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Introduction: Gomez-Lopez-Hernandez Syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia is an extremely rare neuro-cutaneous disease, classically described by the triad of rhombencephalosynapsis (RES), bilateral focal alopecia and trigeminal anesthesia. The clinical and radiographic spectrum of GLHS is now known to be broader, including craniofacial and supra-tentorial anomalies, as well as neurodevelopmental issues. Case presentation: Here, we present a case of antenatally diagnosed GLHS with RES, hydrocephaly and craniofacial anomalies identified on ultrasound (low-set ears with posterior rotation, hypertelorism, midface hypoplasia, micrognathia and anteverted nares) which were confirmed by autopsy after termination of pregnancy at 23 weeks gestation. Discussion: As no known genetic causes have been identified and the classical triad is not applicable to prenatal imaging, prenatal diagnosis of GLHS is based on neuro-imaging and the identification of supporting features. In presence of a RES associated with cranio-facial abnormalities in prenatal (brachycephaly, turricephaly, low-set ears, midface retrusion, micrognathia), GLHS should be considered as "possible” according to postnatal criteria.

Background. Pulmonary alveolar proteinosis (PAP) is a pulmonary disease characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. PAP is classically classified into three categories (Table 1): 1/primary (or autoimmune) with antibodies targeting the GM-CSF pathway, 2/secondary to another disease, typically a hematologic malignancy, and 3/genetic. Case-report. A 30 year-old woman received an allogenic hematopoietic stem cell transplantation (HSCT) after treatment for acute myeloid leukemia (AML). Within the first 6 months post HSCT, she developed an ocular, oral, digestive and hepatic graft-versus-host disease associated with a mixed ventilatory defect with a very severe obstructive syndrome and a severe CO diffusion impairment. High resolution computed tomography showed a classical “crazy paving” pattern. Aspect and differential cell count of BAL were normal. All microbiological samples remained culture negative. Histo-pathological analysis of transbronchial biopsies was unremarkable. Because of the severity of the respiratory insufficiency, open-lung biopsy (OBL) could not be performed. Despite multiple immunosuppressive therapies, lung function deteriorated rapidly; the patient also developed an excavated fungal lesion unresponsive to treatment. She underwent a bilateral lung transplant 48 months after HSCT. Histo-pathological analysis of explanted lungs showed obliterative bronchiolitis (OB), diffuse PAP and invasive cavitary pulmonary aspergillosis. Conclusions. This case illustrates the simultaneous occurrence of OB, PAP and a fungal infection in a 30-year old female patient who underwent HSCT for acute myeloid leukemia (AML). To our knowledge this is the only documented case of PAP associated with OB treated by lung transplantation., Highlights • PAP is characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. • Secondary PAP represent less than 10 % of all cases, hematologic disorders account for the majority of them. • Bronchoalveolar-lavage can establish diagnosis in 75% of cases however lung biopsy remains thegold standard. • There is no specific treatment, whole-lung lavage remains the standard of care. • This case illustrates the simultaneous occurrence of OB, PAP and invasive pulmonary aspergillosis treated by BLT.

Cancer diagnosis, prognosis, and therapy response predictions from tissue specimens highly depend on the phenotype and topological distribution of constituting histological entities. Thus, adequate tissue representations for encoding histological entities is imperative for computer aided cancer patient care. To this end, several approaches have leveraged cell-graphs, capturing the cell-microenvironment, to depict the tissue. These allow for utilizing graph theory and machine learning to map the tissue representation to tissue functionality, and quantify their relationship. Though cellular information is crucial, it is incomplete alone to comprehensively characterize complex tissue structure. We herein treat the tissue as a hierarchical composition of multiple types of histological entities from fine to coarse level, capturing multivariate tissue information at multiple levels. We propose a novel multi-level hierarchical entity-graph representation of tissue specimens to model the hierarchical compositions that encode histological entities as well as their intra- and inter-entity level interactions. Subsequently, a hierarchical graph neural network is proposed to operate on the hierarchical entity-graph and map the tissue structure to tissue functionality. Specifically, for input histology images, we utilize well-defined cells and tissue regions to build HierArchical Cell-to-Tissue (HACT) graph representations, and devise HACT-Net, a message passing graph neural network, to classify the HACT representations. As part of this work, we introduce the BReAst Carcinoma Subtyping (BRACS) dataset, a large cohort of Haematoxylin & Eosin stained breast tumor regions-of-interest, to evaluate and benchmark our proposed methodology against pathologists and state-of-the-art computer-aided diagnostic approaches. Through comparative assessment and ablation studies, our proposed method is demonstrated to yield superior classification results compared to alternative methods as well as individual pathologists. The code, data, and models can be accessed at https://github.com/histocartography/hact-net., Medical Image Analysis, 75, ISSN:1361-8415, ISSN:1361-8423

Neonatal hemochromatosis caused by a gestational alloimmune mechanism or gestational alloimmune liver disease (GALD) is a rare perinatal disorder characterized by intra- and extrahepatic iron overload. It is believed to result from complement-mediated liver injury, in which the classical complement pathway is activated by maternal antibody/fetal antigen complexes, leading to hepatocyte lysis by the membrane attack complex C5b9. According to some authors, C5b9 expression in more than 75% of liver parenchyma is specific for GALD. We conducted a retrospective multicentric immunohistochemical study with anti-C5b9 in GALD cases (n = 25) and non-GALD cases with iron overload (n = 36) and without iron overload (n = 18). C5b9 was expressed in 100% of GALD cases but involved more than 75% of the liver parenchyma in only 26% of the cases. C5b9 was detected in 26.75% of the non-GALD cases with more than 75% of positive parenchyma in maternal erythrocytic alloimmunization, herpes and enterovirus hepatitis, bile acid synthetic defect, DGUOK mutation, Gaucher disease, cystic fibrosis, and giant-cell hepatitis with autoimmune hemolytic anemia. Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease.

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare uterine neoplasms of uncertain etiology that resemble the sex cord tumors of the ovary and display a combined sex cord, epithelial, and smooth muscle immunophenotype. Most tumors are associated with a benign clinical course. We report the first cytological description of uterine UTROSCTs in liquid-based cervical cytology (LBC). A menopausal woman was discovered to have a uterine intraluminal polypoid mass protruding through the vagina. A Pap test was performed, and the LBC preparation showed isolated tumor cells with scant cytoplasm and slightly irregular, ovoid nuclei with fine chromatin and small nucleoli. Final histological evaluation identified a UTROSCT. This diagnostic possibility, albeit rare, should be included in the differential diagnosis when isolated malignant-appearing adenocarcinomatous cells are seen in women in the above scenario. As these features are not specific, they may result in misinterpretation with tumors that are more common and aggressive.

Although epithelial-to-mesenchymal transition (EMT) has been described in the development of complete hydatidiform moles and the invasion of the maternal decidua by trophoblasts during normal human placentation, its implication in gestational trophoblastic neoplasm (GTN) without villi is totally unknown. We studied the immunoexpression of EMT transcription factors (TWIST1, ZEB1, ZEB2), E-cadherin, and vimentin in 18 trophoblastic tumors and pseudo-tumors. Weak nuclear TWIST1 immunostaining was seen in 5% to 10% of all trophoblastic cells, without ZEB1 and ZEB2 nuclear staining. Trophoblastic cells did not express vimentin, and the expression of E-cadherin was maintained in all cases, indicating the absence of EMT features in GTN.

No data exist regarding the effect on fetuses of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first or second trimester of pregnancy, and data are limited regarding infections that occur during the third trimester. However, reports of newborns with fetal distress or requiring admission to the intensive care unit1,2 and a stillbirth after maternal coronavirus disease 2019 (COVID-19)3 in the third trimester suggest the possibility of COVID-19–induced placental pathology. We present a case of miscarriage during the second trimester in a pregnant woman with COVID-19.

Objective To define an algorithm to improve diagnosis of neonatal hemochromatosis (NH) related to gestational alloimmune liver disease (GALD), which is diagnosed by immunohistochemistry demonstrating activated complement at hepatocytes (IDACH). Study design We assessed 56 instances of fetal death or neonatal liver failure (NLF; 2006-2009), 29 (7 stillborns, 22 NLF) with NH, and 27 (5 stillborns, 22 NLF) without NH (non-NH). Immunohistochemistry was retrospectively performed in 21 cases. Cases were grouped as follows: (1) GALD as demonstrated by IDACH (n = 17); (2) indeterminate for GALD (n = 28); or (3) alternate diagnosis found (n = 11). We compared cases of immunohistochemically proven GALD with those with an alternate diagnosis. Results Of the 12 stillborns, 7 had NH because of GALD (NH-GALD), one was undeterminate, and 4 had alternate diagnoses (GALD excluded). Of the 22 newborns with NH, 6 had NH-GALD, one had mitochondrial respiratory chain disorder (MRCD), and 15 were indeterminate for GALD. Of 22 non-NH newborns, extrahepatic siderosis (EHS) was not assessed in 13 (3 GALD, 1 alternate diagnosis [MRCD] and 9 indeterminate GALD) and excluded in 9 (5 alternate diagnoses and 4 indeterminate GALD). The only clinical features found to be associated with GALD were intrafamilial recurrence, prematurity, and EHS. Conclusions In unexplained fetal death or NLF, the diagnosis of subsets of NH requires tissue analysis (autopsy) to assess EHS. In patients with NH, if MRCD is ruled out, NH-GALD is likely. The rate of IDACH in the diagnosis of GALD in cases without NH requires further study.

Extensive cytogenetic testing is slowly unveiling the complexity of the genomics of melanocytic tumors. NRAS mutations have been the first genetic abnormality described in malignant melanomas. We report the cases of two children, presenting a melanocytic lesion located on the ear. One appeared as a combined dermal clone inside a congenital nevus and the other as a centimetric purely dermal tumor. Both tumors were composed of spindled spitzoid melanocytes with atypical histologic features. aCGH and FISH revealed an amplification of the NRAS gene. Sequencing showed an exon 3 NRAS mutation. In the combined case, the amplification was limited to the spitzoid component, underscoring a possible phenotypic shift induced by the alteration. Similarly an overexpression of CyclinD1 and elevation of ki-67 was found in the spitzoid component confirming a raise in proliferation. Such combination of mutation and copy number increase has been previously reported for the HRAS gene in a subset of Spitz nevi. Further studies must evaluate if mutated NRAS is also amplified in melanomas arising in this clinical setting. These combined alterations could represent an early event ultimately leading to malignancy.

A girl patient born to healthy nonconsanguineous parents was referred at age 3 years and 2 months to our genetics department for testing due to developmental delay and postnatal microcephaly. Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin. Postnatal microcephaly and progressive ataxia and spasticity appeared later. Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin. β-catenin is a sub-unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report. Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice. Point mutations in CTNNB1 in human have recently been reported but this is the first observation of a new recognizable multiple congenital anomaly/mental retardation syndrome caused by CTNNB1 haploinsufficiency. This clinical report should prompt a search for point mutations in CTNNB1 in patients presenting developmental delay, mild hair, skin and facial anomalies, and neurodegeneration characterized by postnatal microcephaly, and progressive ataxia and spasticity. © 2014 Wiley Periodicals, Inc.

Background Alloimmunization against human platelet antigens (HPAs) can occur prenatally and induce fetal/neonatal alloimmune thrombocytopenia (FNAIT). The aim of this study was to identify placental histological features associated with platelet alloimmunization and their clinical significance. Methods This study examined 21 placentas from FNAIT-affected pregnancies and 42 age-matched control cases, all collected from pathology departments in the Rhone-Alpes region. Clinical and laboratory findings were collected for each FNAIT case. Two pathologists reviewed the placental slides of each FNAIT and control case. Histological features, with special emphasis on chronic inflammatory lesions, were evaluated. Differences between the two groups were calculated with odds ratios (ORs) and assessed with Wald's chi-square. Results FNAIT was associated with a significantly higher frequency of chronic chorioamnionitis (CC) (OR 14, 95%CI 1.7–113.8), basal chronic villitis (BCV) (OR 17, 95%CI 2–145.6) and chronic intervillositis (CIV). Chronic villitis (CV) (OR 3.7, 95%CI 0.9–15.2) and chronic deciduitis (CD) (OR 4.7, 95%CI 0.79–28.2) were also more frequent in the FNAIT than the control group, but these differences were not statistically significant. Conclusions FNAIT is significantly associated with CC, BCV, and CIV. This chronic inflammatory reaction is preferentially localized on the maternofetal interface. Anti-HPA alloimmunization may trigger an immunological conflict similar to graft-versus-host disease.

Extensive cytogenetic testing is slowly unveiling the complexity of the genomics of melanocytic tumors. NRAS mutations have been the first genetic abnormality described in malignant melanomas. We report the cases of two children, presenting a melanocytic lesion located on the ear. One appeared as a combined dermal clone inside a congenital nevus and the other as a centimetric purely dermal tumor. Both tumors were composed of spindled spitzoid melanocytes with atypical histologic features. aCGH and FISH revealed an amplification of the NRAS gene. Sequencing showed an exon 3 NRAS mutation. In the combined case, the amplification was limited to the spitzoid component, underscoring a possible phenotypic shift induced by the alteration. Similarly an overexpression of CyclinD1 and elevation of ki-67 was found in the spitzoid component confirming a raise in proliferation. Such combination of mutation and copy number increase has been previously reported for the HRAS gene in a subset of Spitz nevi. Further studies must evaluate if mutated NRAS is also amplified in melanomas arising in this clinical setting. These combined alterations could represent an early event ultimately leading to malignancy.

Background Apparently balanced chromosomal rearrangements (ABCR) are associated with an abnormal phenotype in 6% of cases. This may be due to cryptic genomic imbalances or to the disruption of genes at the breakpoint. However, breakpoint cloning using conventional methods (ie, fluorescent in situ hybridisation (FISH), Southern blot) is often laborious and time consuming. In this work, we used next generation sequencing (NGS) to locate breakpoints at the molecular level in four patients with multiple congenital abnormalities and/or intellectual deficiency (MCA/ID) who were carrying ABCR (one translocation, one complex chromosomal rearrangement and two inversions), which corresponded to nine breakpoints. Methods Genomic imbalance was previously excluded by array comparative genomic hybridisation (CGH) in all four patients. Whole genome paired-end protocol was used to identify breakpoints. The results were verified by FISH and by PCR with Sanger sequencing. Results We were able to map all nine breakpoints. NGS revealed an additional breakpoint due to a cryptic inversion at a breakpoint junction in one patient. Nine of 10 breakpoints occurred in repetitive elements and five genes were disrupted in their intronic sequence ( TCF4 , SHANK2 , PPFIA1 , RAB19 , KCNQ1 ). Conclusions NGS is a powerful tool allowing rapid breakpoint cloning of ABCR at the molecular level. We showed that in three out of four patients, gene disruption could account for the phenotype, allowing adapted genetic counselling and stopping unnecessary investigations. We propose that patients carrying ABCR with an abnormal phenotype should be explored systematically by NGS once a genomic imbalance has been excluded by array CGH.