Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4–5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

none42siTo assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.Nowotny, Hanna; Neumann, Uta; Tardy-Guidollet, Véronique; Ahmed, S Faisal; Baronio, Federico; Battelino, Tadej; Bertherat, Jérôme; Blankenstein, Oliver; Bonomi, Marco; Bouvattier, Claire; Brac de la Perrière, Aude; Brucker, Sara; Cappa, Marco; Chanson, Philippe; Claahsen-van der Grinten, Hedi L; Colao, Annamaria; Cools, Martine; Davies, Justin H; Dörr, Helmut-Günther; Fenske, Wiebke K; Ghigo, Ezio; Giordano, Roberta; Gravholt, Claus H; Huebner, Angela; Husebye, Eystein Sverre; Igbokwe, Rebecca; Juul, Anders; Kiefer, Florian W; Léger, Juliane; Menassa, Rita; Meyer, Gesine; Neocleous, Vassos; Phylactou, Leonidas A; Rohayem, Julia; Russo, Gianni; Scaroni, Carla; Touraine, Philippe; Unger, Nicole; Vojtková, Jarmila; Yeste, Diego; Lajic, Svetlana; Reisch, NicoleNowotny, Hanna; Neumann, Uta; Tardy-Guidollet, Véronique; Ahmed, S Faisal; Baronio, Federico; Battelino, Tadej; Bertherat, Jérôme; Blankenstein, Oliver; Bonomi, Marco; Bouvattier, Claire; Brac de la Perrière, Aude; Brucker, Sara; Cappa, Marco; Chanson, Philippe; Claahsen-van der Grinten, Hedi L; Colao, Annamaria; Cools, Martine; Davies, Justin H; Dörr, Helmut-Günther; Fenske, Wiebke K; Ghigo, Ezio; Giordano, Roberta; Gravholt, Claus H; Huebner, Angela; Husebye, Eystein Sverre; Igbokwe, Rebecca; Juul, Anders; Kiefer, Florian W; Léger, Juliane; Menassa, Rita; Meyer, Gesine; Neocleous, Vassos; Phylactou, Leonidas A; Rohayem, Julia; Russo, Gianni; Scaroni, Carla; Touraine, Philippe; Unger, Nicole; Vojtková, Jarmila; Yeste, Diego; Lajic, Svetlana; Reisch, Nicol

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of CAH due to 21-hydroxylase deficiency. Design and Methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36 % of the surveyed centres. The treatment is initiated by different specialties i.e. paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23 % stated to initiate therapy at 4 to 5 weeks post conception (wpc), 31 % at 6 wpc, and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/d is used. Dose distribution among the centres varies between once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72 % of the responding centres. Cases treated per country and year vary between 0.5 to 8.25. Registries for long-term follow-up are only available at 46 % of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy on the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence based guidelines on prenatal diagnostics, treatment and follow up of pregnancies at risk for CAH

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting &gt;500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (&gt;50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.</p

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Detection of structural variants (SVs) is currently biased towards those that alter copy number. The relative contribution of inversions towards genetic disease is unclear. In this study, we analysed genome sequencing data for 33,924 families with rare-disease, from the 100,000 Genomes Project. From a database hosting &gt;500 million SVs, we focussed on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24bp to 36.4Mb, 20/47 de novo). Validation utilised a number of orthogonal approaches, including retrospective exome analysis. RNAseq data supported the respective diagnoses for 6 participants. Phenotypic blending was apparent in 4 probands. Diagnostic odysseys were a common theme (&gt;50 years for one individual) and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving 9 rearranged segments, confirmed a clinical diagnosis for 3 family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare-disease, likely explaining the aetiology in around 1/750 families across heterogeneous clinical cohorts