Kypho-scoliotic ehlers-danlos syndrome Q79.6

Ehlers-Danlos Syndrome (EDS) is a heterogeneous group of hereditary connective tissue diseases whose main clinical features are overstretchability of the skin and hyperreflexia of the joints. Depending on the type of disease and the underlying gene mutations, vessels, muscles, ligaments, tendons and internal organs are also affected (Brady A et al. 2017).

So far, 19 gene mutations are known to trigger EDS. The various mutations lead to changes in the structure, production or processing of collagen or of proteins that interact with collagen. The frequency of occurrence in the population is assumed to be 1:5,000 to 1:10,000, making EDS a rare disease (orphan disease).

The very rare kypho-scoliotic Ehlers Danlos syndrome (kEDS, formerly Ehlers Danlos type VI) is an autosomal recessive inherited, rare variant of Ehlers Danlos syndrome (Brady A et al. 2017)

Mutations can be detected in the kEDS-PLOD1 gene, which is located on chromosome 1p36.22 and codes for lysyl hydroxylase PLODI. Less frequent are mutations in the FKBP 14 gene, which is located on chromosome 7p14.3 (Shin YL et al. 2020).

The clinical symptoms are classified according to major and minor symptoms (Brinckmann J 2018)

Major symptoms are:

• Neuromuscular symptoms: Congenital muscular hypotension
• Skeletal system: Congenital or early kyphoscoliosis (progressive or non-progressive), severe generalized hypermobility of the joints with dislocations or subluxations (shoulders, knees, hips)

Minor symptoms:

• Skin: Hyperelasticity, hematoma formation with risk of subcutaneous hematoma and hemorrhages
• Vascular system: Rupture or aneurysm of medium-sized arteries
• Skeletal system: clubfoot, breast deformity, Marfanoid habitus,. osteopenia/osteoporosis,

Other: Hernias, eyes: blue sclerae, ametropia,

Determination of the genetic defect; analysis of the cross-links of collagen in urine

Major criterion congenital muscle hypertension +

Major symptoms congenital or early onset kyphoscoliosis + either

• Major symptom severe generalized hypermobility of the joints

or

• three other minor symptoms

Note: The diagnosis of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome is made in a subject with typical clinical findings and biallelic pathogenic (or likely pathogenic) PLOD1 variants identified by molecular genetic testing. If only one or no pathogenic variant is identified, testing for a markedly elevated urinary deoxypyridinoline to pyridinoline crosslink ratio measured by high-performance liquid chromatography (HPLC) may be required to confirm the diagnosis (Yeowell HN et al (2022).

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13. Yeowell HN et al (2022) PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome. 2000 Feb 2 [updated 2018 Oct 18]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.