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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

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
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.


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

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

Rheumatologists should include MPS in the differential diagnosis for all patients with either joint contracture or laxity with or without inflammation.1,10

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


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

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

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

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

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

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)

General features

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

Features revealed by speciality-specific assessment

  • Hepatosplenomegaly

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

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