Hunter's Syndrome

Synonyms: Hunter syndrome, Mucopolysaccharidosis Type II, MPS II, MPS 2, Iduronate-2-sulphatase deficiency, IDS deficiency, mild form known historically as gargoylism.

• The mucopolysaccharidoses are a group of inherited lysosomal storage diseases.
• There is an accumulation of incompletely degraded glycosaminoglycans (acid mucopolysaccharides) in tissues, in this case heparan and dermatan sulphate.
• Glycosaminoglycans are polysaccharide chains containing amino-sugars that are part of the structure of proteoglycans.
• Proteoglycans play an important structural and functional role throughout the body. They consist of a central protein core with multiple glycosaminoglycan polysaccharide chains attached.
• Proteoglycans are found intracellularly, on the cell surface, as part of the extracellular matrix and in basement membranes. Their roles are thought to be varied and largely undefined, predominantly of structural importance.

In cartilage, proteoglycans play an important role in its 'shock-absorber' function by retaining water to form a yielding sponge-like structure. They have a complex biosynthetic pathway and are degraded by specific enzymes, one for each particular type of glycosaminoglycan chain. In Hunter's syndrome the deficient enzyme is iduronate-2-sulphatase. The condition is X-linked recessive (Xq28) and there are a range of mutations/chromosomal abnormalities causing the syndrome.¹ Thus it is seen almost exclusively in boys, but rare sporadic cases in females do occur.²

Incidence 1 in 140,000 live births (1 in 72,00 male live births) in a survey conducted in Northern Ireland. The overall rate of mucopolysaccharidoses was 1 in 25,000 live births.³

There are two clinical manifestations of the genetic abnormality:

1. Type A - severe form with relentless progression towards profound mental retardation. It usually presents in late infancy and is progressive, leading to neurological impairment, deafness and somatic dysfunction with death by adolescence/3rd decade.
   
   Problems usually start before age 3, common presenting features include:
   • Coarsening of facial features
   • Thickening of the tongue
   • Decline in intellectual function
   • Hearing problems
   • Swollen and stiff joints
   • Abdominal hernias
   • Hepatosplenomegaly
   Skin features:
   • Pebble-like ivory-coloured papular skin lesions occur in a reticular pattern between the angles of the scapulae and the posterior axillary line, and over the pectoral area and lateral aspects of the upper arms and legs. The skin changes are virtually pathognomonic for the disease.
   • The skin may also show hypertrichosis and excessive Mongolian spots.⁴
   Other features:
   • Macrocephaly - common with a short trunk length compared to the extremities
   • Short stature - develops gradually after the age of three
   • Airways obstruction - from accumulation of heparan and dermatan sulphate in the trachea
   • Cardiomyopathy and valvular abnormalities e.g. aortic regurgitation - from cardiac infiltration
   • Flexion contractures
   • Progressive deafness - usually mixed sensorineural/conductive variety
   • Abnormal retinal pigmentation and papilloedema - leading to visual impairment
2. Type B - mild form. This usually presents later and may not be noticed until adulthood. Life expectancy can be near-normal in this group, with relatively normal intellectual abilities but impaired reading and verbal skills. Behavioural problems such as aggression, restlessness and sleep disturbance may occur in both forms of the illness.⁵
   • Diagnosis often not made until later childhood or even adulthood
   • Physical features are similar to those in type A but there is an absence of, or much less severe, neurocognitive involvement
   • May also be dysplasia of the pelvis or femoral head and/or small carpal bones and early osteoarthritis
   • Life expectancy varies from fourth through to seventh decade

• Hurler syndrome (MPS I-H) - corneal clouding present
• Scheie syndrome (MPS I-S)
• Multiple sulphatase deficiency (mucosulphatidosis)

• Urine - glycosaminoglycan variants in the urine suggests the diagnosis (namely chondroitin sulfate B and heparitin sulfate)
• Measuring iduronate-2-sulphatase activity in fibroblasts/leucocytes will confirm diagnosis
• Deposition products can be shown in biopsy samples with special stains
• X-rays - show features of dysostosis multiplex which are due to disordered ossification at varied sites
• Audiometry
• Brain CT/MRI - characteristic cerebral changes
• Spirometry to look for airflow obstruction
• Echocardiography - to reveal cardiac abnormalities

• No curative therapy is currently available.
• Treatment is supportive and symptomatic and often focuses on cardiac complications.
• Parents often have difficulty coping with behavioural disturbance in their children and need psychosocial support.⁵
• Trials of haematopoietic stem cell transplantation have had mixed results with evidence of biochemical/dermatological amelioration which does not necessarily translate into clinical improvement.^6,7
• Enzyme replacement therapy has, as yet, been unsuccessful.
• Gene therapy using a retroviral vector may offer future hope of definitive treatment.⁸

Carpal tunnel syndrome due to median nerve hypertrophy may become a problem, particularly in older sufferers of the mild form.

Death is usually as a result of cardiorespiratory complications. Severe variant sufferers have average onset 2.5 years with an average age of death of ~12 years - but some may survive into their thirties. Mild variant sufferers have an average age of onset of 4.3 years with average age of death 21.7 years -but some may survive into their fourth decade and beyond.⁹

Genetic counselling with prenatal diagnosis may be helpful within families already with an affected child.