title: Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation.
abstract: BACKGROUND
  The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal.
  
  
  METHODS
  We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome.
  
  
  RESULTS
  Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients.
  
  
  CONCLUSIONS
  In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.
authors.affiliation: Division of Metabolism, University Children's Hospital and Children's Research Centre, Zurich, Switzerland. marianne.rohrbach@kispi.uzh.ch
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Anthony
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Uluç
authors.initials: U
authors.lastname: Yiş
authors.forename: Gul
authors.initials: G
authors.lastname: Serdaroglu
authors.forename: Esra
authors.initials: E
authors.lastname: Ataman
authors.forename: Maya
authors.initials: M
authors.lastname: Chopra
authors.forename: Sixto
authors.initials: S
authors.lastname: Garcia
authors.forename: Kristi
authors.initials: K
authors.lastname: Jones
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.forename: Marius
authors.initials: M
authors.lastname: Kraenzlin
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
mesh_terms: D000293:Adolescent; D000328:Adult; D000596:Amino Acids / Q000652:urine; D001706:Biopsy; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D007738:Kyphosis / Q000235:genetics / Q000473:pathology*; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics; D012600:Scoliosis / Q000235:genetics / Q000473:pathology*; D012867:Skin / Q000473:pathology
chemical_list: D000596:Amino Acids; C015484:pyridinoline; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase