Searchable abstracts of presentations at key conferences in endocrinology

ea0085oc1.1 | Oral Communications 1 | BSPED2022

Defects in QSOX2, a novel regulator of STAT5B nuclear import and transcriptional activity, lead to severe post-natal growth restriction

Maharaj Avinaash , Andrews Afiya , Chatterjee Sumana , Hwa Vivian , Storr Helen

Background: Growth Hormone Insensitivity (GHI) is characterised by short stature and functional IGF-I deficiency associated with normal/elevated GH levels. Marked genetic and phenotypic heterogeneity exist, and heritable defects in GH-IGF-I axis associated pathways account for mild-moderate to severe GHI. We report non-consanguineous twin brothers who present with short stature and bi-allelic mutations in QSOX2 encoding a nuclear membrane protein. Genome-wide associat...

ea0074oc1 | Oral Communications | SFENCC2021

A rare heterozygous IGFI variant causing postnatal growth failure and offering novel insights into IGF-I physiology

Cottrell Emily , Chatterjee Sumana , Hwa Vivian , Storr Helen L.

Section 1: Case history: A 10-year-old girl presented with significant postnatal growth failure. Her birth weight was normal (–0.15SDS) but poor growth was observed from a few months of age. She had no other symptoms. On examination, height was –3.4SDS and head circumference –1.6SDS. She had no dysmorphic features and normal development. Section 2: Investigations: Baseline serum analyses were unremarkable. Karyotype was normal (46XX). Bone age was delayed by 2.5...

ea0085p46 | Pituitary and Growth 1 | BSPED2022

A rare heterozygous IGFI variant impairing IGF-I cleavage and causing postnatal growth failure: a novel disease mechanism offering insights into IGF-I physiology

Cottrell Emily , Andrews Afiya , Williams Jack , Chatterjee Sumana , Edate Sujata , Metherell Louise A. , Hwa Vivian , Storr Helen L.

Background: Pathogenic IGFI gene mutations causing childhood growth failure are extremely rare. Only five autosomal recessive mutations, one IGFI copy number variant and two heterozygous frameshift mutations are reported. Heterozygous missense IGFI mutations haven’t previously been described.Objectives: To identify and functionally characterise a novel missense IGFI variant in a patient with postnatal growth failu...

ea0039oc5.3 | Oral Communications 5 | BSPED2015

Dominant negative STAT5B variants in two families with mild GH insensitivity and eczema

Pease-Gevers Evelien , Klammt Jurgen , Andrew Shayne , Kowalczyk Julia , Metherell Lou , Neumann David , Dattani Mehul , Hwa Vivian

Background: Homozygous mutations in STAT5B result in GH insensitivity and immune dysfunction. Heterozygous dominant negative mutations have not been described.Aims and objectives: To assess STAT5B sequence in children selected for a phenotype suggestive of Stat5b deficiency. To further characterize genomic STAT5B variants in two families.Methods: Selection of children from a tertiary Paediatric Endocrine ...

ea0066p73 | Pituitary | BSPED2019

Three novel Growth Hormone Receptor (GHR) splicing mutations causing a spectrum of Growth Hormone Insensitivity

Cottrell Emily , Maharaj Avinaash , Ladha Tasneem , Chatterjee Sumana , Grandone Anna , Cirillo Grazia , del Giudice Emanuele Miraglia , Kostalova Ludmila , Vitariusova Eva , Hwa Vivian , Metherell Louise A , Storr Helen L

Introduction: Growth Hormone Insensitivity (GHI) is characterised by a triad of short stature (SS), IGF-1 deficiency and normal/high GH levels. ‘Classical’ GHI due to homozygous exonic GHR mutations results in extreme SS with dysmorphic and metabolic abnormalities. Heterozygous exon 9 GHR mutations are rare and exert dominant negative effects due to impairment of GHR dimerization/downstream signalling associated with a milder GHI phenotype. Only sev...

ea0030p8 | (1) | BSPED2012

The effect of homozygosity versus heterozygosity for IGFALS gene mutations on growth, bone strength and insulin resistance

Hogler Wolfgang , Martin David , Crabtree Nicola , Barrett Timothy , Frystyk Jan , Tomlinson Jeremy , Metherell Lou , Rosenfeld Ron , Hwa Vivian , Rose Stephen , Walker Joanna , Shaw Nick

Background: Acid-labile subunit (ALS) deficiency inhibits ternary complex formation leading to primary IGF1 deficiency and short stature. Potential metabolic consequences such as diabetes and low bone mass are not well studied.Objective: This study measured insulin sensitivity, lipid profile, bone density and structure in members of 4 affected families and explore possible gene-dose effects.Methods: Four patients (7–21 years) ...

ea0078oc4.3 | Oral Communications 4 | BSPED2021

Growth hormone receptor 6Ω pseudoexon activation: a novel cause of severe growth hormone insensitivity

Cottrell Emily , Maharaj Avinaash , Williams Jack , Chatterjee Sumana , Cirillo Grazia , del Giudice Emanuele Miraglia , Festa Adalgisa , Palumbo Stefania , Capalbo Donatella , Salerno Mariacarolina , Pignata Claudio , Savage Martin O. , Schilbach Katharina , Bidlingmaier Martin , Hwa Vivian , Metherell Louise A. , Grandone Anna , Helen L. Storr

Context: Severe or ‘classical’ growth hormone insensitivity (GHI) is characterised by extreme short stature, dysmorphism and metabolic anomalies. It is caused by homozygous or compound heterozygous mutations of the Growth Hormone Receptor gene (GHR). Genetic analysis traditionally focuses on the exonic regions of gene(s). The non-coding regions of the genome may harbour numerous disease-causing mutations that are not well recognised or understood.<p clas...

ea0085p44 | Pituitary and Growth 1 | BSPED2022

Understanding the molecular basis of short stature in six patients with pathogenic variants in HMGA2

Maharaj Avinaash , Cottrell Emily , van Duyvenvoorde Hermine , de Bruin Christiaan , Joustra Sjoerd , Kant Sarina , van der Kaay Danielle , Inmaculada Castilla de Cortazar Larrea Maria , Massoud Ahmed , Metherell Louise , Hwa Vivian , Hombach-Klonisch Sabine , Klonisch Thomas , Storr Helen

Background: Silver-Russell syndrome (SRS) is a unique disorder characterised by characteristic features and growth restriction due to 11p15 LOM or upd(7)Mat in ~60% cases. Monogenic defects are a rare cause of SRS and HMGA2 mutations have been identified in 4 cases to date. The function of HMGA2 is poorly understood.Objectives: Assess the clinical phenotypes of 6 new patients with novel heterozygous HMGA2 defects and evaluate t...

ea0085oc8.3 | Oral Communications 8 | BSPED2022

Characterisation of the first heterozygous missense HMGA2 variant helps delineate the crucial functional roles of a novel growth gene

Cottrell Emily , Maharaj Avinaash , Triggs-Raine Barbara , Thanasupawat Thatchawan , Williams Jack , Fujimoto Masanobu , A. Van Duyvenvoorde Hermine , De Bruin Christiaan , Joustra Sjoerd , Kant Sarina , Van der Kaay Danielle , Inmaculada Castilla de Cortazar Larrea Maria , Massoud Ahmed , Metherell Louise A , Hwa Vivian , Hombach-Klonisch Sabine , Klonisch Thomas , Storr Helen L.

Background: Silver Russell syndrome (SRS) is genetically heterogenous and around 30% of patients with clinical SRS have no genetic diagnosis. Point mutations in HMGA2 have been reported in 4 patients worldwide causing growth failure and an SRS-like phenotype. Despite strong evidence of the crucial role of HMGA2 in growth across species, the mechanism of action of HMGA2 in human linear growth is unclear.Objective: Identify and f...