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Hunter syndrome: Mucopolysaccharidosis type II

Hunter syndrome (MPS-II) is an inherited disorder of metabolism caused by deficiency of an enzyme, iduronate-2-sulfatase (I2S). As a consequence, there is accumulation of incompletely-degraded material in major target organs, such as the soft tissues of the upper and lower airways, liver, spleen, cartilage and bone.

The condition is named after Charles A Hunter, who first described two young male siblings with distinctive features, including short stature and joint deformities. The term ‘syndrome’ is used for a recognisable pattern of malformations or combination of clinical findings that point to a particular disease or group of diseases. In this instance, mucopolysaccharidosis represents a group of conditions caused by different lysosomal enzymes, but associated with overlapping clinical manifestations.

Additionally, these conditions are characterised by a common finding, ie, the excessive urinary excretion of mucopolysaccharides or glycosaminoglycans (GAGs) in urine. Qualitative analysis of urinary GAGs by electrophoresis can distinguish the type of mucopolysaccharidosis, which can be subsequently confirmed by enzyme assays and gene (DNA) testing.

Diagnosis

There are two clinical subtypes of Hunter syndrome: A severe and attenuated form. Children with the severe form have coarse facial features, short stature, skeletal dysplasia and joint stiffness associated with progressive and profound mental retardation. Additional findings include hearing loss and cardiac valve disease.

Diagnosis is often made by 12-to-36 months of age, with recurrent and prolonged rhinitis and persistent nasal discharge evident beforehand, and representing the first non-specific symptoms of airway disease that manifest as noisy breathing and later obstructive sleep apnoea (OSA). Inguinal and umbilical hernias are also often noted.

Patients with the attenuated form have normal intelligence and a slower rate of disease progression, although ultimate adult height is reduced in most cases. Diagnosis is often delayed in patients with the attenuated form, especially in those without a positive family history. In these cases, the presence of joint contractures may lead to referral to a rheumatologist or orthopaedic surgeon; an invaluable clue is the presence of ‘claw-hand deformity’ and the absence of signs of inflammation. X-rays reveal characteristic findings, including bullet-shaped phalanges noted in views of the hands and platyspondyly (flattened vertebral bodies, often with anterior beaking) seen on films of the lateral spine. This constellation of findings, including macrocephaly, is consistent with dysostosis multiplex, caused by abnormalities in development of skeletal cartilage and bone.

Hunter syndrome is transmitted as an X-linked trait, which primarily affects males, although rare cases of affected females have been described, often due to an underlying chromosomal defect. Thus, family history can provide an invaluable clue to diagnosis, eg, the presence of an affected maternal uncle or an older affected male sibling. Occasionally, the gene defect or mutation can arise de novo; that is, spontaneously. In such cases, the risk of having an affected child in future pregnancies is low. Appropriate genetic counselling is recommended for family members of an affected individual.

Disease course

In the most severely-affected children with primary neurologic complications, disease progression leads to death by 10-to-12 years of age or earlier; whereas those with a ‘milder’ course may live into their 50s and 60s.

The airway problems seen in patients with Hunter syndrome necessitate caution and careful planning for any procedures requiring sedation/anaesthesia. Patients should have pulmonary function tests and be assessed for the presence of OSA, in which case positive pressure ventilation (BiPAP or CPAP) may be required. Severe cases may necessitate tracheostomy.

Other problems include carpal tunnel syndrome requiring nerve conduction studies and tendon release and cardiac valve disease, which may necessitate replacement.

Tonsillectomy and adenoidectomy are often undertaken in childhood. Hearing tests should be regularly performed, so hearing aids can be fitted when required.

Comprehensive care includes occupational and physical therapy. Hip dysplasia is the most common long-term orthopaedic problem and can become a significant source of disability with early-onset arthritis.

Behavioural and cognitive impairment can lead to major challenges in the care of patients with severe Hunter syndrome. Chronic communicating hydrocephalus may complicate the clinical picture.

It is evident that patient care requires a multidisciplinary team, including developmental specialists, pulmonologist, cardiologist, neurologist, neurosurgeons and orthopaedic surgeons, organised through a centre of excellence.

The majority of these patients will be diagnosed before 18 years of age and care provided by the metabolic team at the National Centre for Inherited Metabolic Diseases based at the Children’s University Hospital, Temple Street, Dublin. Care for adult patients is increasingly being provided by the metabolic unit set up at the Mater Hospital, Dublin.

Treatment

Enzyme replacement therapy (ERT) is available for the treatment of the systemic manifestations of Hunter syndrome. ERT involves the regular weekly infusion of a recombinant enzyme formulation. Treatment is well tolerated, although some patients may develop an allergic or infusion reaction to the drug, which may be managed by premedication and a slower rate of administration. Ultimate neurologic prognosis in patients with severe Hunter syndrome is not altered by ERT and ultimately, patients started on therapy may need to discontinue further infusions, with attention paid to symptomatic management and ultimately, palliative care.

Patients with the attenuated form of Hunter syndrome given ERT experience increased energy level and physical endurance; there is softening of the coarse features and improvements in pulmonary function and in range of joint motion. Decrease in liver and spleen volume and urinary GAG levels have also been observed.

A number of interventions are being evaluated for potential use in MPS II, including intrathecal delivery of the enzyme I2S, in the hope of altering the course of neurodevelopmental and cognitive impairment.

A retrospective examination of data on patients with MPS II, largely from the period preceding the availability of ERT, revealed median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years) (Jones SA et al, J Inherit Metab Dis, 32(4):534-43, 2009). Respiratory failure and cardiac failure were the two major causes of death in these patients.

There is limited experience with hematopoietic stem cell transplantation (HSCT), but unlike the improvement/stabilisation in cognitive function noted among patients with Hurler syndrome (MPS-I) following HSCT, the outcome in patients with Hunter syndrome (MPS-II) has not led to consistent benefit and associated procedural risks have led to its consideration for this condition as investigational.

Suggested reading

Muenzer J, et al. Ten years of the Hunter Outcome Survey (HOS): Insights, achievements and lessons learned from a global patient registry. Orphanet J Rare Dis 2017;12(1):82.

Jones SA, et al, HOS Investigators. Mortality and cause of death in mucopolysaccharidosis type II — a historical review based on data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2009;32(4):534-43.

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