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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

Is there a rare genetic disease hiding in your department?

Often mischaracterised as either purely a childhood disorder or a musculoskeletal disease, MPS might not be as uncommon as you think

Mucopolysaccharidosis (MPS) disorders are a group of inherited enzyme deficiencies with heterogeneous presentation and variable disease progression that are suspected to affect 1 in 22,500 live births worldwide.1,2

Similar clinical manifestations and rates of progression are seen across MPS disorders. The images below illustrate patterns of MPS disease progression as seen in a patient with MPS VI.

All patients, regardless of initial presentation, are at risk for end-organ damage.

Variable disease progression in patients with MPS VI

  • Rapidly-progressing-MPS-VI-patient-as-a-newborn
  • Rapidly-progressing-MPS-VI-patient-at-2-years-old
    2 Years
  • Rapidly-progressing-MPS-VI-patient-at-6-years-old
    6 Years
  • Rapidly-Progressing-MPS-VI-patient-at-10-years-old
    10 Years
  • Rapidly-Progressing-MPS-VI-patient-at-16-years-old
    16 Years
  • Rapidly-Progressing-MPS-VI-patient-at-26-years-old
    26 Years
  • Slowly-progressing-MPS-VI-patient-at-7-months-old
    7 Months
  • Slowly-progressing-MPS-VI-patient-at-3-years-old
    3 Years
  • Slowly-progressing-MPS-VI-patient-at-7-years-old
    7 Years
  • Slowly-progressing-MPS-VI-patient-at-10-years-old
    10 Years
  • Slowly-progressing-MPS-VI-patient-at-11-years-old
    11 Years
  • Slowly-progressing-MPS-VI-patient-at-13-years-old
    13 Years

Delay in diagnosis is common and can be devastating for patients3

Perceived disease rarity, variability in disease progression and presentation and the myriad of nonspecific symptoms associated with MPS make diagnosis challenging. Time to diagnosis from first symptom manifestation can range from six months to decades.3


Early diagnosis is essential to optimise patient outcomes3,5

Early diagnosis can enable improved patient outcomes through access to disease-specific management and enzyme replacement therapy (ERT).3,5–8

For many MPS disorders, there is an ERT either already available or in development. The best way to diagnose MPS and, in turn, initiate treatment, is to refer any patient you suspect to a geneticist or metabolic centre familiar with testing for it.9

Look for early signs and symptoms of MPS, especially:3,10–12

  • Classical
    • Hernias
    • Joint and skeletal abnormalities
    • Short stature
    • Any gradual, progressive changes in physical appearance
  • Non-classical
    • Subtle expressions of skeletal abnormalities, including thickened ribs or clavicles, subtle genu valgum, and joint abnormalities or pain
    • Reduced exercise capacity and/or unexplained cardiovascular involvement, especially heart murmur in paediatric patients
    • Unexplained hearing or visual impairment (corneal clouding)
A constellation of suggestive findings is especially significant, but the absence of a particular finding or characteristic does not necessarily rule out an MPS diagnosis.10

When should you suspect MPS?

When you see any number or pattern of signs that span multiple body systems and are indicative of MPS, don’t delay; refer to a geneticist or metabolic specialist

Symptomatology for MPS:

  • Spans multiple body systems8
  • May be either overt or discoverable through speciality-specific assessments

Overt symptoms are those that can be observed during any routine office visit or physical examination. Investigate the key visual features of MPS that are listed below.

General features and overt signs that should raise suspicion of MPS3,4,8,10,11,13-26


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


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

Ear, nose and throat

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


  • Cataracts
  • Diffuse corneal clouding
  • Glaucoma


  • 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)


  • Reduced endurance/exercise intolerance


  • Reduced endurance/exercise intolerance
  • Sleep apnoea


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


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

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

Prevalence of symptoms varies across MPS disorders. The example below outlines the prevalence of symptoms in patients with Morquio A (MPS IVA).

Slower walking speed, reduced cadence and lower than average stride length should trigger your suspicion of MPS.28

Short stature, while common in MPS, may not present in all MPS patients

  • As evidenced by a natural history study of patients with Morquio A, the majority of patients present with short stature and corresponding short trunk and neck16
  • Heights can range due to variability of disease progression; however, patients with slowly progressing or non-classical forms of MPS may not present with short stature13,14

The chart below, representative of the growth trajectory that is typical of individuals with MPS, is taken from a cohort of 326 patients with Morquio A who participated in the International Morquio A registry.13

Young patients who fall off the growth curve should raise your suspicion of MPS.

Any number or pattern of signs should increase your clinical suspicion

MPS disorders can present in any number of ways, often with a cluster of seemingly unrelated multisystemic symptoms. However, isolated symptoms also merit referral to a geneticist or metabolic centre.3,9

A patient’s surgical history and need should also alert you to the possibility of MPS

Surgical need is high among patients with MPS. Representative of this need, >70% of patients ≥5 years participating in MorCAP, a natural history study, had at least one surgical procedure.27


Awareness of a patient’s medical history in addition to signs and symptoms can expedite early and accurate diagnosis, and therefore improve patients’ lives.

Take a closer look at the systems affected by MPS

Presentation and disease progression are unpredictable, multisystemic and variable across and within MPS disorders, making diagnosis challenging.3

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.3,7,8 Become familiar with the diverse signs and symptoms of MPS that may present in your department.

Disorders that may look like MPS

MPS disorders can mimic other conditions

As MPS treatment can have a life-changing impact, early and accurate diagnosis is critical.8,29 If there is any suspicion of MPS, consider referring to a geneticist or local metabolic centre.3

MPS presents as a diverse array of signs and symptoms, leading to a long list of potential misdiagnoses.8 Most common misdiagnoses include spondyloepiphyseal dysplasia congenita (SED), multiple epiphyseal dysplasia (MED), and Legg-Calvé-Perthes disease.14

A more extensive table of common misdiagnoses is presented below.


A review of medical records of presenting signs and symptoms in 18 patients with Morquio A identified several misdiagnoses and other clinical diagnoses, shown in the table below.


Similarly, as the table below describes, an analysis of 18 patients with MPS VI conducted by managing physicians identified common misdiagnoses associated with this subtype.

The advancement of specific treatments for MPS highlights the importance of early intervention and referral of patients with suspected SED, MED, or Legg-Calvé-Perthes disease to a geneticist or metabolic centre.3,14,29

When in doubt over differential diagnoses, refer patients to a geneticist or local metabolic centre.3

Read More

Early investigation leads to early intervention.
Avoid delay.

Stay informed about the latest updates and information about MPS.

References:  1. Kakkis ED, Neufeld EF. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.  2. Coman DJ et al. Enzyme replacement therapy and extended newborn screening for mucopolysaccharidoses: opinions of treating physicians. JIMD Rep. 2011;1:9–15.   3. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v41–v48.  4. Jurecka A et al. Attenuated osteoarticular phenotype of type VI mucopolysaccharidosis: a report of four patients and a review of the literature. Clin Rheumatol. 2014;33(5):725–731.   5. Muenzer J, Beck M, Eng CM, et al.Genet Med. 2011;13(2):95–101. doi:10.1097/GIM.0b013e3181fea459.  6. 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. d  7. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v19–v25.   8. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med 2011;72(2):91–95.  9. Wood TC et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis 2013;36(2):293–307.   10. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27–S34.  11. 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.   12. Valayannopoulos V et al. Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010;5:5.   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. 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.   15. Kinirons MJ, 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. 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.   17. Lachman R et al. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med 2010;3(2):109–118.   18. Cimaz R et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J 2009;7:18.   19. Fahnehjelm KTet al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 2012;90(7):595–602.   20. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol 2013;34(1):5–13.   21. Braunlin EA et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–1197.   22. Braunlin E et al. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol 2014;23(3):145–151.   23. Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  24. Berger KI et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):201–210.  25. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32-S46.   26. Clarke LA et al. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.   27. Harmatz P et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab 2013;109(1):54–61.   28. Dhawale AA et al. Gait pattern and lower extremity alignment in children with Morquio syndrome. J Pediatr Orthop B 2013;22(1):59–62. doi:10.1097/BPB.0b013e32835a0e6d.  29. Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol Genet Metab 2014;111(2):63–72.   30. Bhattacharya K et al. Overcoming the barriers to diagnosis of Morquio A syndrome. Orphanet J Rare Dis 2014;9:192. doi:10.1186/s13023-014-0192-7.  31. Choy YS et al. Identifying the need for a multidisciplinary approach for early recognition of mucopolysaccharidosis VI (MPS VI). Mol Genet Metab 2015;115(1):41–47.   32. Data on file. Biomarin Pharmaceutical, Inc.  33. 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.   34. Sharkia Ret 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.