Abstract
BackgroundThe 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.MethodsWe 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.ResultsAge 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.ConclusionIn 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.
Highlights
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
All index patients, suspected with EDS VIA based on clinical findings, were referred to our centre for biochemical workup of EDS VIA, respectively urinary pyridinolines as well as molecular analysis
Most patients were reported to be a product of consanguineous parents; 75% of the patients originating from Turkey, former Yugoslavia and the Middle East, while the remaining originated from Western Europe and Somalia
Summary
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. The disorder is characterized at birth by severe muscular hypotonia often requiring invasive neuromuscular work-up, kyphoscoliosis which is progressive and severe, The kyphoscoliotic type of EDS was the first inborn error of human collagen metabolism to be defined at the biochemical level as early as 1972, based on a family study in which two sisters had severe progressive scoliosis since early infancy, marked joint laxity and recurrent joint dislocations [4,5] It is caused by a deficiency of the collagen-modifying enzyme procollagenlysine, 2-oxoglutarate 5-dioxygenase 1 (LH1; EC 1.14.11.4; MIM 153454; PLOD1 or lysyl hydroxylase 1) [4] due to homozygosity or compound heterozygosity for a mutant PLOD1 allele(s) [1,6]. As a result of underhydroxylation and underglycosylation, the collagen a-chains display a faster electrophoretic mobility on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which in turn is used as a diagnostic test [8]
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