Introduction Chronic Histiocytic Intervillositis (CHI) appears to be among the most severe placental diseases. Its rarity has limited our knowledge of the women in whom it occurs. Objective To search for maternal characteristics linked to the existence of CHI, by first studying the current pregnancy included in the study, then their previous pregnancies. Material and methods We conducted a monocentric case-control study between 2000 and 2020. CHI cases were diagnosed by microscopic examination of the placenta. "Low-risk” controls gave birth just before each case, whatever the outcome. “High-risk” controls benefited from placental microscopy immediately after the case examinations. Results 151 women were included in each group. CHI cases had twice as many previous pregnancies as both controls, but no more living children at home. Regarding obstetric history, fetal losses were significantly higher in CHI cases: compared to “low-risk” controls, there were more early miscarriages (20.0%, OR 2.6 [1.5;4.8]), late miscarriages (4.8%, OR 8.8 [1.1;187]) and in utero deaths (5.4%, OR 5.6 [1.7;19.8]). The risk of fetal loss does not appear to be increased in first pregnancies of CHI cases. However, differences appeared between cases and both “low-risk” and “high-risk” controls with a history of two previous miscarriages (21.7% vs 11.2%, p=0.009 or vs 9.6%, p=0.005) and the outcome of the second pregnancy (number of living children 59.7% vs 78.0%, p=0.033 or vs 63.0%, p=0.71), respectively. Conclusion Women with CHI have a more frequent history of pregnancy failure than other women. This excess fetal loss seems to occur only after the second pregnancy or after two previous miscarriages.

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal disorder, primarily characterised in adults by cutaneous features, pulmonary cysts that predispose to spontaneous pneumothorax and renal tumours. The syndrome is caused by pathogenic variants in theFLCNtumour suppressor gene, which plays a role in the mammalian target of rapamycin (mTOR) signalling pathway. We present the case of a newborn infant diagnosed with BHDS, who died of sudden cardiac death due to complications from cardiac rhabdomyoma. This is only the second reported case of such an association. Both cases were initially misdiagnosed with tuberous sclerosis complex, highlighting the diagnostic challenges. We discuss this differential diagnosis and suggest that cardiac rhabdomyomas, although rare, may be associated with BHDS and potentially life threatening. Therefore, we recommend cardiac screening in newborns at risk.

PURPOSE:MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant. METHODS:Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases. RESULTS:Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants). CONCLUSION:We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging.

El desarrollo de las vías respiratorias superiores comienza muy pronto durante el período embrionario e implica a las hojas embrionarias procedentes de los arcos faríngeos y la lámina intermedia procedente del intestino primitivo. La organización y la diferenciación de los primordios laringotraqueales se induce por la migración de las células derivadas de las crestas neurales bajo el control de muchos genes. Las estructuras laringotraqueales están presentes desde el final del período embrionario, pero su maduración se continúa durante todo el período fetal. Al nacer, la morfología laríngea es muy diferente a la del adulto y sus estructuras siguen siendo muy inmaduras. Las estructuras fibroelásticas de la lámina propia, así como su organización espacial continúan su maduración hasta el final de la adolescencia. El objetivo de este artículo es trazar las grandes líneas del desarrollo de las vías respiratorias superiores, en particular de la laringe, centrándose en los elementos que pueden ser útiles en la práctica clínica. El conocimiento perfecto de estas etapas de maduración y de las modificaciones morfológicas después del nacimiento es esencial para comprender las malformaciones laringotraqueales. Estos conceptos son además esenciales para el tratamiento óptimo de la vía respiratoria del niño y para la adaptación de las técnicas quirúrgicas con el fin de reducir el riesgo de lesión y de conservar el potencial de la maduración de las estructuras laríngeas.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.

Background: Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses. Methods: A cohort of 194 consecutive ICH fetuses were first screened for COL4A1/COL4A2 variants. We manually curated a list of 64 genes involved in IPD and investigated them in COL4A1/COL4A2 negative fetuses, using exome sequencing data from 101 of these fetuses. Result: Pathogenic variants of COL4A1/COL4A2 genes were identified in 36 fetuses (19%). They occurred de novo in 70% of the 32 fetuses for whom parental DNA was available. Pathogenic variants in two megakaryopoiesis genes (MPL and MECOM genes) were identified in two families with recurrent and severe fetal ICH, with variable extraneurological pathological features. Conclusion: Our study emphasizes the genetic heterogeneity of fetal ICH and the need to screen both COL4A1/COL4A2 and IPD genes in the etiological investigation of fetal ICH to allow proper genetic counseling.

Hydrolethalus syndrome (HLS) is a rare lethal fetal malformation disorder related to ciliogenesis disruption. This condition is more frequent in Finland where a founder missense variant in the HYLS1 gene was identified. No other HYLS1 variant has hitherto been implicated in HLS. We report two unrelated French fetuses presenting with a phenotype of HLS with brain abnormalities, limbs malformations with pre and postaxial hexadactyly and abnormal genitalia. These two fetuses have compound heterozygous variants in HYLS1. The first allele carries the same Finnish missense variant (NM_145014.2: c.632A > G, p.[Asp211Gly]) in both fetuses and the second allele carries a new missense variant (c.662G > C, p.[Arg221Pro]) in the first fetus, and a new nonsense variant (c.613C > T, p.[Arg205*]) in the second fetus. This is the first report of HYLS1 mutated cases outside Finland. Both cases presented here are consistent with HLS with additional malformations, allowing expansion of the phenotypic presentation previously described.

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.

Background: Spontaneous hematomas of the umbilical cord are rare and often fatal to the fetus. Little is known about their mechanism or their risk factors. In view of their rarity, the series are limited. No comparative study enabling the identification of factors associated with these hematomas has been published. Material and methods: This retrospective case-control study of 13 spontaneous histologically confirmed hematomas of the umbilical cord over a consecutive 16-year period compared the characteristics of the case mothers and fetuses to those of a group of 39 control mothers who gave birth the same day as the case mothers. Results: In utero death was high in the case group (46.2% vs 0.0%, P < 0.001). Third-trimester oligohydramnios (30.8 vs 2.6%, OR = 16.9, P = 0.01), second-trimester amniocentesis (33.3 vs 5.1%, OR = 9.3, P = 0.02), and a reduction in fetal movements as perceived by the mother (35.7 vs 7.7%, P = 0.02) were significantly associated with spontaneous umbilical cord hematomas. Conclusion: Third-trimester oligohydramnios and second-trimester amniocentesis appear to be associated with the occurrence of a spontaneous hematoma of the umbilical cord.

Objective To assess whether chorioamnionitis is associated with cerebral palsy (CP) or death at 2 years' corrected age in infants born before 32 weeks of gestation after spontaneous birth. Study design EPIPAGE-2 is a national, prospective, population-based cohort study of children born preterm in France in 2011; recruitment periods varied by gestational age. This analysis includes infants born alive after preterm labor or preterm premature rupture of membranes from 240/7 to 316/7 weeks of gestation. We compared the outcomes of CP, death at 2 years' corrected age, and "CP or death at age 2" according to the presence of either clinical chorioamnionitis or histologic chorioamnionitis. All percentages were weighted by the duration of the recruitment period. Results Among 2252 infants born alive spontaneously before 32 weeks of gestation, 116 (5.2%) were exposed to clinical chorioamnionitis. Among 1470 with placental examination data available, 639 (43.5%) had histologic chorioamnionitis. In total, 346 infants died before 2 years and 1586 (83.2% of the survivors) were evaluated for CP at age 2 years. CP rates were 11.1% with and 5.0% without clinical chorioamnionitis (P = .03) and 6.1% with and 5.3% without histologic chorioamnionitis (P = .49). After adjustment for confounding factors, CP risk rose with clinical chorioamnionitis (aOR 2.13, 95% CI 1.12-4.05) but not histologic chorioamnionitis (aOR 1.21, 95% 0.75-1.93). Neither form was associated with the composite outcome "CP or death at age 2." Conclusions Among infants very preterm born spontaneously, the risk of CP at a corrected age of 2 years was associated with exposure to clinical chorioamnionitis but not histologic chorioamnionitis.

p57 immunostaining is performed on hydropic products of conception to diagnose hydatidiform moles (HMs), which can progress to gestational trophoblastic neoplasia. Partial hydatidiform mole (PHM) and hydropic abortion (HA) display positive staining in stromal and cytotrophoblastic cells, whereas complete hydatidiform mole (CHM) is characterized by loss of p57 expression in both cell types. In some cases, an aberrant pattern is observed, called discordant p57 expression, with positive cytotrophoblast staining and negative stromal staining, or vice versa. The aim of this study was to describe the clinical, biological, and pathological characteristics of p57-discordant villi (p57DV) and other associated populations in cases of divergent p57 expression and to compare the evolutions of p57DV-associated and classic CHMs. Seventy cases of p57DV diagnosed by referent pathologists were divided into two groups, G1: p57DV ± non-CHM component (n = 22) and G2: p57DV + CHM component (n = 48). p57DV morphology was similar in the two groups. Observation of more than two populations and hybrid villi on p57 immunostaining were significantly more frequent in G2. The clinical, ultrasound, and biological presentations of p57DV-associated and classic CHMs were similar. The initial pathological diagnosis was more frequently incorrect, missing the CHM component, for the p57DV-associated CHMs. Molecular genotyping was informative in seven cases and identified as androgenetic/biparental mosaicism in four cases. These results show that p57DV are a diagnostic challenge for pathologists and that most are associated with a CHM component. However, the clinical management of p57DV-associated CHMs should be the same as that of classic CHMs.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Objective To study the histoanatomical structure of laryngeal atresia with a focus on the laryngeal functional components in order to evaluate the functional prognosis of laryngeal atresia repair. Methods Twenty‐one consecutives cases of laryngeal atresia were diagnosed at our institution between 2009 and 2016. Morphological analysis by macroscopic exam during autopsy was performed in 19 cases. Histological study of the larynx included hematoxylin and eosin staining and protein S100 immunostaining. Our analysis focused on the vocal folds, structures of the lamina propria, cricoarytenoid joints, muscles, and innervation. For each case, associated malformations were classified into two groups: severe and moderate. Results Antenatal diagnosis was suspected because of congenital high airway obstruction syndrome in nine cases (37%). Associated malformations were present in 19 cases (90%), including severe malformations in 12 cases (57%). Atresia involved the cricoid in all cases, with a residual lumen in only one case and the glottis in 18 cases. Separation between the cricoid and arytenoid cartilages was observed in all cases. Fusion of the vocal process of the arytenoids in the midline was present in 13 cases. According to the gestational age, posterior maculae flavae (MF) were present in 17 of 19 cases, with abnormal structure and median fusion in 13 cases. Anterior MF were present in nine of 18 cases, with fusion on the midline in five cases. Intrinsic abductors and adductors muscles were identifiable in all cases, with fusion of thyroarytenoids muscles in the midline in 18 cases. Both recurrent laryngeal nerves were observed in all cases. Conclusion Laryngeal atresia is generally associated with other malformations, with a high risk of fatal outcomes. We observed that the functional structures of the glottic plane were present in most cases, with the exception of MF, which were frequently abnormal. Level of Evidence 4 Laryngoscope , 130:252–256, 2020

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

The objectives of the study are to describe the obstetric outcomes associated with massive perivillous fibrin deposition (MFD) compared with a control series and to determine if outcome differs according to the extent of fibrin deposition.

OBJECTIVE:To investigate the association between histologic chorioamnionitis (HCA) and bronchopulmonary dysplasia (BPD) in very preterm infants, both in a general population and for those born after spontaneous preterm labor and after preterm premature rupture of membranes (pPROM).STUDY DESIGN:This study included 2513 live born singletons delivered at 24-31 weeks of gestation from a national prospective population-based cohort of preterm births; 1731 placenta reports were available. HCA was defined as neutrophil infiltrates in the amnion, chorion of the membranes, or chorionic plate, associated or not with funisitis. The main outcome measure was moderate or severe BPD. Analyses involved logistic regressions and multiple imputation for missing data.RESULTS:The incidence of HCA was 28.4% overall: 38% in cases of preterm labor, 64% in cases of pPROM, and less than 5% in cases of vascular disorders. Overall, the risk of BPD after adjustment for gestational age, sex, and antenatal steroids was reduced for infants with HCA (HCA alone: aOR 0.6 [95% CI 0.4-0.9]; associated with funisitis: aOR 0.5 [95% CI 0.3-0.8]). This finding was explained by the high rate of BPD and low rate of chorioamnionitis among children with fetal growth restriction. HCA was not associated with BPD in the preterm labor (13.4% vs 8.5%; aOR 0.9; 95% CI 0.5-1.8) or in the pPROM group (12.9% vs 12.1%; aOR 0.6; 95% CI 0.3-1.3).CONCLUSION:In homogeneous groups of infants born after preterm labor or pPROM, HCA is not associated with BPD.