Background Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called ...STING-associated vasculopathy with onset in infancy (SAVI). Objectives We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Methods Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. Results Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Conclusions Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
A study of families from southern Tunisia affected by general pustular psoriasis uncovered the genetic cause of their disease: a mutation affecting the function of the interleukin-36–receptor ...antagonist.
Psoriasis is a chronic inflammatory skin disease affecting 2 to 3% of persons of European descent.
1
Psoriasis vulgaris, the most common form of the disease, accounts for 80% of cases and has a strong, albeit complex, genetic component.
2
Numerous chromosomal loci have been implicated in genomewide association studies, but analyses of these loci have yielded only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses.
3
–
5
The disease follows mendelian transmission in a small minority of families.
Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are characterized by . . .
The patients, aged between 5 and 12 years, exhibited the phenotypic variability associated with TMEM173-activating mutations,2-4 with lung disease and systemic inflammation being the major features ...in patient 1 (P1) and patient 3 (P3), while in patient 2 (P2) skin involvement was most prominent (Fig 1; see Supplemental Text and Table E1 in this article's Online Repository at www.jacionline.org). Modest and incomplete downregulation of ISG was recently described in splenic B cells of mice treated with tofacitinib, a JAK1/3 inhibitor, with differential signaling effects suggesting currently poorly understood facets of IFN regulation.9 In this regard, our kinetic ex vivo experiments provide insights into the rapid dynamic changes in IFN signaling secondary to JAK1 blockade.
Ectodermal dysplasias are genetic conditions affecting the development and/or homeostasis of 2 or more ectodermal derivatives, including hair, teeth, nails, and certain glands. No tool is available ...to assess the burden of ectodermal dysplasias and its multidimensional impact on patients and their families. This study developed and validated a familial/parental 19-item burden questionnaire designed specifically for ectodermal dysplasias. Each group of questions was linked to 1 of the following dimensions: (i) Impact of the disease on social life and hobbies; (ii) Future prospects; (iii) Restraint of the disease on outdoor activities; (iv) Financial burden of the disease; (v) Acceptance of the disease. Cronbach’s alpha was 0.91 for the entire Ectodermal Dysplasias-Burden of Disease (ED-BD) scale, confirming excellent internal coherence. Intradimensional coherences all demonstrated excellent reliability (α > 0.76). The ED-BD questionnaire was highly correlated with the Short Form-12 and Psychological General Well Being Index validated questionnaires. Cultural and linguistic validation in US English was conducted. Development and validation of the questionnaire was based on data from patients with the 2 main ectodermal dysplasias subtypes. This ED-BD questionnaire represents the first specific assessment tool for evaluating the familial/parental burden of ectodermal dysplasias.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
To describe the surgical technique and to assess the outcomes in pediatric patients who underwent tectonic lamellar sclerokeratoplasty using full‐thickness central corneal grafts to treat ...malformative, invasive and inflammatory limbal insufficiency.
Methods
Retrospective, multicenter, non‐comparative analysis of a consecutive interventional case series including five pediatric cases of progressive limbal insufficiency from various severe malformative and inflammatory cause. All patients underwent tectonic lamellar sclerokeratoplasty using full‐thickness central corneal grafts under general anesthesia. Progression of limbal insufficiency after surgery, preoperative and postoperative visual acuity and perioperative complications were recorded retrospectively from patient medical records and external eye imaging.
Minimum post‐operative follow‐up was 6 months for each patient.
Results
In total, 5 children with severe limbal insufficiency from various etiologies were included. Mean age at surgery was 5.6 yo (range 5 w to 11 yo). Four (80%) had severe progressive and invasive choristomas and one (20%) presented a severe case of epidermolysis bullosa.
Two cases (40%) showed a stabilization of the postoperative visual acuity, other cases had non‐quantifiable visual acuity due to various reasons. Four cases (80%) presented a stabilization of the limbal insufficiency and corneal opacification. Two cases (40%) of corneal graft opacification without consequences on visual acuity were noted. One case (20%) of corneal graft infection was followed by limbal insufficiency recurrence. A second procedure for recurrence was performed in one case (20%).
Conclusions
Using full‐thickness central corneal grafts in lamellar sclerokeratoplasty for severe malformative, invasive and inflammatory limbal insufficiency cases seems to help reducing progression. In most of the cases, stable visual acuity was maintained or visual axis preserved, with limited postoperative complications.
Managing extracranial arteriovenous malformations is challenging. Sirolimus (rapamycin) is increasingly being used when surgery and embolization are not advised. Because of its anti-angiogenic ...properties here we report all extracranial arteriovenous malformation cases treated with sirolimus in 2 French tertiary centers for vascular anomalies. The outcomes were efficacy (complete, partial, no response) based on arteriovenous malformation volume and necrosis/hemorrhage and side effects. We retrospectively included 10 patients (7 children). The sirolimus dose ranged from 0.6 to 3.5 mg/m2. Median (interquartile range IQR) treatment time was 24.5 (4.5; 35) months. Five patients showed no response and 5 showed partial response at a median (IQR) of 3 (1; 5) months followed in 2 cases by therapeutic resistance (i.e., progressive disease after 9 and 24 months of treatment). The most frequent side effect was mouth ulcers. This study shows poor efficacy of sirolimus for treating extracranial arteriovenous malformations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor ...mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene
LAMB3
has been the first genetic skin disease successfully tackled by
ex vivo
gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of
LAMB3
-related JEB. Autologous clonogenic keratinocytes will be isolated from patients’ skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human
LAMB3
cDNA and plated onto a fibrin support (144cm
2
). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with
LAMB3
mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses.
Clinical Trial Registration: EudraCT Number: 2018-000261-36.
Food allergies rapidly become a dominant trait, persist throughout life, and are related to a high level of total and specific IgE (sIgE) to foods.2 Clinical manifestations may involve digestive ...symptoms, and recently eosinophilic esophagitis (EoE) in 1 child with NS has been reported.2 We shared this experience of EoE in 1 child with NS in our French reference center (MAGEC Center, Necker-Enfants-Malades Hospital, Paris, France) and thus included digestive endoscopy in the routine workup of patients with NS when presenting with digestive symptoms. Diet was normal in only 1 patient, whereas 11 patients were carrying out an elimination diet of staple foods (milk and dairy products, egg, and/or wheat), in association with more specific eliminations in 9 patients (eg, peanuts, fish, and soy), based on parents' observation. The expression of LEKTI was tested in the esophageal mucosa of all patients with NS, and compared with 15 routine esophageal samples (without EoE), and with 10 esophageal samples of patients with EoE without NS (with comparative analysis of a positive normal skin control and the demonstration of internal negative control areas for every sample). NAFish: NATree nuts: 12.5 Egg white: <0.1Egg yolk: <0.1Other: not done Milk: <0.1Wheat: 0.7Egg white: 0.2Peanut: <0.1Soy: <0.1Fish: <0.1 Milk: 15.2Wheat: 10Egg white: 3.9Peanut: 17.7Soy: 5.5Fish: 0.2Beef: 5.6 Eosinophilic esophagitis No (0 Eo/hpf) Yes (60 Eo/hpf) No (0 Eo/hpf) No (0 Eo/hpf) Yes (22 Eo/hpf) Yes (100 Eo/hpf) No (0 Eo/hpf) Yes (20 Eo/hpf) No (10 Eo/hpf) No (6 Eo/hpf) No (0 Eo/hpf) No (1 Eo/hpf) Colonic...
Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and ...translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a "read through" strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus.
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