The phenotype of the musculocontractural type of Ehlers‐Danlos syndrome due to CHST14 mutations

Abstract

The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with biallelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients hadmildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.

CSGALNACT1‐congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age

“…A dislocated and dysplastic radial head was diagnosed in P3, but it is unclear if this is due to her GAG synthesis disorder, as this symptom has been reported in mosaic trisomy 8 (https://rarediseases.info.nih.gov/diseases/5359/mosaic-trisomy-8) as well as in the EXTL3 ‐associated GAG synthesis disorder (Oud et al, ). Of note, none of the three patients presented with multiple congenital dislocations, which are typically seen in in GAG biosynthesis defects located upstream and downstream of CSGalNAcT‐1 (Dundar et al, ; Janecke et al, ; Nakajima et al, ; Unger et al, ).…”

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

“…In contrast, GAG chains appear to be linear in cross‐sections of skin biopsies from CHST14 patients in which DS has been replaced by CS . This might explain poorer formation and greater dispersion of collagen fibres compared to healthy individuals in the skin of CHST14 patients . The specific defect affecting decorin glycation and its relevance in collagen fibril assembly might account for the skin phenotype common to these disorders.…”

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

“…Pathogenic variants have been detected throughout CHST14 (NM_130468.4): 11 missense variants, five frameshift variants, and three nonsense variants in patients with mcEDS [4,6,7,[14][15][16][17][18][19]22] ( Figure 2A) [25,26]. Three missense variants have been detected in DSE (NM_013352.4): p.(Arg267Gly), p.(Ser268Leu), and p.(His588Arg); and one frameshift variant, p.(Pro384Trpfs*9), has also been detected ( Figure 2B) [18,23,24].…”

“…mcEDS-CHST14 was originally described as three independent conditions: A rare type of arthrogryposis syndrome "adducted thumb-clubfoot syndrome" [4]; a specific type of EDS "EDS, Kosho type" [5,6]; and a subset of kyphoscoliosis type without lysyl hydroxylase deficiency [7]. To date, 41 patients from 28 families have been reported to have mcEDS-CHST14 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. mcEDS-DSE was identified in a patient with a phenotype similar to that of patients with mcEDS-CHST14 [23], as well as in four additional patients from three families [18,24].…”