MPS Reference
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“We hope that when the paediatrician sees the physical findings, and if the radiologist gets some X-rays, [that] they can say that these vertebrae don’t look normal [and] we need to send this child to the geneticist.” – Dr. Paul Harmatz

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Joint manifestations are often among the first signs of MPS

A rheumatologist’s suspicion of MPS is essential for accurate and timely diagnosis

Bone- and joint-related features are common from a very early stage of disease in patients with most types of mucopolysaccharidosis (MPS) disorders. Patients with these types of musculoskeletal manifestations often present to a rheumatologist, and often before MPS is diagnosed.1

Delayed diagnosis can lead to:

  • Severe multisystemic complications1,3
  • Irreversible or end-organ damage1
  • Delayed treatment2
  • Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality1,5–8
Signs and symptoms are unpredictable and clinically heterogeneous across and within MPS disorders, making diagnosis challenging. Patients may exhibit non-classical and/or classical signs of MPS, as well as rapidly or slowly progressing disease.2-4

Suspect, refer and rule out MPS

Because of early and ongoing joint involvement, rheumatology has opportunities to positively impact the lives of patients and families living with MPS through early identification, which can enable disease-specific management and access to available therapies. To expedite early intervention, be aware of signs and symptoms, including:

  • Joint stiffness or laxity6,9
  • Joint involvement in the absence of inflammation10
  • Progressive loss of joint mobility5
  • Carpal tunnel syndrome10
  • Bone abnormalities10
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Rheumatological involvement is uniformly progressive, with incidence and severity increasing over time. Although patients with MPS typically present with a wide range or cluster of symptoms, isolated symptoms may be sufficient to merit referral to a geneticist or metabolic centre.1,11

Signs and symptoms may be subtle or overt. Common bone and joint features suggestive of MPS include:1

  • Early joint involvement without classic inflammatory features or erosive bone lesions
  • ‘Claw hand’
  • Spinal deformity (subtle or overt gibbus, scoliosis, kyphosis, lordosis)
  • Radiological evidence of dysostosis multiplex

Additional signs and symptoms that may be present can be seen in the table below.

Musculoskeletal-manifestations-of-MPS_AMc

Not all joint problems present similarly across all MPS types.

  • Skeletal dysplasia of patients with MPS IV is distinct from the dysostosis multiplex seen in other MPS types6
  • Ligamentous laxity/joint hypermobility associated with MPS IV is also unique; in other MPS types, joint involvement typically presents with decreased mobility and stiffness6

MPS is mistakenly considered a childhood disease; however, patients with slow-progressing MPS may present and should trigger suspicion at any age.6

  • Joint disease with or without inflammation is a key feature of slowly progressing MPS6
  • Rheumatologists should consider an MPS referral in patients with any of the following:
    • Oligoarticular juvenile idiopathic arthritis who do not respond to anti-inflammatory therapy (e.g. nonsteroidal anti-inflammatory drugs)10,7
    • Family history of similarly affected siblings2,7
    • MRI findings of proliferative synovitis without erosions7
    • Joint pain and contractures without systemic and local signs of inflammation6

Stiffness and contractures may affect any joint but are often observed at phalangeal joints.6

  • The characteristic “claw hand” deformity develops when interphalangeal joints of the hands are affected6
    • Patients with MPS are more likely to have distal interphalangeal joint involvement6
    • Patients with inflammatory arthritis are more likely to have proximal interphalangeal or metacarpophalangeal joint involvement6
  • Because carpal tunnel syndrome is uncommon in childhood, its occurrence in a child should prompt suspicion of MPS6

Take a deep dive into signs and symptoms that should elevate your suspicion of MPS

Presentation and disease progression are unpredictable, multisystemic and variable across and within MPS disorders, making diagnosis challenging.1

Delayed diagnosis is common and it can have devastating consequences for your patients. Early identification of signs and symptoms across systems can be critical to early and accurate diagnosis. Become familiar with the diverse signs and symptoms of MPS that may present in your department.1,2,6

Discover the signs and symptoms of MPS

A more common joint condition or MPS?

MPS joint disorders can mimic, and thus be confused with, more common rheumatological conditions.6 Because MPS treatment can have a life-changing impact, early and accurate diagnosis is critical. If there is any suspicion of MPS, refer to a geneticist or local metabolic centre.1

Differential-diagnoses-to-rule-out-MPS-110_AMc
Rheumatologists should include MPS in the differential diagnosis for all patients with either joint contracture or laxity with or without inflammation.1,10
When in doubt over differential diagnoses, refer to rule out MPS

How else might you see MPS?

Patterns of signs and symptoms warrant a high suspicion of MPS

Regardless of the clinical setting, there are overt and generally observable signs that should raise your suspicion. Upon further examination, additional symptomatology may be discovered through speciality-specific targeted clinical assessments, laboratory findings and patient history. This division is illustrated below.

Signs and symptoms of MPS1-4,10,12–25

Musculoskeletal

General features

  • Abnormal gait
  • Bone dysplasia
  • Claw hands
  • Coarse facial features
  • Joint pain
  • Macrocephaly
  • Pectus carinatum
  • Reduced endurance/exercise intolerance
  • Short stature/growth retardationa

Features revealed by speciality-specific assessment

  • Abnormal gait
  • Bone deformities
  • Dysostosis multiplex
  • Genu valgum
  • Joint involvement (contractures, joint laxity) without inflammation
  • Spinal subluxation
Rheumatological

General features

  • Decreased joint mobility
  • Hip stiffness and pain
  • Joint pain
  • Joint stiffness or laxity

Features revealed by speciality-specific assessment

  • Carpal tunnel syndrome
  • Joint involvement without joint swelling or erosive bone lesions
Ear, nose and throat

General features

  • Conductive and/or sensorineural hearing loss
  • Enlarged tongue
  • Recurrent otitis media

Features revealed by speciality-specific assessment

  • Abnormal epiglottis
  • Depressed nasal bridge
  • Hypertrophic adenoids
  • Hypertrophic tonsils
  • Middle ear mucus
  • Narrowing of supraglottic and infraglottic airway
  • Ossicular malformation
  • Recurrent and excessive rhinorrhea
  • Recurrent otitis media
  • Tracheal thickening/compression
  • Tubular obstruction
  • Tympanic membrane thickening
Ophthalmological

General features

  • Cataracts
  • Diffuse corneal clouding
  • Glaucoma

Features revealed by speciality-specific assessment

  • Amblyopia
  • Corneal clouding with characteristic ‘ground glass’ appearance
  • High hyperopia
  • Hypertelorism
  • Optic nerve abnormalities (swelling and atrophy)
  • Peripheral vascularisation of the cornea
  • Progressive pseudo-exophthalmos
  • Reduction in visual acuity
  • Retinopathy
  • Strabismus
Neurological

General features

  • Behavioural abnormalities (typically not present in MPS IVA and VI)
  • Developmental delay (typically not present in MPS IVA and VI)
  • Hearing impairment
  • Seizures (typically not present in MPS IVA and VI)

Features revealed by speciality-specific assessment

  • Arachnoid cysts (typically not present in MPS IVA and VI)
  • Brain atrophy (typically not present in MPS IVA and VI)
  • Carpal tunnel syndrome
  • Cervical cord compression/myelopathy/subluxation
  • Enlarged perivascular space
  • Hydrocephalus
  • Odontoid dysplasia
  • Pachymeningitis cervicalis
  • Papilledema/optic atrophy
  • Sensorineural deafness
  • Signal-intensity abnormalities
  • Spinal canal stenosis
  • Ventriculomegaly
Cardiovascular

General features

  • Reduced endurance/exercise intolerance

Features revealed by speciality-specific assessment

  • Pulmonary hypertension
  • Thickened, regurgitant or stenotic mitral or aortic valves in presence of left ventricular hypertrophy
  • Tricuspid regurgitation
Pulmonary

General features

  • Reduced endurance/exercise intolerance
  • Sleep apnoea

Features revealed by speciality-specific assessment

  • Obstructed upper and lower airways (bronchial narrowing, narrowing of supraglottic and infraglottic airway)
  • Progressive reduction in lung volume
  • Respiratory infections
  • Sleep disorders (obstructive sleep apnoea/hypopnoea syndrome and upper airway resistance syndrome)
Gastrointestinal

General features

  • Abdominal pain
  • Constipation
  • Hepatosplenomegaly
  • Hernias
  • Loose stools

Features revealed by speciality-specific assessment

  • Hepatosplenomegaly
Dental

General features

  • Abnormal buccal surfaces
  • Dentinogenesis imperfecta
  • Hypodontia
  • Pointed cusps
  • Spade-shaped incisors
  • Thin enamel

Features revealed by speciality-specific assessment

  • Abnormal buccal surfaces
  • Thin enamel

aSkeletal involvement and short stature may be less overt in some patients.

Patients with undiagnosed MPS often have joint-related signs and symptoms (which may mimic other rheumatological disorders) and thus may present to a rheumatologist.6 Rheumatology consequently plays an essential role in identifying individuals with MPS. Appropriate patients should be referred to a geneticist or metabolic centre for definitive diagnosis and, when available, initiation of treatment.1
Refer to rule out MPS

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Early investigation leads to early intervention.
Avoid delay.

Refer patients to your local metabolic centre

Stay informed about the latest updates and information about MPS.

References:  1. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v41–v48.  2. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med 2011;72(2):91–95.  3. Hendriksz CJ et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A 2014;9999A:1–15.   4. Lachman RS et al. Mucopolysaccharidosis IVA (Morquio A syndrome) and VI (Maroteaux-Lamy syndrome): under-recognized and challenging to diagnose. Skeletal Radiol. 2014;43(3):359–369.   5. Clarke LA. Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. Rheumatology (Oxford). 2011;50(suppl 5):v13–18.   6. Morishita K et al. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v19–v25.   7. Muenzer J, Beck M, Eng CM, et al.Genet Med. 2011;13(2):95–101. doi:10.1097/GIM.0b013e3181fea459.  8. Spinello CM et al. Anesthetic management in mucopolysaccharidoses. ISRN Anesthesiol 2013;2013:1-10.   9. Lampe C et al. Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series. J Inherit Metab Dis 2014;37(5):823–829.   10. Cimaz R et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J. 2009;7:18.   11. Wood T et al. Expert recommendations for the laboratory diagnosis of MPS VI. Mol Genet Metab 2012;106(1):73–82.   12. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27-S34.  13. Thümler A et al. Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series. J Inherit Metab Dis 2012;35(6):1071–1079.   14. Montaño AM et al. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis 2007;30(2):165–174.   15. Kinirons MJ et al. Nelson J. Dental findings in mucopolysaccharidosis type IV A (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol. 1990;70(2):176–179.  16. Lachman R et al. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med 2010;3(2):109–118.   17. Fahnehjelm KT et al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol. 2012;90(7):595–602.   18. Zafeiriou DI et al. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol 2013;34(1):5–13.   19. Braunlin EA et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–1197.   20 Braunlin E et al. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol 2014;23(3):145–151.   21. Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  22. Berger KI et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):201–210. doi:10.1007/s10545-012-9555-1.  23. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32–S46.   24. Clarke LA et al. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.   25. Kakkis ED The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.26. Data on file. Biomarin Pharmaceutical, Inc.  27. Drummond JC et al. Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis. Can J Anesth. 2015;62(1):45–49. doi:10.1007/s12630-014-0247-1.  28. Sharkia R et al. Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report. J Med Case Rep 2014;8:78.