The level of urinary glycosaminoglycans (GAGs) is increased in patients with any MPS type, so detection of excessive urinary GAGs is usually the first diagnostic indicator (unless a strong family history allows this stage to be bypassed).1,2 The presence of the specific GAGs dermatan sulfate and heparin sulfate in the urine could indicate Hunter syndrome; however, urinary GAG assays are not diagnostic and enzyme activity assays should be performed for a definitive diagnosis.1
Urine samples should be analyzed via chromatography or electrophoresis to identify abnormal GAG patterns, even if their levels are not elevated.1 A negative GAG test does not necessarily rule out Hunter syndrome (MPS II) as a diagnosis.1,2
Testing for absent or very low iduronate-2-sulfatase (I2S) activity is diagnostic for Hunter syndrome. Enzyme activity can be measured in cultured fibroblasts, leukocytes, plasma or serum, or dried blood spots.1,2
A second sulfatase should be measured to rule out multiple sulfatase deficiency and confirm the diagnosis of Hunter syndrome.1,2
Over 330 alterations in the I2S gene have been reported in Hunter syndrome patients.1 Once a likely disease-causing mutation has been identified, a detailed pedigree analysis should be conducted to identify family members who may be carriers or at risk of the disease, and genetic counseling should be offered to all family members.1,2
Pre-implantation and prenatal genetic diagnosis can identify affected embryos in at-risk pregnancies.2 I2S enzyme assays or testing for GAG levels on amniotic fluid cells, in chorionic villus biopsy tissue or cord blood, can be offered to mothers with a family history of MPS II to allow for informed decisions in family planning.1,2
Newborn screening could prevent diagnostic odysseys and delayed diagnoses experienced by many families who have a child with MPS II, which would likely lead to improved patient outcomes.3 Newborn screening for MPS II is currently ongoing in Taiwan and there are a number of pilot projects in Japan.3 Illinois became the first state in the US to implement population-based newborn screening for MPS II in December 2017.3 This involves measuring I2S enzyme activity and referring newborns with a positive result to a specialist for diagnostic testing.3
Adapted from Burton BK and Giugliani R. Eur J Pediatr. 2012;171(4):631-639, and Scarpa M et al. Orphanet J Rare Dis. 2011;6:72.
1. Burton BK, Giugliani R. Eur J Pediatr. 2012;171(4):631-639. 2. Scarpa M et al. Orphanet J Rare Dis. 2011;6:72. 3. Burton BK et al. Int J Neonatal Screen. 2020;6(3):73.
Hunter syndrome is a
progressive genetic disease
If you suspect Hunter syndrome, refer your patient to a metabolic geneticist for an accurate diagnosis.