RESUMO
Recombination activating genes (RAG)1 and RAG2 deficiency leads to combined T/B-cell deficiency with varying clinical presentations. This study aimed to define the clinical/laboratory spectrum of RAG1 and RAG2 deficiency. We retrospectively reviewed the clinical/laboratory data of 35 patients, grouped them as severe combined immunodeficiency (SCID), Omenn syndrome (OS), and delayed-onset combined immunodeficiency (CID) and reported nine novel mutations. The male/female ratio was 23/12. Median age of clinical manifestations was 1 months (mo) (0.5-2), 2 mo (1.25-5), and 14 mo (3.63-27), age at diagnosis was 4 mo (3-6), 4.5 mo (2.5-9.75), and 27 mo (14.5-70) in SCID (n = 25; 71.4%), OS (n = 5; 14.3%), and CID (n = 5; 14.3%) patients, respectively. Common clinical manifestations were recurrent sinopulmonary infections 82.9%, oral moniliasis 62.9%, diarrhea 51.4%, and eczema/dermatitis 42.9%. Autoimmune features were present in 31.4% of the patients; 80% were in CID patients. Lymphopenia was present in 92% of SCID, 80% of OS, and 80% of CID patients. All SCID and CID patients had low T (CD3, CD4, and CD8), low B, and increased NK cell numbers. Twenty-eight patients underwent hematopoietic stem cell transplantation (HSCT), whereas seven patients died before HSCT. Median age at HSCT was 7 mo (4-13.5). Survival differed in groups; maximum in SCID patients who had an HLA-matched family donor, minimum in OS. Totally 19 (54.3%) patients survived. Early molecular genetic studies will give both individualized therapy options, and a survival advantage because of timely diagnosis and treatment. Further improvement in therapeutic outcomes will be possible if clinicians gain time for HSCT.
Assuntos
Linfopenia , Doenças da Imunodeficiência Primária , Imunodeficiência Combinada Severa , Humanos , Masculino , Feminino , Lactente , Proteínas de Homeodomínio/genética , Estudos Retrospectivos , Imunodeficiência Combinada Severa/genética , Mutação , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genéticaRESUMO
Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Humanos , Ictiose Lamelar/genética , Ictiose Lamelar/patologia , DNA Complementar , Genes Recessivos , Mutação , Ictiose/genética , Eritrodermia Ictiosiforme Congênita/genética , Estudos de Associação Genética , Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic, and ultrastructural features and to evaluate their association with genetic findings in ARCI patients. METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed. RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients. CONCLUSION: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Lipase , Mutação , Fenótipo , Índice de Gravidade de Doença , Transglutaminases , Humanos , Criança , Pré-Escolar , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Lactente , Pessoa de Meia-Idade , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/patologia , Itália , Estudos Transversais , Ictiose Lamelar/genética , Ictiose Lamelar/patologia , Transglutaminases/genética , Lipase/genética , Proteínas de Membrana/genética , Transportadores de Cassetes de Ligação de ATP/genética , Genótipo , Araquidonato 12-Lipoxigenase/genética , Pele/patologia , Pele/ultraestrutura , Ictiose/genética , Ictiose/patologia , Fosfolipases , Receptores de Superfície Celular , Aciltransferases , Esfingosina N-Aciltransferase , Sistema Enzimático do Citocromo P-450 , Oxirredutases , LipoxigenaseRESUMO
Advanced clinical practitioners (ACPs) encounter patients with acute dermatological presentations ranging from minor to life-threatening conditions in both primary and secondary care settings. However, ACPs often feel unprepared to assess and treat patients with dermatological emergencies. This article aims to provide guidance to trainee and qualified ACPs, whether in acute hospital settings or primary care, in understanding the essential aspects to consider when consulting with patients presenting with acute dermatological emergencies. It also emphasises appropriate referrals to relevant specialties for necessary inpatient or outpatient investigations and ensure prompt treatment.
Assuntos
Emergências , Dermatopatias , Humanos , Dermatopatias/terapia , Doença Aguda , Encaminhamento e Consulta , EmpoderamentoRESUMO
INTRODUCTION: PRP is a rare entity of unknown etiopathogenesis. Lack of management guidelines makes it a challenge for clinicians. OBJECTIVE: To add our experience to increase evidence about PRP. METHODS: We performed a retrospective, descriptive and multicentric study of 65 patients with PRP, being the largest European case series of patients with PRP. RESULTS: PRP was more frequent in male patients with an average age of 51 years, but erythrodermic forms presented in older patients (average age 61 years). Six (75%) paediatric patients and ten (60%) non-erythrodermic adults controlled their disease with topical corticosteroids. On the contrary, 26 (68%) erythrodermic patients required biologic therapy as last and effective therapy line requiring an average of 6.5 months to achieve complete response. CONCLUSION: Our study showed a statistical difference in terms of outcome and response to treatment between children or patients with limited disease and patients who develop erythroderma.
RESUMO
INTRODUCTION: PRP is a rare entity of unknown etiopathogenesis. Lack of management guidelines makes it a challenge for clinicians. OBJECTIVE: To add our experience to increase evidence about PRP. METHODS: We performed a retrospective, descriptive and multicentric study of 65 patients with PRP, being the largest European case series of patients with PRP. RESULTS: PRP was more frequent in male patients with an average age of 51 years, but erythrodermic forms presented in older patients (average age 61 years). Six (75%) paediatric patients and ten (60%) non-erythrodermic adults controlled their disease with topical corticosteroids. On the contrary, 26 (68%) erythrodermic patients required biologic therapy as last and effective therapy line requiring an average of 6.5 months to achieve complete response. CONCLUSION: Our study showed a statistical difference in terms of outcome and response to treatment between children or patients with limited disease and patients who develop erythroderma.
RESUMO
Cutaneous lymphomas are a heterogeneous group of several distinct entities of lymphoproliferative diseases. The diagnosis of a cutaneous lymphoma is a challenge, and it is always the result of a careful analysis of several information's consisting of clinical history, clinical picture, histological and molecular analyses. For this reason, experts taking care of patients with a skin lymphoma need to know all the peculiar diagnostic elements very well, in order not to run into mistakes. In this article, we will focus the discussion on some issues as the skin biopsy (when and where). In addition, we will discuss the approach to the erythrodermic patient, whose differential diagnoses include mycosis fungoides, and Sézary syndrome, beside more frequent inflammatory conditions. Finally, we will address the issue of quality of life and the possible support of the suffering patient with a cutaneous lymphoma, well knowing that the current therapeutic possibilities are unfortunately limited.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Qualidade de Vida , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Micose Fungoide/patologia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Dermatophytes are the most common causative pathogens of mycoses worldwide and usually cause superficial infections. However, they can enter deep into the dermis lead to invasive dermatophytosis such as deeper dermal dermatophytosis on rare occasions. Erythroderma is a severe dermatological manifestation of various diseases resulting in generalized skin redness, but erythroderma due to fungi infections is barely reported. In this article, we reported the first case of erythroderma combined with deeper dermal dermatophytosis due to Trichophyton rubrum (T. rubrum) in a patient with myasthenia gravis. CASE PRESENTATION: A 48-year-old man was hospitalized because of erythema with scaling and nodules covering his body for a month. The patient had a history of myasthenia gravis controlled by regularly taking prednisolone for > 10 years and accompanied by onychomycosis and tinea pedis lasting > 8 years. Based on histopathological examinations, fungal cultures, and DNA sequencing results, the patient was finally diagnosed with dermatophyte-induced erythroderma combined with deeper dermal dermatophytosis caused by T. rubrum. After 2 weeks of antifungal treatment, the patient had recovered well. CONCLUSIONS: This case report shows that immunosuppressed patients with long histories of superficial mycoses tend to have a higher risk of developing invasive dermatophytic infections or disseminated fungal infections. Dermatologists should be alert to this condition and promptly treat the superficial dermatophytosis.
Assuntos
Arthrodermataceae , Dermatite Esfoliativa , Miastenia Gravis , Tinha , Masculino , Humanos , Pessoa de Meia-Idade , Tinha/complicações , Tinha/diagnóstico , Tinha/tratamento farmacológico , Dermatite Esfoliativa/complicações , Trichophyton/genéticaRESUMO
CARD14-associated papulosquamous eruption (CAPE) is a rare inflammatory skin eruption that can have features of psoriasis, pityriasis rubra pilaris, and erythroderma. This skin condition is known for its resistance to topical or conventional systemic therapies. Successful treatment of CAPE with anti-IL-12/IL-23 and IL-17 inhibitors has been reported. We present a case of a 2-year-old girl with CAPE who was successfully treated with ustekinumab.
Assuntos
Dermatite Esfoliativa , Fármacos Dermatológicos , Pitiríase Rubra Pilar , Psoríase , Criança , Feminino , Humanos , Pré-Escolar , Ustekinumab/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Pitiríase Rubra Pilar/tratamento farmacológico , Psoríase/tratamento farmacológico , Guanilato Ciclase , Proteínas de Membrana , Proteínas Adaptadoras de Sinalização CARDRESUMO
BACKGROUND: Erythroderma is an inflammatory skin condition that causes extensive erythema and skin scaling amounting ≥90% of the body surface area. This retrospective cohort study describes the prevalence of malignancy-associated erythroderma in a single centre where there was concerted effort to systematically offer malignancy screens to all adult erythroderma patients above the age of 65 years. METHODS: Clinical charts were reviewed for all adult inpatients and outpatients with erythroderma who attended the National University Hospital (NUH) from 1 July 2019 to 31 December 2021. Data collected included patient demographics, clinical findings, laboratory investigations, disease-specific investigations such as endoscopic procedures and biopsies, follow-up duration and mortality data. RESULTS: Seventy-four patients were analysed. The median age of the patients was 73 years old (interquartile range: 59-81 years old). An underlying dermatosis was the most common cause of erythroderma-63 patients having atopic dermatitis/asteatotic eczema or psoriasis. Three patients had erythroderma from drug eruptions, and 1 patient had chronic actinic dermatitis. Four patients had associated malignancies (5.4%). Half of our patients completed further evaluation for malignancy (52.7%). The rest had either declined or were eventually unable to complete the investigations. There was a higher prevalence of associated malignancy (7.8%) in elderly patients above 65 years old. CONCLUSION: When compared to existing literature, our cohort reflects a higher observed occurrence of malignancy in association with erythroderma. As delays in evaluation for underlying malignancy could result in potentially deleterious outcomes, it is prudent to consider systematic screening for malignancy in high-risk populations such as elderly erythroderma patients.
Assuntos
Dermatite Atópica , Dermatite Esfoliativa , Toxidermias , Neoplasias , Adulto , Humanos , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Dermatite Esfoliativa/epidemiologia , Dermatite Esfoliativa/etiologia , Estudos Retrospectivos , Pele/patologia , Toxidermias/epidemiologia , Toxidermias/etiologia , Dermatite Atópica/complicaçõesRESUMO
BACKGROUND: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). OBJECTIVE: We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. METHODS: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. RESULTS: Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. CONCLUSIONS: This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
Assuntos
Hipersensibilidade , Síndrome de Netherton , Dermatopatias , Epiderme/patologia , Humanos , Hipersensibilidade/patologia , Interferon-alfa , Interleucina-17/genética , Síndrome de Netherton/genética , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Pele/patologia , Dermatopatias/patologiaRESUMO
Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.
Assuntos
Interleucina-18 , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Dermatite Esfoliativa/metabolismo , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Leucócitos Mononucleares/metabolismo , Síndrome de Sézary/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.
Assuntos
Eritroceratodermia Variável , Ictiose Lamelar , Ictiose , Ceratodermia Palmar e Plantar , Humanos , Eritroceratodermia Variável/genética , Ictiose Lamelar/genética , Ictiose/genética , Mutação , Glucosilceramidas , Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
Background: Erythrodermic psoriasis is an acute inflammatory condition presenting as erythema and scaling involving more than 90% of body surface area in patients with a history of psoriasis vulgaris. If not treated promptly, metabolic complications and infections due to acute skin failure can cause significant morbidity and mortality in this condition. Interleukin-17 (IL-17) is considered to be the key player in initiating the inflammatory cascade in psoriasis. IL-17 blockers have been successfully used in the management of psoriasis vulgaris. However, its use in unstable erythrodermic psoriasis is limited to isolated case reports. Methods: We hereby report an observational study of nine patients of unstable psoriatic erythroderma successfully managed with injection secukinumab and followed up over the next 24 months. Results: Nine patients were managed during the study period, and a successful outcome was noted in all the patients. The Psoriasis Area and Severity Index response rate improved by at least 75% from baseline in 33.3% (3/9) at week 4 and improved to 88.9% (8/9) at week 12. None of the patients had a recurrence of erythroderma till 24 months of followup. Conclusion: The study concluded that secukinumab is quick, safe, and efficient in psoriatic erythroderma, and there was no relapse of erythroderma in any of the patients in the 24 months of followup.
RESUMO
Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.
Assuntos
Ceramidas , Ictiose Lamelar , Lactente , Recém-Nascido , Humanos , Colódio , Ceramidas/metabolismo , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Testes GenéticosRESUMO
RATIONALE & OBJECTIVE: Allopurinol should be started at lower doses in patients with chronic kidney disease (CKD) to avoid adverse effects. We examined the risk of severe cutaneous reactions in older adults with CKD who were newly prescribed allopurinol at varied doses. STUDY DESIGN: Population-based cohort study using linked health care databases. SETTING & PARTICIPANTS: Patients in Ontario, Canada (2008-2019) aged ≥66 years, with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, and who were new users of allopurinol. EXPOSURE: A new prescription for allopurinol >100 mg/d versus a dose ≤100 mg/d. OUTCOME: The primary outcome was a hospital visit with a severe cutaneous reaction within 180 days of starting allopurinol. Secondary outcomes included all-cause hospitalization and all-cause mortality. ANALYTICAL APPROACH: The exposure and referent groups were balanced on indicators of baseline health using inverse probability of treatment weighting on the propensity score. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. RESULTS: Of 47,315 patients (median age, 76 years; median eGFR, 45 mL/min/1.73 m2), 55% started allopurinol at >100 mg/d. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of a severe cutaneous reaction: number of events (weighted), 103 of 25,802 (0.40%) versus 46 of 25,816 (0.18%), respectively (weighted RR, 2.25 [95% CI, 1.50-3.37]; weighted RD, 0.22% [95% CI, 0.12%-0.32%]. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of all-cause hospitalization but not with all-cause mortality. LIMITATIONS: This study was underpowered to detect risk differences in the association of allopurinol dose with outcomes across eGFR categories (ie, 45-59, 30-44, and <30 mL/min/1.73 m2). CONCLUSIONS: Older patients with CKD who started allopurinol at >100 mg/d versus ≤100 mg/d were twice as likely to visit a hospital with a severe cutaneous reaction in the next 180 days.
Assuntos
Alopurinol , Insuficiência Renal Crônica , Humanos , Idoso , Alopurinol/efeitos adversos , Supressores da Gota/efeitos adversos , Estudos de Coortes , Insuficiência Renal Crônica/tratamento farmacológico , Ontário/epidemiologiaRESUMO
BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) refers to non-syndromic ichthyosis caused by mutations in one of the 13 identified genes. There are limited data on the genotype of ARCI and its phenotypic correlation from India. OBJECTIVES: The aim of this study was to characterize the genotype of ARCI among patients from the Indian subcontinent. METHODS: Twenty-eight patients clinically diagnosed as ARCI were recruited prospectively from September 2017 to June 2019 (21 months). DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel. The variants identified were confirmed by Sanger sequencing and compared with known pathogenic variants to establish pathogenicity. We also attempted to correlate the phenotype with the genotype. RESULTS: Among the 28 patients recruited (M = 17, F = 11), we identified phenotypes of congenital ichthyosiform erythroderma in 12 (42.9%), 8 with lamellar ichthyosis (28.6%), 5 with intermediate phenotype (17.9%), and 3 with bathing suit ichthyosis (10.7%). Pathogenic and likely pathogenic variants were identified in 22 (78.6%) patients, involving 7 out of the 13 known ARCI genes while 6 (21.4%) did not have pathogenic variants. These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each. Previously unknown pathogenic variants were found in 59.1 % of patients. CONCLUSIONS: Our patients with ARCI were found to have genotypes as previously described in other populations.
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Aciltransferases , Proteínas de Transporte de Ácido Graxo/genética , Genes Recessivos , Genótipo , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Lipase , Mutação , Fenótipo , Centros de Atenção TerciáriaRESUMO
Methylmalonic acidemia (MMA) is an autosomal recessive genetic disorder caused by decreased activity of methylmalonyl-CoA mutase or metabolic disturbance of its coenzyme cobalamin, cutaneous manifestations are rare clinical signs in this disease. Herein, we describe a Chinese boy with MMA fed with a formula lacking branched-chain amino acids presenting with erythroderma and acrodermatitis enteropathica-like rash, a homozygous nonsense mutation c.742C>T (p.Gln248*) was identified in the MMAA gene. The pedigree exhibited a non-Mendelian inheritance pattern which was attributed to maternal uniparental disomy on chromosome 4q26-q34.1 of the proband, confirmed by chromosomal microarray analysis. Our case highlights the association between skin changes and nutritional deficiency due to therapeutic amino acid restrictions in MMA.
Assuntos
Acrodermatite , Erros Inatos do Metabolismo dos Aminoácidos , Masculino , Humanos , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Acrodermatite/diagnóstico , Acrodermatite/genética , Zinco , MutaçãoRESUMO
BACKGROUND: Erythroderma, characterized by erythema and scaling that affects at least 90% of the body, has diverse causes. Most of the clinical manifestations and laboratory findings are nonspecific, making diagnosis challenging. MATERIAL AND METHODS: Retrospective study of patients treated between January 1, 2010, and June 1, 2020. We reviewed the records to identify all patients with erythroderma who were hospitalized in Hospital Italiano de Buenos Aires and followed for at least 6 months. We extracted information on clinical histories, the characteristics of the episodes, laboratory and histopathologic findings, and clinical course. RESULTS: Seventy patients were studied. The mean age at onset was 63 years, and the ratio of men to women was 1.2:1. Adverse drug reactions caused the largest proportion of the rashes (48%), and vancomycin was the most common culprit (involved in 30% of the cases). The next most frequent cause was a preexisting skin disease, psoriasis being the most common (in 42%). The clinicopathologic correlation was adequate for diagnosis after the first biopsy in 40% of patients, but the diagnostic yield increased to 76% with the second biopsy. The largest number of biopsies required was 8, in 2 patients. The outcome was favorable in 92% of the cases. CONCLUSION: Adverse reactions to medications accounted for the largest proportion of erythroderma cases in this series, and vancomycin was the main culprit. We found no statistically significant associations among the variables studied. Nor did we identify potential predictors of causes, poor outcomes, or mortality.
Assuntos
Dermatite Esfoliativa , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Hospitais de Ensino , Humanos , Masculino , Estudos Retrospectivos , VancomicinaRESUMO
Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.