Mucopolysaccharidosis (MPS) [1] has long been a life-limiting disease, but recent medical advancements have resulted in remarkable changes in prognosis. MPS, a form of lysosomal storage disease, is caused by deficiencies of enzymes involved in the breakdown of glycosaminoglycans (GAGs) [2].GAGs play an important role in cell biology, and signalling pathways and impairment of these molecules lead to multisystemic involvement with a range of somatic, neurologi-cal, haematological, and ocular symptoms [2]. There are seven major types of MPS (MPS I – Hurler syndrome, MPS II – Hunter syndrome, MPS III Sanfilippo syndrome, MPS IV – Morquio syndrome, MPS VI – Maroteaux-Lamy syndrome, MPS VII – Sly syndrome, MPS IX – hyaluronidase deficiency). The syndromes are differentiated by their associated enzyme deficiency and further subtypes, including less-rapidly progressive and intermediate phenotypes such as MPS, IS – Scheie syndrome, and MPS IH/S – Hurler/Scheie syndrome [3].

The musculoskeletal manifestations involving the hip and knee result from GAG-related dysregulation of connective tissue homeostasis and lead to major issues for the orthopaedic surgeon, such as short stature, skeletal dysplasia, joint stiffness, or hypermobility [2]. Joint stiffness and contractures are found in all forms of MPS except for MPS IV and IX. They can be attributed to defective bone modelling in combination with thickened joint capsules secondary to GAG deposition and fibrosis [3]. Patients may present with swollen, stiff joints but without the signs of local inflammation such as erythema and warmth seen with diseases such as rheumatoid arthritis or juvenile idiopathic arthritis [4]. Short stature in MPS follows GAG deposition in the growth plates, disturbing endochondral ossification. Dysostosis multiplex is the characteristic pattern of skeletal dysplasia described in MPS. GAG deposition in the articular cartilage leads to increased apoptosis of articular chondrocytes through mechanisms including activation of lipopolysaccharide (LPS) signalling pathway and reduced differentiation of the chondrocytes leading to poor mineralisation of bone [5]. The LPS pathway is activated as the GAG accumulation has structural similarities to LPS. Hence the musculoskeletal manifestations of MPS are predominantly targeted toward cartilage formation rather than the bone [4].

Modern advancements in hematopoietic stem cell transplantation and enzyme replacement therapy have drastically changed prognosis in patients with MPS [6]. With the increased age of patients with this disease and improvement in many systemic manifestations but minimal improvement in the musculoskeletal manifestations, orthopaedic interventions are increasing [7]. Many patients with MPS types I, II, IV, and VI will undergo orthopaedic procedures during their lifetime due to the associated skeletal dysplasia, nerve compression syndromes, and spinal pathology. Common orthopaedic procedures include guided growth surgery, osteotomies, and soft tissue releases [7, 8].

Arthroplasty is emerging as a procedure in this patient group, as improved multidisciplinary care and systemic therapy mean that patients are living longer, with improved functionality, and seeking a better quality of life [7]. Still, systemic therapies have not been shown to reliably ameliorate joint pathology.

This study aims to summarize the literature on knee and hip arthroplasty performed in this patient population to provide information for clinicians managing this condition and define the direction for future studies.

A literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9]. A search of published literature was conducted in April 2021 by a qualified librarian using the Embase database. Search terms included combinations of “MPS,” “mucopolysaccharidosis,” “arthroplasty,” “replacement,” “hip,” and “knee.” A screening process was then conducted with a review of titles and abstracts. Articles were excluded if they did not include sufficient information or when they were general review articles on MPS (Fig. 1). The initial search identified 22 articles (Fig. 1), of which three were excluded as they reported MPS undergoing cardiac or upper limb procedures [10-12]. Seven general review articles on MPS were excluded, and two articles mentioned arthroplasty but had insufficient information to be included in the final data [13, 14]. The included ten articles reported 15 patients with 25 arthroplasties, 5 knee arthroplasties [15, 16], and 20 hip arthroplasties [17-24].

Information collected included demographic data (gender, MPS type, height and weight, age, previous treatment), surgical indications (symptoms, physical examination findings), surgical details (approach, prosthesis details, intraoperative and early postoperative complications), and postoperative data (timing of final follow up, function quality of life, late postoperative complications).

Descriptive statistics were used with normally distributed data, including mean and standard deviation.

With medical advancements in patients with MPS, arthroplasty of the hip and knee is becoming more common in the multidisciplinary approach. This review collates the current literature on arthroplasty in this rare patient group.

Ten publications reporting knee or hip arthroplasty in 15 patients were identified. Publication bias is difficult to avoid, given the rarity of the disease. Authors may selectively publish complication data; conversely, authors may prefer to publish successful cases. The largest case series of arthroplasty in MPS reported three patients with six hip arthroplasties [23].

The musculoskeletal complications of MPS are well-described and do not satisfactorily respond to modern medical management. These complications include short stature, skeletal dysplasia (termed dysostosis multiplex in MPS), joint stiffness (particularly MPS I, II, VII) or hypermobility (particularly MPS IV), and avascular necrosis (particularly MPS III) [4]. Impaired ossification associated with dysostosis multiplex results in hip dysplasia and genu valgum. Attempts in children to prevent the development of hip osteoarthritis with osteotomies have been proven ineffective [26].

Papers in this review did not detail the multidisciplinary management of patients in the peri-operative period, but this is paramount for safe surgery in MPS patients. Patients with MPS are at high risk for anaesthetic complications due to airway, respiratory and cervical spine manifestations of the disease [27]. With increasing numbers of surgeries being performed on MPS patients, there are increasing case reports of the devastating complication of peri-operative thoracic spinal cord infarction in MPS patients [28]. This complication occurs in the anatomical watershed region of the thoracic spine vascular supply. Recommendations to minimise its occurrence include lower limb neuromonitoring in lower extremity surgeries, careful patient positioning, and judicious blood pressure control [29]. Pre-operative whole spine MRI has been recommended to evaluate the cervical spine and ensure no anomalies to contraindicate spinal anaesthesia [21, 27, 28].

This review highlights the importance of pre-operative planning in this patient group [8]. Intraoperative shortening of the femoral component was required for two knee arthroplasties to accommodate short limb-length and multi-planar deformity [15]. All knee arthroplasties were performed in MPS IV patients. These patients have severe, progressive genu valgum and joint hypermobility, requiring some form of constraint with a prosthesis, and there is the risk of peroneal nerve palsy post-operatively [15, 30]. De Waal et al. reported peroneal palsy in the one knee arthroplasty, which did not have an intra-operative release of the peroneal nerve. Two knees in the same series that underwent nerve release did not have this complication [16]. Atinga et al. described using the tourniquet to help prevent bleeding when undergoing extensive soft tissue releases in patients undergoing knee arthroplasty [15]. Given the small stature of this patient group, a paediatric tourniquet is usually required.

Dysplasia hip, modular, and small/short diameter stems were used to accommodate the varied femoral osteology, including small size and abnormal versions in MPS patients [21]. The use of screw fixation in half the hip arthroplasties may reflect the poor bone quality and the lack of coverage of the acetabular component due to altered osseous anatomy [22]. The most popular hip prosthesis was metal on polyethylene, followed by ceramic on ceramic. Materials are partly due to surgeon preference; however, patient activity levels, risk of higher impact activity, and dislocating should be considered [31]. Intra-operative femoral fracture requiring cerclage wire fixation occurred in 4/20 hip arthroplasty cases. This rate is higher than the reported mean in the literature of 0.23% in cemented arthroplasty and 3.0% in uncemented implants [32]. Given the morphological changes in MPS patients, difficulty in implant placement can be compounded by lower bone mineral density, particularly in MPS types III and IV [33, 34]. For other MPS types, bone mineral density scans are usually within the normal range when corrected for short stature [35]. Considering bone stock and appropriate implants (standard vs. custom-made) may help prevent intra-operative fractures [20, 24].

Postoperative complications were rarely reported in this patient group, with one patient requiring soft-tissue release for stiffness post-knee arthroplasty and one case of hip arthroplasty loosening requiring revision [16, 19]. Longer-term follow-up is required to determine arthroplasty revision rates and complications in this patient group. There is a lack of literature regarding function and quality of life pre- and post-orthopaedic interventions in MPS patients [26]. HHS, WOMAC, IKS, and OKS scores were reported pre- and post-operatively for only four patients [15, 16, 24]. Pleasingly, these scores and pain scores were reliably improved with surgery in MPS patients.

Arthroplasty surgeons should be aware that less-rapidly progressive or attenuated forms of MPS can present for the first time in early adulthood and are commonly misdiagnosed or have a delayed diagnosis [25, 36]. Joint stiffness without signs of joint inflammation, carpal tunnel syndrome, and hip dysplasia are common presentations of less-rapidly progressive MPS subtypes in early adulthood [25].

Although not the focus of this paper, it is important to consider that the management of MPS, including systemic and orthopaedic management in childhood, is evolving. Acetabular and femoral osteotomies improve radiological parameters for patients with MPS in the short to medium-term [16] but have failed to prevent the development of clinically significant osteoarthritis in adulthood [37]. The benefits of achieving improved anterior and superior hip coverage with osteotomy [16] must be weighed against literature that reports that patients who have undergone prior osteotomies show lower activity scores and higher revision rates post-hip arthroplasty [38]. Guided growth for progressive, pathological genu-valgum in children is a relatively low-risk procedure increasingly used in MPS, particularly in MPS IV [30, 39]. Its role in minimising the development of knee osteoarthritis in these patients is yet to be established.

The findings of this review are that knee and hip arthroplasty can be performed safely in patients with MPS but with a higher complication rate than in the non-MPS population. Careful pre-operative planning and multidisciplinary management, including an experienced anaesthetist and awareness of the potential for underlying atlantoaxial instability, are required. Surgeons should be encouraged to share their experiences, including reporting functional and quality-of-life outcomes and longer-term follow-up to help facilitate decision-making and surgical planning in patients with this rare and complex disease.

Authors’ Contributions: Kimon Toumazos was involved in data collection and manuscript production. Both Nicole Williams and Kimon Toumazos were involved in data analysis/interpretation.