Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.

Pathogenic variants of collagen type IV alpha 1 and 2 (COL4A1/COL4A2) genes cause various phenotypic anomalies, including intracerebral hemorrhage and a wide spectrum of developmental anomalies. Only 20% of fetuses referred for COL4A1/COL4A2 molecular screening (fetuses with a suspected intracerebral hemorrhage) carry a pathogenic variant in these genes, raising questions regarding the causative anomaly in the remaining 80% of these fetuses. We examined, following termination of pregnancy or in-utero fetal death, a series of 113 unrelated fetuses referred for COL4A1/COL4A2 molecular screening, in which targeted sequencing was negative. Using exome sequencing data and a gene-based collapsing test, we searched for enrichment of rare qualifying variants in our fetal cohort in comparison to the Genome Aggregation Database (gnomAD) control cohort (n = 71 702). Qualifying variants in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) were overrepresented in our cohort, reaching genome-wide significance (P = 2.11 × 10-7 ). Heterozygous PDHA1 loss-of-function variants were identified in three female fetuses. Among these three cases, we observed microcephaly, ventriculomegaly, germinolytic pseudocysts, agenesis/dysgenesis of the corpus callosum and white-matter anomalies that initially suggested cerebral hypoxic-ischemic and hemorrhagic lesions. However, a careful a-posteriori reanalysis of imaging and postmortem data showed that the observed lesions were also consistent with those observed in fetuses carrying PDHA1 pathogenic variants, strongly suggesting that these two phenotypes may overlap. Exome sequencing should therefore be performed in fetuses referred for COL4A1/COL4A2 molecular screening which are screen-negative, with particular attention paid to the PDHA1 gene. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Placental antiangiogenic prolactin fragments are increased in human and rat maternal diabetes.

INTRODUCTION/OBJECTIVES: The role of the placenta in diabetic mothers on fetal development and programming is unknown. Prolactin (PRL) produced by decidual endometrial cells may have an impact. Although full-length PRL is angiogenic, the processed form by bone morphogenetic protein-1 (BMP-1) and/or cathepsin D (CTSD) is antiangiogenic. The objectives were to investigate the involvement of decidual PRL and its antiangiogenic fragments in placentas from type-1 diabetic women (T1D) and from pregnant diabetic rats with lower offspring weights than controls. METHODS: PRL, BMP-1, and CTSD gene expressions and PRL protein level were assessed in T1D placentas (n=8) at delivery and compared to controls (n=5). Wistar rats received, at day 7 of pregnancy, streptozotocin (STZ) (n=5) or nicotinamide (NCT) plus STZ (n=9) or vehicle (n=9). Placental whole-genome gene expression and PRL western blots were performed at birth. RESULTS: In human placentas, PRL (p<0.05) and BMP-1 (p<0.01) gene expressions were increased with a higher amount of cleaved PRL (p<0.05) in T1D than controls. In rats, diabetes was more pronounced in STZ than in NCT-STZ group with intra-uterine growth restriction. Decidual prolactin-related protein (Dprp) (p<0.01) and Bmp-1 (p<0.001) genes were up-regulated in both diabetic groups, with an increased cleaved PRL amount in the STZ (p<0.05) and NCT-STZ (p<0.05) groups compared to controls. No difference in CTSD gene expression was observed in rats or women. CONCLUSIONS: Alterations in the levels of the PRL family are associated with maternal diabetes in both rats and T1D women suggesting that placental changes in these hormones impact on fetal development.

Transposition of the great arteries: factors influencing prenatal diagnosis.

OBJECTIVE: The objective of this study is to highlight the factors that may affect prenatal diagnosis of transposition of the great arteries (TGA) in order to improve it. METHODS: This is a retrospective study performed between 2004 and 2009 in the maternity units from North of France. We identified a total of 68 cases of TGA (isolated or associated with only VSD or coarctation of aorta), of which 32 (47.1%) had prenatal diagnosis (PND+) and 36 did not (PND-). Maternal characteristics and ultrasound factors were studied in relation to PND. RESULTS: Maternal weight and body mass index were significantly higher in the PND- group (70.4 kg and 26.5 kg/m(2) vs 63.6 kg and 23.6 kg/m(2) , respectively). Maternal obesity (body mass index >30) was significantly more frequent in the PND- group (27.8% vs 12.5%). More than a quarter of TGA (28.1%) were diagnosed during the third trimester. CONCLUSION: Obesity is the main cause of missed PND of TGA. Obese patients with suboptimal prenatal scans may benefit from reassessment of fetal cardiac anatomy and/or from referral for fetal echocardiography.

Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

[Placenta accreta spectrum disorder: Management and morbidity in a French type-3 maternity]. / Placenta du spectre accreta : prise en charge et morbidité dans une maternité française de niveau 3.

OBJECTIVES: Placenta accreta spectrum disorder (PASD) is a rare obstetrical pathology, however its incidence is increasing. Morbidity associated with PASD is still high. Even if hysterectomy is considered to be the reference standard treatment, the conservative treatment by leaving the placenta in situ is now an approved option. The objective was to describe management and morbidity of patients with PASD, during the decade, in our French high-level maternity. METHODS: It was a retrospective study of management and morbidity of PASD in our department between 2007 and 2017. RESULTS: Forty-six PASD cases were admitted in our center. Thirty-three (71.7%) had a prenatal suspicion of PASD. Conservative treatment was considered for 22 patients (47.8%). It was successful in 12 cases (54.5%). Thirty-four (73.9%) had a primary hysterectomy, eight (17.3%) had a delayed hysterectomy, four (8.6%) had a uterine conservation. Primary Morbidity included 28 blood transfusions, 12 bladder injuries, 1 ureteral injury and 13 transfers to intensive care unit. Secondary morbidity after conservative treatment included two Hemorrhages (16.6%), five endometritis (41.6%) and three disseminated intravacular coagulations (25%). CONCLUSIONS: Morbidity associated with this pathology is severe. Conservative treatment became an option for PASD. Thanks to a better antenatal diagnosis, it can be proposed to more women. Morbidity seems the same as other centers. Our rate of primary and secondary hysterectomy is higher than other centers. Conservative treatment seems an effective option for women who desire to preserve their fertility to avoid peripartum hysterectomy and its related morbidity and consequences on fertility.

Is chronic histiocytic intervillositis a severe placental disease? A case-control study.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a placental disease that has been associated with unfavorable obstetric outcomes in small, noncomparative series. The objective was to measure the excess risk of adverse obstetric outcomes associated with the discovery of CHI after birth. METHODS: Retrospective single-center case-control study from 2000 through 2016. The case patients had a CHI diagnosis after a pathology analysis of the placenta. Two types of controls were defined for each case: low-risk control women were those who gave birth in our hospital immediately before each case patient, and the high-risk controls were the next women after each case for whom microscopic examination of the placenta was indicated. RESULTS: We observed 111 cases of CHI during the study period. Compared with the 111 low-risk controls, the cases had a significantly higher frequency of late miscarriages (5.4 vs 0.0%, p < .03), small for gestational age (SGA) babies <3rd centile (70.4 vs 0.9%, p < .001, OR 140, 95% CI, 19.9-2800), and in utero deaths (35.1 vs 0.9%, p < .001, OR 59.6, 95% CI 8.5-1192), with significantly fewer children surviving to discharge (54.9 vs 99.1%, p < .001, OR 0.01, 95% CI, 0.00-0.08). All of these factors also differed significantly compared with the high-risk women (severe SGA: OR 3.7, 95% CI 1.9-7.0; in utero death: OR 4.1, 95% CI 1.9-8.7; children surviving to discharge: OR 0.27, 95% CI, 0.14-0.52). DISCUSSION: Even compared with high-risk pregnancies, CHI is a severe placental disease associated with a substantial excess rate of late miscarriages, severe SGA and in utero death.

[Practical questions in case of maternal death]. / Questions pratiques en cas de survenue d'un décès maternel.

Every year, in France, about 70 women die during their pregnancy or the delivery. Any maternal death during labour is a traumatic event for the medical team and the family. The medical team has to face many "new" problems. We try to identify all the problems which the medical team has to face in front of a maternal death and try to solve them by a medical literature and French laws review. The medical team often feels powerless when a maternal death occurs. This work was made to be a guideline.

[Placenta accreta: diagnosis and management in a French type-3 maternity hospital]. / Placenta accreta: diagnostic et prise en charge Etat des lieux dans une maternité de type 3.

OBJECTIVE: Placenta accreta is a rare obstetrical pathology but leads to a high morbidity. It is likely to become increasingly frequent as the rate of cesarean section increases in developed countries. The aim of our study was to describe the diagnostic and management of patients with placenta accreta, during the last ten years, in a French high-level maternity. MATERIAL AND METHOD: This is a retrospective study of the prenatal diagnosis and management of placenta accreta with histological confirmation in our department between 1996 and 2006. RESULTS: The rate of placenta accreta in our study was 0.52 per thousand. Ninety-six percent of the patients had risk factors for placenta accreta. Placenta accreta was diagnosed in 24% of the patients by sonographic examination. Magnetic resonance imaging did not increase sensitivity. Eighty-eight percent of the patients required a hysterectomy. No digestive or urinary complications occurred. There were no maternal deaths. CONCLUSION: Despite established ultrasound and MRI-based diagnostic criteria for placenta accreta, this condition remains difficult to diagnose in the general population. Morbidity associated with this pathology is serious, especially in cases of hemostatic hysterectomy. When placenta accreta is diagnosed prior to delivery, care in a high-level maternity hospital must be considered to improve management.

[Liver hernia. Prognosis and report of 11 cases]. / Les hépatocèles exclusives. Evaluation du pronostic. A propos de 11 observations.

OBJECTIVES: Exclusive hepatocele is defined as a hernia containing in majority the liver with possibly some intestinal loops. This study was undertaken to evaluate neonatal morbidity and mortality in this series of exclusive hepatoceles. MATERIALS AND METHODS: We reviewed 11 cases of exclusive hepatoceles with delivery at the hospital Jeanne-de-Flandre in the CHRU of Lille, in France. RESULTS: The mean gestational age of diagnosis was 14.5+/-3.4 weeks of gestation. Karyotype determination was performed in 100% of cases: it was abnormal in one case of 11. One termination of pregnancy was performed because of trisomy 13. The mean gestational age at delivery was 38+/-1.8 weeks of gestation. Cesarean deliveries were performed in nine cases. Morbidity was important with: one case of fetal growth retardation on total hepatocele, three cases of severe respiratory distress, two cases of severe digestive complications. The mean length of stay was 42.8 days. The mean length of parenteral feeding was 14.4 days. Postnatal mortality concerned one child, which died because of a severe respiratory distress due to pulmonary hypoplasia. CONCLUSION: In this series, morbidity is thus important, making of exclusive hepatoceles a full entity among the omphaloceles. The multidisciplinary take care is more complex but conceivable.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

[Benckiser's hemorrhage: severe and inevitable?]. / Hémorragie de Benckiser: grave et inévitable?

Benckiser's hemorrhage is a rare affection associated with 75-100% neonatal mortality. It is due to the rupture of one or more velamentous and previa vessels. We report two cases, one of which was fatal for the child despite immediate neonatal management. This illustrates how difficult the obstetrical and neonatal management of this affection is. Risk factors for velamentous insertion of the cord and vasa previa are multiple pregnancies, low lying placenta, bilobed and succenturiate-lobed placenta. First we specify the pathophyisiological implication of this severe hemorrhage, then the means to diagnose fetal bleeding or vasa previa. This knowledge could allow us to develop strategies to screen women sonographically to detect vasa previa. Unfortunately the benefits, risks, limits and cost of such strategies remain unknown.

[Genetics and orthopedics: genetic implications of congenital limb abnormalities]. / Génétique et orthopédie: gènes impliqués dans les malformations congénitales des membres.

Limb malformations are frequent. These malformations are isolated or associated with anomalies of other developmental fields and accurate diagnostic is essential for prognosis evaluation, treatment and genetic counseling. Animal embryology and molecular biology techniques, have given us a better understanding of the processes of growth and patterning of the limb buds. The key genes that are involved in these processes have been identified and their interactions recognized. Human genetics has been able to identify, or at least localize, several genes implicated in limb development. We here review the present knowledge on these genes and their mutations responsible for limb anomalies.

[Twin pregnancy with complete mole and coexisting fetus: Reach fetal viability is possible]. / Grossesse gémellaire avec môle complète et fœtus sain coexistant : atteindre la viabilité fœtale est possible.

Twin pregnancies combining complete hydatidiform mole and coexistent fetus are a rare situation (incidence in 1/20,000 in 1/100,000 pregnancies) and a challenge for diagnosis. Their complications can be important - bleeding, preeclampsia, miscarriage - and their management remains complex and controversial. In case of continuing the pregnancy, nearly 40% of women have lives babies. Three quarters of fetal loss occur before 24weeks gestation. We report here three new cases; only one of these cases had a favorable outcome.

Normal respiratory mucosa, precursor lesions and lung carcinomas: differential expression of human mucin genes.

Mucins are glycoproteins synthesized by epithelial cells and thought to promote tumor-cell invasion. Eight human mucin genes have been well characterized: MUC2, MUC5AC, MUC5B, MUC6 map to 11p15.5 and encode secretory gel forming mucins while MUC1, MUC3, MUC4, MUC7 are scattered on different chromosomes and encode membrane-bound or secreted mucins. The expression pattern of the mucin genes is complex in normal airways involving six genes, mainly MUC5AC and MUC5B in mucus-producing cells and MUC4 in a wide array of epithelial cells. MUC5AC overexpression in metaplasia, dysplasia and normal epithelium adjacent to squamous cell carcinoma provides additional arguments for a mucous cell origin of preneoplastic squamous lesions. MUC5AC and MUC5B expression is related to mucus formation in adenocarcinomas. Mucinous bronchioloalveolar carcinoma (BAC) has a particular pattern of mucin gene expression indicating that it has sustained a well-differentiated phenotype similar to the goblet cell, correlated with distinctive features i.e. a noninvasive pattern and a better prognosis than nonBACs. MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas. These findings are in favor the histogenetic theory of non-small-cell carcinoma originating from a pluripotent mucous cell.

Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma.

Studies were undertaken to provide information regarding cell-specific expression of mucin genes in stomach and their relation to developmental and neoplastic patterns of epithelial cytodifferentiation. In situ hybridization was used to study mRNA expression of eight mucin genes (MUC1-4, MUC5AC, MUC5B, MUC6, MUC7) in stomach of 13 human embryos and fetuses (8-27 weeks' gestation), comparing these with normal, metaplastic, and neoplastic adult tissues. These investigations have demonstrated that MUC1, MUC4, MUC5AC, MUC5B, and MUC6 are already expressed in the embryonic stomach at 8 weeks of gestation. MUC3 mRNA expression can be observed from 10.5 weeks of gestation. MUC2 is expressed at later stages, concomitant with mucous gland cytodifferentiation. Normal adult stomach is characterized by strong expression of MUC1, MUC5AC, and MUC6, less prominent MUC2, and sporadic MUC3 and MUC4, without MUC5B and MUC7. Intestinal metaplasia is characterized by an intestinal-type pattern with MUC2 and MUC3 mRNA expression. Gastric carcinomas exhibit altered mucin gene expression patterns with disappearance of MUC5AC and MUC6 mRNAs in some tumor glands, abnormal expression of MUC2, and reappearance of MUC5B mRNAs. In conclusion, we have observed that patterns of mucin gene expression in embryonic and fetal stomach could show similarities with some gastric carcinomas in adults. Differences in mucin gene expression in developmental, metaplastic, and neoplastic stomach compared to normal adult stomach suggest a possible regulatory role for their products in gastric epithelial cell proliferation and differentiation.

Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. II. Duodenum and liver, gallbladder, and pancreas.

Studies were undertaken to provide information regarding cell-specific expression of mucin genes and their relation to developmental and neoplastic patterns of epithelial cytodifferentiation. In situ hybridization was used to study mRNA expression of mucin genes in duodenum and accessory digestive glands (liver, gallbladder, pancreas) of 13 human embryos and fetuses (6. 5-27 weeks' gestation), comparing these with normal and neoplastic adult tissues. These investigations demonstrated that the pattern of mucin gene expression in fetal duodenum reiterated the patterns we observed during gastric and intestinal ontogenesis, with MUC2 and MUC3 expression in the surface epithelium and MUC6 expression associated with the development of Brünner's glands. In embryonic liver, MUC3 was already expressed at 6.5 weeks of gestation in hepatoblasts. As in adults, MUC1, MUC2, MUC3, MUC5AC, MUC5B, and MUC6 were expressed in fetal gallbladder, whereas MUC4 was not. In contrast, MUC4 was strongly expressed in gallbladder adenocarcinomas. MUC5B and MUC6 were expressed in fetal pancreas, from 12 weeks and 26 weeks of gestation, respectively. Surprisingly, MUC3 which is strongly expressed in adult pancreas, was not detected in developmental pancreas. Taken together, these data show complex spatio-temporal regulation of the mucin genes and suggest a possible regulatory role for mucin gene products in gastroduodenal epithelial cell differentiation.

New autosomal recessive syndrome of severe microcephaly and skeletal anomalies including posterior rib-gap defects.

We describe two female fetuses conceived by a nonconsanguineous couple. The pregnancies were interrupted at 31 and 26 weeks of gestation, respectively, because of severe microcephaly. Postmortem X-ray and autopsy studies showed in both fetuses: 1) severe intrauterine growth retardation; 2) facial anomalies characterized by severe microcephaly, sloping forehead, low set and posteriorly angulated ears, prominent eyes, down-slanting palpebral fissures, large nose, small mouth with full lips, and mild microretrognathia; 3) severe brain hypoplasia that was more pronounced in the second fetus; 4) severe rib hypoplasia with posterior rib-gap defects and in case 2 hypoplasia of several bones (right clavicle, right radius and ulna, several phalanges of hands and feet); 5) contracture at large joints. No other visceral malformations were observed, and chromosomes were normal in patient 2 and parents. This phenotype has some similarities with different syndromic entities but an identical malformation syndrome seems not to have been described previously. Autosomal recessive inheritance is the most likely cause of this putative "new syndrome."

Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome?

We describe a multiple congenital anomalies (MCA) syndrome dominantly transmitted through three generations. Radial ray abnormalities with wide variability of expression were observed in four female patients. Moreover, a 14-week-gestation male fetus had severe radial ray malformation, anencephaly, unilateral renal agenesis, and a common dorsal mesentery. Results of high-resolution karyotyping were normal in the malformed fetus and his affected mother. Furthermore, several spontaneous abortions of male fetuses had occurred in this pedigree. To our knowledge, a similar association has not been described previously. It could represent a new X-linked dominant MCA syndrome, or an autosomal dominant condition with severe expression limited to males.

Tetrachloroethylene and trichloroethylene fatality: case report and simple headspace SPME-capillary gas chromatographic determination in tissues.

We describe a simple, precise, and sensitive assay of tetrachloroethylene and trichloroethylene in tissues, suitable both for emergency cases and forensic medicine. The method employs headspace solid phase microextraction-capillary gas chromatography and electron capture detection. The case is relative to a 45-year-old woman discovered unconscious in a laundry area. The concentrations of the solvents in tissues were determined and compared to other previously published fatalities.

Fryns syndrome and erupted teeth in a 24-weeks-old fetus.

We describe a 24-weeks-old fetus with Fryns' syndrome (FS) and two erupted incisors. The present observations is another example of prenatal diagnosis of FS, based on ultrasonographically detected hernia diaphragmatica and cystic hygroma. It also adds an hitherto non described finding in FS. The presence of prenatally erupted teeth without any similar family history is discussed.