Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency

Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency (kEDS-PLOD1), formerly known as Ehlers-Danlos syndrome type VIA, is a rare heritable connective tissue disorder caused by biallelic pathogenic variants in the PLOD1 gene, which encodes the enzyme lysyl hydroxylase 1 (LH1). This enzyme is essential for the hydroxylation of lysine residues in collagen, a critical step in collagen cross-linking. Deficiency of LH1 leads to structurally weakened connective tissue affecting multiple body systems, including the musculoskeletal, ocular, vascular, and integumentary systems. Key clinical features are present from birth and include severe generalized muscle hypotonia (often the presenting sign in neonates), progressive kyphoscoliosis that begins in infancy, marked joint hypermobility with frequent dislocations, and skin hyperextensibility with fragility and atrophic scarring. Ocular complications are characteristic and include scleral and ocular fragility, with a risk of globe rupture. Vascular fragility may lead to arterial rupture, which is a potentially life-threatening complication. Additional features can include marfanoid habitus, osteopenia, and delayed motor development. There is currently no cure or disease-specific therapy for kEDS-PLOD1. Management is supportive and multidisciplinary, focusing on physical therapy to strengthen muscles and stabilize joints, orthopedic monitoring and intervention for progressive scoliosis, ophthalmologic surveillance, and cardiovascular monitoring. Patients should avoid activities that increase the risk of trauma. Ascorbic acid (vitamin C) supplementation has been considered as a cofactor for lysyl hydroxylase, though its clinical benefit remains uncertain. Genetic counseling is recommended for affected families. Diagnosis is confirmed by demonstrating a reduced ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine or by molecular genetic testing of the PLOD1 gene.

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