RESUMO
BACKGROUND: Hidradenitis suppurativa (HS) is a frequent and severe disease of the skin, characterized by recurrent or chronic skinfold suppurative lesions with a high impact on quality of life. Although considered inflammatory, antimicrobial treatments can improve or lead to clinical remission of HS, suggesting triggering microbial factors. Indeed, mixed anaerobic microbiota are associated with a majority of HS lesions. Our aim in this study was to characterize the landscape of anaerobic infections in HS using high-throughput sequencing. METHODS: We sampled and cultured 149 lesions and 175 unaffected control skinfold areas from 65 adult HS patients. The microbiome of 80 anaerobic lesions was compared to that of 88 control samples by 454 high-throughput sequencing after construction of 16S ribosomal RNA gene libraries. RESULTS: Bacterial cultures detected anaerobes in 83% of lesions vs 53% of control samples, combined with milleri group streptococci and actinomycetes in 33% and 26% of cases, respectively. High-throughput sequencing identified 43 taxa associated with HS lesions. Two gram-negative anaerobic rod taxa, Prevotella and Porphyromonas, predominated, contrasting with a reduced abundance of aerobic commensals. These rare taxa of normal skinfold microbiota were associated with lesions independently of gender, duration and familial history of HS, body mass index, and location. Two main additional taxa, Fusobacterium and Parvimonas, correlated with the clinical severity of HS. CONCLUSIONS: In this study we reveal the high prevalence and particular landscape of mixed anaerobic infection in HS, paving the way for rationale targeted antimicrobial treatments.
Assuntos
Bactérias Anaeróbias/genética , Bactérias Gram-Negativas/genética , Hidradenite Supurativa/microbiologia , Metagenômica , Adulto , Bactérias Anaeróbias/isolamento & purificação , Bactérias Anaeróbias/fisiologia , Feminino , Bactérias Gram-Negativas/isolamento & purificação , Hidradenite Supurativa/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Microbiota , Prevotella/isolamento & purificação , Estudos Prospectivos , Qualidade de Vida , Pele/microbiologia , Pele/patologia , Infecções dos Tecidos Moles/microbiologiaRESUMO
OBJECTIVES: Hidradenitis suppurativa (HS) is an inflammatory skin disease typically localized in the axillae and inguinal and perineal areas. In the absence of standardized medical treatment, severe HS patients present chronic suppurative lesions with polymicrobial anaerobic abscesses. Wide surgery is the cornerstone treatment of severe HS, but surgical indications are limited by the extent of lesions. Intravenous broad-spectrum antibiotics may help control HS, but their efficacy is not documented. This study was designed to assess the efficacy of a 6 week course of ertapenem (1 g daily) and of antibiotic consolidation treatments for 6 months (M6) in severe HS. PATIENTS AND METHODS: Thirty consecutive patients with severe HS were retrospectively included in this study. The clinical severity of HS was assessed using the Sartorius score, which takes into account the number and severity of lesions. RESULTS: The median (IQR) Sartorius score dropped from 49.5 (28-62) at baseline to 19.0 (12-28) after ertapenem (P < 10(-4)). Five patients were lost to follow-up thereafter. At M6 the Sartorius score further decreased for the 16 patients who received continuous consolidation treatments, since 59% of HS areas reached clinical remission at M6 (i.e. absence of any inflammatory symptoms, P < 10(-4)). Nine patients interrupted or received intermittent consolidation treatments due to poor observance or irregular follow-up. Their Sartorius score stopped improving or returned to baseline. No major adverse event occurred. CONCLUSIONS: Ertapenem can dramatically improve severe HS. Consolidation treatments are needed to further improve HS and are mandatory to prevent relapses. Combined with surgery, optimized antibiotic treatments may be promising in severe HS.
Assuntos
Antibacterianos/uso terapêutico , Hidradenite Supurativa/tratamento farmacológico , beta-Lactamas/uso terapêutico , Adolescente , Adulto , Terapia Combinada/métodos , Ertapenem , Feminino , Hidradenite Supurativa/patologia , Hidradenite Supurativa/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Índice de Gravidade de Doença , Procedimentos Cirúrgicos Operatórios/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Pyoderma gangrenosum, severe acne, and suppurative hidradenitis (PASH) syndrome can prove refractory to treatment and is characterized by relapses and recurrences. The combination of antibiotic therapy and surgery can produce success in the management of the syndrome. Acute treatment is required, but maintenance therapy is also necessary to prevent disease relapse. The response to antibiotic therapy is hypothesis generating, raising the issue of a modified host response. To date, anecdotal reports support the use of surgery and medical therapy, but controlled investigations with extended follow-up are necessary to substantiate preliminary data observed with individual cases.
Assuntos
Acne Vulgar/tratamento farmacológico , Antibacterianos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Hidradenite Supurativa/tratamento farmacológico , Pioderma Gangrenoso/tratamento farmacológico , Acne Vulgar/complicações , Acne Vulgar/diagnóstico , Acne Vulgar/cirurgia , Adulto , Terapia Combinada , Feminino , Seguimentos , Hidradenite Supurativa/complicações , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/cirurgia , Humanos , Masculino , Microbiota/efeitos dos fármacos , Pioderma Gangrenoso/complicações , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/cirurgia , Estudos de Amostragem , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/microbiologia , Síndrome , Resultado do Tratamento , Adulto JovemRESUMO
We recently described a new neonatal diabetes syndrome associated with congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys. Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor. In the original family, we identified a frameshift mutation predicted to result in a truncated protein. In two other families with an incomplete syndrome, we found that affected individuals harbor deletions affecting the 11 or 12 5'-most exons of the gene. The absence of a major transcript in the pancreas and thyroid (deletions from both families) and an eye-specific transcript (deletion from one family), together with residual expression of some GLIS3 transcripts, seems to explain the incomplete clinical manifestations in these individuals. GLIS3 is expressed in the pancreas from early developmental stages, with greater expression in beta cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic beta cells and the thyroid, eye, liver and kidney.
Assuntos
Hipotireoidismo Congênito/genética , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Mutação , Fatores de Transcrição/genética , Alelos , Animais , Proteínas de Ligação a DNA , Feminino , Humanos , Recém-Nascido , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Proteínas Repressoras , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome , TransativadoresRESUMO
Importance: Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective: To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants: This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures: Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures: Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results: Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance: This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.
Assuntos
Cloridrato de Erlotinib/administração & dosagem , Ceratodermia Palmar e Plantar/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/administração & dosagem , Adolescente , Brasil , Criança , Pré-Escolar , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Imunossupressores/administração & dosagem , Lactente , Ceratodermia Palmar e Plantar/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Síndrome , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do TratamentoRESUMO
Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin associated with specific lesional dysbiotic features. We studied the microbiome of clinically unaffected typical HS sites (armpits, inguinal folds, and gluteal clefts) in 60 patients with HS and 17 healthy controls. A total of 192 samples obtained by swabbing were analyzed by bacterial cultures. Of these, 116 randomly selected samples were studied by 16S rRNA gene amplicon sequencing. Patients and controls showed similar characteristics, except for smoking (87% vs. 6%, respectively). HS skinfolds were characterized by an increased abundance of anaerobes, predominantly Prevotella, but also Actinomyces, Campylobacter ureolyticus, and Mobiluncus, contrasting with a lower abundance of skin commensals such as Staphylococcus epidermidis, a major component of the skin microbiome; Kocuria; and Micrococcus luteus. The following three independent factors were associated with an abundance of high anaerobes by multivariate analysis: samples originating from patients with HS patients (P = 2.1 × 10-4); body mass index (P = 5 × 10-5); and the sampling site, the gluteal cleft being the most anaerobic area, followed by inguinal folds and axilla (P = 3 × 10-6). The microbiome of clinically unaffected HS skinfolds is reminiscent, albeit to a minor extent, of the microbiome of chronic suppurative HS lesions and may fuel inflammation at a preclinical stage of the disease.
Assuntos
Bactérias Anaeróbias/imunologia , Hidradenite Supurativa/imunologia , Microbiota/imunologia , Pele/microbiologia , Adulto , Bactérias Anaeróbias/genética , Bactérias Anaeróbias/isolamento & purificação , Estudos Transversais , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Feminino , Voluntários Saudáveis , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/microbiologia , Humanos , Masculino , Microbiota/genética , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Índice de Gravidade de Doença , Pele/imunologia , Adulto JovemRESUMO
Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway-inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.
Assuntos
Hidradenite Supurativa/genética , Inflamação/genética , Receptores de Hidrocarboneto Arílico/genética , Pele/metabolismo , Triptofano/metabolismo , Adulto , Axila/microbiologia , Axila/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Hidradenite Supurativa/microbiologia , Hidradenite Supurativa/patologia , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Inflamação/microbiologia , Inflamação/patologia , Cinurenina/genética , Masculino , Metabolismo/genética , Pessoa de Meia-Idade , Pele/microbiologia , Pele/patologiaRESUMO
Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.
Assuntos
Desmossomos/patologia , Epiderme/patologia , Ceratodermia Palmar e Plantar/genética , Proteínas de Membrana/genética , Adulto , Adesão Celular/genética , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Desmossomos/ultraestrutura , Epiderme/ultraestrutura , Éxons/genética , Feminino , Mutação da Fase de Leitura , Genes Supressores de Tumor , Heterozigoto , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/patologia , Masculino , Proteínas de Membrana/metabolismo , Microscopia Eletrônica , Adulto JovemRESUMO
The PTPN22 gene, encoding the lymphoid-specific protein tyrosine phosphatase, a negative regulator in the T-cell activation and development, has been associated with the susceptibility to several autoimmune diseases, including type 1 diabetes. Based on combined case-control and family-based association studies, we replicated the finding of an association of the PTPN22 C1858T (R620W) functional variant with type 1 diabetes, which was independent from the susceptibility status at the insulin gene and at HLA-DR (DR3/4 compared with others). The risk contributed by the 1858T allele was increased in patients with a family history of other autoimmune diseases, further supporting a general role for this variant on autoimmunity. In addition, we found evidence for an association of 1858T allele with the presence of GAD autoantibodies (GADA), which was restricted to patients with long disease duration (>10 years, P < 0.001). This may help define a subgroup of patients with long-term persistence of GADA. The risk conferred by 1858T allele on GAD positivity was additive, and our meta-analysis also supported an additive rather than dominant effect of this variant on type 1 diabetes, similar to previous reports on rheumatoid arthritis and systemic lupus erythematosus.
Assuntos
Autoimunidade/genética , Proteínas de Ligação a DNA/imunologia , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Glutamato Descarboxilase/imunologia , Fragmentos de Peptídeos/imunologia , Proteínas Tirosina Fosfatases/genética , Proteínas Repressoras/imunologia , Alelos , Autoanticorpos/genética , Biomarcadores , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-DR/genética , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 22RESUMO
A functional variant located in the promoter region of the Fc receptor like 3 gene (FCRL3, -169CT variant) has been recently shown to be associated with several autoimmune diseases in the Japanese population. Following the concept of shared genetic determinants between autoimmune diseases, we tested this variant for association to Type 1 diabetes (T1D) and T1D-related phenotypes in two independent settings: a family-based association study (French and US families) and a case-control study (French population). We found suggestive evidence for association of the FCRL3 -169CC genotype, corresponding to the susceptibility genotype for rheumatoid arthritis, with an increased risk of additional autoimmunity markers (OR=1.97, P=0.01) and of other autoimmune diseases (OR=1.75, P=0.05). However, there was no evidence of association of this variant with T1D in these cohorts, separately and combined, nor in subgroups of patients defined based on their major T1D risk factors at HLA-DRB1, insulin and PTPN22. Hence, this variant may help define subgroups of T1D patients with contrasted risk of other autoimmune diseases.
Assuntos
Doenças Autoimunes/genética , Diabetes Mellitus Tipo 1/genética , Receptores Imunológicos/genética , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , França/epidemiologia , Genótipo , Haplótipos , Humanos , Polimorfismo Genético , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Erythrokeratodermia variabilis et progressiva (EKVP) is a genodermatosis with clinical and genetic heterogeneity, most often transmitted in an autosomal dominant manner, caused by mutations in GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3, respectively. In this issue, Boyden et al. (2015) report for the first time de novo dominant mutations in GJA1 encoding the ubiquitous Cx43 in patients with EKVP. These results expand the genetic heterogeneity of EKVP and the human disease phenotypes associated with GJA1 mutations. They disclose that EKVP is allelic to oculo-dento-digital dysplasia, a rare syndrome previously known to be caused by dominant GJA1 mutations.
Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/genética , Eritroceratodermia Variável/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Mutação , Dermatopatias/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Feminino , Humanos , MasculinoRESUMO
Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.
Assuntos
Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Humanos , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Mutação , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismoAssuntos
Alopecia/genética , Displasia Ectodérmica/genética , Mutação/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adulto , Argélia/etnologia , Transtornos Cromossômicos , Segregação de Cromossomos , Feminino , França/epidemiologia , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemAssuntos
Secretases da Proteína Precursora do Amiloide/genética , Hidradenite Supurativa/genética , Mutação , Adolescente , Adulto , Idoso , Secretases da Proteína Precursora do Amiloide/fisiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Presenilina-1/genética , Adulto JovemRESUMO
BACKGROUND: Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias. OBJECTIVE: To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. METHODS: Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. RESULTS: The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential. CONCLUSION: We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.
Assuntos
Fibrilação Atrial/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Síndrome do Nó Sinusal/genética , Adulto , Arritmias Cardíacas/genética , Células Cultivadas , Técnicas Eletrofisiológicas Cardíacas , Feminino , Predisposição Genética para Doença , Sistema de Condução Cardíaco/fisiopatologia , Proteínas de Homeodomínio/genética , Humanos , Potenciais da Membrana/genética , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Transfecção , Proteína Homeobox PITX2RESUMO
IMPORTANCE: Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. OBSERVATIONS: Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging. CONCLUSIONS AND RELEVANCE: This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome.
Assuntos
Eritromelalgia/genética , Regulação da Expressão Gênica , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto/genética , Canais de Cátion TRPV/genética , Adolescente , Biópsia por Agulha , Progressão da Doença , Eritromelalgia/complicações , Eritromelalgia/diagnóstico , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Ceratodermia Palmar e Plantar/complicações , Ceratodermia Palmar e Plantar/diagnóstico , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , SíndromeAssuntos
Cardiomiopatia Dilatada/etiologia , DNA/genética , Epidermólise Bolhosa Simples/genética , Mutação , Proteínas Repressoras/genética , Adolescente , Adulto , Cardiomiopatia Dilatada/genética , Criança , Análise Mutacional de DNA , Epidermólise Bolhosa Simples/complicações , Epidermólise Bolhosa Simples/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Proteínas Repressoras/metabolismo , Adulto JovemRESUMO
BACKGROUND: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. METHODS AND RESULTS: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. CONCLUSIONS: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.