RESUMO
Anhidrotic/hypohidrotic ectodermal dysplasia (A/HED) is a congenital disorder characterized by anhidrosis/hypohidrosis and inadequate hair and dental dysplasia. Large-scale case studies of patients with A/HED have already been conducted overseas, while there has been no large-scale study, but only a few case reports in Japan. Furthermore, an epidemiological study of this disease has not been conducted in Japan to date. The purpose of this study was to investigate the clinical characteristics of A/HED patients, the status of genetic aberrations and complications of A/HED in Japan. Initially, we conducted a physician-initiated questionnaire survey of A/HED patients who visited medical institutions across Japan to investigate their backgrounds, clinical symptoms, genotypes, diagnostic methods and complications of A/HED. We also investigated the presence or absence of various allergic diseases (atopic dermatitis-like skin manifestations, bronchial asthma and food allergies). Questionnaires were also obtained from 26 patients with ectodermal dysplasia (ED) who visited four medical institutions. We compared the incidence of allergic diseases in healthy controls in a similar study to that of patients. Twenty-four of those patients were considered to have A/HED, of which 18 had a confirmed genetic diagnosis and were genotyped. All patients had anhidrosis or hypohidrosis, hair and dental dysplasia, and unique facial appearance; 23 patients had several cutaneous manifestations and seven patients had periorbital pigmentation. In addition, there was a significantly higher incidence of atopic dermatitis-like cutaneous manifestations, bronchial asthma and food allergies in the A/HED patients than in healthy controls. We report the results from a questionnaire survey of 24 patients with A/HED. This is the first report of a large number of A/HED patients in Japan. This study clarifies the status of clinical diagnosis and genetic testing of A/HED patients in Japan, as well as the characteristics of their skin symptoms and allergic complications.
Assuntos
Displasia Ectodérmica Anidrótica Tipo 1 , Displasia Ectodérmica , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica Anidrótica Tipo 1/complicações , Displasia Ectodérmica Anidrótica Tipo 1/epidemiologia , Displasia Ectodérmica Anidrótica Tipo 1/genética , Humanos , Japão/epidemiologia , Prevalência , Inquéritos e QuestionáriosAssuntos
Osteoartropatia Hipertrófica Primária/diagnóstico , Osteoartropatia Hipertrófica Primária/urina , Prostaglandinas E/urina , Ácidos Prostanoicos/urina , Adolescente , Adulto , Alelos , Biomarcadores/urina , Estudos de Casos e Controles , Mãos , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Masculino , Pessoa de Meia-Idade , Mutação , Transportadores de Ânions Orgânicos/genética , Fenótipo , Adulto JovemRESUMO
Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia caused by mutated HPGD or SLCO2A1. Plasma prostaglandin (PG)E2 levels are increased in these patients. However, other eicosanoids have not been quantitated. We aimed to quantitate plasma eicosanoid levels in four patients carrying SLCO2A1 mutations by high-performance liquid chromatography-tandem mass spectrometry. PGE2 level was elevated in all patients; PGD2 and 11ß-PGF2 α levels were also increased in some patients, whereas eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were decreased in all patients. Our data indicate a dysfunctional eicosanoid homeostasis and varied levels of PG in patients with a complete form of PDP carrying SLCO2A1 mutations. PGE2 levels seem to mostly affect the symptoms, with other eicosanoids possibly having a minor effect.
Assuntos
Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Dinoprostona , Eicosanoides , Humanos , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico , Osteoartropatia Hipertrófica Primária/genéticaAssuntos
Síndrome CHARGE/complicações , Síndrome CHARGE/diagnóstico , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Subpopulações de Linfócitos T/imunologia , Biomarcadores , Síndrome CHARGE/etiologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Heterozigoto , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/etiologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Male, 41 years old (yo) had been complaining of severe arthralgia. Past History indicated obstruction of intestinal tract at 12 yo and gastric ulcer at 13 yo. He had been suffered from polyarthralgia especially at PIP and MP joints of both hands from 38 yo. Finally, he complained severe arthralgia at PIP and MP joints with clubbed fingers without swelling. Biochemical finding indicated negative rheumatoid factor and anti-CCP antibody and normal MMP-3 level, but slightly increased CRP and ESR levels. Radiological finding indicated periostosis ofãlong bone without bone erosion and osteoporosis. His facial appearance was acromegalic with cutaneous manifestation of pachydermia and cutis vertices gyrate without abnormal growth hormone response. Histological findings of skin indicated oedema and hyperplasia of sebaceous glands with infiltration of lymphocytes around small blood vessels compatible with pachydermoperiostosis. In this case mutation of SLCO2A1 gene, which coded prostaglandin transport protein, was identified. The mutation c.940 + 1G > A of SLCO2A1 gene results in deletion of exon 7 and truncation of PG transporter (p.Arg288Glyfs*7). We suggest that severe arthralgia was originated from over production of prostaglandin E2. Further studies will be required.
Assuntos
Artralgia , Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Adulto , Artralgia/diagnóstico , Artralgia/genética , Humanos , Masculino , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico , Osteoartropatia Hipertrófica Primária/genéticaRESUMO
INTRODUCTION: Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients. METHODS: We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules. RESULTS: Among 94 enrolled patients (mean age, 21 years; range 3-53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0-86.3%], 66.7% (95% CI 51.1-80.0%), and 72.2% (95% CI 46.5-90.3%), respectively. CONCLUSIONS: The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02634931.
Assuntos
Doenças da Unha/diagnóstico , Osteoartropatia Hipertrófica Primária/diagnóstico , Adulto , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Masculino , Doenças da Unha/congênito , Doenças da Unha/genética , Doenças da Unha/urina , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/genética , Osteoartropatia Hipertrófica Primária/patologia , Osteoartropatia Hipertrófica Primária/urina , Prostaglandinas/urina , Pele/patologiaRESUMO
OBJECTIVE: To further disseminate the nomenclature of chronic enteropathy associated with SLCO2A1 (CEAS), especially for physicians in China and Korea where the genetic feature of SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. DESIGN: A case report with literature review of SLCO2A1 gene mutations-related disorders. RESULTS: A 38-year-old Korean presented to a tertiary hospital with dizziness, abdominal pain and melena. He had a positive faecal occult blood test on initial workup. Oesophagogastroduodenal endoscopy (OGD), colonoscopy and CT scan were unremarkable and showed no obvious cause for his melena. Capsule endoscope and roentgen barium studies were performed, revealing an erythematous mucosa with ulcers in the jejunum and stenosis to the jejunal-ileal junction. Next-generation sequencing was then performed and discovered point mutations of SLCO2A1 gene's seven exon (940+1 G>A) and 13 exon (1807 C>T) allele. This Korean patient with CEAS is the first documented case noted outside of the Japanese population. CONCLUSION: CEAS is not uniquely found in Japanese individuals. There are lots of similarities between CEAS and primary hypertrophic osteoarthropathy, the two entity may just be the two sides of one same coin. International and multidisciplined efforts are required to further study this complicated disorder.
RESUMO
Importance: Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. Objective: To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. Design, Setting, and Patients: Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. Interventions: Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. Main Outcomes and Measures: The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." Results: Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. Conclusions and Relevance: Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality. Trial Registration: ClinicalTrials.gov Identifier: NCT02635789.
Assuntos
Angiofibroma/tratamento farmacológico , Neoplasias Faciais/tratamento farmacológico , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Esclerose Tuberosa/complicações , Administração Cutânea , Adolescente , Adulto , Angiofibroma/etiologia , Criança , Método Duplo-Cego , Neoplasias Faciais/etiologia , Feminino , Géis , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Sirolimo/efeitos adversos , Neoplasias Cutâneas/etiologia , Adulto JovemRESUMO
BACKGROUND: Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis is a rare genetic disease which predominantly affects skin, bone and soft connective tissue. It is characterized by the triad of pachydermia, digital clubbing and periostosis of long bones. Arthralgia or arthritis is also present in most of the cases. Genetic studies have identified the impaired PGE2 metabolism as a culprit for hypertrophic osteoarthropathy in PHO cases. We conducted a systematic review to examine the effectiveness of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), a PGE2 synthesis blocker to reduce the symptoms among PHO patients. METHODS: We searched the evidence in five databases; Cochrane Library, CINAHL, EMBASE, MEDLINE, and PubMed. We reported the evidence using narrative synthesis. RESULTS: Out of 238 identified studies, we selected 26 for the synthesis. All were case reports which included a total of 54 patients. Among them, 39 patients were treated with at least one type of NSAIDs. Around 70% of the patients treated with NSAIDs had clinical improvement for their symptoms, mostly arthritis or arthralgia symptoms. CONCLUSION: NSAIDs were effective in improving arthralgia or arthritis symptoms in majority of the PHO patients. Therefore, we recommend the use of NSAIDs in PHO patients to treat arthralgia or arthritis.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Dinoprostona/antagonistas & inibidores , Osteoartropatia Hipertrófica Primária/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Dinoprostona/biossíntese , Humanos , Osteoartropatia Hipertrófica Primária/genética , Osteoartropatia Hipertrófica Primária/patologia , Doenças Raras/genética , Doenças Raras/patologia , Resultado do TratamentoAssuntos
Proteínas de Ligação a DNA/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/genética , Códon sem Sentido , Diagnóstico Precoce , Hospitais Universitários , Humanos , Lactente , Japão , Masculino , Análise de Sequência de DNA , Envelhecimento da Pele , Neoplasias Cutâneas/prevenção & controleAssuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Transtornos de Estresse por Calor/genética , Idade de Início , Pré-Escolar , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Testes Genéticos , Transtornos de Estresse por Calor/diagnóstico , Humanos , Masculino , Linhagem , Deleção de SequênciaAssuntos
Domínio AAA/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Doenças do Cabelo/genética , Perda Auditiva Neurossensorial/genética , Doenças Mitocondriais/congênito , Criança , Feminino , Cabelo/patologia , Doenças do Cabelo/patologia , Perda Auditiva Neurossensorial/patologia , Heterozigoto , Humanos , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Deleção de SequênciaAssuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Folículo Piloso/metabolismo , Hipertricose/congênito , Transportadores de Cassetes de Ligação de ATP/metabolismo , Feminino , Folículo Piloso/patologia , Humanos , Hipertricose/genética , Lactente , Japão , Linhagem , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismoAssuntos
Albinismo Oculocutâneo/genética , Antígenos de Neoplasias/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/etnologia , Povo Asiático/genética , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Lactente , Japão , Masculino , FenótipoRESUMO
BACKGROUND: Atopic dermatitis (AD) is characterized by skin barrier dysfunction. Few studies have used noninvasive techniques to measure epidermis function in asymptomatic neonates. METHODS: Data of 116 infants from our previous randomized controlled study were analyzed. Skin barrier function was measured through transepidermal water loss (TEWL), stratum corneum hydration (SCH), and pH. The association between skin barrier function and time to AD development was evaluated. Patients were classified with high or low TEWL, and SCH and pH were assessed. The survival function of the time to AD development and hazard ratios were estimated. Allergic sensitization to egg white and ovomucoid at 32 weeks was assessed. RESULTS: Regardless of a filaggrin mutation, TEWL (optimal cutoff, 6.5 g/m(2)/h) of the forehead within the first week of life showed a lower p-value than TEWL of the leg, and the SCH and pH measurements. Baseline TEWL of the forehead was not different between groups, except for the mean gestational age, and it was not affected by humidity. We found a significant difference in the cumulative AD incidence between the high and low TEWL groups for the forehead only (p < 0.05). The probability without AD was lower in the high TEWL group than in the low TEWL group. For only the high TEWL group, AD development decreased significantly with daily emollient use. The high TEWL group exhibited a higher rate of sensitization to ovomucoid (p = 0.07). CONCLUSIONS: TEWL of the forehead during the first week of life is associated with AD development.