DSE – Musculocontractural Ehlers-Danlos Syndrome

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective tissue disorder characterized by craniofacial malformations, congenital contractures, skin fragility, ocular refractive errors, and visceral complications. mcEDS arises from biallelic pathogenic variants in either CHST14 or DSE, the latter encoding dermatan sulfate epimerase-1 essential for dermatan sulfate biosynthesis (MONDO:0011142).

Genetic evidence for DSE involvement includes seven probands across six unrelated families, with variant spectrum comprising two frameshift deletions (c.1150_1157del (p.Pro384TrpfsTer9)), two truncating substitutions (c.960T>G (p.Tyr320Ter)), a single-base duplication (c.996dup (p.Gly387AlafsTer14)), a missense change (c.799A>G (p.Arg267Gly)), and a novel missense variant (c.2813T>A (p.Val938Asp)) (PMID:31655143, PMID:32130795, PMID:25703627, PMID:34184791).

Autosomal recessive inheritance is confirmed by homozygosity of DSE variants in consanguineous families. In a Pakistani kindred, c.2813T>A (p.Val938Asp) segregated with disease in five affected siblings (four additional relatives) and obligate carriers (PMID:34184791).

Functional studies demonstrate loss of dermatan sulfate in patient urine and fibroblast assays, compensatory glycosaminoglycan alterations, and ultrastructural collagen bundle loosening on electron microscopy, consistent with epimerase deficiency and connective tissue fragility (PMID:32130795, PMID:31655143).

No conflicting evidence has been reported. Phenotypic variability is noted, with DSE-related mcEDS generally presenting a milder cutaneous and cardiovascular burden compared to CHST14 cases, yet common features include myopia (HP:0000545) and congenital contractures (HP:0002803).

Key take-home: Biallelic DSE variants cause mcEDS through haploinsufficient epimerase activity loss, and genetic confirmation informs prognosis, surveillance (ocular and gastrointestinal), and family counseling.

References

• European journal of medical genetics • 2020 • DSE associated musculocontractural EDS, a milder phenotype or phenotypic variability. PMID:31655143
• Molecular genetics & genomic medicine • 2020 • Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency. PMID:32130795
• Human mutation • 2015 • Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis. PMID:25703627
• Congenital anomalies • 2021 • A novel variant in the DSE gene leads to Ehlers-Danlos musculocontractural type 2 in a Pakistani family. PMID:34184791

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