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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

Ocular involvement in MPS: frequent presentation, potentially overlooked

Ophthalmology plays a key role in early MPS diagnosis

Ocular manifestations often arise prior to other features of mucopolysaccharidosis (MPS) and vary by type and severity among the MPS disorders. Corneal clouding is a hallmark feature of MPS.1

Delayed diagnosis can lead to:

  • Severe multisystemic complications3,5
  • Irreversible or end-organ damage5
  • Delayed treatment2
  • Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality5–9
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 emerging knowledge and therapeutic options, ophthalmology 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. Be aware of signs and symptoms to expedite early intervention.10

Ocular features, often leading to visual impairment, have been described in all types of MPS and should raise suspicion of MPS.1

Common ocular manifestations include:10

  • Corneal clouding
  • Retinopathy
  • Glaucoma
  • Optic nerve swelling and atrophy
  • High hyperopia
  • Peripheral vascularisation of the cornea
  • Progressive pseudo-exophthalmos
  • Hypertelorism
  • Amblyopia
  • Strabismus

Corneal clouding is a very common feature of MPS I, VI, and VII and can also occur in all other MPS types.1 Corneal clouding in MPS has a characteristic ‘ground glass’ appearance, which is also observed in inherited corneal dystrophies such as congenital hereditary corneal dystrophy and Harboyan syndrome.11 In patients with MPS, corneal clouding is progressive and often present from infancy. It may initially be asymptomatic (detected at screening) or present as photophobia with slow but progressive loss of visual acuity. In a later stage, it can lead to loss of vision.1

Although patients with MPS typically present with a wide range or cluster of unusual symptoms, isolated symptoms may be sufficient to merit referral to a geneticist or metabolic centre.12

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.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.2,5,7 Become familiar with the diverse signs and symptoms of MPS that may present in your department.2

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 MPS2-5,10,13-26


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.

Ophthalmology can play a key role in identifying individuals with MPS and should refer appropriate patients to a geneticist or metabolic centre for definitive diagnosis and, when available, initiation of treatment.12

Case study: ocular manifestations lead to referral and subsequent diagnosis of MPS27

Ocular manifestations in an infant lead to subsequent diagnosis of MPS I-H


  • Infant referred for ocular assessment because of abnormally increasing head circumference at 12 months of age
  • Corneal opacities of unknown origin detected, together with a dysmorphic face, telecanthus and atypical eyebrows
  • Diagnosed with MPS I-H at 18 months of age
Patients with slowly progressing MPS can easily remain undiagnosed.

Case history

Age 12 months:

  • Referred for ocular assessment to rule out papilledema because of an abnormally increasing head circumference
  • Corneal opacities of unknown origin detected, together with a dysmorphic face, telecanthus and atypical eyebrows
  • After ventriculoperitoneal shunting surgery, subject’s pre-existing strabismus disappeared, but hypersensitivity to light remained

Age 18 months:

  • Diagnosed with MPS I
  • Underwent stem cell transplantation
  • Grating acuity was 3.6 cycles/degree binocularly, but reflexes from ocular fundi reported as dull

Age 3 years:

  • Binocular visual acuity, 0.5; stereopsis negative; hyperopia (+5 in right and left eyes) detected
  • Refractive filter glasses prescribed and well accepted

Age 4.5 years:

  • Right-sided microesotropia and amblyopia detected
  • Intensive occlusion therapy started
  • Right eye remained amblyopic
  • Corneas remained slightly cloudy

Age 6.7 years:

  • Corneal thickness showed no remarkable deviation from normal


Delayed diagnosis of MPS leads to disease progression and poses a threat to patients.

However, clinical evaluation of children with MPS poses challenges for ophthalmology:

  • Retinoscopy may be difficult to perform due to dull fundus reflexes
  • Examination may be hampered by severe photophobia and lack of cooperation, cognitive delay or hyperactivity disorders

In this case, early diagnosis of MPS I-H enables early intervention and management, which are associated with improved clinical outcomes.

Better knowledge of the ocular and non-ocular manifestations of MPS may help in the early diagnosis of children with MPS who present with ocular problems but are not yet diagnosed with the disease.1,10

Any number of ocular manifestations, especially if coupled with other classical or non-classical signs, should prompt referral to a geneticist or metabolic centre.12

Read More

Early investigation leads to early intervention.
Avoid delay.

Stay informed about the latest updates and information about MPS.

References:  1. Ashworth JL et al. Ocular manifestations in the mucopolysaccharidoses – a review. Clin Experiment Ophthalmol 2010;38(suppl 1):12–22.   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. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v41–v48.  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.   7. Morishita K et al. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v19–v25.   8. Muenzer J, Beck M, Eng CM, et al.Genet Med. 2011;13(2):95–101. doi:10.1097/GIM.0b013e3181fea459.  9. Spinello CM et al. Anesthetic management in mucopolysaccharidoses. ISRN Anesthesiol 2013;2013:1–10.   10. Fahnehjelm KT et al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 2012;90(7):595–602.   11. Desir J, Abramowicz M. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome). Orphanet J Rare Dis 2008;3:28.   12. Wood TC et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis 2013;36(2):293–307.   13. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27–S34.  14. 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.   15. 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.   16. 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.  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. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol 2013;34(1):5–13.   20. Braunlin EA et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–1197.   21. Braunlin E et al. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol 2014;23(3):145–151.   22. Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  23. Berger KI et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):201–210.   24. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32–S46.   25. Clarke LA et al. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.   26. Kakkis ED, Neufeld EF. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.  26. Fahnehjelm KT et al. Ocular findings in four children with mucopolysaccharidosis I-Hurler (MPS I-H) treated early with haematopoietic stem cell transplantation. Acta Ophthalmol Scand 2006: 84:781–785.