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PURPOSE: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). METHODS: 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling. CONCLUSION: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.
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BACKGROUND: Lymphatic malformations are vascular developmental anomalies varying from local superficial masses to diffuse infiltrating lesions, resulting in disfigurement. Patients' outcomes range from spontaneous regression to severe sequelae notwithstanding appropriate treatment. The current classification guides, in part, clinicians through the decision-making process, prognosis prediction and choice of therapeutic strategies. Even though the understanding of molecular basis of the disease has been recently improved, a standardized management algorithm has not been reached yet. RESULTS: Here, we report our experience on five children with different lymphatic anomalies of the head and neck region treated by applying a multidisciplinary approach reaching a consensus among specialists on problem-solving and setting priorities. CONCLUSIONS: Although restitutio ad integrum was rarely achieved and the burden of care is challenging for patients, caregivers and healthcare providers, this study demonstrates how the referral to expert centres can significantly improve outcomes by alleviating parental stress and ameliorating patients' quality of life. A flow-chart is proposed to guide the multidisciplinary care of children with LMs and to encourage multidisciplinary collaborative initiatives to implement dedicated patients' pathways.
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Anomalías Linfáticas , Humanos , Anomalías Linfáticas/terapia , Anomalías Linfáticas/patología , Femenino , Masculino , Niño , Cuello/patología , Cabeza , Preescolar , Lactante , Calidad de VidaRESUMEN
BACKGROUND: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. PROBLEM: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.
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Cromosomas Humanos Par 22 , Mosaicismo , Trisomía , Humanos , Trisomía/genética , Femenino , Cromosomas Humanos Par 22/genética , Embarazo , Diagnóstico Prenatal , Masculino , Asesoramiento Genético , Disomía Uniparental/genética , Recién Nacido , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/diagnósticoRESUMEN
BACKGROUND: The Pediatric Eating Assessment Tool (PEDI-EAT-10) is a reliable and valid tool for rapid identification of dysphagia in patients aged 18 months to 18 years. AIMS: To translate and adapt the PEDI-EAT-10 into the Italian language and evaluate its validity and reliability. METHODS & PROCEDURES: The translation and cross-cultural adaptation of the tool consisted of five stages: initial translation, synthesis of the translations, back translation, expert committee evaluation and test of the prefinal version. The internal consistency of the translated tool was analysed in a clinical group composed of 200 patients with special healthcare needs aged between 18 months and 18 years. They were consecutively enrolled at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome. For test-retest reliability, 50 caregivers filled in the PEDI-EAT-10 questionnaire for a second time after a 2-week period. Construct validity was established by comparing data obtained from patients with data from healthy participants (n = 200). The study was approved by the local ethics committee. OUTCOMES & RESULTS: Psychometric data obtained from patients (104 M; mean age = 8.08 ± 4.85 years; median age = 7 years) showed satisfactory internal consistency (Cronbach's α = 0.89) and test-retest reliability (Pearson r = 0.99; Spearman r = 0.96). A total of 30% of children were classified as having a high risk of penetration/aspiration. The Italian PEDI-EAT-10 mean total score of the clinical group was significantly different from that resulting from healthy participants. CONCLUSIONS & IMPLICATIONS: The PEDI-EAT-10 was successfully translated into Italian, validated and found to be a reliable one-page rapid screening tool to identify dysphagia in children and adolescents with special needs. WHAT THIS PAPER ADDS: What is already known on the subject The PEDI-EAT-10 is a valid and reliable quick discriminative paediatric tool for identifying penetration/aspiration risks. What this paper adds to the existing knowledge In the present study we successfully translated and adapted the PEDI-EAT-10 into the Italian language. What are the potential or actual clinical implications of this work? This translation and adaptation increase access to valid feeding and swallowing assessment for children of Italian-speaking families. In addition, the I-PEDI-EAT-10 can suggest further assessment of patients' swallowing abilities.
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CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.
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Apraxias , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Sialorrea , Niño , Humanos , Síndrome , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Apraxias/genética , beta Catenina/genéticaRESUMEN
Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9-32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS 'deleted' patients may show a dyslipidemic pattern, while SMS 'mutated' patients are more likely to develop early-onset obesity along with hyperinsulinism.
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CTNNB1 [OMIM *116806] encodes ß-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.
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Cardiopatías Congénitas , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Niño , beta Catenina/genética , Cardiopatías Congénitas/diagnóstico , Síndrome , Discapacidad Intelectual/genéticaRESUMEN
Noonan syndrome (NS) belongs to RASopathies, a family of disorders caused by unregulated signaling through the RAS-MAPK pathway. Herein, we report on an individual with molecularly confirmed diagnosis of NS showing asymptomatic enlarged spinal nerve roots, which are distinctive features of neurofibromatosis type 1. To date, a total of 16 patients with neurogenic tumors resembling neurofibromas/schwannomas and a molecularly confirmed diagnosis of a non-NF1 RASopathy have been reported, adding this further feature shared among RASopathies.
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Neurofibromatosis , Neurofibromatosis 1 , Síndrome de Noonan , Humanos , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genética , Raíces Nerviosas Espinales/diagnóstico por imagen , MutaciónRESUMEN
Chromosome 9p deletion syndrome is a rare autosomal dominant disorder presenting with a broad spectrum of clinical features, including congenital heart defects (CHDs). To date, studies focused on a deep characterization of cardiac phenotype and function associated with this condition are lacking. We conducted a multicentric prospective observational study on a cohort of 10 patients with a molecular diagnosis of 9p deletion syndrome, providing a complete cardiological assessment through conventional echocardiography and tissue Doppler imaging echo modality. As a result, we were able to demonstrate that patients with 9p deletion syndrome without major CHDs may display subclinical cardiac structural changes and left-ventricle systolic and diastolic dysfunction. Albeit needing validation in a larger cohort, our findings support the idea that a complete cardiac assessment should be performed in patients with 9p deletion syndrome and should be integrated in the context of a long-term follow-up.
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Anomalías Múltiples , Humanos , Anomalías Múltiples/genética , Síndrome , Deleción Cromosómica , Fenotipo , Estudios Observacionales como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Achondroplasia is an autosomal dominant genetic disease representing the most common form of human skeletal dysplasia: almost all individuals with achondroplasia have identifiable mutations in the fibroblast growth factor receptor type 3 (FGFR3) gene. The cardinal features of this condition and its inheritance have been well-established, but the occurrence of feeding and nutritional complications has received little prominence. In infancy, the presence of floppiness and neurological injury due to foramen magnum stenosis may impair the feeding function of a newborn with achondroplasia. Along with growth, the optimal development of feeding skills may be affected by variable interactions between midface hypoplasia, sleep apnea disturbance, and structural anomalies. Anterior open bite, prognathic mandible, retrognathic maxilla, and relative macroglossia may adversely impact masticatory and respiratory functions. Independence during mealtimes in achondroplasia is usually achieved later than peers. Early supervision of nutritional intake should proceed into adolescence and adulthood because of the increased risk of obesity and respiratory problems and their resulting sequelae. Due to the multisystem involvement, oral motor dysfunction, nutrition, and gastrointestinal issues require special attention and personalized management to facilitate optimal outcomes, especially because of the novel therapeutic options in achondroplasia, which could alter the progression of this rare disease.
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Acondroplasia , Enfermedades Óseas , Síndromes de la Apnea del Sueño , Recién Nacido , Adolescente , Humanos , Acondroplasia/genética , Cabeza , MandíbulaRESUMEN
Since the introduction of cell-free (cf) DNA analysis, Non-Invasive Prenatal Testing (NIPT) underwent a deep revolution. Pregnancies at high risk for common fetal aneuploidies can now be easily identified through the analysis of chromosome-derived components found in maternal circulation, with the highest sensitivity and specificity currently available. Consequently, the last decade has witnessed a widespread growth in cfDNA-based NIPT use, enough to be often considered an alternative method to other screening modalities. Nevertheless, the use of NIPT in clinical practice is still not devoid of discordant results. Hereby, we report a case of confined placental mosaicism (CPM) in which a NIPT false-positive result for trisomy 13 required not only amniocentesis but also cordocentesis, to rule out the fetal aneuploidy, with the additional support of molecular cytogenetics on placental DNA at delivery. Relevant aspects allowing for precision genetic diagnosis and counselling, including the number of analysed metaphases on the different fetal cells compartments and a repeated multidisciplinary evaluation, are discussed.
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AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. METHODS AND RESULTS: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). CONCLUSIONS: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
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Canal de Potasio KCNQ1 , Taquicardia Ventricular , Arritmias Cardíacas , Calmodulina , Muerte Súbita Cardíaca/etiología , Humanos , Canal de Potasio KCNQ1/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/diagnósticoRESUMEN
BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
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Agammaglobulinemia/terapia , Terapia Genética/métodos , Vectores Genéticos , Trasplante de Células Madre Hematopoyéticas , Lentivirus/genética , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/deficiencia , Adolescente , Niño , Preescolar , Terapia Genética/efectos adversos , Humanos , Lactante , Recuento de Linfocitos , Supervivencia sin Progresión , Estudios Prospectivos , Trasplante AutólogoRESUMEN
PURPOSE: Early differentiation of adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID) from other forms of SCID may initiate appropriate treatment interventions with the aim of metabolic detoxification and improved outcome. Our hypothesis was that previously described radiological features (inferior scapular angle squaring and spurring and costochondral cupping) can differentiate ADA-SCID from other forms of SCID. METHODS: Chest radiographs at clinical presentation between 2000 and 2017 of children with ADA-SCID were retrospectively included, provided that the radiological features were assessable. Random chest radiographs of children with other forms of SCID were included for comparison. Three paediatric radiologists (2 senior, 1 junior) assessed the radiographs for the specific radiological features and stated their diagnosis (ADA-SCID or non-ADA-SCID). An optimal threshold for test performance was defined using a ROC curve. RESULTS: Thirty-six patients with ADA-SCID and twenty-five patients with non-ADA-SCID were included (median age 3.8 months). The optimal threshold for test performance was at approximately < 7 months old: sensitivity 91.7%, specificity 80.7%, interreader agreement was k = 0.709, AUC 0.862. The positive likelihood ratio for scapular squaring, scapular spur, and costochondral cupping was 4.0, 54.6 and 7.8, respectively. The test was valid when performed by both senior and junior paediatric radiologists. CONCLUSION: Radiological features such as scapular spurring, scapular squaring and costochondral cupping can reliably differentiate between ADA-SCID and other forms of SCID. This is true for children aged approximately < 7 months, and this is reliable when assessed by both senior and junior paediatric radiologists.
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Adenosina Desaminasa/genética , Agammaglobulinemia/diagnóstico , Inmunodeficiencia Combinada Grave/diagnóstico , Tórax/diagnóstico por imagen , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Curva ROC , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Tórax/patologíaRESUMEN
Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m2 /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Asparaginasa , Niño , Preescolar , Dexametasona , Doxorrubicina , Femenino , Humanos , Lactante , Masculino , Neoplasia Residual , Polietilenglicoles , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Inhibidores de Proteasoma , Inducción de Remisión , Terapia Recuperativa/métodos , Análisis de Supervivencia , Vincristina , Adulto JovenRESUMEN
BACKGROUND: The presence of hypovitaminosis D in patients with autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), is debated. In a previous study we found an increased prevalence of vertebral fractures (VFx) and hypovitaminosis D in PV and BP patients. The present study extends the sample size of the previous one, for investigating the 25-hydroxyvitamin D (25OHVitD) levels in relation with the skeletal health and disease intensity in these patients. METHODS: The previous study was performed in 13 PV and 15 BP patients and 28 controls. Data from 39 additional patients (22 PV and 17 BP) were now added. Eventually, we studied 67 patients (35 PV, 32 BP, 51 females), aged 64.7 ± 16.9 years and 67 age- gender- and body mass index-matched controls. In all subjects, serum 25OHVitD, calcium and alkaline phosphatase (ALP) levels were measured, bone mineral density (BMD) was evaluated by Dual-energy X-ray. Absorptiometry at lumbar spine (LS) and femoral neck (FN) and the presence of VFx were ascertained by visual assessment from spinal radiographs. In patients, the disease intensity was evaluated by the autoimmune bullous skin disorder intensity score (ABSIS). RESULTS: As compared with controls, both PV and BP patients showed lower 25OHVitD (22.2 ± 11.1 vs 13.9 ± 8.3 ng/mL, p < 0.001 and 22.4 ± 14.9 vs 9.5 ± 7.7 ng/mL, p < 0.0001, respectively) and higher prevalence of severe hypovitaminosis D (22.9 vs 48.6%, p < 0.02 and 31.1 vs 75.0%, p < 0.0001, respectively) and VFx (28.6 vs 57.1%, p = 0.03 and 34.4 vs 62.5%, P = 0.02, respectively). In both PV and BP patients, LS and FN BMD did not differ from controls. In the whole patients' group, ABSIS score was inversely associated with 25OHVitD levels (R = -0.36, p < 0.005), regardless of age (ß = -3.2, P = 0.009). CONCLUSIONS: PV and BP patients have an increased prevalence of hypovitaminosis D and VFx. The extended study shows, for the first time, that the 25OHVitD levels are inversely associated with disease intensity and that VFx occur in spite of a not reduced BMD.
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Enfermedades Autoinmunes/patología , Densidad Ósea , Penfigoide Ampolloso/complicaciones , Pénfigo/complicaciones , Deficiencia de Vitamina D/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/complicaciones , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina DAsunto(s)
Acné Vulgar/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Artritis Infecciosa/genética , Proteínas del Citoesqueleto/genética , Hidradenitis Supurativa/genética , Piodermia Gangrenosa/genética , Acné Vulgar/fisiopatología , Adolescente , Artritis Infecciosa/fisiopatología , Femenino , Hidradenitis Supurativa/fisiopatología , Humanos , Mutación , Piodermia Gangrenosa/fisiopatología , SíndromeRESUMEN
BACKGROUND: Pyoderma gangrenosum (PG) is a rare, relapsing inflammatory disorder classified within the neutrophilic dermatoses. It can be idiopathic or associated with various conditions. The management of PG includes several immunosuppressants, but definite guidelines are still lacking. OBJECTIVE: To propose a 'clinicotherapeutic' classification for PG; namely, a therapeutic algorithm for this disease on the basis of the clinical extent of lesions. METHODS: Twenty-one patients with PG referred to our department during the last 3½ years were prospectively studied. They were subdivided into three subsets - localized, multilesional and disseminated - on the basis of the number of lesions and percentage of involved body surface area. RESULTS: The end point was fulfilled in all the aforementioned settings of PG. Topical tacrolimus proved to be useful in localized PG. Multilesional PG was successfully treated with prednisone alone or in combination with cyclosporine. Disseminated PG responded well to prednisone plus cyclosporine, except for refractory cases in which infliximab was employed. CONCLUSIONS: This clinicotherapeutic classification seems to work well in PG, although its impact on the incidence of relapses is poorly evaluable due to the short follow-ups in our study; controlled trials are needed to confirm its value.
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Piodermia Gangrenosa/clasificación , Piodermia Gangrenosa/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Infliximab , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Piodermia Gangrenosa/patología , Tacrolimus/uso terapéutico , Adulto JovenRESUMEN
Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis which may present in a classic ulcerative form or in atypical bullous, vegetative or pustular variants. It can be associated with several disorders or be idiopathic. Although systemic immunosuppressants remain the choice therapy for most cases of PG, a local approach should be considered in localized disease. Recently, topical tacrolimus has successfully been used as an off-label drug in localized PG. In the present study, five patients with localized, idiopathic, newly diagnosed PG were treated with topical tacrolimus monotherapy. Localized PG was defined as disease involving no more than 5% of the body surface area and presenting with no more than three lesions. Cultures performed on PG lesions both before and during tacrolimus treatment were negative. In all five patients complete remission was achieved within a mean time of 6 weeks and no relapses occurred; in three cases, tacrolimus was discontinued, while the remaining two patients were applying the drug as maintenance therapy at the time of writing. Thus, we suggest that topical tacrolimus monotherapy could represent the first-line treatment for PG that fulfils the following criteria: localized disease, idiopathic form and recent onset with negative microbiological tests on PG lesions.