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 ¼ 14), congenital alveolar dysplasia (n ¼ 2), and other lethal lung hypoplasias (n ¼ 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n ¼ 8 and n ¼ 2, respectively) or FGF10 (n ¼ 2 and n ¼ 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping $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.

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Young age represents a recurrence risk independent of histological and clinical characteristics of the tumor. Initial treatment, especially for nonfree margins, is also a predictive factor. Appropriate initial surgery with particularly wide margins appears essential for the treatment of young women with DCIS.

our study aimed to assess perinatal outcomes and recurrence rate of chronic intervillositis of Unknown etiology (ciUe). We conducted an observational retrospective study in a tertiary care university hospital in France from January 1, 1997 to July 31, 2018. 122 pregnancies (102 women) with CIUE were included. Cases of the Department of Histopathology placenta database were re-analysed independently by three pathologists specializing in fetal pathology. Diagnosis of CIUE was confirmed according to: (1) the presence of cellular infiltrate in the intervillous space, (2) ~ 80% of the mononuclear cells in the intervillous space positive for CD68, (3) infiltration occupying at least 5% of the intervillous space, and (4) no clinical or histopathological sign of infection. Outcomes of pregnancies with CIUE (miscarriages, stillbirths, terminations of pregnancy, live birth with or without prematurity or fetal growth restriction) and proportion of ciUe recurrence were analysed. the lost pregnancies comprised 17 (13.9%) miscarriages, 17 (13.9%) stillbirths, and 18 (14.8%) terminations of pregnancy. Of the 70 (57.4%) pregnancies that led to a live birth, 38 (54.3%) new-borns were premature and 50 (72.5%) exhibited fetal growth restriction. Among the 102 women, 23 subsequently became pregnant, half of whom (n = 11) developed recurrent CIUE. CIUE was associated with high rates of adverse perinatal outcomes, including pregnancy loss, fetal growth restriction, and preterm birth with a risk of recurrence nearly 50%. Abbreviations aPL Antiphospholipid AZA Azathioprine BMI Body mass index CIUE Chronic intervillositis of unknown etiology HCQ Hydroxychloroquine HES Hematoxylin-eosin-saffron FGR Fetal growth restriction LDA Low-dose aspirin LMWH Low-molecular-weight heparin TOP Termination of pregnancy MVM Maternal vascular malperfusion of the placental bed PIg Polyvalent immunoglobulin