Title: Is Growth Hormone treatment a long term benefit for patients with Silver Russell syndrome?
Funder: Department of Health and Social Care

Abstract: Background Silver Russell syndrome is a recognised genetic imprinting disorder causing significant short stature often with a final height between 140 cm (female) and 151 cm (male). Children are born small and have poor catch up growth. The long term prognosis for SRS is unknown as few studies of adults with confirmed SRS have ever been done. The only known treatment is Growth Hormone, a drug that costs approximately &pound;5,000 per year for approximately 10 years and involves daily injections(7). However parents of children diagnosed with Silver Russell syndrome face difficult decisions when deciding whether to accept Growth Hormone for their children s poor growth. Growth Hormone impacts on many metabolic pathways and there are potential risks but also benefits for long term health. While there is some evidence that it improves final height there is no information on positive or negative effects on cardiovascular risk factors or quality of life. The Childhood Growth Foundation have indicated that decisions for parents of children with SRS and information on long term outcomes is a major priority area for research. Aims The aim of this retrospective cohort study is to provide data on long term outcome in Silver Russell syndrome (SRS) so preliminary data are available for families of young children with SRS who are making the decision about treatment with Growth Hormone or not. This study may lead to a prospective study in the future. Plan a) Engage 100 people with genetically confirmed SRS above the age of 13 years; approach families through the Clinical Research Facility network, the NIHR Clinical Genetics, paediatric and adult endocrine networks, and Childhood Growth Foundation; including patients who have and have not had growth hormone treatment. b) At a local Clinical Research Facility to the patient, investigate participants with a comprehensive range of investigations including:- a standard clinicial history and systematic examination, anthropomorphic measurements, two quality of life surveys, metabolic markers of cardiovascular disease and diabetes and genetic testing to confirm subtype. c) In depth semistructured interviews with approximately 30 SRS patients to explore the meaning of the condition from the lived experience using a phenomenological approach. d) Review past medical notes of particpants to confirm treatment history and past anthropomorphic measurements, including those of parents if recorded e) Analyse outcomes and perform i) statistical analysis of height SDS by Growth Hormone treatment ii) observational outcome data on quality of life and metabolic markers of disease by GH treatment group, standardising for genetic subtype and iii) identify themes from the indepth interviews and find any differences/simularities between GH treated and non-treated participants. f) Develop medical information for patients and data for professional recommendations with the benefit of a user group from the Childhood Growth Foundation to help families weigh up the benefit and potential adverse outcomes of Growth Hormone treatment Patient benefit This project is primarily aimed at finding information on the long term health impact of Silver Russell syndrome and literature will be produced that is aimed at families with children with Silver Russell syndrome who have to decide whether it is beneficial to treat their child with Growth Hormone or not. It will also provide much needed data on the long term outcome for patients with this rare disorder, particularly the impact on the lived experience. This will be the largest cohort of SRS adults ever studied. It will be based on robust established tests of metabolic health combined with contemporary genetic data and will impact on current clinical practice in the UK. It is also envisaged that it will provide data necessary in order to establish a nationally commissioned service for SRS famlies.

Lay abstract: Silver Russell syndrome is a rare genetic disorder of growth which starts in the womb and which significantly restricts final height (between 140-150 cm)(1,2,3). It is usually due to a genetic fault on chromosome 11(3). At present children are offered Growth Hormone (GH) to improve adult height by about 4cm even though patients are not necessarily GH deficient and families don t know if there are any potential long term risks with treatment(5,6,7,8). There are few studies on the outcome of the disorder in adults or whether GH makes a difference in this particular syndrome compared to other causes of short stature and low birth weight(5,6). Patients write Many SRS parents agonise over the Growth Hormone decision. Do you put your child through years of injections or do you potentially hold them back if as an adult they are at a disadvantage because of their height? What are the long-term risks of GH? Am I putting my child at risk? Maybe 20-30 years down the line, something will crop up, that relates to treatment." Not much is known about adult life with SRS or whether patients are particularly susceptible to early onset metabolic disease like diabetes or heart disease. The genes causing SRS are predicted to alter metabolism and GH may be more or less beneficial in this subgroup(3,9). This study, therefore, is to investigate patients with SRS from around the country measuring height, quality of life, factors which indicate metabolic disease like lipid levels, weight, BP and blood sugar levels and compare SRS patients with the same genetic cause who have been given GH with those who have not been given the treatment. At the same time we will interview a subgroup of adults with SRS to identify important themes in people's life experiences."

Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS
Health categories: CONGENITAL DISORDERS