In many genetic conditions, diagnostic delay is common due to lack of clinical suspicion

Many patients with mucopolysaccharidosis (MPS) disorders experience significant diagnostic delay because of disease rarity, phenotypic heterogeneity, and a myriad of seemingly unrelated symptoms associated with the disease.^1-3 In a recent survey of patients with rare diseases (N=920) sponsored by the Global Genes Project, the mean reported length of time from symptom onset to accurate diagnosis was 4.8 years, with a range of 0 to 20 years.⁴ Commonly misperceived as musculoskeletal conditions, MPS disorders are a group of inherited enzyme deficiencies that manifest in progressive, multisystemic, and life-threatening complications.^5-7

Watch key opinion leader Dr Offiah talk about variability in phenotype and disease progression.

The emergence of specific therapies for some MPS disorders has increased the need for accurate and early diagnosis.^1,6,8-10 Any delay in diagnosis or treatment may result in the following:

Serious systemic complications^11,12

Irreversible organ damage¹²

Delay in initiating enzyme replacement therapy (ERT) to address underlying enzyme deficiency²

Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality^1,6,9,10,13

Since treatment exists for several MPS disorders, delay in diagnosis can mean delay in therapy and/or delay in disease-specific management.^6,9,10

MPS: hiding in plain sight

Early recognition hinges on early suspicion

MPS disorders are clinically heterogeneous and result in serious complications regardless of the rate of progression, which can range from slowly to rapidly progressing. While rates of progression are gross characterisations of disease severity, patients with slowly progressing disease are also at risk for the serious morbidities and mortality commonly associated with rapidly progressing disease.^2,6,14

If untreated, many individuals do not live far into adulthood (second and third decade).¹⁵
Individuals with slowly progressing disease typically present with symptoms later in life.^14,16

Patients with MPS can present with classical or non-classical patterns of signs and symptoms.¹⁶

Classical symptomology may present as more easily recognisable patterns of signs and symptoms that have been extensively documented in literature and in clinical practice.¹⁶
Non-classical symptomology may present more subtly – without the distinct facial features, short stature, or obvious musculoskeletal involvement of classical forms of MPS – making this phenotype more difficult to distinguish from other, more common skeletal or metabolic disorders.¹⁶
As an example, in an international registry, approximately 25% of patients with Morquio A syndrome.²⁷

Non-classical patient
Non-classical patient

Slowly progressing disease – and/or non-classical phenotypic appearance – can belie severe clinical course in specific organ progression.¹⁸ Regardless of phenotype, symptoms can progress into end-organ damage.¹²

Overt and generally observable signs should raise your suspicion

Regardless of the clinical setting, there may be 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 MPS^{1,2,5,11,12,16-28}

Musculoskeletal

General features

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

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
Otitis media