Between myopathy and mortality: Challenges in the diagnosis of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome.

ObjectivePLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by generalized joint laxity, severe congenital hypotonia, progressive kyphoscoliosis, hyperextensible and easily bruised skin, ocular abnormalities, and significant vascular complications.MethodsWe report on nine patients from seven families, eight of them carrying the common homozygous duplication of exons 10-16 in PLOD1. Longitudinal clinical assessments included muscle ultrasound (n=6) and vascular ultrasound (n=4). Genetic diagnostics varied, with most patients ultimately undergoing trio exome or genome sequencing. Urine pyridinoline analysis was performed in seven of nine patients. A literature review and age-stratified recalculation of vascular incidence, including our cohort, were conducted.ResultsDiagnosis was challenging in five families, as the exon 10-16 duplication often escaped detection due to its high allele frequency. Seven patients were initially diagnosed with congenital myopathy. Muscle ultrasound revealed abnormalities in five of six sonographically examined cases. Severe vascular events included neonatal intracranial hemorrhage, fatal aortic aneurysm rupture at the age of 13 years, multiple aneurysms/dissections (ages 14-19 years), and mesenteric dissection at the age of 10 years. Four younger patients (aged 3-9 years have had no vascular complications to date. Urine pyridinoline analysis was abnormal in all tested cases.DiscussionPLOD1-related kEDS often presents with a phenotype of congenital myopathy, complicating genetic diagnosis and potentially leading to underdiagnosis - especially in cases where the common PLOD1 duplication may be missed by strict frequency filters in exome or genome sequencing data. Literature and our data indicate a vascular event incidence from childhood age of ∼25%.