A pediatric case of TEK-Related malformations and marfanoid habitus: an incidental finding or a feature?

Vascular malformations encompass a wide range of complex vascular lesions. Due to the extreme variability of clinical presentation, classification and their related syndromes presents a challenge. Here we describe a case of a boy presenting with Marfanoid habitus, cutaneous vascular malformations, and severe acute anemia due to ileal venous malformations. Although a panel of genetic markers for the Marfan phenotype was negative, we identified a de novo mutation in the TEK gene in the patient. This case supports expansion of the phenotypic spectrum of TEK-related vascular malformations.

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.

Immunofluorescence mapping, electron microscopy and genetics in the diagnosis and sub-classification of inherited epidermolysis bullosa: a single-centre retrospective comparative study of 87 cases with long-term follow-up.

BACKGROUND: Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course. OBJECTIVES: Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB. METHODS: A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard. RESULTS: The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54 months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations. CONCLUSIONS: Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases.

Skin manifestations of COVID-19 in children: Part 3.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discuss one of the first and most widespread cutaneous manifestations of COVID-19, chilblain-like lesions, and in Part 2 we expanded to other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome. In this part of the review, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children for both COVID-19 and any other pre-existing conditions.

Skin manifestations of COVID-19 in children: Part 2.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults, as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discussed one of the first and most widespread cutaneous manifestations of COVID-19, chilblain-like lesions. In this part of the review, we describe other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome. In Part 3, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children for both COVID-19 and any other pre-existing conditions.

Skin manifestations of COVID-19 in children: Part 1.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discuss one of the first and most widespread cutaneous manifestation of COVID-19, chilblain-like lesions. In Part 2, we review other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome, while in Part 3, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children, for both COVID-19 and any other pre-existing conditions.

Multidisciplinary consensus recommendations from a European network for the diagnosis and practical management of patients with incontinentia pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is a rare multisystemic X-linked dominant genetic disorder characterized by highly diagnostic skin lesions. The disease can be misdiagnosed in infants, and complications affecting the eyes and/or the brain can be severe. Our objective was to highlight the urgency of an appropriate diagnosis and management strategy, as soon as the first symptoms appear, and the need for a well-codified monitoring strategy for each child. METHODS: An in-depth literature review using a large number of databases was conducted. The selection criteria for articles were literature review articles on the disease, case series and retrospective studies based on the disease, clinical studies (randomized or not) on treatment, articles discussing patient care and management (treatment, diagnosis, care pathways), and recommendations. The research period was from 2000 until 2018. A group of multidisciplinary experts in IP management was involved, issued from different healthcare providers of the European Network for Rare Skin Diseases (ERN-Skin). The final recommendations have been submitted to two patient representative associations and to a general practitioner and a neonatal specialist prior to their finalization. RESULTS AND CONCLUSION: The diagnosis of IP must be promptly performed to detect potential extracutaneous manifestations, thus allowing the timely implementation of specific therapeutic and monitoring strategies. Eye involvement can be a therapeutic urgency, and central nervous system (CNS) involvement requires a very rigorous long-term follow-up. Assessments and patient support should take into account the possible co-occurrence of various symptoms (including motor, visual and cognitive symptoms).

A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection.

BACKGROUND: Acral chilblain-like lesions are being increasingly reported during COVID-19 pandemic. However, only few patients proved positivity for SARS-CoV-2 infection. The relationship between this skin manifestation and COVID-19 infection has not been clarified yet. OBJECTIVE: To thoroughly characterize a prospective group of patients with chilblain-like lesions and to investigate the possible relationship with SARS-CoV-2 infection. METHODS: Following informed consent, patients underwent (i) clinical evaluation, (ii) RT-PCR and serology testing for SARS-CoV-2, (iii) digital videocapillaroscopy of finger and toe nailfolds, (iv) blood testing to screen for autoimmune diseases and coagulation anomalies, and (v) skin biopsy for histopathology, direct immunofluorescence and, in selected cases, electron microscopy. RESULTS: Nineteen patients, all adolescents (mean age: 14 years), were recruited. 11/19 (58%) of them and/or their cohabitants reported flu-like symptoms one to two months prior to skin manifestation onset. Lesions were localized to toes and also heels and soles. Videocapillaroscopy showed pericapillary oedema, dilated and abnormal capillaries, and microhaemorrhages both in finger and toe in the majority of patients. Major pathological findings included epidermal basal layer vacuolation, papillary dermis oedema and erythrocyte extravasation, perivascular and perieccrine dermal lymphocytic infiltrate, and mucin deposition in the dermis and hypodermis; dermal vessel thrombi were observed in two cases. Blood examinations were normal. Nasopharyngeal swab for SARS-CoV-2 and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3. CONCLUSIONS: Chilblain-like lesions during COVID-19 pandemic have specific epidemiologic, clinical, capillaroscopic and histopathological characteristics, which distinguish them from idiopathic perniosis. Though we could not formally prove SARS-CoV-2 infection in our patients, history data and the detection of anti-SARS-COV-2 IgA strongly suggest a relationship between skin lesions and COVID-19. Further investigations on the mechanisms of SARS-CoV-2 infection in children and pathogenesis of chilblain-like lesions are warranted.

Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases.

BACKGROUND: Cutaneous mosaicism is an area of dermatology in which there has been an explosion of knowledge within the current decade. This has led to fundamental changes in the understanding of the conditions in this field, and to an ongoing paradigm shift in the approach to management of mosaic skin disorders. OBJECTIVES: To lay out the general principles of mosaicism as they are currently understood, summarize the known cutaneous mosaic abnormalities of the skin with associated phenotypic and genotypic information, review the latest trials on targeted therapies and propose guidelines for the general approach to a patient with suspected mosaicism. METHODS: This was a consensus expert review as part of the European Reference Network project (ERN-Skin). CONCLUSIONS: This study provides clinicians with a practical approach to the patient with suspected mosaicism, redefines mosaicism for the modern genetic era, and proposes a new classification system based on genetic mechanism. What's already known about this topic? Cutaneous mosaicism is a complex field of dermatology that encompasses most birthmarks, and many rare syndromes. Some cutaneous patterns are known to be seen in mosaicism. Very few treatment options are available for most mosaic abnormalities of the skin. Recent high-sensitivity genetic techniques have led to an explosion of knowledge about genotype and phenotype in the literature. What does this study add? Expert consensus from the European Reference Network project. Review of knowledge of confirmed mosaic abnormalities of the skin, including cutaneous phenotype, extracutaneous associated features and genotype. Proposed new classification of mosaic abnormalities of the skin by genetic mechanism and therefore inheritance potential. Practical tips on correct sample collection and genetic investigation. Review of trials of targeted therapies. Guidelines for a practical clinical approach to the patient with suspected mosaicism.

Glanular Venous Malformation in Pediatric Age: An Uncommon Vascular Disorder.

Glanular venous malformations are uncommon in pediatric patients. The diagnosis can be easily achieved by observation, even if color Doppler ultrasound is useful for a better characterization. Abdomino-pelvic MRI is necessary to assess the extension of complex lesions and check for associated anomalies. Several therapeutic options are reported in literature. We report 3 paediatric cases successfully treated by surgery with no complications and functional sequelae. Cosmetic results were satisfactory, with minimal surgical scarring. In our opinion, surgery for small glanular venous malformations is indicated within puberty to prevent traumatic bleeding and psychological impact.

MicroRNA-145-5p regulates fibrotic features of recessive dystrophic epidermolysis bullosa skin fibroblasts.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder caused by mutations in the COL7A1 gene encoding type VII collagen, a cutaneous basement membrane component essential for epidermal-dermal adhesion. Hallmarks of the disease are unremitting blistering and chronic wounds with severe inflammation and fibrosis. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression also implicated in fibrotic processes. However, the role of miRNAs in RDEB fibrosis is almost unexplored. OBJECTIVES: Our study aimed to identify miRNAs deregulated in primary RDEB skin fibroblasts (RDEBFs) and to characterize their function in RDEB fibrosis. METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) was used to screen RDEBFs for expression levels of a group of miRNAs deregulated in hypertrophic scars and keloids, pathological conditions with abnormal wound healing and fibrosis. Contractility, proliferation and migration rate were evaluated by different in vitro assays in RDEBFs transfected with a miR-145-5p inhibitor. Expression levels of fibrotic markers and miR-145-5p targets were measured using qRT-PCR and western blot. RESULTS: The miR-143/145 cluster was upregulated in RDEBFs compared with fibroblasts from healthy subjects. RDEBFs transfected with a miR-145-5p inhibitor showed attenuated fibrotic traits of contraction, proliferation and migration, accompanied by reduced expression of the contractile proteins α-smooth muscle actin and transgelin. These effects were associated with upregulation of Krüppel-like factor 4 transcriptional repressor and downregulation of Jagged1, a known inducer of fibrosis. CONCLUSIONS: Our results highlight the profibrotic role of miR-145-5p and its regulatory networks in RDEB, shedding light on novel disease pathomechanisms and targets for future therapeutic approaches. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB) is a highly disabling genetic skin disease caused by mutations in the collagen VII gene and characterized by unremitting blistering and defective wound healing, leading to inflammation and fibrosis. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression in health and disease, and their deregulation has been implicated in fibrotic skin conditions. To date, only miR-29 has been associated with injury-driven fibrosis in RDEB. What does this study add? In patients with RDEB, miR-145-5p is overexpressed in RDEB skin fibroblasts (RDEBFs), where it plays a profibrotic role, as its inhibition reduces RDEBF fibrotic traits (contraction, proliferation and migration). miR-145-5p inhibition in RDEBFs determines the reduction of contractile markers α-smooth muscle actin and transgelin through upregulation of Krüppel-like factor 4, a transcriptional repressor of contractile proteins, and downregulation of Jagged1 (JAG1), an inducer of fibrosis. What is the translational message? Our findings expand the knowledge on miRNA-driven pathomechanisms implicated in RDEB fibrosis. miR-145-5p and its targets (e.g. JAG1) could represent relevant molecules for the development of novel therapeutic strategies to counteract fibrosis progression in patients with RDEB.

Management of congenital ichthyoses: European guidelines of care, part two.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.