Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis

Abstract

Background: Undiagnosed patients with the attenuated form of mucopolysaccharidosis (MPS) type I often have joint symptoms in childhood that prompt referral to a rheumatologist. A survey conducted by Genzyme Corporation of 60 European and Canadian rheumatologists and pediatric rheumatologists demonstrated that < 20% recognized signs and symptoms of MPS I or could identify appropriate diagnosis tests. These results prompted formation of an international working group of rheumatologists, pediatric rheumatologists, and experts on MPS I to formulate a rheumatology-based diagnostic algorithm. The resulting algorithm applies to all MPS disorders with musculoskeletal manifestations.Bone and joint manifestations are prominent among most patients with MPS disorders. These life-threatening lysosomal storage diseases are caused by deficient activity of specific enzymes involved in the degradation of glycosaminoglycans. Patients with attenuated MPS disease often experience diagnostic delays. Enzyme replacement therapy is now commercially available for MPS I (laronidase), MPS II (idursulfase), and MPS VI (galsulfase).

Presentation of the hypothesis: Evolving joint pain and joint contractures in the absence of inflammation should always raise the suspicion of an MPS disorder. All such patients should undergo urinary glycosaminoglycan (uGAG) analysis (not spot tests for screening) in a reputable laboratory. Elevated uGAG levels and/or an abnormal uGAG pattern confirms an MPS disorder and specific enzyme testing will determine the MPS type. If uGAG analysis is unavailable and the patient exhibits any other common sign or symptom of an MPS disorder, such as corneal clouding, history of hernia surgery, frequent respiratory and/or ear, nose and throat infections; carpal tunnel syndrome, or heart murmur, proceed directly to enzymatic testing. Refer patients with confirmed MPS to a geneticist or metabolic specialist for further evaluation and treatment.

Testing of the hypothesis: We propose that rheumatologists, pediatric rheumatologists, and orthopedists consider our diagnostic algorithm when evaluating patients with joint pain and joint contractures.

Implications of the hypothesis: Children and young adults can suffer for years and sometimes even decades with unrecognized MPS. Rheumatologists may facilitate early diagnosis of MPS based on the presenting signs and symptoms, followed by appropriate testing. Early diagnosis helps ensure prompt and appropriate treatment for these progressive and debilitating diseases.

Figure 1

Diagnostic Algorithm for Attenuated Mucopolysaccharidoses. *Newborn infants with the most severe form of MPS I (Hurler syndrome), although normal appearing, often have radiologic evidence of bone and joint abnormalities. **Note that overall skin texture in patients with MPS I can be thickened and rough. MPS II [6,7] and rarely MPS I [30] can be associated with a distinctive skin lesion consisting of white "pebbly" papules 2-10 mm in diameter, sometimes coalescing in ridges. †We recommend both quantitative and qualitative (GAG profile) analysis in a reputable laboratory. False negatives can occur with spot screening. ^§See Table 1 for listing of enzyme deficiencies. Abbreviations: IDUA: α-L-iduronidase; uGAG: urinary glycosaminoglycan; JIA: juvenile idiopathic arthritis; RA: rheumatoid arthritis.

Figure 2

Physical and Radiographic Appearance of Hands in MPS I versus Juvenile Idiopathic Arthritis. The images on the left depict typical findings in MPS I - the curled "claw hand," abnormal metacarpal bones, proximal widening of phalanges, and the V-shaped deformity of the distal ulna and radius, particularly evident in severe MPS I. In contrast, the images on the right of a child with juvenile arthritis show the typical joint swelling and erosive bone lesions. Photos courtesy of J. Edmond Wraith, Rolando Cimaz, and Bianca Link.

Figure 3

Spine in Attenuated MPS I. Left Panel: Cervical spine X-ray of an adolescent with attenuated MPS I showing ossification disturbance in the anterior part of column resulting in oval shaped vertebral bodies with anterior beaking and hypoplastic dens axis. Photo courtesy of Bianca Link. Right Panel: Complete spine X-ray in an adult patient with attenuated MPS I showing nearly normal shaped vertebral bodies and gibbus deformity at the thoracolumbar junction. Note that lateral X-rays of the thoracolumbar spine can also reveal anterior beaking. Photo courtesy of Bianca Link.

Figure 4

Corneal Clouding in Patients with MPS I. Corneal clouding is an early and almost universal sign of MPS I in both severe and attenuated phenotypes. It can be very marked, as in the right eye of the patient shown in the upper panel, or less obvious as in the eye shown in the lower panel. Typically, it is bilateral; in the patient shown in the upper panel, a corneal transplant was performed in the left eye. Photos courtesy of J. Edmond Wraith.