Neuromuscular and sensorimotor degeneration caused by stroke or any other disease significantly reduce the physical, cognitive, and social well-being across the life span. Mostly, therapeutic interventions are employed in order to restore the lost degrees-of-freedom (DOF) caused by such impairments and automating these therapeutic tasks through exoskeletons/robots is becoming a common practice. However, aligning these robotic devices with the complex anatomical and geometrical motions of the joints is very challenging. At the same time, a good alignment is required in order to establish a better synergy of human-exoskeleton system for an effective intervention procedure. In this paper, a case study of an exoskeleton and shoulder joint alignment were studied through different size and orientation impairment models through motion capture data and musculoskeletal modeling in OpenSim. A preliminary result indicates that shoulder elevation is very sensitive to misalignment and varies with shoulder joint axes orientation; this is partly due to drastic displacement of the upper arm axes with respect to the shoulder joint origin during elevation. Additional study and analysis is required to learn any possible restraint on shoulder elevation that could potentially help in the exoskeleton development.