Hunter Criteria for Diagnosing Mucopolysaccharidosis Type II
The diagnosis of MPS II (Hunter syndrome) is confirmed by demonstrating deficient iduronate-2-sulfatase (IDS) enzyme activity in plasma or leukocytes, followed by molecular genetic testing of the IDS gene to identify pathogenic mutations. 1
Diagnostic Algorithm
Step 1: Biochemical Confirmation
- Measure plasma IDS enzyme activity as the primary screening test 1
- Simultaneously assay a second sulfatase (either arylsulfatase A [ARSA] or arylsulfatase B [ARSB]) to exclude multiple sulfatase deficiency (MSD), which is caused by SUMF1 gene mutations 1
- If only IDS is deficient, proceed with MPS II-specific testing 1
- If both IDS and the second sulfatase are deficient, sequence SUMF1 to confirm MSD rather than isolated MPS II 1
Critical caveat: Plasma IDS enzyme activity levels cannot predict disease severity or distinguish between severe and attenuated phenotypes 1. Enzymatic analysis also cannot determine female carrier status 1.
Step 2: Molecular Genetic Testing
Once biochemical deficiency is confirmed, perform IDS gene sequencing and deletion/duplication analysis 1:
- Approximately 20% of patients have gross gene rearrangements resulting from recombination with the IDS pseudogene 1
- Patients with extensive deletions may present with contiguous gene deletion syndrome and atypical features including seizures 1
- Over 450 unique mutations have been identified, with limited genotype-phenotype correlation for most variants 1
Step 3: Clinical Phenotyping
After diagnostic confirmation, comprehensive multidisciplinary evaluation is essential 1:
Severe phenotype characteristics (typically diagnosed 18-36 months) 1:
- Cognitive regression and neurodevelopmental decline
- Aggressive or difficult behavior
- Earlier onset and more rapid progression
Attenuated phenotype characteristics (typically diagnosed 4-8 years) 1:
- Learning disabilities or normal intelligence without neurodegeneration
- Slower disease progression
- Later symptom onset
Common somatic manifestations across all phenotypes 1, 2:
- Joint contractures and stiffness (90.7% of patients) 3
- Musculoskeletal abnormalities (95.0%) 3
- Ear, nose, and throat abnormalities (95.7%) 3
- Hepatosplenomegaly (median onset 3.8 years) 3
- Facial dysmorphism (median onset 3.8 years) 3
- Characteristic "pebbly" skin thickening 1
- Obstructive and restrictive airway disease 2
- Cardiac valve dysfunction and cardiomyopathy 2
- Corneal clouding visible only on slit-lamp examination (does not impair vision) 1
Step 4: Post-Diagnostic Evaluation
Following confirmed diagnosis 1:
- Metabolic genetics consultation with genetic counseling
- Neurodevelopmental assessment to establish baseline cognitive function
- Multidisciplinary subspecialty evaluations (cardiology, pulmonology, orthopedics, ophthalmology, ENT)
- Baseline urinary glycosaminoglycan (GAG) measurement
- Imaging for hepatosplenomegaly and skeletal abnormalities
Key Diagnostic Pitfalls
Enzyme activation requirement: IDS requires post-translational modification of cysteine 59 to formyl-glycine for enzymatic activity 1. This modification is performed by the SUMF1 gene product, making concurrent testing of a second sulfatase mandatory to avoid misdiagnosis.
Female patients: While MPS II is X-linked and affects almost exclusively males, rare symptomatic females have been documented 1. Newborn screening programs will identify females with low IDS activity who require confirmatory testing 1.
Genotype-phenotype uncertainty: Many mutations lack clear phenotype prediction, including p.A85T, p.P86L, p.R468Q, p.R468W, p.R172X, and p.R443X, which have been reported across the severity spectrum 1. Clinical monitoring every 3-4 months with serial neurodevelopmental assessments is essential when phenotype cannot be predicted from genotype 1.