Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma.

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes.

In a 24-year-old man with mild intellectual disability, congenital heart defects and obesity, we identified up to 4 small supernumerary marker chromosomes (sSMCs) in blood metaphases. The ring-shaped sSMCs were derived from chromosomes 11, 12 and X as well as a fourth, unidentified chromosome. In interphase nuclei of epithelial cells from the urinary tract and buccal mucosa, the presence of the r(11), r(12) and r(X) was confirmed by FISH. Using Illumina Infinium 317K SNP-arrays, we detected 3 copies of the pericentromeric regions of chromosomes 11, 12 and X. The r(X) was present in 84-89% of cells in the various tissues examined, lacks the XIST gene, but contains FAM123B, a potential dosage-sensitive candidate gene for congenital cardiac abnormalities, and ARHGEF9, a candidate gene for intellectual disability. ARHGEF9 encodes collybistin (CB), which is required for localization of the inhibitory receptor-anchoring protein gephyrin and for formation and maintenance of postsynaptic GABAA and glycine receptors. We propose that the 2-fold increase in dosage of ARHGEF9 disturbs the stoichiometry of CB with its interacting proteins at inhibitory postsynapses. SNP alleles and short tandem repeat markers on the r(11) and r(X) were compatible with a maternal origin of both sSMCs through a meiosis II error. The sSMCs may have resulted from predivision chromatid nondisjunction, leading to anaphase lagging, followed by incomplete degradation of the supernumerary chromosomes.

Guidelines for the genetic diagnosis of hereditary recurrent fevers.

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report.

UNLABELLED: Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3-7 days and recurring every 4-6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C-reactive protein are elevated during the episode, and in addition, high levels of interleukine-1 (IL-1), IL-6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF-alpha inhibitor, and three children with anakinra, IL-1 receptor antagonist. CONCLUSION: This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5-year-old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented.

Overexpression of components of the Frizzled-Dishevelled cascade results in apoptotic cell death, mediated by beta-catenin.

Frizzled (fz) functions as a 7-transmembrane receptor in the Frizzled-Dishevelled signal transduction cascade. It is involved in architectural control of development in species as divergent as Drosophila and vertebrates. Regulation of multicellular architecture requires control of cell alignment, but also involves an equilibrium among cell proliferation, differentiation, and apoptosis. Recently, modulation of the Frizzled-Dishevelled (Dvl) cascade has been related to apoptosis. However, the role of beta-catenin, a second messenger in the Frizzled-Dishevelled cascade, in programmed cell death is a matter of debate. To elucidate the role of this cascade in apoptosis, we studied the effect of overexpression of fz1, fz2, dvl1, and beta-catenin. The signal transduction pathway and the involvement of beta-catenin were further investigated by using different inhibitors. These experiments were performed in different cell types: COS7, 293, and PC12. Overexpression of fz1, fz2, and dvl1 induced apoptosis in COS7 and 293 cells. beta-Catenin appears to be the mediator for this process since beta-catenin overexpression as well as lithium and valproate induced apoptosis. In contrast, lithium treatment did not result in apoptosis in PC12 cells. We conclude that different components of the Frizzled-Dishevelled cascade can induce apoptosis, but that this effect is dependent on the cell type.

Frizzled 2 is transiently expressed in neural crest-containing areas during development of the heart and great arteries in the mouse.

Frizzled 2 acts as a 7-transmembrane receptor in the Wnt-Dishevelled signal transduction cascade. Among others, this cascade has been associated with neural crest cell proliferation and early migration during development in mammals. The genes for some components of this cascade are located in chromosomal regions that are deleted in human syndromes associated with neural crest cell defects, like DiGeorge and Velo-Cardio-Facial Syndrome. These syndromes are often accompanied by abnormalities in cardiac morphology. Furthermore, we have reported in previous studies the upregulation of the tissue polarity gene frizzled 2 in myofibroblasts during their migration into the necrotic area after myocardial infarction in the adult heart. It is known that genes that are upregulated during cardiac remodeling due to pathology often play a role during development. To investigate whether frizzled 2 can be associated with the process of cardiac morphogenesis we studied its expression in the thoracic arterial system and heart of mouse embryo's of 10, 12, 14, 16 and 18 days after conception by means of in situ hybridization. At day 10 after conception signal could be found in the pharyngeal arches and arch arteries. The outflow tract, the ascending aorta and the pulmonary trunk were positive for frizzled 2 from day 12 on. This expression decreased with time and at day 18 only some signal could be detected in the aorta and pulmonary trunk. In contrast, in coronary and pulmonary arteries no expression was observed at any time point. Minor myocardial expression was observed in the ventricular septum at days 12 and 14. Atrial expression, although considerably lower than ventricular expression, could be detected somewhat later at days 14 and 16. Our results indicate that there is transient expression of frizzled 2 in areas that are invested by neural crest cells. This expression is downregulated upon neural crest cell differentiation. The frizzled 2 expression supports a role for the Wnt-frizzled pathway in neural crest-related disorders.

Beta-catenin, an inducer of uncontrolled cell proliferation and migration in malignancies, is localized in the cytoplasm of vascular endothelium during neovascularization after myocardial infarction.

Beta-catenin is a protein involved in cell-cell adhesion and proliferation. In neoplastic diseases, defects in the regulation of the cellular beta-catenin content and cytoplasmic accumulation of the protein contribute to the uncontrolled cell proliferation and migration. Whether beta-catenin plays a role in the controlled proliferative and migratory responses to injury, eg, of vascular endothelial cells during neovascularization after myocardial infarction (MI), is not known. In the present study, we examined the localization of beta-catenin in the infarcted rat heart at different time points after MI. Cytoplasmic beta-catenin was observed in the endothelial cells of the newly formed and pre-existing blood vessels in the infarct area in the first week after MI, but not in the uninjured parts of the heart and not at later time points. Adenomatous polyposis coli (APC) protein was also detected; interaction of APC with beta-catenin has been reported to be critical in epithelial tube formation in vitro. Moreover, the expression of dishevelled-1, an upstream regulatory molecule of the cellular beta-catenin content, was observed in vascular endothelial cells in the infarct area. These findings suggest a role for the beta-catenin-APC complex in the proliferation and migration of vascular endothelial cells during neovascularization of the infarct area.