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

Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS):new insights from the fetal perspective

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.</p

Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome.

International audienceThe Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS

La Cappadoce méridionale de la Préhistoire à l'époque byzantine

Il y a environ 25 ans, Olivier Pelon organisait à l’Institut Français d’Études Anatoliennes d’Istanbul un colloque destiné à faire l’état des recherches sur la Cappadoce méridionale jusqu’à la fin de l’époque romaine. Un quart de siècle après ce premier colloque, il était intéressant de faire un nouveau point sur l’avancée des recherches dans cette Cappadoce méridionale, de la préhistoire à la période byzantine. Ce nouveau colloque, placé cette fois encore sous l’égide de l’Institut Français d’Études Anatoliennes et intégré à la série des Rencontres d’archéologie de l’IFEA réunit vingt-trois communications. Si les périodes néolithique et chalcolithique ont été particulièrement bien représentées, ce qui témoigne bien de l’importance de cette phase de la préhistoire cappadocienne, liée aux gisements d’obsidienne des Melendiz Dağları, on soulignera en revanche l’absence presque totale du Bronze Ancien. Cette phase est en effet peu représentée dans l’archéologie locale. La même remarque peut s’appliquer au Bronze Moyen. La fin du Bronze Moyen, fort heureusement, est représentée à Porsuk, de même que le Bronze Récent qui bénéficie, depuis peu, tout comme l’Âge du Fer, du démarrage fructueux des fouilles de Kınık Höyük. Enfin, l’Antiquité tardive et Byzance ont pu être représentées, principalement autour de Tyane, ce qui n’avait pas pu être le cas lors du premier colloque. En octobre 2012, quelques semaines avant la tenue de la Rencontre, on apprenait malheureusement le décès brutal et inattendu d’Olivier Pelon, ancien directeur de la mission de Porsuk (jusqu’en 2002) et organisateur de ce premier colloque cappadocien. C’est bien en hommage à sa mémoire que notre Rencontre cappadocienne de 2012 et sa publication ont été naturellement dédiées

Occurrence of tosudite in the Guezouman, Tarat and Tchirezrine 2 formations, hosts of uranium deposits in Niger (Tim Mersoï basin)

International audienceTosudite, a regularly interstratified chlorite-smectite, crystallizes as an alteration mineral of several preexisting Al-bearing silicates (feldspars, kaolin minerals, chlorites) present in arkosic sandstones hosted in uranium deposits in Niger. X-ray diffraction patterns show a sharp superstructure at 29–29.6 Å for an air-dried state and a peak at 30.8–31.6 Å following ethylene glycol solvation. The 060 reflection at 1.507–1.509 Å indicates an overall dioctahedral character, and the very low coefficient of variation of the d00l reflections for the solvated mineral (0.03–0.13) permits validation of the regular interstratification justifying its identification as tosudite. Microprobe analysis allowed specification of the component layers of this mixed-layer mineral. The chlorite is a di-trioctahedral type analogous to sudoite (Si3Al4Mg2(OH)8), and the smectite component is a low-charge montmorillonite type (Si4Al1.67Mg0.33M+0.33(OH)4). Tosudite is characterized by large Al2O3 and MgO contents and small Fe content; its composition corresponds approximately to the formula ((Si7Al)O20(Al4.5Mg2.3Fe3+0.2) M+0.3(OH)10), where octahedral occupancy is ∼7. Scanning electron microscope (SEM) observations show that tosudite is closely associated with some uranium minerals: tosudite crystallization occurred during a late alteration event which post-dates burial diagenesis and during which uranium was remobilized by Mg-rich oxidizing fluids

Synthèse des minéralocorticoïdes, mastocytes surrénaliens et adaptation à la vie extra-utérine

International audienceChez le nouveau-né, l’aldostéronémie élevée, indépendante des valeurs maternelles fait évoquer une régulation autonome de la synthèse des minéralocorticoïdes. Chez l’adulte, les mastocytes intrasurrénaliens régulent de façon paracrine la synthèse d’aldostérone via la sécrétion de sérotonine. Récemment chez le fœtus, la présence de mastocytes intrasurrénaliens dès 20 semaines d’aménorrhée (SA) suggère l’existence d’un mécanisme similaire. Le but de notre étude était : (i) d’analyser la densité mastocytaire ; (ii) d’étudier l’expression des enzymes de la voie de synthèse des minéralocorticoïdes et des protéines de la voie de signalisation sérotoninergique, dans la glande surrénale en période fœtale et néonatale selon le terme et les conditions de naissance. Nous avons réalisé une étude immunohistochimique sur des tissus fœtaux (n =17) et néonataux (n =7) humains entre 23 et 41 SA. Un comptage des cellules tryptase-immunopositives (mastocytes) a été effectué dans la zone 3β-hydroxystéroïde déshydrogénase de type 2 (3β-HSD2) positive. Une expression des enzymes 3β-HSD2 et aldostérone synthase (CYP11B2) plus intense ainsi qu’une densité mastocytaire plus élevée sont observées chez les nouveau-nés comparés aux fœtus entre 28 SA et 32 SA. Les mastocytes sont détectés au voisinage des cellules immunopositives pour la tryptophane hydroxylase de type 1, le récepteur sérotoninergique de type 4, la 3β-HSD2 et CYP11B2. Enfin, la densité mastocytaire apparaît plus élevée en cas d’hypoxie anténatale. Collectivement, ces résultats suggèrent un contrôle de la synthèse d’aldostérone néonatale par les mastocytes dans l’adaptation à la vie extra-utérine, notamment en cas de grande prématurité, via la voie de signalisation sérotoninergique

Assessment of 226Ra and U colloidal transport in a mining environment

International audienc

Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal

International audienceMast cells are present in the human adult adrenal with a potential role in the regulation of aldosterone secretion in both normal cortex and adrenocortical adenomas. We have investigated the human developing adrenal gland for the presence of mast cells in parallel with steroidogenic enzymes profile and serotonin signaling pathway. RT-QPCR and immunohistochemical studies were performed on adrenals at 16-41 weeks of gestation (WG). Tryptase-immunopositive mast cells were found from 18 WG in the adrenal subcapsular layer, close to 3βHSD- and CYP11B2-immunoreactive cells, firstly detected at 18 and 24 WG, respectively. Tryptophan hydroxylase and serotonin receptor type 4 expression increased at 30 WG before the CYP11B2 expression surge. In addition, HDL and LDL cholesterol receptors were expressed in the subcapsular zone from 24 WG. Altogether, our findings suggest the implication of mast cells and serotonin in the establishment of the mineralocorticoid synthesizing pathway during fetal adrenal development