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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

Respiratory involvement in MPS: heterogeneous expression, far-reaching consequences

Pulmonology plays a critical role in MPS diagnosis

Respiratory symptoms are commonly seen in individuals with mucopolysaccharidosis (MPS) and may lead to an MPS diagnosis. Airway obstruction and respiratory impairment are prominent features of MPS and may progress early in the course of the disease.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, pulmonology 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. If left untreated, upper airway compromise can have life-altering consequences:10,11

  • Obstructive sleep apnoea syndrome will progress
  • Chronic respiratory failure may eventually occur, resulting in premature death
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.12
Respiratory disorders are prevalent across most MPS types and have a variety of manifestations, including narrow airways and obstructive sleep apnoea.11
A cross-sectional study assessing upper airway obstructive disease in 11 patients with MPS demonstrates the consequences of upper airway compromise.10
Measurements-indicated-upper-airway-obstructive-disease-in-MPS_AMc

Although presentation, progression and prevalence of respiratory symptoms vary across MPS disorders, the table below illustrates the most frequent respiratory complications in MPS patients.

Most-frequent-respiratory-involvement-in-patients-with-MPS_AMc

Many respiratory manifestations associated with MPS have airway obstruction as a prominent feature.11

  • Initially, obstructive symptoms are more pronounced in the upper airway11
  • Tracheobronchial manifestations occur later but are frequently the cause of death in patients with MPS I and II11
  • In patients with significant skeletal involvement (MPS IV and VI), restrictive lung disease predominates11

Along with the preceding common respiratory signs, the following should also raise your index of suspicion for MPS:

  • Progressive respiratory insufficiency and abdominal distension, which are indicative of restrictive lung disease11
  • Significantly smaller retropalatal and retroglossal spaces in both children and adults10
  • Abnormalities that can reduce ventilatory capacity, manifesting as reduction in vital capacity:
    • Hepatosplenomegaly11
    • Kyphoscoliosis11
    • Pectus carinatum11
    • Short stature11
    • Skeletal dysplasia10
Respiratory manifestations, especially if coupled with other classical or non-classical signs, should prompt 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 specialty-specific targeted clinical assessments, laboratory findings and patient history. This division is illustrated below.

Signs and symptoms of MPS2-5,13–27

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 speciality-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 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 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 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
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 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
Cardiovascular

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
Pulmonary

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)
Gastrointestinal

General features

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

Features revealed by speciality-specific assessment

  • Hepatosplenomegaly
Dental

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 respiratory symptoms often appear early in the natural history of MPS, pulmonology can play a key role in identifying individuals with MPS. Pulmonology can help optimise patient outcomes by early referral of appropriate patients to a geneticist or metabolic centre for definitive diagnosis and, when available, initiation of treatment.

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