X
X
X
X
MPS Reference
The information contained in this section of the site is intended for Healthcare Professionals only.

Are you a Healthcare Professional?

YesNo
Back to Top
Make this site experience relevant for you

“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

Scroll down page for more

Skeletal manifestations – classical 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

Refer to rule out MPS
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

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 MPS.1
  • 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 MPS.1
  • Early in disease manifestation, skeletal symptoms may appear in isolation or be less overt.1
Stay informed about emerging research in MPS
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
The-manifestations-of-dysostosis-multiplex_AMc

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 primarily from CNS-related symptoms.7
  • Among patients with MPS, the severity of the dysostosis multiplex is variable, and features may present early in isolation.7
Of 151 cases in the International Skeletal Dysplasia Registry with confirmed dysostosis multiplex submitted for evaluation, approximately 75% of referring doctors 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.

Patients-showing-thoracolumbar-kyphosis-and-gibbus-in-first-months-of-life

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.

Learn more about the hallmark skeletal features of MPS

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 diagnosis.1
  • One hallmark feature in these patients was dysplastic capital femoral epiphyses (CFE), a finding that may be useful in identifying non-classical MPS phenotypes.1

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 practice.

Discover the signs and symptoms of MPS

How else might you see MPS?

Patterns of signs and symptoms should raise 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 specialty-specific targeted clinical assessments, laboratory findings and patient history. This division is illustrated below.

Signs and symptoms of MPS1,5,7,9,11-24

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 specialty–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 specialty–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 specialty-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 specialty-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 specialty-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 specialty-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 specialty-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 specialty-specific assessment

  • Hepatosplenomegaly

Dental

General features

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

Features revealed by specialty-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, initiate management to improve outcomes.1,4,25

Refer to rule out MPS

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 Because management of MPS can improve patient outcomes, early and accurate diagnosis is critical. If there is any suspicion of MPS, consider referring to a geneticist or local metabolic centre.

Differential-diagnoses-to-rule-out-MPS_AMc

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 the following1:

  • Growth delay
  • Abnormal gait
  • Hip pain

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

Watch key opinion leader Dr Offiah discuss the importance of performing a full skeletal survey as a critical confirmatory measure in ruling out skeletal dysplasias.

When you suspect MPS, refer to a geneticist or metabolic centre

Paediatric case of slowly progressing MPS VI seen in orthopaedic practice1

Summary:

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 non-classical features, can help in reducing time to diagnosis.
Take a closer look at the systems affected by MPS
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.

It's a new era in management. Stay informed.

References:  1. Lachman RS, Burton BK, Clarke LA, 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. doi:10.1007/s00256-013-1797-y.  2. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(suppl 5):v26-v33. doi:10.1093/rheumatology/ker393.  3. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.  4. White KK, Sousa T. Mucopolysaccharide disorders in orthopaedic surgery. J Am Acad Orthop Surg. 2013;21:12-22. doi:10.5435/JAAOS-21-01-12.  5. Lehman TJA, Miller N, Norquist B, Underhill L, Keutzer J. Diagnosis of the mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v41-v48.  6. Wood TC, Harvey K, Beck M, et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013;36(2):293-307. doi:10.1007/s10545-013-9587-1.  7. Lachman R, Martin KW, Castro S, Basto MA, Adams A, Teles EL. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med. 2010;3(2):109-118. doi:10.3233/PRM-2010-0115.  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, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v19-v25. doi:10.1093/rheumatology/ker397.  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, Miebach E, Lampe C, et al. Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series. J Inherit Metab Dis. 2012;35(6):1071-1079. doi:10.1007/s10545-012-9474-1.  13. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30(2):165-174. doi:10.1007/s10545-007-0529-7.  14. 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.  15. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.  16. Cimaz R, Coppa GV, Koné-Paut I, et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J. 2009;7:18. doi:10.1186/1546-0096-7-18.  17. Fahnehjelm KT, Ashworth JL, Pitz S, et al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol. 2012;90(7):595-602. doi:10.1111/j.1755-3768.2011.02280.x.  18. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol. 2013;34(1):5-13. doi:10.3174/ajnr.A2832.  19. Braunlin EA, Harmatz PR, Scarpa M, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis. 2011;34(6):1183-1197. doi:10.1007/s10545-011-9359-8.  20. Braunlin E, Orchard PJ, Whitley CB, Schroeder L, Reed RC, Manivel JC. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol. 2014;23(3):145-151. doi:10.1016/j.carpath.2014.01.001.  21. Mesolella M, Cimmino M, Cantone E, et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital. 2013;33(4):267-272.  22. Berger KI, Fagondes SC, Giugliani R, 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, Dualibi AP, Norato D, et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr. 2009;155(4)(suppl 2):S32-S46. doi:10.1016/j.jpeds.2009.07.005.  24. Clarke LA, Winchester B, Giugliani R, Tylki-Szymańska A, Amartino H. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab. 2012;106(4):396-402. doi:10.1016/j.ymgme.2012.05.003.  25. Wood T, Bodamer OA, Burin MG, et al. Expert recommendations for the laboratory diagnosis of MPS VI. Mol Genet Metab. 2012;106(1):73-82. doi:10.1016/j.ymgme.2012.02.005.