hrp0092fc12.5 | Growth and Syndromes (to include Turner Syndrome) | ESPE2019

Integrated Analysis of Baseline Blood Transcriptome and Genome Identifies Clusters of Turner Syndrome Patients with Different Responses to Recombinant Human Growth Hormone

Sellers Robert , Amin Amina , Patel Kajal , Garner Terence , Whatmore Andrew , Koledova Ekaterina , Murray Philip , Chatelain Pierre , Clayton Peter , Stevens Adam

Responsiveness to recombinant human growth hormone (rhGH) treatment in Turner syndrome (TS) is highly variable. Previous research has characterised genetic variants associated with rhGH response but these only have a minor impact. The relationship of these genetic variants to the blood transcriptome is unknown. The aim of this analysis was to relate unsupervised baseline blood transcriptome and genetic data from TS patients to their phenotype, karyotype and responsiveness to r...

hrp0092fc12.6 | Growth and Syndromes (to include Turner Syndrome) | ESPE2019

An Integrated Systems Biology Analysis of the Genome, Epigenome and Transcriptome Identifies a Distinct Pattern of Hypermethylation Associated with Low Childhood Growth

Garner Terence , Sellers Robert , Guo Hui , Whatmore Andrew , Clayton Peter , Stevens Adam , Murray Philip

Background: Current data from genome wide association studies (GWAS) explains 24.6% of the variation in adult height from 3290 single nucleotide polymorphisms (SNPs)1. Data on the genetic control of growth velocity during childhood is more limited and no previous studies have linked childhood growth to changes in the transcriptome (gene expression) or epigenome (DNA methylation). Here we present a systems biology approach to understand mid-child...

hrp0092fc13.1 | Adrenals and HP Axis | ESPE2019

Peptide MC2R Antagonists as a New Potential Therapeutic Approach for Congenital Adrenal Hyperplasia

Schubert Tina , Nicke Lennart , Schanze André , Reisch Nicole , Geyer Armin , Koehler Katrin , Huebner Angela

Current hormone substitution therapy of patients with congenital adrenal hyperplasia (CAH) is suboptimal and cannot mimic physiological daily rhythms of hormone secretion. As supra-physiological corticoid doses are necessary to avoid adrenal androgen excess, patients show substantially increased comorbidities such as hyperglycemia, arterial hypertension, reduced growth and osteoporosis. Moreover plasma ACTH is often inadequately suppressed, resulting in undesired excess adrena...

hrp0092fc13.2 | Adrenals and HP Axis | ESPE2019

Sexual Dimorphism in Cortisol Production and Metabolism Throughout Pubertal Development: A Longitudinal Study

van Keulen Britt , Dolan Conor , van der Voorn Bibian , Andrew Ruth , Walker Brian , Boomsma Dorret , Hulshoff-Pol Hilleke , Rotteveel Joost , Finken Martijn

Background: Sex differences in disease susceptibility might be explained by a sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. The aim of this study is to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.Methods: Participants, born between 1995 and 1996, were enrolled from the population-based N...

hrp0092fc13.3 | Adrenals and HP Axis | ESPE2019

YAP1-HIPPO Pathway as a Novel Prognostic Marker and Therapeutic Target for Pediatric Patients with Adrenocortical Tumors (ACT)

More Candy Bellido , Bueno Ana Carolina , Castro Margaret , Antonini Sonir

Background: There is no effective adjuvant therapy for patients with advanced ACT. YAP1, a HIPPO pathway effector, interacts with Wtn\beta-catenin pathway and plays a crucial role in the maintenance of postnatal adrenal cortex and regulates cell proliferation and apoptosis in several tissues. We recently showed that overexpression of YAP1 associates with worse prognosis in our cohort of pediatric ACT (pACT).Aim: To analy...

hrp0092fc13.4 | Adrenals and HP Axis | ESPE2019

Biphasic Glucocorticoid Rhythm in One Month Old Infants: Reflection of a Developing HPA-Axis?

Hollanders Jonneke J. , de Goede Paul , van der Voorn Bibian , Honig Adriaan , Rotteveel Joost , Dolman Koert , Kalsbeek Andries , Finken Martijn J.J.

Background: The hypothalamus-pituitary-adrenal (HPA) axis displays a diurnal rhythm, peaking in the morning and with a nadir at night. However, not much is known about the development of the HPA- axis, although strikingly some evidence suggests that a rhythm with a peak in the afternoon is already present antenatally. We aimed to describe HPA-axis activity at age 1 month as well as study possible influencing factors.Methods</stro...

hrp0092fc13.5 | Adrenals and HP Axis | ESPE2019

SGPL1 Deficiency Leads to Downregulation of Key Enzymes Within the Steroidogenic Pathway

Maharaj Avinaash , Meimaridou Eirini , Williams Jack , Güran Tülay , Braslavsky Debora , Metherell Louise , Prasad Rathi

Background: SGPL1 deficiency is associated with a pathological accumulation of sphingolipid intermediates and a multi-systemic condition incorporating primary adrenal insufficiency. Sphingolipid intermediates such as ceramide, sphingosine and sphingosine 1-phosphate are postulated to act as modulators of the steroidogenic pathway, often acting as second messengers altering downstream expression of steroid responsive transcriptional elements. Ceramide and sphin...

hrp0092fc13.6 | Adrenals and HP Axis | ESPE2019

Insights Into the Role of Cortisol in the Formation of the Clock/Bmal1 Complex and its Interaction with dsDNA, via Molecular Dynamics Simulations

Nicolaides Nicolas , Raftopoulou Sofia , Kino Tomoshige , Vlachakis Dimitrios , Chrousos George

Background: The circadian rhythm-generating peripheral Clock/Bmal1 heterodimer complex regulates the circadian activities of many biological systems, including the hypothalamic-pituitary-adrenal (HPA) axis, by trans-activating or trans-repressing downstream target genes.Objective and Hypotheses: To investigate the potential role of elevated cortisol in Clock/Bmal1 heterodimer complex-generated circadian biorhythms, both ...

hrp0092fc14.1 | GH and IGF1 | ESPE2019

Inhibition of IGF1R by IGF1R/IR Inhibitor OSI906 as a Targeted Therapy for Glioblastoma: in vitro & in vivo Studies

Fernandez Maria Celia , Martin Ayelen , Clément Florencia , Venara Marcela , Fernanda Castro Julia , Lombardi Mercedes Garcia , Bergadá Ignacio , Pennisi Patricia

Background: CNS tumours are the most frequent solid tumours in children. In pediatric gliomas, IGF1R nuclear localization was significantly associated with both high grade tumours and increased risk of death and contributed to the aggressive phenotype of glioblastoma by increasing motility and metabolism of tumour cells rather than increasing its proliferation. For children chemotherapy after surgical resection is the mainstay of therapy. However, the best reg...

hrp0092fc14.2 | GH and IGF2 | ESPE2019

Pubertal Onset in 1572 Girls with Short, Normal and Tall Stature: Associations to Height, Serum IGF-I and PAPP-A2 Genotypes

Upners Emmie N , Busch Alexander S. , Almstrup Kristian , Petersen Jørgen Holm , Main Katharina , Jensen Rikke Beck , Juul Anders

Background: Sexual maturation is closely linked to growth, suggesting common pathways between the reproductive development and the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. IGF-I bioavailability is regulated by Pregnancy associated plasma protein-A (PAPP-A), Pregnancy associated plasma protein-A2 (PAPP-A2) and Stanniocalcin 2 (STC2). A large genome-wide association study (GWAS) identified PAPP-A, PAPP-A2 and STC2 to represent loci strongly a...