A child’s failure to grow can be the first sign of a serious underlying disease, yet the UK has no consistent, evidence-based system for spotting it. This project will place a new genetic testing pipeline—called GRASP—at the centre of how doctors diagnose true pathological short stature (TPSS), testing it on roughly 712 children from local, national, and international referrals. The problem is that short stature is often dismissed or investigated haphazardly, delaying treatment for conditions ranging from genetic syndromes to inflammatory disease. East London, with high rates of childhood poverty and consanguinity, offers an ideal population to develop and pilot a screening algorithm. The team will also use genetic data to discover new disease-causing genes and molecular mechanisms, potentially identifying novel therapeutic targets. If successful, this work will transform TPSS care from inconsistent referral to a streamlined, evidence-based pathway—from population screening through genetic diagnosis to targeted therapy. The validated algorithm could inform national guidelines and health policy, while the genetic resource will fuel fundamental discoveries about growth failure for years to come.
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Research question How can we optimise the diagnosis, recognition and referral of suspected true pathological short stature (TPSS) in children? Background Impaired 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.
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