ABSTRACT
BACKGROUND: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders. METHODS: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF. RESULTS: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica. CONCLUSION: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.
Subject(s)
Nevus , Skin Diseases , Skin Neoplasms , Humans , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins p21(ras)/genetics , Nevus/genetics , Nevus/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce. OBJECTIVES: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP. METHODS: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18â years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0â years (range 3â months-18â years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3â years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5â years available for 33 patients and at 15â years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19â years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19â years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP.
Lymphomatoid papulosis is a very rare skin condition caused by an abnormal increase in white blood cells (called 'lymphocytes') in the skin. The condition rarely affects children, so most of the scientific data published about this disease focuses on adults. This study involved 12 academic dermatology centres in Europe, the Middle East and North America, and gathered data from about 87 children who presented with symptoms of lymphomatoid papulosis before the age of 19â years. The aim of this study was to better describe this disease in the paediatric population and discuss its treatment options and evolution. We found that the presentation of the disease in children is roughly the same as in adults. Safe and effective treatment options exist. The disease is not life threatening, but it requires investigation by a dermatologist, both to make a careful diagnosis and to monitor it as sometimes associated cancers that originate from blood cells can occur, mostly on the skin.
Subject(s)
Lymphomatoid Papulosis , Skin Neoplasms , Humans , Lymphomatoid Papulosis/pathology , Lymphomatoid Papulosis/epidemiology , Male , Retrospective Studies , Child , Female , Adolescent , Child, Preschool , Infant , Skin Neoplasms/pathology , Skin Neoplasms/epidemiology , Skin Neoplasms/mortality , Age of Onset , Prognosis , Diagnostic Errors/statistics & numerical data , Pityriasis Lichenoides/epidemiology , Pityriasis Lichenoides/pathology , Pityriasis Lichenoides/diagnosis , Insect Bites and Stings/epidemiology , Insect Bites and Stings/complications , Molluscum Contagiosum/epidemiology , Molluscum Contagiosum/pathology , Molluscum Contagiosum/diagnosisABSTRACT
Psoriasis may present in childhood with skin, nail and scalp lesions but sometimes also articular involvement. It has an import impact on the quality of life of young patients. In this article we present an overview of the treatments that may be used in children according to skin area involved and severity of lesions with special interest for the biological treatments, already available and under investigation.
Le psoriasis peut déjà se manifester dans l'enfance avec des lésions cutanées, des ongles, du scalp, mais parfois aussi une atteinte articulaire. Cette maladie a un impact important sur la qualité de vie de l'enfant. Dans cet article, nous présentons une revue des traitements en ce moment possibles chez les enfants, selon la surface de peau atteinte, la sévérité des lésions, en mettant surtout en lumière les traitements par biologiques déjà possibles et en étude.
Subject(s)
Psoriasis , Quality of Life , Child , Humans , Severity of Illness Index , Psoriasis/therapy , Skin , Nails/pathologyABSTRACT
Darier Disease is a rare autosomal dominant inherited skin disorder classified as an acantholytic dermatosis. It manifests around puberty as brownish keratotic papules of skin folds and seborrheic areas, associated with onychopathy and mucosal involvementand have a chronic relapsing-remitting course with frequent exacerbations triggered by sun exposure, heat, friction, or infections. Darier patients have an increased risk of neuropsychiatric disorders, type 1 diabetes and heart failure. Short-term management relies on antibiotics/antiviral, topical corticosteroids and/or retinoids. Moisturizers, sun protection and avoiding triggers are essential for long-term management. Conventional long-term treatment is not standardized and many topical treatments, physical and surgical measures and systemic treatments are described in the literature.
La maladie de Darier est une génodermatose rare à transmission autosomique dominante. Elle se manifeste autour de la puberté par des papules kératosiques brunâtres des plis et des zones séborrhéiques, associées à une onychopathie et une atteinte muqueuse, et évolue par poussées déclenchées par les UV, la chaleur, les frottements ou les infections. Les patients atteints présentent un risque accru de diabète de type 1, d'insuffisance cardiaque et de troubles neuropsychiatriques. La prise en charge à court terme consiste en des antibiotiques/antiviraux, des corticostéroïdes topiques et/ou des rétinoïdes. Celle à long terme repose sur les émollients et l'éviction des facteurs déclenchants. Le traitement à long terme n'étant pas codifié, de nombreux traitements locaux et sytémiques, mesures physiques et chirurgicales sont décrits dans la littérature.
Subject(s)
Darier Disease , Humans , Darier Disease/therapy , Darier Disease/drug therapy , Skin , Retinoids/therapeutic use , Anti-Bacterial Agents/therapeutic useABSTRACT
Auto-immune bullous diseases (AIBD) are rare in children. Although their pathogenesis is similar to their adult counterpart, there are differences in the clinical presentation. Moreover certain AIBD prevail at certain ages. There are no guidelines for the treatment of AIBD specific for children. In this review the recent literature is summarised with attention to recent data including diagnostic criteria. We also propose a treatment algorithm.
Les maladies bulleuses auto-immunes (MBAI) sont rares chez les enfants. Bien que la pathogenèse soit similaire à celle de l'adulte, il existe des différences concernant la présentation clinique et la prévalence des MBAI selon l'âge. À ce jour, il n'y a pas de recommandations spécifiques pour leur prise en charge chez l'enfant. Dans cet article, nous présentons une revue des données actuelles, des critères diagnostiques et proposons un algorithme de prise en charge.
Subject(s)
Autoimmune Diseases , Skin Diseases, Vesiculobullous , Child , Humans , Algorithms , Autoimmune Diseases/diagnosis , Autoimmune Diseases/therapy , Skin Diseases, Vesiculobullous/diagnosis , Skin Diseases, Vesiculobullous/pathologyABSTRACT
BACKGROUND: A popular antiseptic spray in Switzerland (Merfen spray), containing chlorhexidine digluconate, benzoxonium chloride and lauramine oxide, is frequently used to treat skin wounds. However, it is also increasingly reported as a major cause of adverse skin reactions, including allergic contact dermatitis (ACD). OBJECTIVES: To investigate the contact allergens responsible for ACD from this antiseptic. PATIENTS/METHODS: Patch tests were performed on seven patients with a clinical history compatible with contact dermatitis from this antiseptic mixture. RESULTS: All patients presented with acute eczematous reactions following contact with either Merfen spray alone, or with multiple products including this spray. Patients showed positive reactions to this product in both patch tests and repeated open application tests (ROATs). Four patients showed dose-dependent reactions to both benzoxonium chloride and lauramine oxide. One patient showed a dose-dependent reaction to the former and a non-dose-dependent reaction to the latter. Finally, two subjects showed responses only to lauramine oxide. One patient reacted to chlorhexidine digluconate 0.5% aq. in addition to both other allergens. CONCLUSIONS: Two commercially unavailable allergens, that is, benzoxonium chloride and/or lauramine oxide were identified as major causes of ACD from Merfen antiseptic spray, whereas chlorhexidine digluconate was a contributing culprit in only one patient.
Subject(s)
Anti-Infective Agents, Local , Dermatitis, Allergic Contact , Humans , Anti-Infective Agents, Local/adverse effects , Chlorhexidine/adverse effects , Allergens/adverse effects , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/etiology , Switzerland , Patch Tests/adverse effects , OxidesABSTRACT
Juvenile dermatomyositis is a rare multi-system auto-immune disease, particularly causing inflammation of skin and muscles of children. The diagnosis is based on the clinical picture with typical cutaneous lesions, which frequently are the first signs of the disease in contrast to muscle involvement. Muscular MRI is nowadays the first line investigation to diagnose myositis. Recently specific auto-antibodies have been detected allowing a better understanding of the disease and being important prognostic factors. An early diagnosis and aggressive treatment is crucial to induce remission of the disease, especially restore muscular function and to prevent severe complications such as calcinosis and lipodystrophy, which are difficult to treat as well as vital organ dysfunction.
La dermatomyosite juvénile est une maladie auto-immune multisystémique rare caractérisée par une faiblesse musculaire et/ou une éruption cutanée. Le diagnostic se pose par la reconnaissance des signes cutanés caractéristiques qui, contrairement à l'atteinte musculaire, se voit au stade initial de la maladie. L'IRM est l'examen de choix pour détecter la myosite. La mise en évidence récente d'auto-anticorps spécifiques de la maladie a permis de mieux comprendre et d'établir des pronostics sur l'évolution clinique des patients. Un diagnostic précoce et un traitement agressif sont cruciaux pour aider à obtenir une rémission. Ils permettent d'améliorer la fonction musculaire, de prévenir d'importantes séquelles cutanées difficilement traitables comme la calcinose et la lipodystrophie et d'éviter l'atteinte d'organes vitaux.
Subject(s)
Dermatomyositis , Muscular Diseases , Myositis , Child , Humans , Dermatomyositis/diagnosis , Dermatomyositis/therapy , Dermatomyositis/complications , Dermatologists , Myositis/therapy , SkinABSTRACT
Tinea capitis is a superficial dermatophytic infection of the scalp. This common dermatosis occurs predominantly in children. The clinical manifestation of the disease is heterogeneous, and vary widely depending on the pathogenic fungal agent. Direct mycological examination and cultures are mandatory for an accurate diagnosis and species identification. Treatment should be both local and systemic, and ideally is tailored to the dermatophytic species identified by the laboratory diagnostic work up. Secondary prophylaxis through supplementary measures is crucial to avoid epidemic outbreak and patient reinfection.
Tinea capitis (ou teigne du cuir chevelu) est une infection fongique superficielle du cuir chevelu par un dermatophyte. Cette dermatose est fréquente et prédomine en population pédiatrique. Le tableau clinique est hétérogène et varie beaucoup en fonction de l'espèce de dermatophyte associée. L'examen mycologique direct et des cultures doivent être effectués pour un diagnostic précis et une identification de l'espèce. Le traitement devrait être à la fois local et systémique, et adapté au diagnostic de l'espèce dermatophyte identifiée en laboratoire de mycologie. La prophylaxie secondaire, par des mesures associées, est déterminante pour limiter l'émergence de foyers épidémiques ou la réinfection du patient.
Subject(s)
Epidemics , Tinea Capitis , Child , Humans , Tinea Capitis/diagnosis , Tinea Capitis/epidemiology , Tinea Capitis/drug therapy , Scalp/microbiology , Scalp/pathology , Disease OutbreaksABSTRACT
BACKGROUND: Contact allergy is increasingly recognized as being important in children with eczema. OBJECTIVES: To retrospectively analyse the patch test results in children over the past 10 years, aiming to (1) evaluate demographic characteristics and lesion locations, (2) describe frequencies of positive patch test reactions, and (3) investigate the relationship with atopic dermatitis (AD). METHODS: A total of 329 children were patch tested between January 2010 and December 2019 with the European (children) baseline series and/or other series, and the personal product(s) used. RESULTS: A total of 119 (36%) children presented with at least one positive reaction. Children with AD had a higher prevalence of positive reactions compared with the non-AD group (P = .002), but without statistically significant difference regarding sensitization to more than one hapten (P = .39). The face (20.2%), hands (19.3%), feet (16.8%), arms (12.6%), and body folds (10.9%) were the most common sites of primary localizations. The most frequent contact allergens were nickel sulfate and linalool hydroperoxide (both 16%), limonene hydroperoxide (13.5%), and para-phenylenediamine (10.9%). No statistically significant difference for nickel sulfate was found between the AD and non-AD group (P = .20). CONCLUSIONS: Contact allergy in children with eczema was frequently observed in our tertiary referral centre in Belgium as well, confirming the need for patch testing.
Subject(s)
Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/epidemiology , Eczema/diagnosis , Eczema/epidemiology , Allergens , Belgium , Child , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/epidemiology , Female , Humans , Male , Patch Tests/statistics & numerical data , Retrospective Studies , Tertiary Care CentersABSTRACT
Epithelioid sarcoma is a rare soft-tissue tumor that occurs mainly in children and young adults. It typically presents as a subcutaneous or deep dermal mass in distal extremities. Due to its benign-appearing clinical presentation, infrequent occurrence, and histologic similarities with other pathologies, the diagnosis of epithelioid sarcoma in its early stages can be extremely difficult and can be easily confused with benign lesions such as warts or foreign body granuloma. In this paper, we report the case of a 12-year-old boy with a distal-type epithelioid sarcoma of the hand and wish to emphasize the difficulties of diagnosing this potentially lethal tumor both clinically and histologically.
Subject(s)
Papilloma , Sarcoma , Soft Tissue Neoplasms , Warts , Child , Diagnosis, Differential , Humans , Male , Sarcoma/diagnosis , Soft Tissue Neoplasms/diagnosis , Young AdultABSTRACT
Keratinocytic epidermal nevi (KEN) are characterized clinically by permanent hyperkeratosis in the distribution of Blaschko's lines and histologically by hyperplasia of epidermal keratinocytes. KEN with underlying RAS mutations have been associated with hypophosphatemic rickets and dysplastic bone lesions described as congenital cutaneous skeletal hypophosphatemia syndrome. Here, we describe two patients with keratinocytic epidermal nevi, in one associated with a papular nevus spilus, who presented with distinct localized congenital fibro-osseous lesions in the lower leg, diagnosed on both radiology and histology as osteofibrous dysplasia, in the absence of hypophosphatemia or rickets, or significantly raised FGF23 levels but with distinct mosaic HRAS mutations. This expands the spectrum of cutaneous/skeletal mosaic RASopathies and alerts clinicians to the importance of evaluating for bony disease even in the absence of bone profile abnormalities.
Subject(s)
Hypophosphatemia , Keratosis , Nevus , Skin Neoplasms , Epidermis , Fibroblast Growth Factor-23 , Humans , Keratinocytes , Nevus/genetics , Skin Neoplasms/diagnosis , Skin Neoplasms/geneticsABSTRACT
Corticophobia is a major problem in adherence to therapy. This study examined corticophobia among healthcare professionals using the Topical Corticosteroid Phobia (TOPICOP) questionnaire. The TOPICOP questionnaire was adapted for use with professionals (TOPICOP-P). Four groups of professionals: pharmacists, paediatricians, general practitioners and dermatologists were observed. The mean global TOPICOP score was 41.9 ± 14.9%. Pharmacists had the highest scores for corticophobia: a global score of 48.5 ± 13.9%, followed by general practitioners, 46.0 ± 13.5%, paediatricians 39.7 ± 14.5%, and dermatologists 32.3 ± 12.1%. Overall, there was a statistically significant difference in the mean score between the 4 groups (p < 0.05). In conclusion, there is prominent corticophobia among healthcare professionals, especially among pharmacists and general practitioners, which is probably based on insufficient knowledge of topical corticosteroids. In order to improve patient compliance, re-education of healthcare providers is suggested.
Subject(s)
Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Attitude of Health Personnel , Health Knowledge, Attitudes, Practice , Health Personnel/psychology , Phobic Disorders/psychology , Practice Patterns, Physicians' , Administration, Topical , Adult , Dermatologists/psychology , Female , General Practitioners/psychology , Health Personnel/education , Humans , Inservice Training , Male , Medication Adherence , Pediatricians/psychology , Pharmacists/psychology , Prospective Studies , Risk Assessment , Surveys and QuestionnairesABSTRACT
A retrospective study in which we reviewed the hospital files of a subset of 7 patients with Duchenne muscular dystrophy participating in the open-label phase I/II PRO051-02 study in Leuven. The objective of this study was to describe in detail the injection site reactions in these children treated with drisapersen (PRO-051), a 2'-O-methyl phosphorothioate RNA antisense oligonucleotide, that induces exon 51 skipping in Duchenne muscular dystrophy. Antisense oligonucleotides, restoring the reading frame by skipping of exons, have become a potential treatment of Duchenne muscular dystrophy and other monogenetic diseases. Erythema followed by hyperpigmentation, fibrosis, and calcification were seen at the injection sites in all children. Ulcerations, which were difficult to heal, occurred in 5 of 7 children. Progression still occurred after switching to intravenous administration of drisapersen or even after stopping therapy. Systemic reactions included a reversible proteinuria and α1-microglobulinuria. Moreover, hypotrichosis was a common feature.Conclusion: Subcutaneous administration of drisapersen causes severe and progressive injection site effects. What is known: ⢠Antisense oligonucleotides offer the possibility to convert Duchenne muscular dystrophy to the less severe Becker type. This can potentially be achieved by targeting and skipping specific exons of the Duchenne muscular dystrophy gene to restore the disrupted reading frame and to induce the production of a semi functional dystrophin protein. ⢠Drisapersen is such an antisense oligonucleotides which can be administered subcutaneously. Its use has been tested extensively in the escalating dose pilot study (PRO051-02). What is new: ⢠This report describes the injection site reactions caused by this type of agent in detail which has never been done before. We therefore reviewed the hospital files of 7 patients with Duchenne muscular dystrophy participating in the phase I/II open-label, escalating dose pilot study (PRO051-02) with drisapersen. ⢠Severe side effects starting with erythema, hyperpigmentation, and later fibrosis, calcification, and difficult to treat ulcerations developed in all patients, and these continued to progress even after cessation of drisapersen. We discuss some possible underlying mechanisms. The exact mechanism however is still not known.
Subject(s)
Injection Site Reaction/epidemiology , Muscular Dystrophy, Duchenne/drug therapy , Oligonucleotides, Antisense/adverse effects , Oligonucleotides/adverse effects , Child , Humans , Injection Site Reaction/etiology , Injections, Subcutaneous/adverse effects , Oligonucleotides/administration & dosage , Oligonucleotides, Antisense/administration & dosage , Pilot Projects , Retrospective StudiesABSTRACT
Pediatric teledermatology (PTD) allows offering long distance health care advice in pediatric dermatology trough telecommunication technologies. Due to the lack of pediatric dermatologists, the frequency of dermatological questions in general pediatrics, the visual nature of the specialty, and the rare occurrence of vital emergencies in dermatology, PTD appears to be a good option for giving long distance advice in a certain number of skin conditions. In this article, we will discuss benefits and limitations of PTD. We will also talk about diagnostic and therapeutic concordance between PTD and traditional consultations, as well as the most frequent advices asked.
La télédermatologie pédiatrique (TDP) correspond à l'utilisation des technologies de télécommunication pour offrir à distance des conseils de prise en charge spécialisés de l'atteinte cutanée chez l'enfant. La TDP semble adaptée pour un grand nombre de pathologies cutanées, étant donné le caractère visuel de la spécialité, l'occurrence rare d'urgence vitale en dermatologie, le faible nombre de spécialistes en dermatologie pédiatrique et la fréquence des motifs dermatologiques en consultation de pédiatrie. Nous discuterons, dans cet article, des avantages et limites de la TDP. Nous aborderons également les concordances diagnostique et thérapeutique entre la TDP et la consultation traditionnelle, ainsi que les demandes d'avis les plus fréquentes.
Subject(s)
Dermatology , Skin Diseases , Telemedicine , Child , Dermatology/trends , Humans , Referral and Consultation , Skin Diseases/diagnosis , Skin Diseases/therapyABSTRACT
A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term.
Subject(s)
Abnormalities, Multiple/diagnosis , Class I Phosphatidylinositol 3-Kinases/genetics , Lipoma/diagnosis , Megalencephaly/diagnosis , Musculoskeletal Abnormalities/diagnosis , Nevus/diagnosis , Skin Diseases, Vascular/diagnosis , Telangiectasis/congenital , Vascular Malformations/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/therapy , Base Sequence , Bronchodilator Agents/therapeutic use , Diagnosis, Differential , Enteral Nutrition , Humans , Immunosuppressive Agents/therapeutic use , Infant, Newborn , Lipoma/genetics , Lipoma/therapy , Male , Megalencephaly/genetics , Megalencephaly/therapy , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/therapy , Mutation , Nevus/genetics , Nevus/therapy , Phenotype , Respiration, Artificial/methods , Sirolimus/therapeutic use , Skin Diseases, Vascular/genetics , Skin Diseases, Vascular/therapy , Telangiectasis/diagnosis , Telangiectasis/genetics , Telangiectasis/therapy , Vascular Malformations/genetics , Vascular Malformations/therapyABSTRACT
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.
Subject(s)
Inflammation/genetics , Interferon Type I/genetics , Membrane Proteins/genetics , Adolescent , Adult , Amino Acid Substitution , Child , Female , HEK293 Cells , Humans , Interferon Type I/metabolism , Male , Mutation , STAT1 Transcription Factor/metabolism , Signal TransductionABSTRACT
We describe the characterization of Xeroderma Pigmentosum variant (XPV) in a young Caucasian patient with phototype I, who exhibited a high sensitivity to sunburn and multiple cutaneous tumors at the age of 15 years. Two novel mutations in the POLH gene, which encodes the translesion DNA polymerase η, with loss of function due to two independent exon skippings, are reported to be associated as a compound heterozygous state in the patient. Western blot analysis performed on proteins from dermal fibroblasts derived from the patient and analysis of the mutation spectrum on immunoglobulin genes produced during the somatic hypermutation process in his memory B cells, show the total absence of translesion polymerase η activity in the patient. The total lack of Polη activity, necessary to bypass in an error-free manner UVR-induced pyrimidine dimers following sun exposure, explains the early unusual clinical appearance of this patient.
Subject(s)
DNA-Directed DNA Polymerase/genetics , Skin Neoplasms/genetics , Sunburn/genetics , Xeroderma Pigmentosum/genetics , Adolescent , DNA Damage/genetics , DNA Repair/genetics , Fibroblasts/metabolism , Humans , Male , Mutation , Skin Neoplasms/physiopathology , Sunburn/physiopathology , Sunlight , Xeroderma Pigmentosum/physiopathologyABSTRACT
Heightened cutaneous immune surveillance in atopic patients may inhibit development of melanoma. The aim of this study was to analyse the association between atopy and melanoma (development and outcome). A total of 188 cases of melanoma and 596 healthy controls were interviewed by telephone with a standardized questionnaire on atopic, demographic and melanoma characteristics. Cases were matched with controls on important confounders (age, sex, sunburn sensitivity, hair colour, number of moles, sunburn as juvenile, ever solarium, familial melanoma). Melanoma outcome data (disease relapse and death) within cases were retrieved. Analysis showed a general inverse association between atopy and melanoma development, but this was statistically significant only for a history of personal atopy (odds ratio 0.53, 95% confidence interval: 0.30-0.96, p-value = 0.04). Among melanoma patients, atopy did not affect survival or progression. In conclusion, this study suggests an inverse association between a history of atopy and melanoma development, but not with disease progression.