Genetic Skeletal Disorders with Defects in Glycosaminoglycan Biosynthesis
Molecular Syndromology, pp.1-28, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Review
- Publication Date: 2026
- Doi Number: 10.1159/000551137
- Journal Name: Molecular Syndromology
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Health Research Premium Collection (ProQuest), Pharma Collection (ProQuest)
- Page Numbers: pp.1-28
- Keywords: Desbuquois dysplasia, Diastrophic dysplasia, Glycosaminoglycan, Linkeropathy, Proteoglycan, Skeletal dysplasia
- Hacettepe University Affiliated: Yes
Abstract
Abstract – Background: Proteoglycans are a major component of the connective tissue matrix, which consists of a core protein and covalently attached glycosaminoglycan (GAG) chains, which are highly sulfated polysaccharides with a tetrasaccharide linker for the core protein attachment. Impaired synthesis or degradation of GAG causes genetic disorders. In the 1950s, deficient lysosomal GAG degradation was discovered in mucopolysaccharidoses. In the 1990s, a defective enzyme for GAG synthesis was implicated in a variant of Ehlers-Danlos syndrome and an impaired GAG sulfation in diastrophic dysplasia. Newer studies have uncovered that abnormal GAG synthesis causes a large group of genetic skeletal disorders with joint and skin abnormalities. Summary: The prototype of this group includes diastrophic dysplasia and Desbuquois dysplasia. The former is attributed to abnormal GAG sulfation, while the latter to impaired GAG chain elongation. Defective linker formation causes distinctive phenotypes termed linkeropathy. Moreover, there remain many disorders with defective GAG synthesis, in which the phenotypes are poorly documented and thus the clinical suspicion and even interpretation of molecular findings are challenging. Here, we attempt to review the skeletal manifestations of abnormal GAG synthesis disorders, based on our own experiences and previous reports. Each disorder has distinct clinical and radiological features, but they share some common skeletal manifestations, such as distal humeral hypoplasia, misshapen proximal femora, accelerated carpal ossification, and malsegmentation of the short tubular bones. Key Message: Awareness of the phenotypic similarities and differences among this group of disorders facilitates our clinical and genetic practices for affected individuals.Plain Language Summary Proteoglycans are scaffold proteins in the extracellular matrix that carry long, highly sulfated sugar chains called glycosaminoglycans (GAGs). When the making or sulfating of these GAG chains goes wrong, cartilage and other connective tissues lose strength, causing genetic skeletal dysplasias with bone, joint, and sometimes skin/visceral complications. This review outlines disorders caused by (1) defective GAG sulfation, (2) defective GAG chain elongation, and (3) defects in the four-sugar “linker” that tethers GAGs to core proteins and briefly comments on diseases from abnormal core proteins. Among these conditions, common findings include epiphyseal dysplasia, characteristic hip changes (e.g. “monkey-wrench” proximal femur), accelerated carpal ossification, and joint laxity or, less often, restriction (radioulnar involvement is common). Clubfeet, spinal malalignment, and EDS-like skin features may occur; the severity varies widely, and all disorders are inherited in an autosomal recessive manner. Because many entities are rare and phenotypes overlap, genotype-phenotype correlations remain incomplete, and diagnosis can be challenging. Recognizing the common imaging and clinical patterns helps guide targeted genetic testing and management. Key examples include SLC26A2-related diastrophic dysplasia, a classic sulfate-transport defect characterized by hitchhiker thumb, clubfeet, and kyphoscoliosis; animal studies suggest N-acetylcysteine may ameliorate undersulfation, and the allelic spectrum spans from mild autosomal-recessive multiple epiphyseal dysplasia (AR-MED) to lethal achondrogenesis type 1B (ACG1B). PAPSS2 deficiency produces prominent vertebral changes reminiscent of brachyolmia. Defects in CHST3, CHST11, GPAPP, or CHST14 disrupt the sulfotransferase pathway and yield phenotypes that include recessive Larsen-like chondrodysplasia and musculocontractural Ehlers-Danlos syndrome. CANT1-related Desbuquois dysplasia frequently shows strikingly advanced carpal bone age with the characteristic “monkey-wrench” configuration of the proximal femora. Linkeropathies due to XYLT1, B4GALT7, B3GALT6, or B3GAT3 feature joint laxity with skin and craniofacial findings, alongside diverse spinal and hip abnormalities. Finally, EXT1/EXT2 haploinsufficiency underlies hereditary multiple exostoses through impaired heparan-sulfate polymerization.