Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822 ). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2 nd and 3 rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands’ features.

Introduction Pregnant women with covid-19 are more likely to experience preterm birth. The virus seems to be associated with a wide range of placental lesions, none of them specific. Method We collected cases of Covid-19 maternal infection during pregnancy associated with poor pregnancy outcomes, for which we received the placenta. We studied clinical data and described pathological findings of placenta and post-mortem examination of fetuses. We performed an immunohistochemical study and RT-PCR of SARS-Cov-2 on placenta samples. Results We report 5 cases of poor fetal outcome, 3 fetal deaths and 2 extreme premature neonates, one with growth restriction, without clinical and biological sign of SARS-Cov-2 infection. All placenta presented massive perivillous fibrin deposition and large intervillous thrombi associated with strong SARS-Cov-2 expression in trophoblast and SARS-CoV-2 PCR positivity in amniotic fluid or on placenta samples. Chronic histiocytic intervillositis was present in 4/5 cases. Placental ultrasound was abnormal and the sFLT1-PIGF ratio was increased in one case. Timing between mothers’ infection and the poor fetal outcome was ≤10 days in 4 cases. The massive placental damage are directly induced by the virus whose receptors are expressed on trophoblast, leading to trophoblast necrosis and massive inflammation in villous chamber, in a similar way it occurs in diffuse alveolar damage in adults infected by SARS-Cov-2. Discussion SARS-Cov-2 can be associated to a rare set of placental lesions which can lead to fetal demise, preterm birth, or growth restriction. Stronger surveillance of mothers infected by SARS-Cov-2 is required.

We confirm that PD-L1 is constitutively expressed in all GTD premalignant and malignant trophoblast subtypes, independently from FIGO score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role for PD-L1 in the development and tolerance of GTD. Assessment of anti-PD-L1 drug in GTD patients has been activated.

By review of a series of cases, we set out to identify sonographic features suggestive of an obstructive mechanism in second-trimester fetuses with ventriculomegaly and describe developmental disorders related to pathological differentiation of the diencephalon, mesencephalon CASE SERIESThis case series included 11 fetuses referred to our institution for severe second-trimester ventriculomegaly of undetermined origin over a 10-year period (2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012). The mean gestational age at referral was 23 (range, 17-28) weeks. All patients underwent neurosonography and four underwent fetal magnetic resonance imaging. In all cases except one, the parents elected for termination of pregnancy after prenatal counseling owing to the severity of the ventriculomegaly. In one case, the parents elected to continue the pregnancy with minimal neonatal intervention.The prenatal cerebral imaging data were reviewed. Both biometric (head circumference, transverse cerebellar diameter and atrial width) and morphological cerebral parameters were recorded, including analysis of diencephalic and mesencephalic anatomical structures. (For comparison, Figure 1 shows the normal appearance of the diencephalon and mesencephalon on ultrasound at 22 weeks' gestation.) Anomalies outside the central nervous system were also documented. The cerebral imaging data were compared with neuropathological data, with a focus on the level and etiology of the obstruction.Data from the 11 cases refered for severe ventriculomegaly are summarized in Table 1. Mean atrial width was 27 (range, 16-40) mm. Head circumference was above the 90 th percentile in five cases and between the 50 th and 90 th percentiles in six. Ventriculomegaly was asymmetrical in the four most severe cases and was associated with an interhemispheric cyst in two cases (Figure 2). In all cases, analysis of the supratentorial space showed parenchymal thinning and reduction or absence of pericerebral spaces (Figure 3). Midline analysis demonstrated an incomplete or absent cavum septi