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.
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.
Background Incontinentia pigmenti (IP; MIM308300) is a severe, male-lethal, X-linked, dominant genodermatosis resulting from loss-of-function mutations in the IKBKG gene encoding nuclear factor κB ...(NF-κB) essential modulator (NEMO; the regulatory subunit of the IκB kinase IKK complex). In 80% of cases of IP, the deletion of exons 4 to 10 leads to the absence of NEMO and total inhibition of NF-κB signaling. Here we describe a new IKBKG mutation responsible for IP resulting in an inactive truncated form of NEMO. Objectives We sought to identify the mechanism or mechanisms by which the truncated NEMO protein inhibits the NF-κB signaling pathway. Methods We sequenced the IKBKG gene in patients with IP and performed complementation and transactivation assays in NEMO-deficient cells. We also used immunoprecipitation assays, immunoblotting, and an in situ proximity ligation assay to characterize the truncated NEMO protein interactions with IKK-α, IKK-β, TNF receptor–associated factor 6, TNF receptor–associated factor 2, receptor-interacting protein 1, Hemo-oxidized iron regulatory protein 2 ligase 1 (HOIL-1), HOIL-1–interacting protein, and SHANK-associated RH domain–interacting protein. Lastly, we assessed NEMO linear ubiquitination using immunoblotting and investigated the formation of NEMO-containing structures (using immunostaining and confocal microscopy) after cell stimulation with IL-1β. Results We identified a novel splice mutation in IKBKG (c.518+2T>G, resulting in an in-frame deletion: p.DelQ134_R256). The mutant NEMO lacked part of the CC1 coiled-coil and HLX2 helical domain. The p.DelQ134_R256 mutation caused inhibition of NF-κB signaling, although the truncated NEMO protein interacted with proteins involved in activation of NF-κB signaling. The IL-1β–induced formation of NEMO-containing structures was impaired in fibroblasts from patients with IP carrying the truncated NEMO form (as also observed in HOIL-1−/− cells). The truncated NEMO interaction with SHANK-associated RH domain–interacting protein was impaired in a male fetus with IP, leading to defective linear ubiquitination. Conclusion We identified a hitherto unreported disease mechanism (defective linear ubiquitination) in patients with IP.
Background Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent ...years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. Objective We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. Methods The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. Results It was agreed that currently the nosology should remain clinically based. “Syndromic” versus “nonsyndromic” forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, “keratinopathic ichthyosis”–under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. “Autosomal recessive congenital ichthyosis” is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. Limitations As more becomes known about these diseases in the future, modifications will be needed. Conclusion We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research.
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...
Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. ...in a series of 5 patients treated with anti-TNF- agents,3 infections ...were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. Because patients 3 and 6 experienced improvement in their pseudomass lesions after 6 and 12 months (see Figs E2 and E3), patients 4 and 5 did not show any improvement in their interstitial pattern, fibrotic pattern, or both (see Fig E4).
We report the rapid and dramatic efficacy of propranolol in 8 infants with infantile hepatic hemangiomas. The degree of response varied from a significant improvement to a complete resolution of ...hepatic lesions. Heart failure and hypothyroidism resolved, and hepatomegaly decreased. No side-effects of the drug were noted.
Infantile myofibromatosis: A series of 28 cases Mashiah, Jacob, MD, MHA; Hadj-Rabia, Smail, MD, PhD; Dompmartin, Anne, MD, PhD ...
Journal of the American Academy of Dermatology,
08/2014, Volume:
71, Issue:
2
Journal Article
Peer reviewed
Background Infantile myofibromatosis (IM) is a rare disorder of fibroblastic/myofibroblastic proliferation in children. Objectives We sought to document common and unusual characteristics of patients ...with IM. Methods This was a retrospective study of 28 children diagnosed with histopathologically confirmed IM between 1992 and 2012. Epidemiologic, clinical, and treatment data were reviewed. Results IM was more frequent in boys (60.8%). Skin lesions were congenital in 64.3% of cases. The solitary form accounted for 50% of cases. Most nodules were painless, arising in cutaneous or subcutaneous tissue. The multicentric form accounted for 39% of cases; the skin, subcutaneous tissue, or muscle was involved in 97.8% of cases, and the bones in 50% of cases. The generalized form had a mortality rate of 33% (one-third of cases). Multicentric and generalized forms regressed spontaneously; severe local complications were observed, and late recurrent nodules developed in a few cases. Limitations The retrospective review and the ascertainment of patients (from the departments of obstetrics and pediatrics) may have introduced bias in the analysis of severity of the different forms of IM. Conclusion The diagnosis of IM must be confirmed histopathologically because the clinical presentation can be misleading. The prognosis is usually good, although local morbidity can occur. The generalized and multicentric forms merit long-term follow-up.
Background Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. Objective We ...sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. Methods We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. Results A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This “early rash” was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis ( Staphylococcus aureus ) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. Limitations This was a retrospective study with a small number of patients. Conclusion When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment.
Abstract Objectives We studied the clinical phenotypes and tolerance to treatments in a series of patients affected by both inflammatory joint diseases and mastocytosis. Methods This retrospective ...multicenter study was conducted on behalf of 3 networks focused on mastocytosis, pediatric, and adults’ inflammatory joint diseases. Patients who displayed both mastocytosis and inflammatory joint diseases were included. Results A total of 31 patients were included. They had spondyloarthritis (SpA) (16 patients), rheumatoid arthritis (6 patients), juvenile idiopathic arthritis (2 patients), and undifferentiated arthritis (7 patients). The median ages at diagnosis of arthritis and mastocytosis were 44 and 40.5 years, respectively. Disease-modifying anti-rheumatic drugs (DMARDs) were required in 22 patients, comprising mostly methotrexate (13 patients), salazopyrin (8 patients), anti-tumor-necrosis-factor agents (7 patients), and corticosteroids (9 patients). They were well tolerated. Adverse events occurred in 2/24 patients receiving non-steroidal anti-inflammatory drugs. The prevalence of SpA among the 600 patients included in the mastocytosis cohort was 2.33%, which is significantly higher than the prevalence of SpA in the French population ( p < 0.001). Conclusions This study suggests that mastocytosis is associated with a higher prevalence of SpA than expected, and that DMARDs, notably anti-TNFα agents, are well tolerated in patients with mastocytosis. Mast cells might be involved in the development of SpA.
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