonatal colitis. Both patients had chronic bloody diarrhea and failure to thrive; 1 patient since the age of 1 month and the other since the age of 12 days. Total parenteral nutrition was required. A marked elevation of acute phase reactants was present, and no evidence of infection was found. In patient 1, ileocolonoscopy revealed ulcerative colitis at the age of 5 months. Patient 2 suffered from enterocolitis and shock, associated with multiple bowel adhesions at age 5 weeks; the rectosigmoidoscopy showed aphtoid lesions of the sigmoid colon. Pathologic findings of colonic biopsies revealed a dense polymorph inflammatory infiltrate associated with deep ulcerations. Febrile attacks occurred 2 months after the onset of digestive symptoms in patient 1, and at onset of disease in patient 2. Genomic sequencing of the mevalonate kinase gene revealed compound heterozygous mutations in both patients. Anti-interleukin-1 agent produced long-term remission of all digestive features and laboratory parameters. This report emphasizes that MKD may be the cause of severe early-onset inflammatory colitis, and must be considered by physicians, even in the absence of fever, after ruling out infections. Anti-interleukin-1 therapy may result in a dramatic improvement of MKD-related inflammatory bowel disease.

Pseudoamniotic band syndrome is a rare complication that occurs after invasive procedures for complicated monochorionic twins. We report 2 cases of intrauterine recipient fetal death after laser therapy for twin-twin transfusion syndrome due to umbilical cord constriction by the amniotic band.

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.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.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).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 WileySons, Ltd.

International audience; Inflammatory myofibroblastic tumors (IMT) are rare tumors in children and young adults, considered by the World Health Organization to be intermediate malignancies and rarely metastasizing, with the presence of an anaplastic lymphoma kinase rearrangement in about 50% of the cases. We report the case of a teenager who presented with a metastatic aggressive IMT that was life-threatening despite multiple treatments, and which responded repeatedly to anaplastic lymphoma kinase–targeted crizotinib therapy. Crizotinib induced drastic primary tumor regression, which was sufficient to allow surgical resection and to control distant disease. This case shows that crizotinib is a promising therapy in IMT, even in adolescents and young adults.

Peripheral neuroblastic tumors are the most commonly occurring extracranial tumors in children. Although a reliable diagnosis is achievable in the majority of cases, diagnosis of a minority of peripheral neuroblastic tumor cases (especially undifferentiated neuroblastoma) poses a challenge compared with that of other pediatric small round blue-cell tumors. A panel of immunohistochemical markers and fusion transcripts is available for the diagnosis of such tumors, but the markers for neuroblastoma lack specificity and sensitivity. As the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system from which peripheral neuroblastic tumors are derived, we have assessed PHOX2B immunolabeling as a diagnostic tool in pediatric small round blue-cell tumors. We observed PHOX2B expression in all peripheral neuroblastic tumors, paragangliomas, and pheochromocytomas tested but in no other pediatric tumors among the 388 cases studied by expression microarray and the 109 cases studied by immunohistochemical analysis. We then assessed the results of PHOX2B immunohistochemistry in 12 cases of undifferentiated pediatric neoplasms: PHOX2B was expressed in 6/6 undifferentiated neuroblastomas and in no other small round blue-cell tumors. Finally, we showed that PHOX2B immunohistochemical analysis improves the diagnosis of undifferentiated neuroblastoma with high specificity and sensitivity.

Objective To compare results of array comparative genomic hybridization (CGH) on cell-free fetal (cff) DNA from amniotic fluid supernatant and DNA from cultured amniocytes in high-risk pregnancies. Method We selected 48 cases of high-risk pregnancies (in utero growth retardation [IUGR] and/or at least two fetal malformations [polymalformation]). Bacterial artificial chromosome array CGH (BlueGnome) was performed on 38 fetal samples (frozen cff DNA and DNA from cultured cells) with previously normal karyotypes. Results From the 38 specimens, we obtained an adequate amount of sufficient quality DNA with a better quality profile using cff DNA compared to cellular DNA. Aberrations of clinical relevance were detected in three fetuses, and copy number variations considered as benign polymorphism were detected in one case using both sources of DNA. This results in an 8% detection rate of significant abnormalities in high-risk pregnancies with a normal karyotype using array CGH (two cases with IUGR, one with polymalformation). Conclusion These findings indicate the possibility of using cff DNA from amniotic fluid supernatant for array CGH with excellent results, even in late pregnancy when culture is no longer available. In this small series, pathogenic copy number variations are detected more often in the presence of IUGR than with polymalformation. © 2011 John Wiley & Sons, Ltd.

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail.We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM.Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years.Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling.

Purpose Since the recent development of biologic agents targeting oncogenes, increasing attention has been focused on determining the role of tyrosine kinase receptors in the pathogenesis of tumors. Our study was designed to investigate the status of region 4q12, which contains the candidate gene c-kit, and the expression of c-kit by immunohistochemistry (IHC). Patients and Methods Paired blood and biopsy specimens of 68 children treated for high-grade primary osteosarcomas were collected. Microsatellite analysis at two genomic sites containing c-kit gene was performed on paired DNA using a sensible fluorescent polymerase chain reaction technology. To confirm the DNA data, we studied c-kit protein expression by IHC in 56 available paraffin-embedded tumor tissues. Results The frequency of allelic imbalance (AI) at locus 4q12 was 39% in the overall population. In agreement with previous studies, we did not detect microsatellite instability, allowing us to hypothesize that this pathway is not implicated. Furthermore, the normal status at locus 4q12 was associated with a significantly better survival in the whole osteosarcoma population (P = .05). IHC overexpression of c-kit was concordant in all cases presenting an AI. However, normal status at locus 4q12 was correlated to an absence of c-kit protein expression in 19 (65.5%) of 29 informative cases. Conclusion Allelotyping of locus 4q12, which contains the c-kit gene, could help pediatric osteosarcoma prognostic screening and showed a strong correlation with overexpression of c-kit protein. These results allowed us to hypothesize that, in some cases, a mutation of c-kit gene could lead to a protein overexpression.

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.

e17048 Background: Brain metastases (BM) EOC are rare and late events. We explored tumoral genetic variations of HR system. We identify genomic alterations with NGS in both primary tumor and BM EOC Methods: Seven patients suffering from histologically proven EOC and BM, which underwent neurosurgery, were included in the study. Seven matched samples (primary tumor and BM) were analyzed by high throughput sequencing after enrichment by capture of the whole exome. After bioinformatics procedures (BWA, HaplotypeCaller, Varscan2, Outlyzer) the analysis was restricted firstly to a in silico panel of 69 genes involved in HR system. Results: Mean age was 56 years (47 to 71). Five had serous and 2 endometrioid carcinomas. All the patients had an initial FIGO stage ≥IIIA, were platine-sensitive. Median time from diagnosis of EOC to BM was 29 months (24 to 76). BM occurred after first line treatment in 5 cases and after at least 2 relapses in the 2 other cases. Median Overall survival (OS) from diagnosis of BM was 17 months (1 to 45). Five primary tumor showed a variation of at least one HR gene: pathogenic variants inactivating in BRCA2 (n = 2), CDK12 (n = 1) and probably pathogenic missenses in BRIP1 (n = 1) and TOPB1 (n = 1). These 5 variations have been also found in the BM tissues. Among the 2 patients without variations in the primary tumor, 2 probably pathogenic missenses were detected in the BM tumor (1 FANCD2 and 1 FANCM). Time to BM relapse and OS were longer among these 2 last patients compared to the remaining 5 patients (median 68 vs 29 months and 90 vs 56 months, respectively). Conclusions: Patients with BM presented HR somatic mutations and are susceptible to have high response to Parp inhibitors.

Prenatal diagnosis of conjoined twins is rare. An accurate diagnosis is important to provide the parents the best information about the prognosis of the twins. We report a first-trimester diagnosis of an extremely rare type of conjoined twins using two-dimensional transvaginal ultrasound.

Pai syndrome is a rare disorder that includes midline cleft lip, pericallosal lipoma and cutaneous polyp of the face. We report a case of prenatal diagnosis using sonography and MRI. We emphasize the importance of facial examination with prenatal association of midline cleft lip and pericallosal lipoma in making the diagnosis of Pai syndrome.

We report on a fetus with Meckel syndrome diagnosed during the 21st gestational week, hydrocephalus and bilateral hyperechogenic kidneys were then detected on ultrasonography. Fetal pathological examination showed facial dysmorphism, occipital meningoencephalocele, characteristic renal cysts, mild hepatic ductal dysplasia, hydrocephalus in association with extreme cerebellar vermis hypoplasia and brainstem anomalies. Molecular and cytogenetic analysis identified a paternally inherited CEP290/MKS4 (MIM611134) (12q21) nonsense mutation and a maternal 12q21 microdeletion. Two cases with such a mechanism have previously been described in the literature, one of them involves an inherited microdeletion. The observation of such cases highlights the existence of a pathogenic mechanism which involves deletion and point mutation, and illustrates how homozygosity can hide hemizygosity when usual sequencing methods are used. The identification of hemizygosity enables to determine precisely the molecular mechanism and to understand some phenotypic variations. As they act as complete loss of function allele, deletions might give indication on the severity of the associated point mutation. This clinical report highlights the importance of fetal pathology following termination of pregnancies in order to guide molecular analysis and the potential role of cytogenetic cryptic disorders in autosomal recessive disease. The use of polymorphic marker analysis in association with FISH or arrayCGH provided an accurate identification of molecular mechanisms, accurate genetic counseling and optimized strategy for next pregnancies or preimplantation diagnosis.

Among diagnostic tests for stillbirth, fetal autopsy is an important audit tool to identify the cause of death. However, many countries have reported a decrease in autopsy rates,1 ,2 due either to more frequent refusal from parents or to fewer proposals of this examination. We measured the evolution of autopsy refusal rate over a 10-year period in a French region and identified the circumstances associated with refusal: all fetal deaths registered in the Lower Normandy perinatal death registry from 2005 to 2014 were included (except induced abortions). The decade was divided into three periods to reduce …

Self-healing juvenile cutaneous mucinosis (SHJCM) is a rare disorder of unknown origin, which occurs in children in good health. It is characterized by the multiplication of transient cutaneous papules and nodules, mainly located on the head and periarticular areas that spontaneously resolve. Histological features of SHJCM have been well described; therefore, the diagnosis is usually made easily when papules are biopsied. We report a series of 3 new cases of SHJCM presenting mainly with nodular lesions. Histological examination of these nodules showed either lesions consistent with nodular or proliferative fasciitis or nonspecific panniculitis. Mucinous deposits were present but often inconspicuous, so could be disregarded. We wanted to emphasize this misleading presentation because a biopsy for histological examination is always mandatory in cases of proliferating nodules to rule out malignant tumors. Therefore, the diagnosis always requires discussion between pathologists and clinicians to rapidly reassure the parents and avoid inappropriate therapy.

To compare results of array comparative genomic hybridization (CGH) on cell-free fetal (cff) DNA from amniotic fluid supernatant and DNA from cultured amniocytes in high-risk pregnancies.We selected 48 cases of high-risk pregnancies (in utero growth retardation [IUGR] and/or at least two fetal malformations [polymalformation]). Bacterial artificial chromosome array CGH (BlueGnome) was performed on 38 fetal samples (frozen cff DNA and DNA from cultured cells) with previously normal karyotypes.From the 38 specimens, we obtained an adequate amount of sufficient quality DNA with a better quality profile using cff DNA compared to cellular DNA. Aberrations of clinical relevance were detected in three fetuses, and copy number variations considered as benign polymorphism were detected in one case using both sources of DNA. This results in an 8% detection rate of significant abnormalities in high-risk pregnancies with a normal karyotype using array CGH (two cases with IUGR, one with polymalformation).These findings indicate the possibility of using cff DNA from amniotic fluid supernatant for array CGH with excellent results, even in late pregnancy when culture is no longer available. In this small series, pathogenic copy number variations are detected more often in the presence of IUGR than with polymalformation.

International audience; Holoprosencephaly (HPE) is the most frequent malformation of the brain. To date, 12 different HPE loci and 8 HPE genes have been identified from recurrent chromosomal rearrangements or from the sequencing of genes from Nodal and SHH pathways. Our cohort of HPE patients presents a high genetic heterogeneity. Point mutations were found in SHH, ZIC2, SIX3, and TGIF genes in about 20% of cases (with 10% in SHH). Deletions in these same genes were found in 7.5% of the patients and 4.4% presented with other subtelomeric gain or losses. Consequently, the molecular basis of HPE remains unknown in 70% of our cohorts. To detect new HPE candidate genes, we used array-CGH to refine the previous karyotype based HPE loci map. We analyzed 111 HPE patients with high-performance Agilent oligonucleotidic arrays and found that 28 presented anomalies involving known or new potential HPE loci located on different chromosomes but with poor redundancy. This study showed an impressive rate of 19 patients among 111 with de novo chromosomal anomalies giving evidence that microrearrangements could be a major molecular mechanism in HPE. Additionally, this study opens new insights on HPE candidate genes identification giving an updated HPE candidate loci map.

We report a rare case of fibrosarcoma of the thigh suspected prenatally. At 27 weeks of gestation a voluminous, vascularised mass was discovered at ultrasound on the foetus’ left leg, suggestive of haemangioma or a fibrosarcoma. There were no signs of heart failure. A rapid increase in the tumour mass was noted and a caesarean section was carried out at 39 weeks because of abnormal foetal heart rate. Postnatal ultrasound examination was comparable to that carried out prenatally; pathological examination of the mass biopsied and immunohistochemical investigation provided a diagnosis of congenital fibrosarcoma. After neoadjuvant chemotherapy and surgery the infant is now in complete remission without amputation.

We report two cases of spontaneous neonatal gastric perforation in neonates born at term. The first neonate experienced on the second day of life a shock related to gastric perforation and he died 24 hours postoperatively from multisystemic failure. In the second case, gastric perforation occurred in a twin on the third day of life. Total gastrectomy was performed and the baby was well at the age of 13 months. Among the different causes of neonatal gastric perforation reported in the literature, none was found in our two cases. To our knowledge, our second case is the fourth case of survival after total gastrectomy for spontaneous neonatal gastric perforation described in the literature.