Pulmonary hypertension associated with congenital heart block and neonatal lupus syndrome: A series of four cases.

OBJECTIVE: Neonatal lupus syndrome has multisystemic manifestations among which pulmonary involvement has been rarely reported. We describe the clinical presentation, management, and outcome of a series of four neonates who developed reversible pulmonary hypertension associated with auto-immune congenital complete heart block. METHOD: Data from the French registry of neonatal lupus syndrome were retrospectively reviewed. RESULTS: Between 2000 and March 2020, 231 children were included in the French registry, four/73 followed in our institution developed pulmonary hypertension. Diagnosis was suspected on transthoracic echocardiography at a median age of 42 days [range 10-58], and confirmed by right heart catheterization in all; 2 of them where paced at time of diagnosis and 2 were not. All had some degree of hypoxemia and respiratory distress. Hypoxemia was always reversible under O2 et NO. Lung CT demonstrated ground glass anomalies in all. One patient had a lung biopsy consistent with pulmonary hypertension secondary to lung disease. Management included immunosuppressive therapy in 3 associated with sildenafil in 2. Pulmonary hypertension resolved in all at a median age of 4 weeks [range 3-6] after treatment initiation and after one year for the one child who did not receive specific treatment. CONCLUSION: Clinical, hemodynamical, imaging and histological findings advocate for pulmonary hypertension associated with respiratory disease as a rare manifestation of neonatal lupus syndrome.

Antibody-mediated rejection in pediatric small bowel transplantation: Capillaritis is a major determinant of C4d positivity in intestinal transplant biopsies.

The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor-specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy-eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome.

Child dermoid cyst mimicking a craniopharyngioma: the benefit of MRI T2-weighted diffusion sequence.

BACKGROUND: Brain dermoid cysts are very rare lesions. Although benign, these cysts may be associated with devastating complications due to mass effect or meningitis. The discovery of completely asymptomatic dermoid cysts in the pediatric population is exceedingly rare. Despite the advances in imaging modalities, it sometimes remains difficult to exclude the differential diagnosis of craniopharyngioma. CASE REPORT: We describe a 12-year-old boy addressed for suspicion of craniopharyngioma diagnosed by decreased visual acuity, bitemporal hemianopia and a CT scan showing a large hypodense suprasellar lesion with intralesional calcifications. Despite the unusual localization and size of this lesion, the absence of dermal sinus commonly found, and before visualizing a hyperintense mass on MRI-diffusion, the diagnosis of craniopharyngioma was ruled out in favor of a dermoid cyst. Radical excision was performed. CONCLUSION: In the suprasellar area, craniopharyngioma and dermoid cyst may have very similar radiological aspects: low density masses on CT scan and a hyperintense signal on T1-weighted MRI sequences with a variable signal on T2-weighted sequences. Hitherto, only two cases in literature have described suprasellar dermoid cyst. Their initial diagnosis was facilitated by the presence of a dermal sinus.

Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches.

Background: Eosinophilic oesophagitis (EoE) is a chronic food allergic disorder limited to oesophageal mucosa whose pathogenesis is still only partially understood. Moreover, its diagnosis and follow-up need repeated endoscopies due to absence of non-invasive validated biomarkers. In the present study, we aimed to deeply describe local immunological and molecular components of EoE in well-phenotyped children, and to identify potential circulating EoE-biomarkers. Methods: Blood and oesophageal biopsies were collected simultaneously from French children with EoE (n=17) and from control subjects (n=15). Untargeted transcriptomics analysis was performed on mRNA extracted from biopsies using microarrays. In parallel, we performed a comprehensive analysis of immune components on both cellular and soluble extracts obtained from both biopsies and blood, using flow cytometry. Finally, we performed non-targeted plasma metabolomics using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Uni/multivariate supervised and non-supervised statistical analyses were then conducted to identify significant and discriminant components associated with EoE within local and/or systemic transcriptomics, immunologic and metabolomics datasets. As a proof of concept, we conducted multi-omics data integration to identify a plasmatic signature of EoE. Results: French children with EoE shared the same transcriptomic signature as US patients. Network visualization of differentially expressed (DE) genes highlighted the major dysregulation of innate and adaptive immune processes, but also of pathways involved in epithelial cells and barrier functions, and in perception of chemical stimuli. Immune analysis of biopsies highlighted EoE is associated with dysregulation of both type (T) 1, T2 and T3 innate and adaptive immunity, in a highly inflammatory milieu. Although an immune signature of EoE was found in blood, untargeted metabolomics more efficiently discriminated children with EoE from control subjects, with dysregulation of vitamin B6 and various amino acids metabolisms. Multi-blocks integration suggested that an EoE plasma signature may be identified by combining metabolomics and cytokines datasets. Conclusions: Our study strengthens the evidence that EoE results from alterations of the oesophageal epithelium associated with altered immune responses far beyond a simplistic T2 dysregulation. As a proof of concept, combining metabolomics and cytokines data may provide a set of potential plasma biomarkers for EoE diagnosis, which needs to be confirmed on a larger and independent cohort.

Activating mutations in the luteinizing hormone receptor gene: a human model of non-follicle-stimulating hormone-dependent inhibin production and germ cell maturation.

CONTEXT: Familial male-limited precocious puberty is a dominant autosomal genetic disease caused by activating LH receptor gene mutations, clinically expressed only in males. In preliminary studies, in addition to the expected testosterone increase, we found high inhibin B levels before the age of normal puberty. OBJECTIVES: The objective of the study was to assess the cellular origin of serum inhibin thanks to testis section immunostaining. MAIN OUTCOME MEASURES: Serum testosterone, gonadotropin, inhibin B, pan-alphaC-inhibin, and anti-Mullerian hormone levels were measured. Immunostaining was performed using specific anti-alpha- and anti-beta-subunit antibodies. SUBJECTS AND METHODS: Five boys from three families (mutation M398T or I542L) were investigated at onset (2-6 yr), on ketoconazole treatment, and at adolescence. Testis biopsies were performed in three subjects before the disease was fully characterized. RESULTS: The high testosterone levels were suppressed by ketoconazole. Anti-Mullerian hormone levels were inversely related to testosterone: low at diagnosis, elevated after testosterone suppression. Despite FSH suppression, inhibin B and pan-alphaC-inhibin levels were high from clinical onset to adolescence. Biopsy specimens showed normal Sertoli cell complement and germ cell maturation until the spermatocyte II stage. Sertoli and Leydig cells displayed positive inhibin alpha-subunit immunostaining. Only Leydig cells and spermatogonia stained positively for the inhibin betaB-subunit. CONCLUSIONS: Familial male-limited precocious puberty is a unique model of inhibin B secretion, demonstrating that Leydig cells can produce significant amounts of the dimeric molecule. Our results also suggest that the pubertal FSH rise is not required for full expression of the two inhibin B genes and for the initiation of germ cell maturation.

Deeper rectal biopsies and better yield of neuronal structures with Scheye vs Noblett forceps--preliminary results.

OBJECTIVE: The aim of the study was to compare 2 different forceps designed to perform biopsies of the rectal mucosa, those of Noblett and Scheye, the latter having a similar design and differing by the disposable cutting system. METHODS: This historical study compares biopsies obtained with the Noblett forceps in 13 girls and 20 boys (mean ± SD age, 13 ± 30 months) and biopsies obtained with the Scheye forceps in 19 girls and 21 boys (mean ± SD age, 8.5 ± 19 months). RESULTS: The thickness of the material obtained with the Scheye forceps was significantly greater for the specimens obtained with the Scheye forceps (total biopsy: 1.74 ± 0.46 mm vs 0.67 ± 0.2 mm, P < .0001; submucosa: 1.12 ± 0.4 mm vs 0.14 ± 0.17 mm, P < .001). The Scheye forceps considerably increased the yield of neuronal structures, both for submucosal plexus (P < .003) and ganglia (P < .0001). No complication occurred in either group. CONCLUSION: The Scheye disposable rectal biopsy system provides larger mucosal biopsy samples than the Noblett with increased recovery of neuronal structures.

Histological basis of the liver hanging maneuver.

BACKGROUND: Liver hanging maneuver (LHM) consists in passing a tape between the retrohepatic inferior vena cava (RHIVC) and the liver to perform various kinds of hepatectomies. LHM is a well-known procedure but its histological basis remains poorly documented. METHODS: Ten anatomical specimens comprising RHIVC, and surrounding hepatic parenchyma were studied after conventional staining and immunohistochemistry with specific antibody for alpha smooth muscle actin. RESULTS: RHIVC wall structure consists of a thick muscular layer of longitudinal smooth muscle fibers and a peripheral loose connective tissue without smooth muscle fibers adherent to the liver parenchyma. This loose connective tissue between the liver and the RHIVC is the avascular plane for the passage of the clamp during LHM. CONCLUSION: The histological structure of the RHIVC does not seem to have any special hemostatic property. The low bleeding rate during LHM can be only explained by the very low density of RHIVC afferent veins.

Cyclopia: a radiological and anatomical craniofacial post mortem study.

Cyclopia is a rare foetal malformation characterized by a single palpebral fissure and a proboscis associated with severe brain malformation. Approximately 1.05 in 100 000 births including stillbirths are identified as cyclopian. Cyclopia is not compatible with life. The authors present an anatomical and histological study of the fronto-orbito-maxillary region carried out after 3-D CT reconstruction in a 21 week-old foetus with cyclopia. Anatomical and histological observations suggest that the integrity of the trigeminal nerves is very important for the normal development of the embryological structures of the face. Fusion of the facial processes in the midline takes place even if central prosencephalic structures are absent. For this reason the face in cyclopia, in both its positive and negative aspects, constitutes a model for the study of the normal development of this region. Copyright 2001 European Association for Cranio-Maxillofacial Surgery.

Six and Eya expression during human somitogenesis and MyoD gene family activation.

This report describes the characterisation of the expression profile of several myogenic determination genes during human embryogenesis. The data were obtained from axial structures and limb buds of human embryos aged between 3 and 8 weeks of development. Using in situ hybridisation to detect Pax3 and MyoD gene family mRNAs, and immunochemistry to follow Six and Eya protein accumulation, we have been able to establish the chronology of accumulation of these gene products. As in mouse, the first transcripts detected in myotomes of 3 week-old embryos are Pax3 and Myf5, followed by the expression of myogenin. MyoD appears to be activated well after Myf5, myogenin and MRF4 in the early myotome, whereas, in limb bud muscles, the presence of all four of these mRNAs is concomitant from 6 weeks. Six1, Six4 and Six5 homeoproteins are detected later than Myf5 activation. These Six homeoproteins are first observed in the cytoplasm of myogenin expressing cells. At later stages of development, Six1 and Six5, but not Six4, are translocated into the nuclei of myogenic cells, concomitantly with MyHCemb expression. Eya1 and Eya2 proteins, potential Six cofactors, were also detected in myogenin positive cells, but their accumulation was delayed and was mainly cytoplasmic. These results preclude that early activation of Myf5, myogenin and MRF4 is under the control of Six and Eya proteins, while Six and Eya proteins would be involved in later steps of myogenic differentiation.