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

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.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

“…Vascular involvement has been described mainly in vascular EDS (type IV; Pepin et al 20 ), although arterial fragility occasionally has been reported in classical, 21 and kyphoscoliotic EDS. 22 Non-progressive aortic root dilatation has occasionally been observed in EDShypermobility type. 23 The vascular manifestations in XL-PH are different from those observed in the hypermobility and classic types of EDS; they can be more extensive, progressive and may involve peripheral arteries.…”

Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

“…Rarely, vascular complications can also be observed in the kyphoscoliotic type of EDS (EDS VIA), characterized by a deficiency of collagen lysyl hydroxylase 1 and caused by mutations in the PLOD1 gene [Rohrbach et al, 2011]. Unlike the vascular type, this form of EDS is inherited automosal recessively and characterized by progressive scoliosis, muscular hypotonia, tissue fragility with easy bruising, and sometimes cognitive delay [Rohrbach et al, 2011].…”

The Ehlers-Danlos Syndrome

“…The diagnosis relies upon the demonstration of an increased ratio of lysylpyridinoline (LP) to hydroxylysylpyridinoline (HP) crosslinks in the urine measured by HPLC, which is a highly sensitive and specifi c test. In the kyphoscoliotic type of EDS, the LP/HP ratio is ~6, whereas normal ratios are ~0.2 [ 57 ]. In EDS spondylocheirodysplastic subtype, the LP/HP is slightly elevated to ~1 [ 42 ].…”