RESUMO
Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.
Assuntos
Anemia de Fanconi , Melfalan , Humanos , Melfalan/farmacologia , Anemia de Fanconi/patologia , Reparo do DNA , Dano ao DNA , DNARESUMO
During replication, the presence of unrepaired lesions results in the formation of single stranded DNA (ssDNA) gaps that need to be repaired to preserve genome integrity and cell survival. All organisms have evolved two major lesion tolerance pathways to continue replication: Translesion Synthesis (TLS), potentially mutagenic, and Homology Directed Gap Repair (HDGR), that relies on homologous recombination. In Escherichia coli, the RecF pathway repairs such ssDNA gaps by processing them to produce a recombinogenic RecA nucleofilament during the presynaptic phase. In this study, we show that the presynaptic phase is crucial for modulating lesion tolerance pathways since the competition between TLS and HDGR occurs at this stage. Impairing either the extension of the ssDNA gap (mediated by the nuclease RecJ and the helicase RecQ) or the loading of RecA (mediated by RecFOR) leads to a decrease in HDGR and a concomitant increase in TLS. Hence, we conclude that defects in the presynaptic phase delay the formation of the D-loop and increase the time window allowed for TLS. In contrast, we show that a defect in the postsynaptic phase that impairs HDGR does not lead to an increase in TLS. Unexpectedly, we also reveal a strong genetic interaction between recF and recJ genes, that results in a recA deficient-like phenotype in which HDGR is almost completely abolished.
Assuntos
Proteínas de Escherichia coli , Reparo do DNA/genética , Replicação do DNA/genética , DNA Bacteriano/genética , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Recombinases Rec A/genética , Recombinases Rec A/metabolismoRESUMO
BACKGROUND: Verruca vulgaris (VV) is a common viral disease in children. Treatment options are often not well-tolerated in children due to pain or adverse effect risk. Nonthermal atmospheric plasma (NTAP), which generates reactive oxygen/nitrogen species, is well-tolerated and without adverse effects. OBJECTIVE: Determine efficacy of NTAP as compared to standard of care (SOC) therapy for VV in children. METHODS: This prospective open-label study randomized lesions 1:1 to receive NTAP or SOC (cryotherapy). Patients were treated at 4-week intervals for a maximum of 3 treatments. They were evaluated four weeks post-final treatment for sustained response. Primary outcome was lesion response. RESULTS: 112 VV lesions in 14 patients were enrolled. Patients were mostly white (92.9%) males (71.4%) with mean age of 9.5 [±2.5] years. Responses of SOC- and NTAP-treated lesions respectively included: no response (5.4%, 7.1%); partial response (33.9%, 41.1%); and complete resolution (60.7%, 51.8%; p-value=0.679). Patients were more likely to report pain in SOC lesions post-treatment (p-value<0.001). No significant adverse events (AEs) occurred. LIMITATIONS: Limitations include single-site, maximum of three treatments, and short post-treatment follow-up. CONCLUSION: NTAP is an efficacious, safe intervention for treatment of VV in children.
RESUMO
BACKGROUND: Systemic immunomodulatory agents are indicated in the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. Perioperative use of these medications may increase the risk of surgical site infection (SSI) and complication. OBJECTIVE: To evaluate the risk of SSI and complication in patients with chronic autoimmune inflammatory disease receiving immunomodulatory agents (tumor necrosis factor-alfa [TNF-α] inhibitors, interleukin [IL] 12/23 inhibitor, IL-17 inhibitors, IL-23 inhibitors, cytotoxic T-lymphocyte-associated antigen-4 costimulator, phosphodiesterase-4 inhibitor, Janus kinase inhibitors, tyrosine kinase 2 inhibitor, cyclosporine (CsA), and methotrexate [MTX]) undergoing surgery. METHODS: We performed a search of the MEDLINE PubMed database of patients with chronic autoimmune inflammatory disease on immune therapy undergoing surgery. RESULTS: We examined 48 new or previously unreviewed studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. CONCLUSION: For low-risk procedures, TNF-α inhibitors, IL-17 inhibitors, IL-23 inhibitors, ustekinumab, abatacept, MTX, CsA, and apremilast can safely be continued. For intermediate- and high-risk surgery, MTX, CsA, apremilast, abatacept, IL-17 inhibitors, IL-23 inhibitors, and ustekinumab are likely safe to continue; however, a case-by-case approach is advised. Acitretin can be continued for any surgery. There is insufficient evidence to make firm recommendations on tofacitinib, upadacitinib, and deucravacitinib.
Assuntos
Artrite Psoriásica , Metotrexato , Psoríase , Humanos , Artrite Psoriásica/tratamento farmacológico , Psoríase/tratamento farmacológico , Psoríase/imunologia , Metotrexato/uso terapêutico , Assistência Perioperatória/métodos , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Talidomida/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/epidemiologia , Piperidinas/uso terapêutico , Ciclosporina/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/efeitos adversos , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Agentes de Imunomodulação/uso terapêutico , Abatacepte/uso terapêutico , Abatacepte/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversosRESUMO
BACKGROUND/OBJECTIVES: There is a paucity of pediatric hidradenitis suppurativa (HS) literature. The objective of this study was to characterize differences in management of pediatric HS patients by dermatology versus non-dermatology clinicians. METHODS: We examined a retrospective cohort of 195 pediatric patients with HS seen at our institution (3/1/19-3/1/20). Two-sample t-tests and two-proportion z-tests were performed. RESULTS: A total of 76.1% of subjects were seen by dermatology at least once, and of these, 79.1% were referred. HS diagnosis was most often made by dermatology (36.6%), followed by pediatrics (21.6%). Patients managed by dermatology were significantly more likely to have used standard of care therapies (p < .001). Of dermatology-managed patients, 19.7% were currently prescribed a biologic, as compared with zero patients not managed by dermatology. Those managed by dermatology were less likely to undergo surgical excision (13.3% vs. 25.5%, p = .04). CONCLUSIONS: Our results support increased likelihood of treatment escalation with medical management by dermatologists. Relatively high utilization of referral to dermatology exists, but with only moderate patient adherence. There is a need for improved access to dermatologic care and prospective studies to determine whether differences in specialty management translate to improved patient outcomes.
Assuntos
Hidradenite Supurativa , Humanos , Criança , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/terapia , Estudos Retrospectivos , Estudos Prospectivos , Cooperação do PacienteRESUMO
BACKGROUND AND OBJECTIVE: Current regulatory labeling recommends avoiding live vaccine use in dupilumab-treated patients. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in dupilumab-treated patients. METHODS: Children (6 months-5 years old) with moderate-to-severe atopic dermatitis (AD) enrolled in a phase 2/3 clinical trial of dupilumab (LIBERTY AD PRESCHOOL Part A/B; NCT03346434) and subsequently participated in the LIBERTY AD PED-OLE (NCT02612454). During these studies, protocol deviations occurred in nine children who received measles, mumps, rubella (MMR) vaccine with or without varicella vaccine; five with a ≤12-week gap between dupilumab administration and vaccination and four with a >12-week gap after discontinuing dupilumab. RESULTS: Nine children (1 female; 8 male) had severe AD at baseline (8-56 months old). Of the nine children, five had a ≤12-week gap ranged 1-7 weeks between dupilumab administration and vaccination who received MMR vaccine (n = 2) or MMR and varicella vaccines (n = 3); among these, one resumed dupilumab treatment as early as 2 days and four resumed treatment 18-43 days after vaccination. No treatment-emergent adverse events, including serious adverse events and infections, were reported within the 4-week post-vaccination period in any children. CONCLUSIONS: In this case series of dupilumab-treated children with severe AD who received MMR vaccine with or without varicella vaccine, no adverse effects (including vaccine-related infection) were reported within 4 weeks after vaccination. Further studies are warranted to evaluate the safety, tolerability, and immune response to live attenuated vaccines in dupilumab-treated patients.
Assuntos
Anticorpos Monoclonais Humanizados , Dermatite Atópica , Caxumba , Criança , Pré-Escolar , Humanos , Masculino , Feminino , Lactente , Vacinas Atenuadas/efeitos adversos , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Dermatite Atópica/tratamento farmacológico , Vacina contra Varicela/efeitos adversos , Caxumba/induzido quimicamente , Caxumba/prevenção & controle , Vacinação/efeitos adversosRESUMO
BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.
RESUMO
Congenital erosive and vesicular dermatosis (CEVD) is a rare skin condition that most commonly presents as erosive and vesicular lesions on the trunk and extremities in premature infants and heals with characteristic reticulated and supple scarring (RSS). The exact pathogenesis of CEVD is unknown and is typically a diagnosis of exclusion. We present the cases of two extremely premature neonates with Candida septicemia who were found to have diffuse, erythematous skin eruptions shortly after birth that ultimately healed with RSS. Through these cases, we highlight the importance of including fungal infection in the work-up of CEVD healing with RSS.
Assuntos
Micoses , Anormalidades da Pele , Dermatopatias Vesiculobolhosas , Lactente , Recém-Nascido , Humanos , Cicatriz/etiologia , Cicatrização , Dermatopatias Vesiculobolhosas/patologia , Pele/patologia , Anormalidades da Pele/patologia , Micoses/complicações , Micoses/patologia , Doenças Raras/complicações , Doenças Raras/patologiaRESUMO
Hidradenitis suppurativa (HS) is a common skin disease in children and young adults. In this report, we describe an unusual case of HS presenting as a mammillary fistula (MF) in a teenage female. A thorough dermatologic history and exam resulted in diagnosis of HS. Identifying the underlying disease is key to appropriate treatment of a relapsing MF in the setting of HS.
Assuntos
Fístula , Hidradenite Supurativa , Adolescente , Feminino , Humanos , Hidradenite Supurativa/diagnósticoRESUMO
Acne vulgaris is an extremely common chronic disease of the pilosebaceous unit. Despite its ubiquity, acne in the childhood years of approximately ages 1-6 years is exceedingly rare. Physicians should be suspicious of underlying systemic disease processes in patients of this age who present with onset of acne lesions, as pre-pubertal acne in childhood has a distinctly different pathology than that of other age groups. Through a case series, we highlight the importance of a thorough work-up and provide a review on when to refer to pediatric endocrinology to rule out precocious puberty and tumors as the cause of pre-pubertal acne.
Assuntos
Acne Vulgar , Puberdade Precoce , Criança , Humanos , Lactente , Pré-Escolar , Acne Vulgar/diagnóstico , Pele , Puberdade Precoce/diagnóstico , Puberdade Precoce/etiologia , PesquisaRESUMO
Hereditary alpha tryptasemia (HaT), an autosomal dominant condition first described in 2014, has previously been associated with multiple dermatologic, allergic, gastrointestinal, neuropsychiatric, autonomic, and connective tissue abnormalities. We describe a pediatric patient with predominantly mixed cutaneous inflammatory manifestations and atopic manifestations resistant to treatment who was found to have HaT. HaT should be considered in individuals with refractory inflammatory dermatologic disease and signs and/or symptoms concerning for mast cell activation.
Assuntos
Dermatite , Hipersensibilidade Imediata , Hipersensibilidade , Humanos , Feminino , CriançaRESUMO
Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.
Assuntos
Dermatite Atópica , Psoríase , Humanos , Criança , Metotrexato , Consenso , Psoríase/tratamento farmacológico , Dermatite Atópica/tratamento farmacológicoRESUMO
Variants in RAS are known drivers of certain pediatric blood and solid cancers, including brain tumors. Though most RAS-driven cancers are thought to occur sporadically, genetic syndromes caused by germline RAS variants portend a slightly higher risk of rhabdomyosarcoma (RMS) development. Three new cases and a review of the literature demonstrate that in rare cases, certain somatic RAS variants are associated with an increased risk of RMS and that RMS development may be heralded by the presence of concomitant RAS-driven birthmarks. Further prospective studies are needed to establish incidence and recommend appropriate monitoring guidelines for patients at risk.
Assuntos
Leucemia Mieloide Aguda , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Criança , Células Germinativas , Humanos , Rabdomiossarcoma/genéticaRESUMO
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic disease that causes inflammatory lesions typically found in the axillary, inguinal, and perineal regions that can result in permanent scarring, fibrosis, and sinus tract formation. Although HS is more prevalent in patients with skin of color, research in HS has historically been performed in European and White populations. We aimed to explore management differences in skin of color HS patients compared to White patients. METHODS: We performed a cross-sectional retrospective review of HS-associated outpatient encounters in the Medical University of South Carolina’s Research Data Warehouse from 1/2017–12/2020. We performed descriptive statistics and chi-square analyses. RESULTS: We found that Black HS patients were more likely to receive metformin and nonsteroidal anti-inflammatory drugs (NSAIDs) during HS-associated visits. We also found that Black patients were less likely to see dermatology and primary care and more likely to see surgery for their HS-associated visits. Lastly, skin of color HS patients were more likely to have a complex excision (P<0.001). DISCUSSION: We found differences in the medical and procedural care provided to Black HS patients compared to White patients. A limitation of our study is the lack of information concerning efficacy of treatment interventions and clinical outcomes. Future studies should include a representative population of HS patients with a higher proportion of skin of color HS patients and include race as a variable when investigating medical and surgical outcomes to understand mechanisms that could explain differences in disease profiles across racial groups. J Drugs Dermatol. 2022;21(3):270-275. doi:10.36849/JDD.6446.
Assuntos
Hidradenite Supurativa , População Negra , Estudos Transversais , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/terapia , Humanos , Fatores Raciais , Estudos RetrospectivosRESUMO
Keratosis pilaris is a common skin condition associated with a number of syndromes, including collagen type VI-related disorders. Our patient, recently diagnosed with Ullrich congenital muscular dystrophy, presented with severe keratosis pilaris, hypotonia, and velvety skin on the palms and soles. We present this case to highlight the importance of including cutaneous findings, such as keratosis pilaris, to aid in the diagnosis when evaluating patients with syndromic features.
Assuntos
Anormalidades Múltiplas , Doença de Darier , Anormalidades Múltiplas/diagnóstico , Colágeno Tipo VI , Doença de Darier/diagnóstico , Sobrancelhas/anormalidades , HumanosRESUMO
OBJECTIVE: Time to diagnosis of autoimmune disease in pediatric populations can take years but nailfold capillaroscopy (NFC) may identify early signs of autoimmune disease. The aim of this study is to assess the association between nailfold capillary abnormalities and autoimmune disease in children. METHODS: A systematic search of PubMed, EMBASE, and Scopus was performed to identify all studies published before March 17, 2021. Observational studies reporting NFC outcomes in children with autoimmune disease and healthy controls (HC) were eligible for inclusion. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effects meta-analytical model. RESULTS: Nine of 3665 studies reporting on 641 patients (398 subjects, 243 controls) were included. Pediatric patients with autoimmune disease were 9.88 (95% CI 3.16-30.87, I2 = 80.1%) times more likely to have abnormal nailfold capillaries than HC. Of the capillaroscopic features, dilated capillaries (OR 27.90, 95% CI 2.17-349.05, I2 = 59.9%) were the most likely abnormality observed on NFC. This was followed by the likelihood of reduced capillary density (<7 capillaries/mm) (OR 19.91, 95% CI 3.79-105.52, I2 = 0%), giant capillaries (OR 12.87, 95% CI 2.38-69.45, I2 = 0%), hemorrhages (OR 13.89, 95% CI 5.34-36.16, I2 = 0%), and avascularity (OR 10.38, 95% CI 2.20-49.04, I2 = 0%). CONCLUSIONS: Children with autoimmune disease are significantly more likely to have nailfold capillary abnormalities. NFC may be useful in identifying early signs of underlying rheumatic disease and potentially decrease the time to diagnosis for this patient population.
Assuntos
Doenças Autoimunes , Angioscopia Microscópica , Doenças Autoimunes/diagnóstico , Capilares/anormalidades , Criança , Humanos , Unhas , Estudos Observacionais como Assunto , Malformações VascularesRESUMO
BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin disease; its etiology is unknown, though it is often associated with autoimmune diseases. Pyoderma gangrenosum results in significant morbidity and exquisite pain that affects health-related quality of life. Wound healing is delayed, and patients often experience relapse. Pyoderma gangrenosum is susceptible to pathergy and deterioration with surgical intervention or other trauma; therefore, treatment includes atraumatic wound care, infection management, and local or systemic immunosuppression. CASE: We describe the use of modified negative pressure wound therapy (NPWT) with intralesional and topical steroids for the treatment of PG in a 15-year-old female patient with ulcerative colitis and a staged J-pouch ileoanal reconstruction. The patient and her family refused all systemic therapy due to prior steroid-associated weight gain. She was unable to tolerate conscious dressing changes, further complicating the treatment plan. Procedural interventions such as NPWT have been used previously for PG; however, they can cause wound pathergy and subsequent wound deterioration. Modified NPWT in conjunction with topical and intralesional steroids induced wound healing without producing pathergy. CONCLUSION: Timely recognition of PG is crucial to appropriate delivery of care. Modified NPWT and localized corticosteroid treatment were key to promoting wound healing in this case of pediatric PG.
Assuntos
Tratamento de Ferimentos com Pressão Negativa , Pioderma Gangrenoso , Úlcera Cutânea , Adolescente , Corticosteroides , Criança , Feminino , Humanos , Tratamento de Ferimentos com Pressão Negativa/efeitos adversos , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/etiologia , Qualidade de VidaRESUMO
Xia Gibbs syndrome is a genetic disorder first defined in 2014 characterized by hypotonia, intellectual disability, global developmental delay, and dysmorphic facial features. While many additional features may be present, there are few reports of dermatologic findings. We report a case of atypical aplasia cutis in a female infant who was found to have Xia Gibbs syndrome. This case highlights consideration of cutaneous manifestations of Xia Gibbs syndrome which may aid in diagnosis.
Assuntos
Anormalidades Múltiplas , Displasia Ectodérmica , Deficiência Intelectual , Anormalidades Musculoesqueléticas , Anormalidades Múltiplas/diagnóstico , Displasia Ectodérmica/complicações , Displasia Ectodérmica/diagnóstico , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnósticoRESUMO
Intravenous immunoglobulin (IVIg) is a frequently used treatment modality in the pediatric inpatient population for acute diseases such as Kawasaki disease and Stevens-Johnson syndrome. There are few reported cutaneous adverse events after IVIg in the pediatric population. Here, we present two patients with psoriasiform dermatitis appearing after IVIg treatment for two different disease processes, Kawasaki disease and mycoplasma-associated mucositis, suggesting an association with the treatment instead of the disease process.
Assuntos
Dermatite , Imunoglobulinas Intravenosas , Criança , Humanos , Imunoglobulinas Intravenosas/efeitos adversosRESUMO
Carvajal and erythrokeratodermia cardiomyopathy syndromes (EKC) are rare, inherited cardiocutaneous disorders with potentially fatal consequences in young children. Some patients display features of congestive heart failure and rapidly deteriorate; others exhibit no evident warning signs until sudden death reveals underlying heart disease. We present two patients to illustrate the characteristic hair, skin, teeth, and nail abnormalities, which-especially when distinct from that of other family members-should prompt cardiac evaluation and genetic analysis. In this article, we discuss established treatments as well as a promising, novel therapeutic that has led to nearly complete resolution of the cutaneous and cardiac pathology in EKC syndrome.