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Open Access Research

Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

Marianne Rohrbach12*, Anthony Vandersteen3, Uluç Yiş4, Gul Serdaroglu5, Esra Ataman6, Maya Chopra7, Sixto Garcia8, Kristi Jones7, Ariana Kariminejad9, Marius Kraenzlin10, Carlo Marcelis11, Matthias Baumgartner1 and Cecilia Giunta12

Author Affiliations

1 Division of Metabolism, University Children's Hospital and Children's Research Centre, (CRC) Zurich, Switzerland

2 Connective Tissue Unit, University Children's Hospital and Children's Research Centre, (CRC) Zurich, Switzerland

3 NW Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Harrow, Middlesex and Ehlers-Danlos Syndrome National Diagnostic Service, UK

4 Gaziantep Children's Hospital, Division of Child Neurology, Gaziantep, Turkey

5 Ege University Medical School, Department of Pediatrics, Division of Child Neurology Izmir, Turkey

6 Ege University Medical School, Department of Medical Genetics, Izmir, Turkey

7 Children's Hospital at Westmead, Department of Clinical Genetics and University of Sydney, Discipline of Paediatrics and Child Health, Sydney, Australia

8 Unidad de Genètica Clínica i Citogenética, Hospital Materno Infantil Vall d'Hebron, Barcelona, Spain

9 Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran

10 Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital, Basel, Switzerland

11 Department of Human Genetics, St Radboud University Medical Centre Nijmegen, Nijmegen, the Netherlands

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Orphanet Journal of Rare Diseases 2011, 6:46  doi:10.1186/1750-1172-6-46

Published: 23 June 2011

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.

Conclusion

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.