hrp0095fc10.6 | GH and IGFs | ESPE2022

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 genes/associated pathways account for mild-moderate to severe GHI cases. We report twin brothers from a non-consanguineous kindred who present with short stature and bi-allelic mutations in QSOX2 encoding the nuclear m...

hrp0095p1-44 | Diabetes and Insulin | ESPE2022

Characterisation of Type 2 Diabetes mellitus in children and young people across 2 large tertiary Paediatric Diabetes centres

Chatterjee Sumana , Baioumi Alaa , Pryce Rebekah , Williams Georgina , Giri Dinesh

Introduction: The prevalence of paediatric Type 2 diabetes (T2DM) is increasing, contributed by rising incidence of obesity worldwide. Paediatric T2DM is a progressive disease with increased risk of complications and morbidities. Despite recent research, many aspects such as its pathophysiology and optimal management remain unknown.Aim: To characterise the cohort of T2DM patients across 2 large tertiary paediatric diabet...

hrp0089lb-p1 | Late Breaking P1 | ESPE2018

A Second Growth Hormone Receptor Pseudoexon Mutation Causing Frameshift and Severe Postnatal Growth Failure

Cottrell Emily , Maharaj Avinaash , Chatterjee Sumana , Grandone Anna , Cirillo Grazia , del Giudice Emanuele Miraglia , Metherell Louise A , Storr Helen L

Background: Growth Hormone Insensitivity (GHI) is usually caused by mutations in the Growth Hormone receptor (GHR). Patients present with short stature associated with high GH and low IGF-I levels and often have midfacial hypoplasia (typical Laron syndrome facial features). Our centre previously described the first GHR pseudoexon mutation (42700896A>G, c. 618+792A>G). The inclusion of this 108bp pseudoexon is predicted to lead to in-frame insertion of...

hrp0095p1-101 | GH and IGFs | ESPE2022

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

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

Background: Pathogenic IGFI gene mutations causing childhood growth failure are rare. Only 5 autosomal recessive mutations, one IGFI copy number variant and 2 heterozygous frameshift mutations are reported. Heterozygous missense IGFI mutations have not previously been described.Objectives: To identify and functionally characterise a novel missense IGFI variant in a patient with postnat...

hrp0092rfc14.4 | Adrenals and HP Axis | ESPE2019

GHR Transcript Heterogeneity May Explain the Phenotypic Variability in Patients with Homozygous GHR Pseudoexon (6ψ) Mutation

Chatterjee Sumana , Rose Steven J , Mushtaq Talat , Cottrell Emily , Maharaj Avinaash V , Williams Jack , Savage Martin O , Metherell Loiuse A , Storr Helen L

Objectives: The homozygous GHR pseudoexon (6ψ) mutation leads to aberrant splicing of the GHR gene with clinical and biochemical heterogeneity. We investigated whether the phenotypic variability could be explained by transcript heterogeneity i.e. ratio of abnormal (6ψ GHR) to normal (WT GHR) transcripts and/or the presence of concurrent defects in other short stature (SS) genes.Methods: 6&#968...

hrp0094p2-287 | Growth and syndromes (to include Turner syndrome) | ESPE2021

Novel LZTR1 mutations in subjects with features of Noonan Syndrome and GH insensitivity negatively regulate GH-induced IGF-I production and hyperactivate GH-induced ERK1/2 activation in response to GH in vitro

Chatterjee Sumana , Romeo Bertola Debora , Agwu Chizo , Maharaj Avinaash , Williams Jack , Cottrell Emily , Shapiro Lucy , Andrews Afiya , Savage Martin O. , Gaston-Massuet Carles , Metherell Louise A. , Storr Helen L. ,

Background: Noonan Syndrome (NS) can overlap clinically and biochemically with growth hormone insensitivity [GHI; short stature (SS), low IGF-I and normal/elevated GH levels]. Mutations in multiple genes regulating RAS/MAPK pathway have been identified in NS including LZTR1 variants. Function of LZTR1 is poorly understood and its role in growth retardation is unknown.Objectives: To functionally characte...

hrp0089rfc10.1 | Late Breaking | ESPE2018

Patients with GH Insensitivity and IGF-1 Resistance Harbour Copy Number Variants Causing a Silver-Russell-Like Phenotype

Cottrell Emily , Chatterjee Sumana , Moore Gudrun , Ishida Miho , Greening James , Wright Neil , Bossowski Artur , Deeb Asma , Al Basiri Iman , Rose Steven , Mason Avril , Ahn Joowook , Bint Susan , Savage Martin , Metherell Louise A , Storr Helen L

Introduction: Our Centre is an international referral centre for genetic analysis of children with short stature (SS) and features of GH/IGF-1 resistance. Following candidate gene and whole exome sequencing, diagnoses for ~50% patients remained elusive. Copy number variation (CNV) has not previously been investigated in GH/IGF-1 resistance and we hypothesised that CNVs contribute to the phenotype in our undiagnosed cohort.Experimental Design and Methodol...

hrp0094p1-173 | Growth Hormone and IGFs B | ESPE2021

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

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

Context: Severe forms of growth hormone insensitivity (GHI) are characterised by extreme short stature, dysmorphism and metabolic anomalies. They are classically caused by homozygous or compound heterozygous mutations of the growth hormone receptor gene (GHR). Genetic analysis traditionally focuses on the exonic regions of genes that encode proteins rather than the intervening non-coding sequences. These seldom explored non-coding regions may harbour ...