Kyphoscoliotic Ehlers-Danlos Syndrome · kEDS

Description

Kyphoscoliotic Ehlers-Danlos syndrome, kEDS, is an autosomal recessive connective tissue disorder defined by congenital severe muscle hypotonia, kyphoscoliosis present at birth or in early infancy, and generalized joint hypermobility with frequent dislocations. Two molecular forms are recognized in the 2017 international classification (Malfait et al., American Journal of Medical Genetics Part C, 2017). The major form is caused by biallelic loss-of-function variants in PLOD1, which encodes lysyl hydroxylase 1, an enzyme that hydroxylates lysine residues in collagen. The minor form is caused by biallelic variants in FKBP14, which encodes a collagen folding chaperone in the endoplasmic reticulum. The PLOD1 form was first delineated by Pinnell and colleagues in the New England Journal of Medicine in 1972 as a hydroxylysine-deficient collagen disease. The FKBP14 form was reported by Baumann and colleagues in the American Journal of Human Genetics in 2012 and adds congenital sensorineural hearing loss and myopathy to the phenotype.

The 2017 classification requires two of three major criteria for clinical diagnosis: congenital or early-onset kyphoscoliosis that is progressive or non-progressive, generalized joint hypermobility with dislocations or subluxations, and congenital muscle hypotonia. Ocular fragility with risk of globe rupture and arterial fragility with risk of dissection are documented in the PLOD1 form. Skin is hyperextensible and bruises easily.

Confirmation in the PLOD1 form combines a urinary biochemical assay and gene sequencing. The urinary lysylpyridinoline-to-hydroxylysylpyridinoline cross-link ratio is markedly elevated in PLOD1 deficiency and serves as a sensitive and specific biomarker (Steinmann and colleagues, Journal of Inherited Metabolic Disease, 1995). Sequencing of PLOD1 confirms biallelic pathogenic variants. The FKBP14 form has no comparable biochemical screen and is confirmed by FKBP14 sequencing. Both subtypes are rare, with fewer than a few hundred cases reported worldwide.

Treatments to date

Care is supportive and orthopedic. There is no approved disease-modifying therapy, no enzyme replacement, and no gene therapy in clinical use. Management is multidisciplinary and begins in infancy.

Spinal management is central. Bracing is started for progressive kyphoscoliosis, and spinal fusion is considered when the curve advances despite bracing or when pulmonary function declines. Tissue fragility complicates surgical exposure and fixation, so procedures are concentrated at high-volume centers experienced with connective tissue disease.

Ophthalmologic surveillance is lifelong because of the risk of corneal or scleral rupture from minor trauma. Protective polycarbonate eyewear is prescribed in childhood and continued into adulthood. Contact sports and activities with projectile risk are avoided. Vascular imaging is recommended at baseline and on a defined schedule in PLOD1 disease because of reported arterial dissection and rupture.

Joint care follows the broader EDS template: physical therapy oriented toward stabilization rather than stretching, bracing for unstable joints, and pain management. Hearing assessment is part of FKBP14 follow-up, and hearing aids or cochlear implants are used when indicated. Cardiac assessment screens for valve involvement reported in subsets of both molecular forms.

No drug is approved by the FDA or EMA for any form of kEDS. Research interest has focused on collagen post-translational modification and ER quality-control biology rather than on a near-term therapeutic.