Growth is a strong indicator of health and well-being in children, but delays in the diagnosis of growth disorders are common in the UK. We spoke to Helen L. Storr, Professor of Paediatric Endocrinology at Queen Mary University of London, about her research on growth disorders in children.
Helen L. Storr, Professor and Honorary Consultant in Paediatric Endocrinology
In this Q&A, Professor Storr highlights the significance of genetic testing and the potential life changing outcomes her research offers to children and families affected by growth disorders.
Can you provide an overview of your clinical practice and your key clinical interests in paediatric endocrinology, including growth disorders in children?
Alongside my academic role, I am a consultant paediatric endocrinologist at Barts Health NHS Trust. I look after children with a range of hormone problems. It is a fascinating speciality because we diagnose and manage a wide spectrum of conditions. We see patients of all ages for example new-borns who are small for gestational age or with congenital problems to young adults who have not grown adequately or have delayed puberty.
My major interest is growth disorders and I receive referrals from all over the UK. Childhood growth is a fundamental marker of health and well-being. Impaired growth can indicate a wide range of serious underlying diseases or other problems, but the signs are often missed and delay in detection, referral and diagnosis can have major health implications.
Could you share some insights into the current projects your team is working on?
The overarching research focus of my group is improving the recognition and diagnosis of growth disorders in children. Our projects are wide ranging and complementary. They include growth screening in pre-school children, enhancing the genetic diagnosis of growth disorders and seeking new genes and molecular mechanisms that underlie growth failure. We recently developed a novel ‘GrowthMonitor’ app that can be used by parents or healthcare professionals to measure children, monitor their growth, and flag abnormal growth patterns.
You lead an international genetic testing research program for patients with undiagnosed short stature. Could you explain the significance of this program and the goals you hope to achieve through it?
Human height is a highly heritable, polygenic trait; with 80-90% variation determined by genetic factors. Family studies also show that gene defects play a pivotal role in short stature. It is estimated that more than 35% growth disorders have a genetic basis.
Concerns about growth is one of the commonest reasons for children to be referred to our clinics but <20% UK children with short stature reach clear diagnosis. Therefore, enhanced genetic testing and better stratification of growth disorders is a fundamental unmet need.
The aim of our genetic testing programme is to offer a genetic diagnostic pipeline for children with undiagnosed short stature, improve the diagnostic yield and identify new mechanisms of growth failure. We are one of the only groups in the world undertaking research in this field. Very few research groups have the expertise and infrastructure to undertake genetic testing, bioinformatic analysis and confirmatory functional studies.
A genetic diagnosis has many important patient benefits as it may change the treatment strategy. Work in this field is essential to better understand the pathogenesis of these complex, multisystem disorders and develop new therapies.
Your group has developed unique next-generation sequencing pipelines for genetic testing in patients with short stature. How does this technology work, and how has it impacted the diagnosis and treatment of individuals with growth disorders?
The aim was to create a universally accessible genetic diagnostic pipeline for undiagnosed short stature patients, which would evolve to incorporate the latest genetic discoveries, and rapidly secure a diagnosis for the majority of children referred. This was alongside a coordinated programme of research into novel genetic defects and disease mechanisms which would potentially identify new causes of growth failure and therapeutic targets.
In 2017, we developed a novel next generation sequencing short stature gene panel, which would simultaneously test the coding and non-coding regions (intronic/regulatory regions) of 65 short stature genes. This was central to our ‘GRASP’ (Genetic Research Analysing Short Patients) pipeline which also comprised further advanced techniques of whole exome sequencing and copy number variant analysis. This pipeline is continually evolving, and we recently introduced whole genome sequencing.
What are some of the key findings or breakthroughs that your research has produced in the field of growth disorders in children?
Genetic analysis in our cohort of >200 highly selected undiagnosed short stature patients has revealed a diagnosis/putative diagnosis in ~65% children. This is much higher than NHS testing panels which currently secure a diagnosis in <10% patients.
Our wide-ranging publications include novel insights into genotype-phenotype correlations of specific genetic disorders, novel molecular mechanisms and genetic causes of short stature, and expansion of the phenotypic spectrum of several growth conditions. Achieving firm diagnoses and a deeper understanding of disease mechanisms in previously undiagnosed cases has enabled the evidence-based use of appropriate, often expensive therapies e.g., growth hormone. We have observed many patients exhibiting milder phenotypes than previously described and shown significant overlap in clinical features between the conditions, suggesting that traditional clinical diagnostic scoring systems may need re-evaluation.
Importantly, our pipeline directly impacts patient care. As well as identifying children who would benefit from growth promoting therapies, it confirmed unexpected gene defects in children known to cause skeletal dysplasia (with risk of bone fractures), Fanconi anaemia and Bloom syndrome (risk of malignancy and a contraindication for growth hormone therapy) and Glycogen Storage Diseases (neurodevelopmental delay, liver disease, hypoglycaemia).
In 2017, we launched the GRASP website to promote of our work. It was shaped by patient/family feedback and provides a bidirectional portal for receiving clinical referrals and for disseminating research update information to clinicians and the public.
As a medical advisor for the Child Growth Foundation (CGF), could you tell us more about the foundation's mission and your role in supporting it?
The Child Growth Foundation (CGF) is the largest UK charity supporting children, adults and families affected by rare growth conditions. One of their key priorities is achieving rapid, accurate diagnosis so that patients and families can access appropriate therapy. Their mission aligns well with our research goals.
As a key medical advisor over the last 5 years, I am actively involved in many of their activities. I provide the CGF with support and advice for parents and families who contact them with queries or concerns. I am also involved in the annual members congress, helping with the organisation of the programme and I attend to give talks and run sessions. In-between, I facilitate on-line Q and A sessions with parents and patients, contribute to their three times a year newsletter and the content of their website. I am currently advising them on some planned awareness campaigns. As part of this, I recently took part in an X (previously Twitter) ‘take over’ for Children’s Growth Awareness Week. Future activities include organising information days in harder to reach areas and teaching for primary care healthcare professionals with the Royal College of General Practitioners.
In what ways do you envision your research improving the lives of children and families affected by growth disorders?
My paediatric endocrinology growth clinic has a strong growth emphasis and allows our research to be rapidly translated into clinical practice. My research also impacts national practice. As Chair and founder member of the British Society of Paediatric Endocrinology and Diabetes (BSPED) Growth Disorders Special Interest Group over the last 3 years, I have led on several important position statements and clinical standards documents to standardise and improve the care of childhood growth disorders.
The early recognition and diagnosis of growth problems in children is essential to optimally treat poor growth, initiate educational support and allow screening for any other associated serious complications. Our work aims to increase the understanding of the molecular basis of growth and enhance the diagnosis, prognosis, and treatment of severe short stature. Work in this field is essential to better understand the pathogenesis of these complex, multisystem disorders and develop new therapies.