ESPE Abstracts

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...

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...

Background: Hypothalamic obesity (HO), defined as abnormal weight gain due to physical hypothalamic destruction, for example due to suprasellar tumours, is characterised by significant hyperphagia, lack of satiety, and rapid weight gain in the first year of hypothalamic insult. HO is not usually responsive to caloric restriction or lifestyle modification, and no pharmacotherapies are specifically approved for treating HO. GLP-1 agonists, which suppress appetit...

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...

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...

Background: Noonan syndrome (NS) is caused by variants in multiple genes regulating the RAS/MAPK signalling cascade. NS can present with growth failure associated with growth hormone insensitivity (GHI; low IGF-I and normal/elevated GH levels). Variants in LZTR1 lead to NS, although the interaction of LZTR1 with the RAS/MAPK and the GH-IGF-1 pathways remain to be elucidated.Objectives: To gain insights into the ...

Background: The underlying pathogenic mechanisms governing growth restriction of Noonan syndrome (NS) remain elusive. Monoallelic inactivating LZTR1 gene variants have been implicated as a cause of NS due to hyperactivation of the canonical RAS-MAPK signalling pathway. Missense LZTR1 variants have been associated with defective ubiquitination theoretically leading to increased Ras substrate availability. Ubiquitination is implicated in growth...

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...

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...

Background: Whilst recent systematic reviews have suggested potential benefits to exercise interventions on metabolic outcomes for children and young people (CYP) living with obesity, there is a lack of studies examining the qualitative experiences of CYP as to exercise provision within obesity services. It is reported that weight stigma has a negative impact on self-esteem which may be a barrier to participating in physical activity. We describe the experienc...