Centre de Référence Déficits Immunitaires Héréditaires

Abstract Background and Aims C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (ic-MPGN) are chronic kidney disorders characterized by abnormal activation of the alternative complement pathway. The etiology of the conditions is heterogeneous and variably involves C3 activating auto-antibodies, alterations in complement regulating genes and activation of the terminal complement pathway. Classification by diagnostic biomarker panels has been proposed to improve outcome prediction. While currently available non-specific immunosuppressive and antiproteinuric therapies yield highly variable long-term disease outcomes, new treatments targeting individual components of the complement system are in development. These emerging novel therapeutic options increase the need for standardized, comprehensive diagnostic evaluation of C3G/ic-MPGN to empower rational, personalized treatment approaches. The European Rare Kidney Disease Reference Network (ERKNet) and the CompCure Association for complement-mediated diseases have recently established a large prospective registry study following adults and children with C3G/ic-MPGN. The CompCure project aims to explore the association of diagnostic biomarkers with treatment responsiveness and disease outcomes. Here, we analyzed the completeness of available complement diagnostic features and the detection rate of abnormalities in the study cohort. Method A total of 236 patients were analyzed, including 157 with C3G (141 C3GN, 16 DDD) and 70 with ic-MPGN, registered across 36 European nephrology referral centers (30 pediatric, 11 adult). Disease onset was during childhood in 70% of the patients. 77% of patients were enrolled within 6 months of diagnosis. The diagnosis was established by kidney biopsy with immunofluorescence and electron microscopy in all cases. Results At time of diagnosis, global CH50 and AP50 complement tests were conducted in 26% and 15% of cases, respectively. While serum C3 was tested in 71% and C4 in 69% of patients, other complement proteins were rarely assessed: Factor H in 17%, C5 in 3%, and Properdin in 2%. The membrane attack complex (sC5b-9) was measured in 32%, and Bb in 4%. Among autoantibodies, C3Nef was tested in 33%, anti-FH in 31%, anti-FB in 9%, anti-C3b in 11%, and C5Nef in 5% of patients. Genetic testing was performed in 56% of C3GN, 75% of DDD, and 15% of ic-MPGN patients. The assessment of core diagnostic features increased with time during the observation period: Conclusion The diagnostic evaluation of patients with C3G/ic-MPGN in European referral centers primarily relies on histopathological findings and serum C3 levels. Essential tests such as sC5b-9, C3Nef and other autoantibodies as well as complement gene screening are still performed in a minority of patients. Reasons for the incomplete diagnostic assessment may include the low number of specialized complement diagnostic laboratories in Europe, a lack of standardized diagnostic panels, high cost and long processing times. This gap in diagnostic practices hampers accurate disease classification and patient stratification for personalized treatment protocols. The CompCure cohort study will support participating sites to obtain standardized diagnostics in newly diagnosed patients with C3G/ic-MPGN.

Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra-hematological manifestations. The most common cause of CN is variants in ELANE; however, approximately 30 other genes have been implicated. Despite this, the genetic basis remains unknown in roughly 30% of cases. The clinical and genetic heterogeneity of CN makes diagnosis particularly challenging. To address this, we conducted exome or genome sequencing of 60 patients with a suspected diagnosis of CN that remained unresolved following targeted sequencing. A genetic diagnosis was established in 25 patients (42%). Variants were identified in 15 different genes. Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (GINS4, CARD11, ADA2, GINS1, LCP1, SASH3, and WAS). One-third of the cases carried variants in genes linked to syndromic disorders (VPS13B, TAFAZZIN, CLPB, and TONSL), demonstrating variable penetrance of extra-hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (BLM, RPL18, SAMD9, and SRP72), identified incidentally due to atypical presentations. Compared to patients with ELANE-CN, these individuals were diagnosed later, had fewer severe bacterial infections and gingivitis, exhibited less profound neutropenia, lacked monocytosis, and had a granulocytic maturation arrest, often beyond the promyelocytic stage. A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells. This study highlights the significant contribution of exome and genome sequencing in diagnosing CN, given the phenotypic overlap, genetic heterogeneity, and variable penetrance of immunological and extra-hematological features.

BackgroundThe current development of gynecology services for children and adolescents seeks to meet needs both in the overall population and in patients with rare diseases. In France, the referral center for rare gynecological diseases specializes in four major types of conditions, namely, uterovaginal malformations, hereditary hemorrhagic diseases, rare benign breast diseases, and gynecological repercussions of rare chronic diseases.ObjectiveTo describe consecutive patients who had a first visit in 2018–2023 at the referral center for rare gynecological diseases at the Necker Pediatric University Hospital in Paris, France, and who were diagnosed with a condition in any of the four categories listed above.Material and methodsFor this single-center retrospective observational cohort study, data from the referral-center database were collected and reviewed. These data included year of birth, age at and reason for first gynecology visit, and rare chronic disease and referring rare-disease center for patients seen for gynecological repercussions of rare chronic diseases.ResultsThe 704 included patients had a median age of 15.2 years (interquartile range 3.8) at the first visit. Among them, 100 (14.2%) had uterovaginal malformations, 32 (4.6%) hereditary hemorrhagic diseases, 17 (2.4%) rare benign breast diseases, and 555 (78.8%) gynecological repercussions of rare chronic diseases. The leading reasons for the visit were dysmenorrhea (15.6%), menorrhagia (15.5%), uterovaginal malformations (15.2%), and irregular periods (14.9%).ConclusionRepercussions of rare chronic diseases managed at rare-disease referral centers were by far the leading reason for seeking gynecological expertise in rare diseases. In this complex situation, the underlying disease and its treatments interact with the gynecological manifestations and their treatment, requiring close collaboration among all specialists caring for each patient.

Subcutaneous immunoglobulin (SCIg) replacement therapy is indicated for patients with hypogammaglobulinemia caused by primary (PID) and secondary immunodeficiencies (SID). To compare healthcare resource utilization (HCRU) and related direct medical costs of patients in France treated with weekly conventional SCIg (cSCIg) vs monthly hyaluronidase-facilitated SCIg (fSCIg). This retrospective study of Ig-naïve patients with PID or SID newly receiving a SCIg between 2016 and 2018, extracted from the French National Healthcare reimbursement database (SNDS), analyzed the SCIg-related HCRU and reimbursed costs generated from in-hospital (hospitalizations and SCIg doses) or at-home (nurse visits [NV] and pump provider visits [PPV], drug doses) SCIg administration. Overall, 2,012 patients (PID:534; SID:1,478) were analyzed. The follow-up duration varied between 7.5 and 8.7 months according to sub-groups. Compared with fSCIg-treated patients, monthly mean rates of NV and PPV were respectively 2.5 and 3.1 times higher in PID, and 1.6 and 3.1 times higher in SID cSCIg-treated patients. Monthly mean rates for SCIg administration-related hospitalizations were lower overall, while their costs were 1.6 and 1.8 times higher for cSCIg than fSCIg subgroups, in PIDs and SIDs respectively; these results are due to more frequent hospitalizations with fSCIg being mainly shorter, without stayover. Total HCRU costs from the French NHI's perspective were estimated to be lower with fSCIg vs cSCIg, in PIDs and SIDs. This study provides real-world evidence of SCIg administration in a large French population. Patients with PID or SID treated with fSCIg had fewer at-home HCRU and lower overall costs for in-hospital or at-home SCIg administration compared with cSCIg-treated patients.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Introdução: Um sono de qualidade é fundamental para a saúde mental, dado que sua privação impacta negativamente a cognição, o desempenho psicomotor, as habilidades sociais de crianças em idade escolar no estado de vigília e aumenta a propensão de adolescentes à depressão e ansiedade. Desenvolvimento: A relação entre distúrbios do sono e saúde mental é convencionada há muito tempo. Problemas relacionados ao sono podem estar relacionados ao ambiente, às experiências adversas vividas na infância e isso pode aumentar a probabilidade de transtornos mentais como o de déficit de atenção com hiperatividade (TDAH), ansiedade e depressão. Conclusão: A compreensão dessa relação entre esses dois fatores é importante para possíveis profilaxias e tratamentos em saúde mental, sendo ainda necessários mais estudos para melhor elucidação.

Comunicación al VII Congreso de Pedagogía Granada, 1 - 5 de octubre de 1980La ley 30/1974 de 24 de julio y el Decreto 3514/1974 de 20 de diciembre, y más recientemente la O. M. de 9 de octubre de 1979, que regulaban el acceso de los alumnos a la Universidad -la .. selectividad»- suponía un filtro, poco eficaz es cierto, pero selectivo al fin y al cabo, en la demanda de un puesto en Facultades, E. T. S. y Colegios Universitarios. De momento las escuelas Universitarias se convirtieron en el vertedero de los otros centros de la Universidad que canalizaron hacia ellas a los incapacitados de superar unas pruebas de aptitud tan genéricas y vagas, tan poco selectivas, que los porcentajes que ••colaban, por ellas han sido a veces de escándalo. La calidad de los rechazados era, por lo tanto, de una enorme pobreza intelectual, y encontraban en las Escuelas Universitarias en general un portillo sin obstáculos hacia la Universidad, y en las de Profesorado en particular el señuelo de miles de plazas anuales a oposición en la docencia oficial, aparte de otras salidas profesionales.

O Transtorno do Espectro Autista (TEA) é uma condição heterogênea que afeta o neurodesenvolvimento, sendo caracterizado por deficiência na comunicação social, déficits de habilidades comunicativas e por padrões repetitivos e restritos de comportamentos e interesses. O diagnóstico do transtorno é realizado através de instrumentos de triagem, escalas e avaliação padronizada. O tratamento, por sua vez, requer um cuidado multidisciplinar e continuado. Porém, observa-se uma diferença de quadros clínicos e espectros nas meninas com TEA, as quais possuem algumas características que destoam ou não se enquadram nos testes de triagem mais utilizados. Com isso, o diagnóstico nas meninas acaba sendo mais tardio e, consequentemente, o tratamento em prol de desenvolver habilidades sociais e comportamentais não atinge sua excelência. O objetivo deste trabalho é avaliar o perfil epidemiológico dos pacientes com TEA atendidos em um Consórcio Metropolitano do Paraná, bem como diferenciar o tempo para o diagnóstico, quadro clínico e terapias empregadas entre meninos e meninas com diagnóstico de TEA. Trata-se de um estudo multicêntrico, transversal, de âmbito regional, conduzido a partir de 2021. Foram incluídos apenas prontuários completos, de pacientes entre 18 meses a 17 anos. Para análise inferencial foram utilizados os teste T de Student para análise de comparações de médias de variáveis quantitativas. Foram considerados significativos os valores de p menores que 0,05. Dentre os principais resultados, foram obtidos dados de 167 pacientes, sendo 50,9% do sexo feminino e 49,1% do sexo masculino. As meninas foram diagnosticadas com idade média de 5,84 anos, já os meninos, com 6,15 anos. 19,8% dos pacientes apresentavam Transtorno do Déficit de Atenção com Hiperatividade (TDAH). Somente 26,8% das meninas receberam o tratamento no momento do diagnóstico, enquanto no sexo masculino, tal número foi de 46,2%. Em conclusão, foi possível identificar os principais dados epidemiológicos de crianças com TEA, e, embora o diagnóstico das meninas ocorra mais cedo, elas recebem tratamento mais tardio, com menor acompanhamento multidisciplinar.