Hypopituitarisme congénital (description phénotypique et analyse génétique de 990 patients)

INTRODUCTION: L'ontogenèse hypophysaire est régie par l'expression en cascade de facteurs morphogènes et de transcription dont les mutations sont responsables de certains cas d'hypopituitarismes congénitaux. Une grande hétérogénéité phénotype rend difficile l'étalbissement d'une stratégie d'identification des anomalies génétiques chez ces patients. OBJECTIFS: 1) décrire une large cohorte de patients avec hypopituitarisme; 2) définir la prévalence des mutations et les caractéristiques phénotypiques des patients pour chaque gène considéré; 3) proposer une stratégie d'analyse génétique utile au clinicien. METHODES: Les données phénotypiques de 990 patients du réseau international Genhypopit étaient recueillies à partir d'un formulaire standardisé. Dix gènes ont été analysés (HESX1, LHX3, PROP1, POU1F1, TBX19, OTX2, PITX2, PROK2 et PROKR2) pour des sous-groupes de patients selon leur phénotype. RESULTATS: Le diagnostic déhypopituitarisme était le plus souvent réalisé pendant la période pubertaire et l'axe somatotrope était le plus fréquemment atteint (85,7%). L'hypopituitarisme était associé à des malformations extra hypophysaires pour 380 patients, 29,4% présentant un syndrome d'interruption de tige pituitaire (SIT) et 10,9% une anomalie ophtalmologique. Parmi les 934 cas index, la prévalence des anomalies géniques était de 7,9% (27,6% pour les 141 cas familiaux). Les patients avec phénotype hypophysaire pur présentatient 48 mutations (31 PROP1, 2 POU1F1 et 15 TBX19). Les anomalies identifiées pour les patients avec malformations extra hypophysaires comprenaient 9 causes géniques de SIT (3 LHX4, 4 HESX1 et 2 PROPK2), 1 mutation d'OTX2 chez un patient présentant une microphtalmie et 3 mutations de LHX3 dont une en contexte de surdité mais aucune présence d'anomalie de rotation du cou [ ]AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Copeptin assays in children for the differential diagnosis of polyuria‐polydipsia syndrome and reference levels in hospitalized children

International audienc

RAPID DIFFERENTIAL DIAGNOSIS OF POLYURIA-POLYDIPSIA SYNDROME IN CHILDREN: THE COPEPTIN APPROACH. A CASE REPORT

International audienc

RAPID DIFFERENTIAL DIAGNOSIS OF POLYURIA-POLYDIPSIA SYNDROME IN CHILDREN: THE COPEPTIN APPROACH. A CASE REPORT

International audienc

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

International audienceContextThe international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism.AimsTo describe main phenotype patterns and their evolution through life.DesignPatients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.ResultsAmong 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.ConclusionThis large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes

A 3.7 Mb deletion encompassing ZEB2 causes a novel polled and multisystemic syndrome in the progeny of a somatic mosaic bull

Polled and Multisystemic Syndrome (PMS) is a novel developmental disorder occurring in the progeny of a single bull. Its clinical spectrum includes polledness (complete agenesis of horns), facial dysmorphism, growth delay, chronic diarrhea, premature ovarian failure, and variable neurological and cardiac anomalies. PMS is also characterized by a deviation of the sex-ratio, suggesting male lethality during pregnancy. Using Mendelian error mapping and whole-genome sequencing, we identified a 3.7 Mb deletion on the paternal bovine chromosome 2 encompassing ARHGAP15, GTDC1 and ZEB2 genes. We then produced control and affected 90-day old fetuses to characterize this syndrome by histological and expression analyses. Compared to wild type individuals, affected animals showed a decreased expression of the three deleted genes. Based on a comparison with human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation. Finally sperm-FISH, embryo genotyping and analysis of reproduction records confirmed somatic mosaicism in the founder bull and male-specific lethality during the first third of gestation. In conclusion, we identified a novel locus involved in bovid horn ontogenesis and suggest that epithelial-to-mesenchymal transition plays a critical role in horn bud differentiation. We also provide new insights into the pathogenicity of ZEB2 loss of heterozygosity in bovine and humans and describe the first case of male-specific lethality associated with an autosomal locus in a non-murine mammalian species. This result sets PMS as a unique model to study sex-specific gene expression/regulation

Mapping and characterization of the causative mutation for PMS syndrome.

<p>(A) and (B) Results of Mendelian error mapping using the Illumina 50 K and 777 K SNP beadchips, respectively. Markers displaying Mendelian errors between at least one PMS heifer and her sire are represented in purple whereas markers for which at least one of the three PMS animals is heterozygous are represented in blue. Other markers are not represented. (C) Plot of the whole-genome sequencing read depth coverage on the same region. *: artifact due to a local error in genome assembly. (D) Gene content of the region. (E) FISH-mapping with BAC clones located in the deleted region (labeled in red) and in the juxtacentromeric region of BTA2 (labeled in green) on fibroblasts of a PMS animal. (F) Magnification of (E) showing normal (above) and deleted (below) BTA2 chromosomes. (G) Genotyping of PMS using a three-primer PCR system (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049084#s3" target="_blank">methods</a>). Neg.: negative control.</p

Real-time PCR expression analyzes of the deleted genes in different affected tissues at 90 dpc.

<p><i>ZEB2</i>, <i>GTDC1</i>, <i>ARHGAP15</i> (exon13), and <i>KYNU</i> (absent from the deleted fragment) expression is measured in various tissues from wild type (+/+; black histograms) or mutant (+/−; white histograms) fetuses.</p

Clinical features of Polled and Multisystemic Syndrome.

<p>(A) Two-and-half-year old wild-type heifer that was mechanically dehorned when approximately one-year old. (B) Two-and-half-year old affected heifer. Note the slender build, the shaggy hair coat demonstrating the bad health condition, and the hypotonia of hind limbs. (C) Upper part of the skull of the same affected heifer. Note the absence of corneous growth, the ridge-shaped extra bone deposition along the frontal suture and the narrowness of the muzzle insertion. (D) On-farm performance testing statistics of affected (PMS) and wild-type half-sibs. Values expressed as: means ± standard deviation (number of observations). *p<0.05, **p<0.01 and ***p<0.001 versus wild-type half-sisters (Welch’s t-test). Weaning corresponds to 210 days of age. (E and F) Ovaries of the affected (+/−) heifer displayed in (B) and (C). (I) Ovary of a wild-type (+/+) matched control. (G and H, and J and K) Histological analyses of the ovaries displayed in (E) and (I) respectively. (H) and (K) are higher magnifications (X5.5) of (G) and (J). Note the numerous large lacunae surrounded by connective tissue and the absence of follicles in the ovary from the affected heifer. Follicles are surrounded with a green dotted line in the photography of the wild-type ovary. Scale bars represent 1 cm in (F), (E) and (I); 500 µm in (G) and (J); and 50 µm in (H) and (K).</p