RESUMO
BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. METHODS: We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. RESULTS: We now report interim results. The children's mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. CONCLUSIONS: The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.).
Assuntos
Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Iduronidase/metabolismo , Mucopolissacaridose I/terapia , Pré-Escolar , Feminino , Seguimentos , Vetores Genéticos , Glicosaminoglicanos/urina , Humanos , Iduronidase/deficiência , Iduronidase/genética , Lactente , Lentivirus , Masculino , Mucopolissacaridose I/metabolismo , Mutação , Transplante de Células-Tronco , Transplante AutólogoRESUMO
Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.
Assuntos
Imunodeficiência de Variável Comum , Apoptose/genética , Imunodeficiência de Variável Comum/genética , Humanos , Receptor de Morte Celular Programada 1/genética , Células T Auxiliares Foliculares , Linfócitos T Auxiliares-IndutoresRESUMO
OBJECTIVE: To provide information on evolution over time of leg length discrepancy in patients with syndromic and isolated lateralized overgrowth. STUDY DESIGN: This retrospective study investigates leg length discrepancy longitudinally in 105 patients with lateralized overgrowth either isolated (n = 37) or associated with Beckwith-Wiedemann spectrum (n = 56) or PIK3CA-related overgrowth spectrum (n = 12). Discrepancy was measured by standard methods and categorized as minor, mild, severe, and critical, based on the thresholds of 1, 2 and 5, respectively. RESULTS: The period of observation from diagnosis was 1.7 ± 2.6 to 9.0 ± 6.0 years. Leg length discrepancy was 11.0 ± 7.2 mm at diagnosis and 17.1 ± 14.4 mm at last visit. Both final leg length discrepancy and change over time were correlated with discrepancy at diagnosis (r2 = 0.45, P < .001 and r2 = 0.05, P = .019, respectively). Among minor leg length discrepancy at diagnosis, 47.5% remained minor, 40.0% become mild, and 12.5% severe. Among patients with discrepancy classified as severe at diagnosis, 84.6% remained severe and 15.4% evolved to critical. The isolated lateralized overgrowth group showed a milder evolution over time compared with Beckwith-Wiedemann spectrum and PIK3CA-related overgrowth spectrum groups. Among patients with Beckwith-Wiedemann, those with paternal chromosome 11 uniparental disomy had more severe leg length discrepancy at diagnosis and evolution over time. CONCLUSIONS: Leg length discrepancy associated with isolated or syndromic lateralized overgrowth tends to worsen with growth and correlates with discrepancy at first observation. Among the genotypic groups, isolated lateralized overgrowth tends to have a milder evolution, whereas Beckwith-Wiedemann spectrum predisposes to a more severe outcome, especially if associated with paternal chromosome 11 uniparental disomy genotype.
Assuntos
Síndrome de Beckwith-Wiedemann , Perna (Membro) , Genótipo , Humanos , Estudos Retrospectivos , Dissomia UniparentalRESUMO
Autoantibodies (AAbs) are a hallmark of Type 1 diabetes (T1D). Alterations in the frequency and phenotype of follicular helper (Tfh) T cells have been previously documented in patients with type 1 diabetes (T1D), but the contribution of follicular regulatory T (Treg) cells, which are responsible for suppressing AAb development, is less clear. Here, we investigated the frequency and activation status of follicular (CXCR5+) and conventional (CXCR5-) Treg cells in the blood of children with new-onset T1D, and children with risk for developing T1D (AAb-positive) and compared them to AAb-negative controls. Blood follicular and conventional Treg cells were higher in frequency in children with new onset T1D, but expressed reduced amounts of PD-1 as compared to AAb-negative children. Interestingly, the proportion of circulating FOXP3+ Tregs expressing PD-1 was also reduced in AAb-positive at-risk children as compared to AAb-negative controls, suggesting its potential use as a biomarker of disease progression. Follicular Treg cells were reduced in frequency in the spleens of prediabetic NOD mice as they became older and turned diabetic. Interestingly, PD-1 expression declined also on circulating follicular and conventional Treg cells in prediabetic NOD mice as they aged. Together, these findings show that the frequency of circulating follicular and conventional Treg cells and their levels of PD-1 change with disease progression in children at-risk for developing T1D and in NOD mice.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Animais , Autoanticorpos/imunologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Cabelo/imunologia , Humanos , Ilhotas Pancreáticas/imunologia , Masculino , Camundongos Endogâmicos NOD , Receptores CXCR5RESUMO
Patients with Down syndrome (DS) are characterized by increased susceptibility to autoimmunity and respiratory tract infections that are suggestive of humoral immunity impairment. Here, we sought to determine the follicular helper (Tfh) and follicular regulatory (Tfr) T cell profile in the blood of children with DS. Blood was collected from 24 children with DS, nine of which had autoimmune diseases. Children with DS showed skewed Tfh differentiation towards the CXCR3+ phenotype: Tfh1 and Tfh1/17 subsets were increased, while Tfh2 and Tfh17 subsets were reduced. While no differences in the percentage of Tfr cells were seen, the ratio of Tfh1 and CXCR3+PD-1+ subsets to Tfr cells was significantly increased in the affected children. The excessive polarization towards a CXCR3+ phenotype in children with DS suggests that re-calibration of Tfh subset skewing could potentially offer new therapeutic opportunities for these patients.
Assuntos
Doenças Autoimunes/imunologia , Síndrome de Down/imunologia , Centro Germinativo/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Circulação Sanguínea , Diferenciação Celular , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Humoral , Masculino , Fenótipo , Receptores CXCR3/metabolismo , Equilíbrio Th1-Th2RESUMO
In September 2018, an international meeting of doctors of various disciplines, with expertise in the detection and treatment of DDH, was held in Csolyospalos, Hungary. The aim was to achieve consensus on the detection and early treatment of the condition and to develop a standardized system of teaching and training for hip ultrasound. There was strong agreement that US screening is essential. Specifically the Graf technique was selected as the technique of choice. Universal US screening was strongly favored. Screening should be carried out as soon as possible, but not later than the sixth week of age. US screening is cost-effective, does not result in overtreatment, and contributes to a reduction of long-term consequences. The essential principle of treatment is timely application of a device to achieve reduction, retention and maturation, by holding the hips in flexion, and a safe degree of abduction. It was agreed that the effectiveness of any screening policy depends on the correct scanning technique. Therefore, standardization of teaching and training of the Graf technique is mandatory. A unified teaching policy and materials should be developed for this purpose. Certification, re-certification and audit were discussed. The group, which has been formalized as the International Interdisciplinary Consensus Committee On DDH Evaluation (ICODE), will continue to meet and work towards establishing international consensus on DDH, standardizing and developing teaching and training of the Graf technique for hip US, and maintaining standards for detection and management.
Assuntos
Luxação Congênita de Quadril , Ultrassonografia , Consenso , Luxação Congênita de Quadril/diagnóstico por imagem , Humanos , Hungria , Recém-Nascido , Triagem NeonatalRESUMO
Aim of this review article is to evaluate the percentage of ulnar nerve lesion during cross-pinning considering the patient's position (supine or prone) on the surgical bed. Comprehensive research was performed by searching in PUBMED, Cochrane Library, ISI Web of Science, SCOPUS and Clinicaltrials.gov from 2005. Children with extension type supracondylar humeral fractures without clinical signs of ulnar nerve lesion at presentation were included. A total of 28 papers were examined including 2147 patients; 1541 underwent a closed reduction and cross-pinning in supine position and 606 in prone position. Among 1541 patients in supine position, 69 (4.5%) suffered from a ulnar nerve injury while among the 606 patients treated in prone position none ulnar nerve lesions were reported. Despite the apparent safety of prone position, further larger studies, comparing the patient's position on the surgical bed, need to be carried out in order to confirm this likelihood.
Assuntos
Fixação Interna de Fraturas/efeitos adversos , Fraturas do Úmero/cirurgia , Complicações Intraoperatórias/prevenção & controle , Posicionamento do Paciente/métodos , Traumatismos dos Nervos Periféricos , Nervo Ulnar/lesões , Criança , Fixação Interna de Fraturas/métodos , Humanos , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/prevenção & controle , Risco AjustadoRESUMO
Background: Calcaneonavicular (CNC) and talocalcaneal (TCC) coalitions are the most common cause of rigid flatfoot in children. After resection, correction of the most frequent valgus-hindfoot deformity usually requires a second-step surgery. We report results of a retrospective study of patients treated with a one-step correction. Methods: Between 2008 and 2019, data were collected on 26 patients (19 male, 7 female) affected by CNC (n = 18) and TCC (n = 13), all with rigid symptomatic flatfeet. Average age at surgery was 12.5 ± 1.1 (SD) years (range, 9.8-15.2). All patients (26/26) underwent resection, 20 of 26 underwent at the same time subtalar extraarticular screw arthroereisis (SESA) for correction of residual hindfoot valgus deformity. Pre- and postoperative talocalcaneal angle according to Costa Bartani and Talar inclination angle in weightbearing were measured. Twenty-five of 26 patients had postoperative American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score. Results: Pre- and postoperative talocalcaneal average angle for CNC was respectively 141.5 ± 7.7 degrees and 130.5 ± 5.2 degrees (P < .0001) and 143.7 ± 7.7 degrees and 129.7 ± 7.0 degrees (P < .0001) for TCC. Talar inclination average angle for CNC was 29.2 ± 5.3 degrees and 19.3 ± 1.6 degrees (P < .0001) and 31.2 ± 6.4 degrees and 21.4 ± 3.4 degrees (P < .0001) for TCC. Average follow-up (FU) was 4.7 ± 3.0 years (range, 6 months-11.9 years, median 4.9 years), with a mean age at FU of 17.2 ± 5.8 (SD) years (min 12.1, max 25.3, median 16.8 years). The mean AOFAS ankle-hindfoot score for CNC and for TCC was 96.6 (range 83-100) for resection and valgus correction as one-step procedure with no statistical difference (P = .5) between CNC and TCC. No patients had additional surgery for complications or recurrence. Conclusion: Symptomatic rigid flatfeet affected by CNC and TCC treated with coalition resection and minimally invasive subtalar arthroereisis (SESA) for residual hindfoot valgus correction in one step in adolescent age achieved good to excellent results in all cases. Further surgery to correct malalignment was avoided. Level of Evidence: Level IV, retrospective study.
RESUMO
BACKGROUND: During the treatment of unstable hips in developmental hip dysplasia (DDH), the position of the femoral head must be assessed in spica cast (SC) after reduction. A transinguinal sonographic technique (TIT) to the hip joint has been previously described in the literature. The aim of this study is to evaluate the agreement among TIT and MR to identify hip reduction. METHODS: From 2016 to 2019, 14 consecutive newborns (10 female, 4 males) with a mean age of 2.97 ± 1.29 months were treated with closed reduction in SC. A total of 4/14 children had bilateral unstable DDH. Out of 18 hips, there were 8 hips type IV and 10 hips type IIIA, according to Graf. SC were changed monthly and hips were checked both with TIT and MR, looking for persistent dislocation. RESULTS: Overall, a mean of 2.61 SC/hip (mode = 3) was accomplished, accounting for 47 procedures, with 46 reduced hips and 1 dislocated hip: TIT and MR always agreed on the same result (47/47; Cohen k = 1, CI95 1.00 to 1.00). CONCLUSIONS: The inguinal ultrasound technique described by van Douveren showed perfect agreement with MR and might be considered a reliable alternative to check the position of the femoral head during the conservative treatment of hip dysplasia in spica cast.
RESUMO
Visual AbstractThis is a visual representation of the abstract.
RESUMO
Terrorist attacks involving children raised concern regarding the preparedness to treat pediatric trauma patients during mass casualty incidents (MCIs). The purpose of this project was to assess the resources available in Milan to respond to MCIs as the 2016 Bastille Day attack in Nice. Literature and guidelines were reviewed and minimal standard requirements of care of pediatric trauma patients in MCIs were identified. The hospitals that took part in the study were asked to answer a survey regarding their resource availability. An overall surge capability of 40-44 pediatric trauma patients was identified, distributed based on age and severity, hospital resources, and expertise. The findings showed that adult and pediatric hospitals should work in synergy with pediatric trauma centers, or offer an alternative if there is none, and should be included in disaster plans for MCIs. Simulations exercises need to be carried out to evaluate and validate the results.
Assuntos
Planejamento em Desastres , Incidentes com Feridos em Massa , Terrorismo , Humanos , Incidentes com Feridos em Massa/estatística & dados numéricos , Itália , Planejamento em Desastres/métodos , Terrorismo/estatística & dados numéricos , Criança , Inquéritos e Questionários , Pediatria/métodos , Pediatria/estatística & dados numéricos , Pediatria/normas , Pré-Escolar , Adolescente , Capacidade de Resposta ante Emergências/estatística & dados numéricosRESUMO
Background: Dysplasia epiphysealis hemimelica is a rare non-inherited condition characterized by the unilateral predominance of osteochondromas in one or more epiphyses, with ankles and knees being the most affected joints. Treatment approaches vary based on the localization of the disease, encompassing both conservative and surgical options. Due to its rarity, there is a lack of definitive surgical guidelines or specific treatment modalities. Therefore, the objective of this systematic review was to thoroughly investigate dysplasia epiphysealis hemimelica to provide evidence-based guidance for managing this condition, specifically focusing on the foot and ankle. Methods: A systematic search was performed on PubMed and the Cochrane Library to identify all published articles related to dysplasia epiphysealis hemimelica of the foot and ankle. Individual patient information, such as gender, age, disease type, follow-up, localization, clinical presentation, intervention, and complications, were systematically extracted from each article and analyzed. Results: Twenty-five eligible publications were included in the review, involving a total of 70 patients (16 females, 53 males). The mean age was 9.6 years (SD 7.3). The talus was the most prevalent location and clinical presentations included mass and pain in 54% of cases. Surgical procedures were chosen in 92% of patients, with 95% undergoing mass excision. Recurrence was the most frequent complication, observed in 9% of cases. Conclusions: Raising awareness about dysplasia epiphysealis hemimelica is crucial for early diagnosis and treatment, positively impacting clinical outcomes. Vigilant monitoring is essential during observational management, as unchecked mass growth can complicate surgical intervention. Surgical treatment focuses on mass excision, feasible even at a young age but requiring precision to prevent recurrence or secondary arthritis. Level of evidence: IV.
RESUMO
Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.
Assuntos
Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Humanos , Mucopolissacaridose I/terapia , Mucopolissacaridose I/patologia , Mucopolissacaridose I/genética , Masculino , Feminino , Pré-Escolar , Lactente , Resultado do Tratamento , Células-Tronco Hematopoéticas/metabolismo , Criança , Osso e Ossos/patologia , Imageamento por Ressonância MagnéticaRESUMO
PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.
Assuntos
Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/genética , Consenso , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genética , ItáliaRESUMO
The objectives of this study were to collect and analyze current diagnosis and treatment options of symptomatic flexible flatfoot (FFF), as well as to identify treatment expectations, among the members of the Italian Pediatric Orthopedics Society (SITOP). Diagnosis and treatment preferences were recorded according to a web-based survey. The survey was divided into six main sections: (1) general clinical parameters; (2) foot aspects; (3) X-ray angles (or lines); (4) expectations; (5) standard clinical assessment; (6) treatment options. One hundred and ten out of 248 SITOP members answered to the questionnaire. Age (85.5%), pain at the level of the plantar arch or fascia (61.8%), fatigue (59.1%) were the clinical parameters of crucial importance. Heel valgus (85.4%), flexibility (61.8%) and forefoot supination (47.3%) were identified as the most important foot aspects. Ninety-two responders (83.6%) identified the 'improved ability to walk longer without symptoms or discomfort' as the principal treatment expectation. Pain evaluated through the visual analog scale (VAS) was considered crucial in 31.8% of cases. All respondents confirmed they also treat patients with FFF surgically; in particular, 97.3% of SITOP affiliates declare to perform arthroereisis followed by lateral column lengthening (29.1%) and medializing calcaneal osteotomy (9.1%). Although in this survey heterogeneous findings for diagnosis and treatment of patients with symptomatic FFF within SITOP members were found, a large preference for age, heel valgus, flexibility as clinical aspects and parameters, as well as nonoperative treatment and arthroereisis, was reported.
Assuntos
Calcâneo , Pé Chato , Deformidades Adquiridas do Pé , Ortopedia , Criança , Pé Chato/diagnóstico por imagem , Pé Chato/epidemiologia , Pé , Humanos , OsteotomiaRESUMO
AIMS: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. METHODS: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. RESULTS: In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. CONCLUSIONS: Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.
Assuntos
Diabetes Mellitus Tipo 1 , Pâncreas Exócrino , Adulto , Amilases/metabolismo , Autoanticorpos/metabolismo , Biomarcadores/metabolismo , Humanos , Pâncreas/metabolismo , Pâncreas Exócrino/metabolismoRESUMO
Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 and TBX4, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in PITX1 and TBX4 in Italian patients with idiopathic clubfoot. PITX1 and TBX4 genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in TBX4, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on PITX1 and TBX4. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same TBX4-PITX1 axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors.
Assuntos
Pé Torto Equinovaro , Criança , Humanos , Pé Torto Equinovaro/genética , Variações do Número de Cópias de DNA/genética , Mutação , Proteínas com Domínio T/genéticaRESUMO
An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56brightNK cells in T1D. Furthermore, a non-selective decrease of CD3+CD56+ regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Humanos , Criança , Citometria de Fluxo , Linfócitos T Reguladores , Autoanticorpos , Células Matadoras NaturaisRESUMO
Various surgical techniques are known for the treatment of flexible flatfoot in children after failure of nonsurgical attempts. Data collected in a review of the last 10-year period (2010-2020) show that among the 691 feet undergoing subtalar arthroereisis with endorthesis, average age at surgery was 11.40 years and in the 1856 feet that underwent subtalar arthroereisis with calcaneo-stop 11.69 years, while the complications rate was 9.00% and 6.38%, respectively. These data confirm that subtalar arthroereisis with calcaneo-stop may have an advantage over subtalar arthroereisis with endorthesis as the screw is not placed across the subtalar joint but instead into the calcaneus.
Assuntos
Calcâneo , Pé Chato , Articulação Talocalcânea , Parafusos Ósseos , Calcâneo/cirurgia , Criança , Pé Chato/cirurgia , Pé , Humanos , Articulação Talocalcânea/cirurgia , Resultado do TratamentoRESUMO
Tarsal coalition is determined by an absence of segmentation between one or more foot bones. The main symptom is activity-related foot pain, usually dorsolateral for calcaneonavicular coalitions and medial for talocalcaneal ones. At presentation, a symptomatic tarsal coalition must be treated conservatively for at least 6 months. If the conservative treatment fails and the foot is still painful, resection is the treatment of choice. Advantage of surgery is to restore mobility and reduce the risk of subsequent degenerative arthritis. Common pitfalls of surgery include failure to recognize associated coalitions, inadequate or extensive resection, and injury of adjoining bones.