Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis

MPS I is one of the more common mucopolysaccharidoses, a family of seven inherited metabolic diseases caused by deficient activity of various lysosomal enzymes, resulting in the inability to metabolize certain glycosaminoglycans (Table 1). In the case of MPS I, patients have an undetectable activity of the lysosomal enzyme α-L-iduronidase (IDUA)[10]. Lack of IDUA activity results in progressive accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate in lysosomes throughout the body, leading to a multi-systemic disease. Prominently affected organ systems include airways, heart, viscera, skeleton, and (in the most severe cases) the central nervous system. The disease presents across a spectrum of severity, and historically is categorized into three subjectively defined phenotypes. "Hurler syndrome," the most severe form of the disease, begins in infancy, progresses rapidly, and is associated with profound cognitive decline. Untreated children with Hurler syndrome rarely survive beyond age 10 [11]. "Scheie syndrome," the least severe, is characterized by onset in childhood, variable rate of progression and organ involvement, normal intelligence, and survival to adulthood. "Hurler-Scheie syndrome" encompasses patients with onset in early childhood, mild to moderate CNS involvement, and an intermediate rate of progression and organ involvement. Clinical heterogeneity is especially prominent in the less severe end of the spectrum, and Hurler-Scheie and Scheie presentations are often grouped together and referred to as "attenuated MPS I."

Patients with attenuated MPS I, unlike those with the severe, "Hurler" form of the disease, often have no obvious physical abnormalities; facial appearance is usually normal or only subtly altered, stature can be in the normal range, and skeletal abnormalities are often absent or subclinical. Learning issues, if present, can be mild. Common early clinical features include joint pain and stiffness, corneal clouding, umbilical and/or inguinal hernia, carpal tunnel syndrome (note that an MPS disorder is the most frequent cause of carpal tunnel syndrome in children and adolescents [12, 13]), hearing loss, frequent ear, nose and throat infections, and "noisy" breathing. Musculoskeletal abnormalities that can occur later in the disease course include progressive arthropathy, hip dysplasia, dysostosis multiplex, spine deformities, and spinal cord compression. Cardiac valve disease is also very common.

As shown in Table 1, the major clinical manifestations of attenuated MPS I are similar to those of MPS II, MPS VI, and MPS VII (Sly syndrome). MPS IV, Morquio syndrome, is characterized by a distinctive and severe skeletal dysplasia, dysplastic odontoid process, and hyperextendable joints/ligamentous laxity rather than joint contractures [5]. All of the MPS disorders occur across a spectrum of severity, and diagnosis is often challenging for those with the less severe forms of the disease.

Joint symptoms in MPS I patients are almost universal, and in the case of attenuated disease are often the first symptom that brings a child to medical attention [1, 2]. In the MPS I Registry, an ongoing, observational database that tracks natural history and outcomes of patients with MPS I, joint contractures are reported in over 80% of Hurler-Scheie and Scheie patients and usually precede diagnosis [14].

The basis for the abnormal development of bone and cartilage seen in the MPS disorders is not fully understood. Although the absence of clinical signs of inflammation is a hallmark of joint involvement in the MPS disorders, investigations conducted in animal models suggest paradoxically that the pathophysiology of bone disease involves inflammatory cytokines such as tumor necrosis factor α and interleukin-1β in addition to proteins important for lipopolysaccharide signaling (e.g., Toll-like receptor 4 and lipoprotein-binding protein) [15‐17].

Patients with confirmed MPS should be referred to a geneticist or metabolic specialist for further evaluation and treatment. All of the MPS disorders are multisystemic and progressive and are best managed by a multidisciplinary team with comprehensive followup [5, 10, 22]. Both disease-specific treatment as well as symptom-based supportive care are important, in addition to patient education, genetic counseling, psychosocial support, and physical and/or occupational therapy. MPS patients can have significant (and often under-recognized) airway problems and cervical spine issues such as spinal cord compression that increase risk of anesthetic complications; thus, appropriate precautions should be taken before any surgery.

Disease-specific care for patients with attenuated MPS I consists of enzyme replacement therapy with laronidase (0.58 mg/100 U per kg per week). Available enzyme replacement therapies for the other MPS diseases with musculoskeletal manifestations are listed in Table 1. As with any progressive metabolic disease, early initiation of therapy that addresses the underlying pathophysiology improves outcome, and can prevent or at least delay the development of irreversible disease manifestations. Clinical trials of laronidase in patients with attenuated MPS I have demonstrated improved respiration, decreased hepatomegaly, increased walking ability, enhanced joint range of motion, and improved quality of life [23‐26]. Hematopoietic stem cell transplantation (HSCT) is recommended for patients with severe MPS I, if performed before age 2 as it can prolong life and preserve cognition, but is not recommended for patients with attenuated MPS I, because they have little or no cognitive involvement, making the procedural risk-benefit ratio unacceptable (10-15% mortality) [10]. HSCT is used much less frequently in other MPS disorders and only among severely affected patients and transplant outcome has been mixed [7, 27‐29].