Scientific Background
The autosomal recessively inherited kyphoscoliotic EDS (kEDS) is genetically heterogeneous. Characteristic clinical symptoms include kyphoscoliosis, muscle hypotonia, thin, fragile hyperextensible skin, atrophic scarring, hypermobile joints, and variable eye involvement. Further symptoms are various craniofacial abnormalities, joint contractures, and wrinkled palms.
In the majority of patients, the disease is caused by homozygous or combined heterozygous variants in the PLOD1 gene, which encodes the enzyme lysylhydroxylase 1 (LH) (kEDS-PLOD1). LH is responsible for the hydroxylysine-dependent pyridinoline cross-linking of type I and type III collagen that is mainly found in the skeleton. The absence of the LH enzyme can also be detected by an increased ratio of lysyl-pyridinoline (LP) to hydroxylysyl-pyrodinoline (HP) cross-links in urine.
A small number of patients with nearly identical clinical presentation have an inconspicuous urinary LP/HP ratio and no PLOD1 variants. In 2012, another autosomal recessive EDS type with an inconspicuous LP/HP ratio was described as differential to kEDS-PLOD1 and initially named Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKMH). Here, in addition to progressive kyphoscoliosis, muscle hypotonia, joint hypermobility, hyperextensible skin, and myopathy, sensineural hearing loss is particularly characteristic. As a result of clinical overlap with kEDS-PLOD1, EDSKMH is also classified in the kyphoscoliotic EDS (kEDS) group in the current EDS classification, where it is referred to as kEDS-FKBP14. kEDS-FKBP14 is caused by variants in the FKBP14 gene, which encodes FK506-binding protein 22, a member of the peptidyl-prolyl cis-trans isomerases (PPIases).
References
Giunta in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (May 23, 2019) / Giunta et al. 2018, Genet Med 20:42 / Yeowell and Steinmann in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (updated 2018 Oct 18) / Brady et al. 2017, Am J Med Genet C 175:70 / Baumann et al. 2012, Am J Hum Genet 90:201 / Rohrbach et al. 2011, Orphanet J Rare Dis 6:46 / Giunta et al. 2005, Mol Genet Metab 86:269 / Yeowell et al. 2000, Mol Genet Metab 71:212