Diagnosis

Suspicion of Hunter syndrome

It can be very challenging to diagnose Hunter syndrome, because many of the early symptoms overlap with common childhood complaints. This can lead to repeated misdiagnosis, and a delay to proper management of the condition.¹

Suspicion of Hunter syndrome should arise if symptoms such as otitis media and enlarged tonsils/adenoids occur repeatedly, and in combination with more specific features of Hunter syndrome such as abdominal hernias, an enlarged tongue, and a large head circumference. It’s important then to evaluate the patient’s medical history more thoroughly, to check if there were common Hunter syndrome symptom clusters that previously went unnoticed.¹

If you suspect Hunter syndrome, you can then conduct a physical examination for current joint stiffness, enlarged abdomen, and the other non-neuronopathic symptoms of the disease. In older children you can assess for cardiac problems but also, regardless of age, take a step back and look for the characteristic facial features of Hunter syndrome.¹

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There are several stages in diagnosing the Hunter syndrome patient.

URINARY GAGS

Hunter syndrome is characterised by the storage of glycosaminoglycans, or GAGs, which may be excreted in the urine.² In Hunter syndrome specifically, an excessive amount of the GAGs dermatan sulfate and heparan sulfate can be detected in the urine and therefore, a urinary assessment for elevated GAGs is typically the first test to be carried out in patients suspected of Hunter syndrome³ (unless there is already a strong family history of Hunter syndrome, in which case this step may be omitted).
A negative result does not necessarily rule out a lysosomal storage disease, as there is an overlap between GAG urinary levels in healthy patients and those with a storage disorder.³

The urinary GAG test is performed using both quantitative and semi-quantitative assays, and is the first diagnostic indicator of a lysosomal storage disease (although not specifically Hunter syndrome). If GAG levels themselves are not abnormally elevated in patients suspected of a storage disorder, it is recommended that the urine samples are also analysed via chromatography or electrophoresis, in order to identify any abnormal GAG patterns.^2,4
Differential diagnosis

Different lysosomal storage diseases can elevate urinary levels of dermatan sulfate or heparan sulfate, due to lack of different lysosomal enzymes, including Hurler syndrome (MPS I) and Sly syndrome (MPS VII).²

Therefore, excessive or abnormal urinary GAG levels do not specify which disorder the patient has: further diagnostic steps are necessary.²

Heparan sulfate levels alone can be increased in Sanfilippo syndrome (MPS III), and dermatan sulfate levels alone can be increased in Maroteaux–Lamy syndrome (MPS VI).²
I2S enzyme

The characteristic feature of Hunter syndrome is iduronate-2-sulfatase (I2S) deficiency, whereas other lysosomal storage disorders are caused by deficiencies in other enzymes.²

To specify Hunter syndrome, after urinary GAG levels have been found to be elevated, it is essential to assess the reduction in I2S enzyme in the body.²

I2S is normally present in the lysosomes of all cells (except red blood cells), so I2S assays can be performed on fibroblasts, leukocytes, plasma or serum in blood samples.²

Multiple enzyme assays will be able to diagnose a lysosomal storage disorder, and a reduced I2S presence with confirmed normal presence of the other lysosomal enzymes is indicative of Hunter syndrome.²
Mutation identification

Genetic analysis, identifying mutations in the gene IDS, confirms a diagnosis of Hunter syndrome. Even after an I2S enzyme deficiency has been measured, a multiple sulfatase deficiency is still possible, and must be ruled out. Genetic analysis is also the only way to test for carriers of Hunter syndrome mutation (heterozygous females).²

Over 500 different mutations of the IDS gene have been observed, and this variability makes it hard to predict the disease symptoms, however, there is an association between neuronopathic Hunter syndrome and mutations that cause an absence (rather than a deficiency) of I2S enzyme.⁵
Genetic counselling

Confirmation of Hunter syndrome with a genetic analysis has immediate implications for the patient and the family, and therefore genetic counselling is extremely important in the genetic testing process. The genetic counsellor explains the purpose of the genetic test to the family, the cause and symptoms of the disease, and the consequences including the need for specialist multidisciplinary care and to screen the family for Hunter syndrome carriers and other undiagnosed patients.¹

1. Scarpa M et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 2011; 6: 72.
2. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 2012; 171(4): 631–639.
3. Martin R et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008; 121(2): e377–e386.
4. Mahalingam K et al. Diagnosis of mucopolysaccharidoses: how to avoid false positives and false negatives. Indian J Pediatr 2004; 71(1): 29–32.
5. Demydchuk M et al. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun 2017; 8: 15786.

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