Abstract Pathogenic variants in IDUA, encoding α-L-iduronidase (IDUA), cause the autosomal recessive lysosomal storage disorder mucopolysaccharidosis type I (MPS I). Deficiency of α-L-iduronidase leads to the accumulation of partially degraded glycosaminoglycans in various tissues, including the musculoskeletal system. Clinically, typical skeletal manifestations are dysostosis multiplex, joint contractures, and low bone mineral density (BMD). MPS I represents a spectrum of disease severity. Especially in attenuated disease, establishing an accurate diagnosis and initiating disease-specific therapy, including enzyme replacement therapy (ERT) and osteological treatment, is challenging. A 33-year-old female patient presented with a history of juvenile idiopathic arthritis, persistent spinopelvic instability, and reduced BMD. Multiple surgical attempts to stabilize the spinopelvic nonunion had failed, thus osteological co-treatment with teriparatide to promote bone healing was recommended. Despite a significant BMD increase, spinopelvic nonunion persisted. Given the combination of short stature, joint contractures, and corneal clouding, a genetic skeletal dysplasia was suspected. Exome sequencing (ES) was inconclusive, whereas short-read genome sequencing (GS) revealed the combination of a 14 kb deletion and a promotor variant in IDUA. Thus, diagnosis of MPS I in the attenuated form was made, and ERT was initiated. This case highlights the importance of considering MPS I in patients with short stature, joint contractures, skeletal dysplasia, and low BMD. Diagnosis can be overlooked in this attenuated form, underscoring the value of genetic testing, with GS offering advantages over ES. These findings emphasize the need for early diagnosis, systematic osteological evaluation, and individualized treatment strategies in patients with skeletal dysplasia.
Windels et al. (Wed,) studied this question.