Title: Early Recognition, Diagnosis and Treatment of True Pathological Short Stature (TPSS) in Children
Funder: Department of Health and Social Care

Abstract: Research question How can we optimise the diagnosis, recognition and referral of suspected true pathological short stature (TPSS) in children? BackgroundImpaired growth is a critical but under-recognised early marker of major childhood disease. True pathological short stature (TPSS) can reflect a wide range of conditions including primary genetic/chromosomal, growth axis defects, developmental disorders and skeletal dysplasias and may be an indicator serious systemic disease (endocrine, inflammatory, neoplastic etc). In the UK, screening, investigation and diagnosis of TPSS is inconsistent and not evidence-based. Early detection and appropriate therapy mitigates effects of any underlying disease, optimises general health, maximises height potential and improves quality of life. East London has significant childhood poverty and high prevalence of short stature/parental consanguinity, presenting an ideal population in which to explore screening/management pathways and explore novel genetic causes and mechanisms of growth failure.Key aims Transform the care of childhood TPSS by placing our novel next generation genetic pipeline at the centre of the management algorithm Use data from our pipeline to identify novel conditions and enhance understanding of the genetic and molecular mechanisms underlying short stature and to identify new therapeutic targets Develop an evidence-based screening and diagnostic algorithm, to be piloted in East London Methods Test our novel GRASP genetic testing pipeline on ~712 patients from local, national and international referral bases Extended genetic/molecular pathway analysis of TPSS patients to expand panel of known genetic defects, evaluate disease mechanisms and identify novel therapeutic targets Detailed genotype-phenotype characterisation of a large cohort of TPSS patients to develop novel phenotypically-tailored investigation protocols and validate these in a novel growth assessment clinic Collaborative analysis of national data to evaluate the prevalence of growth failure and identify regional TPSS 'hotspots' Develop an 'automated' short stature screening algorithm and pilot in East London before wider implementation (parallel but separately funded work)Timelines for delivery (75% TPSS patients. Functional work underway. Retrospective analysis of current practice complete and growth clinic established. Data acquired on local and national growth failure prevalence. Preliminary growth screening algorithm developed. (2-5 years): Pilot algorithm in East London population. Optimal screening and investigative algorithm validated and published. Novel gene defects and disease mechanisms described. (>5 years): Long term data on growth management interventions, inform changes to health care policy. Novel therapeutic targets. PPI and dissemination My PPI scoping exercise identified rapid diagnosis/management as key priorities in TPSS families. Pre-existing lay panels will advise all stages of research to ensure that aims remain focussed on meeting patients' needs. Findings widely disseminated via: our GRASP website, public media, patient groups/newsletters/website, science festivals, scientific meetings and publications. Anticipated Impact This programme will deliver a comprehensive strategy for TPSS management, from population screening to genetic diagnosis to targeted therapy. Strategies piloted and validated locally and will inform national and international guidelines and future health economic policy. The extensive collated genetic material will provide a rich resource for novel genetic and molecular therapeutic discoveries, generating a stream of impactful publications.

Lay abstract: Growth is an excellent marker of childhood health and well-being. Failure of normal childhood growth is called True Pathological Short Stature (TPSS). TPSS is often the first indicator of serious disease and its early detection is critical (not unlike high cholesterol or blood pressure in adults). TPSS has many potential causes ranging from inherited genetic disorders, impaired foetal growth, hormonal disorders, inflammatory diseases and cancer. Treatments vary for each. Rapid detection of TPSS and diagnosis of its underlying cause allows early access to the best treatment(s), minimising the impact of the disease and ensuring optimal adult height with proven improvements in adult health and quality of life e.g. reducing the risk of adult diabetes and high cholesterol.Although environment can affect growth, most of the difference in height between individual humans is determined by their genetic make-up. We know of many different genetic faults that can cause TPSS, but currently in the UK, a gene defect is found in only a small proportion of children with TPSS.Over the last decade, my team at Bart's Health has been finding genetic faults in short children. We have built our 'GRASP' (Genetic Research Analysing Short Patients) genetic testing pipeline centred on our unique short stature 'gene panel' and to date have fully tested blood samples from 150 short children. We check each patient's DNA against all known genes and currently we detect a likely genetic cause in 69%. Previously the best rates of genetic diagnosis were around 20%.My team has already identified several new 'growth' genes. By studying the way these new genetic defects cause growth failure, we expect to find new ways to treat growth disorders. Each new defect discovered is then added to our gene panel, progressively improving future pick-up rates. If this technique can be offered for all children, it will transform the management of TPSS. Currently in the UK, routine screening for poor growth is inadequate in school age children and non-existent in preschool children. As a consequence, many short children have delayed diagnosis or unrecognised TPSS and suffer as a result. Unlike many other childhood diseases, there are currently no standard guidelines for the management of TPSS and UK practices vary widely. Part of our study will focus on the screening and investigation of growth disorders in East London children.We will examine how clinical features and test results can help predict the underlying genetic cause of growth failure. This will allow us to develop a clear and consistent care pathway so that all children get the best management. East London is an area of significant deprivation with high rates of childhood poverty and consanguinity (family intermarrying causing higher rates of genetic disease in offspring) making this an ideal population in which to study TPSS.This is an ambitious 3-part proposal which aims to transform the care of short children in East London and the UK. Key research aims 1. Transform the investigation and management of children with TPSS by placing our specialist GRASP genetic testing pipeline at the centre of patient care2. Use data from our genetic pipeline to identify novel growth disorders, enhance the understanding of the genetic mechanisms underlying growth failure and identify new potential therapies 3. Develop an evidence-based screening and diagnostic processes, to be piloted in East LondonPatients and the public will be involved at all stages, so that research stays focused on what really matters to patients and families. Important findings will be disseminated online and via public and social media, patient groups, science festivals as well as scientific meetings and publications.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: DISPUTED AETIOLOGY AND OTHER