A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

Giunta C; Baumann M; Fauth C; Lindert U; Abdalla EM; Brady AF; Collins J; Dastgir J; Donkervoort S; Ghali N; Johnson DS; Kariminejad A; Koch J; Kraenzlin M; Lahiri N; Lozic B; Manzur AY; Morton JEV; Pilch J; Pollitt RC; Schreiber G; Shannon NL; Sobey G; Vandersteen A; van Dijk FS; Witsch-Baumgartner M; Zschocke J; Pope FM; Bönnemann CG; Rohrbach M

doi:10.1038/gim.2017.70

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Journal article

A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

Giunta C Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
Baumann M Department of Pediatrics I, Pediatric Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Fauth C Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Lindert U Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
Abdalla EM Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Brady AF Ehlers-Danlos Syndrome, National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, UK.
Collins J Mercy Clinic Pediatric Neurology, Springfield, Missouri, and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Dastgir J Pediatric Neurology, Goryeb Children's Hospital, Morristown, New Jersey, USA.
Donkervoort S Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Ghali N Ehlers-Danlos Syndrome, National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, UK.
Johnson DS Ehlers Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, Sheffield, UK.
Kariminejad A Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
Koch J Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
Kraenzlin M Medical Faculty of the University of Basel, and Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland.
Lahiri N South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, UK.
Lozic B Department of Pediatrics University Hospital Centre Split, Split, Croatia.
Manzur AY Dubowitz Neuromuscular Centre, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK.
Morton JEV West Midlands Regional Clinical Genetics Service and Birmingham Health Partners Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
Pilch J Department of Pediatric Neurology, Medical University of Silesia, Katowice, Poland.
Pollitt RC Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Schreiber G Department of Pediatric Neurology, Children's Hospital, Kassel, Germany.
Shannon NL Nottingham Clinical Genetics Service, Nottingham City Hospital, Nottingham, UK.
Sobey G Ehlers Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, Sheffield, UK.
Vandersteen A Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
van Dijk FS Ehlers-Danlos Syndrome, National Diagnostic Service, Northwick Park and St. Mark's Hospitals, Harrow, UK.
Witsch-Baumgartner M Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Zschocke J Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Pope FM North West Thames Regional Genetics Service, Kennedy Galton Centre, London, UK.
Bönnemann CG Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Rohrbach M Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.

2017-06-16

Published in:

Genetics in medicine : official journal of the American College of Medical Genetics. - 2018

Magnetic Resonance Angiography

English PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

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