Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure
- Equal contributors
1 Department of Paediatrics, Academic Medical Center, University Hospital of Amsterdam, H7-270, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
2 Department of Paediatric Clinical Epidemiology, Academic Medical Center, University Hospital of Amsterdam, Amsterdam, The Netherlands
3 Children's Hospital, University Medical Center, Mainz, Germany
4 Department of General Paediatrics and Neonatology, University Children's Hospital, Vienna, Austria. Current affiliation: Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
5 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
6 Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, University Hospital of Amsterdam, Amsterdam, The Netherlands
7 Division of Genetics, Department of Paediatrics, Mackay Memorial Hospital, Taipei, Taiwan
8 Medical Genetics Service, Hospital de Clinicas, Porto Alegre, Brazil. Current affiliation: Genzyme do Brazil, São Paulo, SP, Brazil
9 Neurogenetics Division, Departments of Neurology and Pediatrics, New York University School of Medicine, New York, USA
10 Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
11 Department of Paediatrics, University of Padova, Padova, Italy
12 National Centre for Inherited Metabolic Diseases, Children's University Hospital, Dublin, Ireland
13 Department of Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland
14 Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, UK
15 Department of Paediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
Orphanet Journal of Rare Diseases 2012, 7:22 doi:10.1186/1750-1172-7-22Published: 23 April 2012
Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed.
A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity.
Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'.
Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.