Deficit in Anterior Pituitary Function and Variable Immune Deficiency (DAVID) in Children Presenting with Adrenocorticotropin Deficiency and Severe Infections

International audienc

François de Dainville

François de Dainville se familiarise tout jeune avec les cartons d'archives en compagnie de son père chartiste. Il entre en 1928 dans la Compagnie de Jésus, où il fait ses premières expériences pédagogiques. Son doctorat d'état, qu'il défend à l'aube de la guerre, embrasse les savoirs des géographes humanistes et leur mode de transmission. Dès l'après guerre, il renonce à en publier le troisième volet et élargit ses contacts avec les sciences humaines. Historien de la pédagogie et de la cartographie, il marque ses auditeurs de l'École pratique des hautes études et de l'École des chartes. Il publie des documents inédits qui piquent la curiosité, des ouvrages qui sont de vrais guides de recherche. En 1964, il réalise la première synthèse sur les signes des cartes anciennes et réfléchit à l'élaboration d'un langage pour les atlas thématiques. Les contributions de ce volume témoignent de l'homme, de sa place dans la communauté scientifique et des travaux qu'il a inspirés

François de Dainville

François de Dainville se familiarise tout jeune avec les cartons d'archives en compagnie de son père chartiste. Il entre en 1928 dans la Compagnie de Jésus, où il fait ses premières expériences pédagogiques. Son doctorat d'état, qu'il défend à l'aube de la guerre, embrasse les savoirs des géographes humanistes et leur mode de transmission. Dès l'après guerre, il renonce à en publier le troisième volet et élargit ses contacts avec les sciences humaines. Historien de la pédagogie et de la cartographie, il marque ses auditeurs de l'École pratique des hautes études et de l'École des chartes. Il publie des documents inédits qui piquent la curiosité, des ouvrages qui sont de vrais guides de recherche. En 1964, il réalise la première synthèse sur les signes des cartes anciennes et réfléchit à l'élaboration d'un langage pour les atlas thématiques. Les contributions de ce volume témoignent de l'homme, de sa place dans la communauté scientifique et des travaux qu'il a inspirés

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

International audienceDAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function

Increasing knowledge in IGF1R defects: lessons from 35 new patients

International audienceBACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS

La qualité des aliments d'origine animale selon les conditions de production et de transformation. Rapport de l'Expertise scientifique collective

Le rapport d'expertise scientifique a été sollicité conjointement par le ministère de l'Agriculture et de l'Alimentation et FranceAgriMer. Il a été élaboré par un collectif d'experts scientifiques sans condition d'approbation préalable par les commanditaires ou d'INRAE. Il n'engage que la responsabilité de ses auteurs. Les documents relatifs à cette expertise sont disponibles sur le site web d'INRAE (www.inrae.fr)

International comparison of glycaemic control in people with type 1 diabetes: an update and extension

To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes