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Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation
Open accessAbstract
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.
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Intelligence is usually normal in kEDS-PLOD1, but learning disabilities have been reported in eight patients (two of whom had antenatal or perinatal intracranial bleeds).
“Intelligence is usually normal but learning disabilities have been reported in eight patients (two of these patients were reported to have antenatal or perinatal intracranial bleeds) [Wenstrup et al., 1989;Rohrbach et al., 2011].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Rohrbach et al., 2011
The Discussion (page unavailable) says intellect was historically considered unaffected and reports delayed cognitive function in 5 of 12 index patients. The Results (Clinical features; page unavailable) document an antenatal/neonatal brain haemorrhage in one patient. This paper does not establish the cited totals of eight patients with learning disabilities or two with intracranial bleeds. (LLM, conf=0.89)
Experimental — accuracy not yet measuredA range of clinical severity is observed in individuals with kEDS-PLOD1 for each of the systems discussed.
“A range of clinical severity is observed in individuals with kEDS-PLOD1 for each of the systems discussed as detailed in the above section [Steinmann et al., 2002;Rohrbach et al., 2011].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Rohrbach et al., 2011
LH1 deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens, and hence impaired cross-link formation with consequent mechanical instability of the affected tissues.
“LH1 deficiency results in underhydroxylation of lysyl residues and underglycosylation of hydroxylysyl residues in collagens and, hence, impaired cross-link formation with consequent mechanical instability of the affected tissues [Rohrbach et al., 2011].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Rohrbach et al., 2011
kEDS-PLOD1 is caused by deficiency of the collagen-modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1 or LH1) due to homozygosity or compound heterozygosity for mutated PLOD1 alleles.
“kEDS-PLOD1 is caused by deficiency of the collagen-modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1 or LH1 [lysylhydroxylase1]) due to homozygosity or compound heterozygosity for mutated PLOD1 alleles.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Rohrbach et al., 2011
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References 24 · Cited by 106
Research works printed but not linked: 16
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Metadata
- Authors
- Rohrbach, M., Vandersteen, A., Yiş, U., Serdaroglu, G., Ataman, E., Chopra, M., Garcia, S., Jones, K., Kariminejad, A., Kraenzlin, M., Marcelis, C., Baumgartner, M., & Giunta, C.
- Affiliations
- University Children's Hospital Zurich (CH)
- London North West Healthcare NHS Trust (GB)
- Gaziantep Children's Hospital (TR)
- Ege University (TR)
- The University of Sydney (AU)
- University Hospital of Basel (CH)
- Radboud University Medical Center (NL)
- Corresponding author
- Rohrbach, Marianne
- ORCID
- Venue
- Orphanet Journal of Rare Diseases
- Published
- 2011
- Volume
- 6
- Issue
- 1
- Pages
- 46
- ISSN
- 1750-1172 (ISSN-L)
- PMC
- PMC3135503
- OpenAlex
- W2119847760
- Cited by
- 106
- References
- 24
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 11 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 13 · 2018: 10 · 2017: 7 · 2016: 6 · 2015: 4 · 2014: 5 · 2013: 3 · 2012: 5
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Ege Üniversitesi
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- PLOD1, connective tissue diseases, phenotypic variability, disease severity spectrum, kyphoscoliosis, hypotonia, developmental delay, vascular rupture, genotype-phenotype correlation, skin ultrastructure
- MeSH terms
- Adolescent, Adult, Amino Acids, Biopsy, Cells, Cultured, Child, Developmental Disabilities, Child, Preschool, DNA Mutational Analysis, Ehlers-Danlos Syndrome, Female, Fibroblasts, Genotype, Humans, Infant, Kyphosis, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Male, Muscle Hypotonia, Phenotype, Scoliosis, Skin
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