Recurrent Increased Nuchal Translucency Led to the Identification of Novel NUP107 Variants.

Five percent of fetuses presents increased fetal nuchal translucency. It is a well-known marker for aneuploidy (T21, Turner syndrome) and a variety of monogenic syndromes such as Noonan syndrome and certain skeletal dysplasias, as well as associated with structural malformations such as congenital heart disease. Current diagnostic algorithms for increased nuchal translucency include a rapid test for aneuploidy (fluorescence in situ hybridization, FISH, or quantitative PCR), a cytogenetic analysis (karyotype or chromosomal microarray, CMA) followed by or concurrent with targeted gene panel analysis for RASopathies/Noonan syndrome. Some centers now propose whole exome sequencing as an adjunct, but its usefulness in isolated increased nuchal translucency remains debated. We describe the recurrence of apparently isolated increased nuchal translucency in 2 euploid fetuses. Whole genome sequencing identified two compound heterozygous variants in the NUP107 gene in both fetuses. Biallelic variants in NUP107 are responsible for severe steroid-resistant nephrotic syndrome, either isolated or syndromic (Galloway-Mowat syndrome); in addition to the renal phenotype, the latter also includes intellectual deficiency and dysmorphic features. Pregnancy termination made it impossible to assess whether the NUP107 variants found would have resulted in isolated or syndromic steroid-resistant nephrotic syndrome. However, identifying the responsible gene improved the accuracy of the genetic counseling. This family is an example of the added benefit of introducing WES/WGS in standardized protocols for prenatal diagnosis of euploid fetuses in "isolated" increased nuchal translucency.

Prenatal Diagnosis of Gómez-López-Hernández Syndrome.

INTRODUCTION: Gómez-López-Hernández syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is an extremely rare neurocutaneous 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 supratentorial 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 of 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 neuroimaging and the identification of supporting features. In presence of an RES associated with craniofacial abnormalities in prenatal (brachycephaly, turricephaly, low-set ears, midface retrusion, micrognathia), GLHS should be considered as "possible" according to postnatal criteria.

Prenatal diagnosis of Aicardi syndrome based on a suggestive imaging pattern: A multicenter case-series.

OBJECTIVES: To characterize a suggestive prenatal imaging pattern of Aicardi syndrome using ultrasound and MR imaging. METHODS: Based on a retrospective international series of Aicardi syndrome cases from tertiary centers encountered over a 20-year period (2000-2020), we investigated the frequencies of the imaging features in order to characterize an imaging pattern highly suggestive of the diagnosis. RESULTS: Among 20 cases included, arachnoid cysts associated with a distortion of the interhemispheric fissure were constantly encountered associated with complete or partial agenesis of the corpus callosum (19/20, 95%). This triad in the presence of other CNS disorganization, such as polymicrogyria (16/17, 94%), heterotopias (15/17, 88%), ventriculomegaly (14/20, 70%), cerebral asymmetry [14/20, 70%]) and less frequently extra-CNS anomaly (ocular anomalies [7/11, 64%], costal/vertebral segmentation defect [4/20, 20%]) represent a highly suggestive pattern of Aicardi syndrome in a female patient. CONCLUSION: Despite absence of genetic test to confirm prenatal diagnosis of AS, this combination of CNS and extra-CNS fetal findings allows delineation of a characteristic imaging pattern of AS, especially when facing dysgenesis of the corpus callosum.

Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease.

Neonatal hemochromatosis: diagnostic work-up based on a series of 56 cases of fetal death and neonatal liver failure.

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.

A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency.

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 ß-catenin. ß-catenin is a sub-unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous ß-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.

Mutated and amplified NRAS in a subset of cutaneous melanocytic lesions with dermal spitzoid morphology: report of two pediatric cases located on the ear.

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.

Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations.

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.

Response of Brain and Meningeal Metastases to Trastuzumab-Deruxtecan in a Patient with HER2-Low Breast Cancer: A Case Report.

Nervous system metastases (CNSm) are late events associated with poor outcomes in endocrine-sensitive HER2-negative breast cancer (BC) patients, especially in the presence of leptomeningeal disease (LMD). Effective treatments are extremely limited in this setting. The antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), which combines the anti-HER2 antibody trastuzumab with a topoisomerase type 1 inhibitor, showed high efficacy not only against HER2-positive but also HER2-low metastatic BCs, expressing HER2 at a lower level. To the best of our knowledge, this is the first report of a patient with metastatic endocrine-sensitive HER2-low BC suffering from BMs associated with LMD and sustained disease control when treated with T-DXd. Several recent case series have reported the activity of T-DXd in patients with HER2-positive disease and brain metastases or LMD, but none in HER2-low patients. This case is particularly relevant since more than 50% of BCs are HER2-low.

Hierarchical graph representations in digital pathology.

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.

Bilateral Silicone Granulomas Mimicking Breast Cancer Recurrence on 18F-FDG PET/CT.

ABSTRACT: We report the case of a 45-year-old woman with a history of right breast reconstruction with silicone implant for breast cancer. An 18F-FDG PET/CT performed several years later revealed the presence of 18F-FDG-avid nodules at the periphery of the silicone implant, in the right internal mammary chain, and in the contralateral breast. Needle core biopsies were positive for bilateral silicone granulomas, without any sign of malignancy. This case displays intense 18F-FDG uptake in silicone granulomas affecting the contralateral breast after implant reconstruction.

Secondary pulmonary alveolar proteinosis treated by lung transplant: A case report.

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.

Gestational trophoblastic neoplasms (GTNs) do not display epithelial-to-mesenchymal transition (EMT) features.

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.

Cytological features of uterine tumors resembling ovarian sex-cord tumors in liquid-based cervical cytology: a potential pitfall. Report of a unique and rare case.

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.

Placental histological lesions in fetal and neonatal alloimmune thrombocytopenia: A retrospective cohort study of 21 cases.

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 Rhône-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.