Synonyms: Hunter syndrome, mucopolysaccharidosis type II (MPS II), MPS 2, iduronate-2-sulfatase 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 sulfate.
• 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.

Genetics

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-sulfatase. 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

Epidemiology

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

Presentation

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, and 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 3
   • Airways obstruction - from accumulation of heparan and dermatan sulfate 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. Some patients may only have involvement of one organ.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 4th through to 7th decade

Behavioural problems such as aggression, restlessness and sleep disturbance may occur in both forms of the illness.⁶

Differential diagnosis

• Hurler's syndrome (MPS IH) - corneal clouding present
• Scheie's syndrome (MPS IS)
• Multiple sulfatase deficiency (mucosulfatidosis)

Investigations

• Urine - glycosaminoglycan variants in the urine suggest the diagnosis (namely chondroitin sulfate B and heparitin sulfate)
• Measuring iduronate-2-sulfatase 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

Management

• 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.⁶
• Trials of haematopoietic stem cell transplantation have had mixed results with evidence of biochemical/dermatological amelioration which does not necessarily translate into clinical improvement.^7,8
• Enzyme replacement therapy has, as yet, been unsuccessful.
• Gene therapy using a retroviral vector may offer future hope of definitive treatment.⁹

Complications

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

Prognosis

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.¹⁰ Cognitive impairment is associated with reduced life expectancy.¹¹

Prevention

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

Document references

1. OMIM; Mucopolysaccharidoses Type II (Hunter's Syndrome). Online Mendelian Inheritance in Man.
2. Tuschl K, Gal A, Paschke E, et al; Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol. 2005 Apr;32(4):270-2. [abstract]
3. Nelson J; Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997 Dec;101(3):355-8. [abstract]
4. Ochiai T, Ito K, Okada T, et al; Significance of extensive Mongolian spots in Hunter's syndrome. Br J Dermatol. 2003 Jun;148(6):1173-8. [abstract]
5. Suzuki Y, Aoyama A, Kato T, et al; Retinitis pigmentosa and mucopolysaccharidosis type II: an extremely attenuated phenotype. J Inherit Metab Dis. 2009 Aug;32(4):582-3. Epub 2009 Jul 9.
6. Bax MC, Colville GA; Behaviour in mucopolysaccharide disorders. Arch Dis Child. 1995 Jul;73(1):77-81. [abstract]
7. Ochiai T, Ito K, Shichino H, et al; Ultrastructural findings of cutaneous nerves in patients with Hunter's syndrome following hematopoietic stem cell transplant. Med Mol Morphol. 2005 Jun;38(2):118-22. [abstract]
8. Ito K, Ochiai T, Suzuki H, et al; The effect of haematopoietic stem cell transplant on papules with 'pebbly' appearance in Hunter's syndrome. Br J Dermatol. 2004 Jul;151(1):207-11. [abstract]
9. Hong Y, Yu SS, Kim JM, et al; Construction of a high efficiency retroviral vector for gene therapy of Hunter's syndrome. J Gene Med. 2003 Jan;5(1):18-29. [abstract]
10. MPS Disorders; Information on mucopolysaccharide disorders for parents, educators, psychologists, and other persons interested in these disorders.
11. Jones SA, Almassy Z, Beck M, et al; 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 Aug;32(4):534-43. Epub 2009 Jul 14. [abstract]

Internet and further reading

• Society for Mucopolysaccharide Diseases; National Registered Charity; 2006
• Charles A. Hunter; whonamedit.com, Hunters Syndrome

Acknowledgements