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“We hope that when the pediatrician 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

Skeletal manifestations, classic and non-classical, are a hallmark of MPS

Orthopaedics plays a critical role in MPS suspicion, referral and long-term management

Skeletal manifestations are hallmark features of mucopolysaccharidosis (MPS) disorders.1,2 With the availability of disease-specific treatments and management, early recognition by orthopaedics has never been more important.1

Identification of MPS is also critical to improve surgical outcomes; patients with MPS have a heightened risk of anaesthetic and perisurgical complications that are a significant cause of mortality in this population.3

Classically, MPS is associated with a cluster of signs and symptoms referred to as dysostosis multiplex. However, recognition of early and non-classical skeletal symptoms prior to, or in lieu of, more robust skeletal progression can enable early recognition of MPS and should prompt referral to a geneticist or metabolic centre.1,2

Suspect, refer and rule out MPS

Because of emerging knowledge and therapeutic options, orthopaedics 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.1,4 Be aware of signs and symptoms to expedite early intervention.

  • Dysostosis multiplex is a cluster of hallmark skeletal manifestations classically associated with MPS1,2
  • Non-classical patterns of skeletal manifestations similar to spondyloepiphyseal dysplasia (SED), multiple epiphyseal dysplasia (MED) and Legg-Calvé-Perthes disease have been identified as symptoms of MPS1
  • Early in disease manifestation, skeletal symptoms may appear in isolation or be less overt1,5
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. Maintain a heightened index of suspicion to enable earlier disease-specific intervention.5,6

Most MPS types are characterised by skeletal abnormalities and joint disease with hallmark features of dysostosis multiplex.7

  • MPS III is an exception — patients manifest with only mild dysostosis multiplex and suffer from primarily CNS-related symptoms7
  • Among patients with MPS, the severity of the dysostosis multiplex is variable and features may present early in isolation7
Of 151 cases in the International Skeletal Dysplasia Registry with confirmed dysostosis multiplex submitted for evaluation, approximately 75% of referring physicians did not recognise this as a hallmark of MPS.1

Early recognition of skeletal symptoms can help to optimise patient outcomes

With the availability of treatment and disease-specific management, early recognition has never been more important.


Example of gibbus (left) early in life and thoracolumbar kyphosis (right).8

Photos courtesy of Dr M Grimaldi, Dr R Parini, Dr L Santoro and Dr O Gabrielli.

Slowly progressing MPS: new insights, new understanding

In a case series of non-classical presentation in patients with Morquio A (MPS IVA) and slowly progressing MPS VI, patients presented with minimal or no features of dysostosis multiplex. Instead, features indicative of MED, SED and bilateral Legg-Calvé-Perthes-like disease were seen.1

  • MPS was distinguished from SED by the absence of platyspondyly or superior/inferior humping of vertebral bodies; the presence of scoliosis, kyphosis, and/or a single superior notched vertebra is not sufficient for a SED diagnosis1
  • One hallmark feature in these patients was dysplastic capital femoral epiphyses (CFE), a finding that may be useful in identifying non-classical MPS phenotypes1

Dysplastic CFE has been reported in patients with non-classical Morquio A and slowly progressing MPS VI.

Anteroposterior pelvis and hips, age 27 years: mildly dysplastic CFE with joint space narrowing; sclerosis (degenerative arthrosis).1

Learn about the 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.5

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.5,9,10 Become familiar with the diverse signs and symptoms of MPS that may present in your department.

How else might you see MPS?

Patterns of signs and symptoms should elevate your clinical 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 MPS1,5,7,9,11–25


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 vascularization 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.

As skeletal manifestations are typically early indicators of MPS disorders, orthopaedics can play a key 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.1,4,26

Is it a common skeletal condition or MPS?

Consider MPS in the differential diagnosis of skeletal conditions

MPS disorders can mimic, and thus be confused with, more common musculoskeletal conditions.1,7 As MPS treatment can have a life-changing impact, early and accurate diagnosis is critical. If there is any suspicion of MPS, consider referring to a geneticist or local metabolic centre.


Consider MPS when patients present with isolated skeletal features of MPS early in life. In such cases, patients have typically presented with additional musculoskeletal abnormalities, such as:1

  • Growth delay
  • Abnormal gait
  • Hip pain

A full skeletal survey is mandated if MPS or other skeletal dysplasia is suspected.1,7 Imaging of only isolated regions can result in missed findings that can impair diagnosis.

Paediatric case of slowly progressing MPS VI seen in orthopaedics1


Earlier consideration of MPS upon observation of MED-like phenotype with additional systemic manifestations, such as corneal clouding, could have improved time to diagnosis and subsequent intervention.

Heightened index of suspicion for MPS in patients with skeletal features of MPS, such as classic dysostosis multiplex or nonclassical features, can help in reducing time to diagnosis.
Age 7 years:
  • Referred to orthopaedics because of short stature
  • Radiographs interpreted as demonstrating bilateral acetabular dysplasia with coxa magna, deformities of femoral heads and epiphyseal and metaphyseal abnormalities
  • Physical exam revealed height of 117.5 cm (<5th percentile), weight of 22 kg (5th percentile), head circumference of 54.5 cm (+1 SD)
  • Limitation in range of motion in shoulder noted
  • Corneal clouding noted
  • Initial diagnosis: MED
  • Action: referred to skeletal dysplasia clinic and to ophthalmology
Age 10 years:
  • Heart murmur detected
  • Cardiology assessments revealed mitral valve thickening with prolapse and regurgitation, mild aortic insufficiency
  • Genetics visit noted mild genu valgum, waddling gait, lordosis of the spine, broad flat nasal bridge
  • MPS was suspected, full skeletal survey and enzymatic panel testing performed
  • Diagnosis: MPS VI

Read More

Early investigation leads to early intervention.
Avoid delay.

Stay informed about the latest updates and information about MPS.

References:  1. 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.   2. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(suppl 5):v26–v33.   3. Walker R et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):211–219.   4. White KK et al. Mucopolysaccharide disorders in orthopaedic surgery. J Am Acad Orthop Surg 2013;21:12–22.   5. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v41–v48.  6. Wood TC et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013;36(2):293–307.   7. Lachman R et al. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med 2010;3(2):109–118.   8. Data on file. Biomarin Pharmaceutical, Inc.  9. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med 2011;72(2):91–95.  10. Morishita K et al. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v19–v25.   11. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27–S34.  12. 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.   13. 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.   14. Kinirons MJ et al. Dental findings in mucopolysaccharidosis type IV A (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol 1990;70(2):176-179.  15. 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.   16. Cimaz R et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J 2009;7:18.   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.   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 Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.  25.Kakkis ED et al. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.  26. Wood T et al. Expert recommendations for the laboratory diagnosis of MPS VI. Mol Genet Metab. 2012;106(1):73–82.