AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

Department of Congenital Heart Defects and Pediatric Cardiology German Heart Center Munich Technical University of Munich Munich Germany

Department of Genetics APHP Robert Debré University Hospital and Université de Paris Medical School Paris France

Department of Paediatric Endocrinology Royal Hospital for Children Glasgow United Kingdom

Department of Pediatrics 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatrics Institute of Clinical Sciences Sahlgrenska Academy Gothenburg University Gothenburg Sweden

Department of Statistics and Data Science Faculty of Statistical Studies Complutense University of Madrid Madrid Spain

DZHK Partner Site Munich Heart Alliance Munich Germany

Endocrine Bone Diseases and Genetics Unit Children's Hospital Toulouse University Hospital RESTORE INSERM UMR1301 Toulouse France

Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

Institute of Human Genetics University Hospital Magdeburg Magdeburg Germany

Institute of Medical and Molecular Genetics Hospital Universitario La Paz Madrid Spain

Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust and University of Manchester Manchester UK

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