Eloïse Giabicani

This international Consensus Statement updates 2016 guidelines for diagnosis and management of individuals with Silver–Russell syndrome (SRS), using a Delphi-like process to reach agreement through iterative expert discussions, based on published data and/or expert opinion. Individuals referred with suspected SRS show substantial clinical and genetic heterogeneity. Advances in genomic and epigenomic technology highlight the need for strict, primarily molecular, criteria for diagnosis, which should be made in those with maternal uniparental disomy for chromosome 7 (upd(7)mat) or 11p15 loss of methylation at H19/IGF2:intergenic differentially methylated region (IG-DMR) (due to an imprinting change, copy number variant or upd(11)mat). Molecular stratification enables tailoring of care pathways towards specific genetic and/or epigenetic subgroups. More widely, recommendations are relevant to other growth-related imprinting disorders (including Temple syndrome) and conditions affecting the insulin-like growth factor 2 pathway. An expert, multidisciplinary approach is required, focusing on growth failure, early severe feeding difficulties, later possible rapid weight gain, abnormal body composition, gastrointestinal problems, hypoglycaemia, insulin resistance, accelerated puberty, body asymmetry, neurocognitive issues and psychosocial challenges. Evidence published since the first Consensus Statement highlights the increased risk of metabolic disease from adolescence into adulthood. These updated recommendations have important implications for accurate diagnosis and optimal life-long management of individuals with SRS.

In humans and other diploid organisms, autosomal genes are typically expressed from both parental alleles at equivalent levels. However, certain genes exhibit preferential monoallelic expression fr...

La croissance fœtale est sous la dépendance de nombreux facteurs environnementaux, génétiques et hormonaux dont les interactions vont en conditionner le bon déroulement. Le système des insulin-like growth factors (IGFs) joue un rôle prépondérant, à l’interface de ces différents facteurs, pour assurer une bonne croissance fœtale. Dans ce travail, nous nous sommes intéressés aux différents acteurs du système des IGFs dans des pathologies de la croissance fœtale. Dans une approche clinique et expérimentale, nous avons décrit les conséquences fonctionnelles d’anomalies génétiques ou épigénétiques intéressant IGF-I, IGF-II et leur récepteur commun IGF1R. Ainsi, nous avons mis au point un test fonctionnel permettant d’apprécier l’activité in vitro d’IGF1R chez les patients présentant une restriction de croissance fœtale et postnatale. Nous avons également documenté la biodisponibilité d’IGF-I chez des patients présentant un syndrome de Silver-Russell, qui est une pathologie liée à l’empreinte parentale responsable d’une restriction de croissance à début ante-natal. Enfin, nous avons caractérisé le chevauchement clinique et moléculaire entre les patients présentant un SRS ou un syndrome de Temple (autre pathologie liée à l’empreinte parentale), confirmant le rôle prépondérant du défaut d’expression d’IGF2 dans ces deux syndromes. Ces résultats confirment un fonctionnement des gènes soumis à empreinte en réseau et le rôle majeur du système des IGFs dans la croissance fœtale, particulièrement altérée en cas de pathologie intéressant ces gènes soumis à empreinte parentale.

Background: Endocrine science remains underrepresented in European Union research programs despite the fundamental role of hormone health in human wellbeing. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritization. At the national funding level, endocrine societies report limited or little attention of national research funding toward endocrinology. The EndoCompass project—a joint initiative between the European Society of Endocrinology and the European Society of Pediatric Endocrinology, aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges. Methods: Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014-2020). Expert consultation in growth disorders was conducted to identify key research priorities, followed by broader stakeholder engagement, including society members and patient advocacy groups. Results: Research priorities encompass genetic diagnosis of growth disorders; growth plate-targeted therapies; molecular mechanisms of Silver-Russell syndrome and imprinting disorders; hypothalamic dysfunction in Prader-Willi syndrome; and characterization of Noonan syndrome and tall stature conditions. Emphasis is placed on creating disease registries to facilitate outcome studies and developing precision therapeutics based on growth regulation pathways. Conclusions: This component of the EndoCompass project provides an evidence-based roadmap for strategic research investment. This framework identifies crucial investigation areas into growth disorder pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society. The findings support the broader EndoCompass objective of aligning research funding with areas of highest potential impact in endocrine health.

Context: Silver-Russell syndrome (SRS) is an imprinting disorder characterized by severe intrauterine and postnatal growth retardation, feeding difficulties, and risk of hypoglycemia. Recombinant growth hormone (rGH) therapy has shown its positive effect on adult height in SRS. Objective: We aimed to assess the short-term effects of rGH therapy on the growth and nutritional status of these children. Methods: Retrospective monocentric data of growth and nutritional characteristics of 77 prepubertal children with molecularly proven SRS during the first 2 years of rGH therapy were analyzed. Results: The mean age at the initiation of rGH therapy was 3.7 (1.4-10.3) years. The mean height gain was 0.8 standard deviation score (SDS) after 1 year of treatment and 1.3 SDS after 2 years. The ideal weight for height (WfH), reflecting the nutritional status, increased from a mean of 81% at rGH initiation, to 84% after 1 year of treatment (P < .001) and 86% after 2 years (P < .001). The proportion of SRS children below a WfH of 75% decreased from 22.1% at rGH therapy initiation to 7.8% after 2 years of treatment. Starting rGH therapy before the age of 4 years was associated with a greater increase in height after 2 years, 1.5 vs 1.1 SDS, P = .012. Conclusion: In prepubertal SRS children, the first 2 years of standard-dose rGH therapy significantly enhance both height and nutritional status. Early initiation of treatment, before the age of 4 years, further optimizes height gain.

Eloïse Giabicani, Amélie Perrière, Irène Netchine; Silver-Russell Syndrome in 2025: Is It Still a Distinct Diagnostic Entity?, The Journal of Clinical Endo

In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver–Russell and Beckwith–Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

Parental imprinting is an epigenetic process leading to monoallelic expression of certain genes depending on their parental origin. Imprinting diseases are characterized by growth and metabolic issues starting from birth to adulthood. They are mainly due to methylation defects in imprinting control region that drive the abnormal expression of imprinted genes. We currently lack relevant animal or cellular models to unravel the pathophysiology of growth failure in these diseases. We aimed to characterize the methylation of imprinting regions in dental pulp stem cells and during their differentiation in osteogenic cells (involved in growth regulation) to assess the interest of this cells in modeling imprinting diseases. We collected dental pulp stem cells from five controls and four patients (three with Silver-Russell syndrome and one with Beckwith-Wiedemann syndrome). Methylation analysis of imprinting control regions involved in these syndromes showed a normal profile in controls and the imprinting defect in patients. These results were maintained in dental pulp stem cells cultured under osteogenic conditions. Furthermore, we confirmed the same pattern in six other loci involved in imprinting diseases in humans. We also confirmed monoallelic expression of H19 (an imprinted gene) in controls and its biallelic expression in one patient. Extensive imprinting control regions methylation analysis shows the strong potential of dental pulp stem cells in modeling imprinting diseases, in which imprinting regions are preserved in culture and during osteogenic differentiation. This will allow to perform in vitro functional and therapeutic tests in cells derived from dental pulp stem cells and generate other cell-types.