Hunter syndrome

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Hunter syndrome

Definition

Hunter syndrome is a defect in the ability to metabolize a type of molecule known as a mucopolysaccharide. Only males are affected. Short stature, changes in the normal curvature of the spine (kyphosis), a distinctive facial appearance characterized by coarse features, an oversized head, thickened lips, and a broad, flat nose characterize the syndrome.

Description

Hunter syndrome is a one of a group of diseases called mucopolysaccharidoses. It is caused by the deficiency of an enzyme that is required to metabolize or break down mucopolysaccharides (also called glycosaminoglycans). It is also called mucopolysaccharidosis Type II (MPS II) because there are several related but similar diseases. The Hunter syndrome involves a defect in the extracellular matrix of connective tissue. One of the components of the extracellular matrix is a molecule called a proteoglycan. Like most molecules in the body, it is regularly replaced. When this occurs, one of the products is a class of molecules known as mucopolysaccharides (glycosoaminoglycans). Two of these are important in Hunter syndrome: dermatan sulfate and heparan sulfate. These are found in the skin, blood vessels, heart and heart valves (dermatan sulfate) and lungs, arteries and cellular surfaces (heparan sulfate). The partially broken-down molecules are collected by lysosomes and stored in various locations in the body. Over time, these accumulations of partially metabolized mucopolysaccharides impair the heart, nervous system, connective tissue, and bones.

Both of these molecules require the enzyme iduronate-2-sulfatase (I2S) to be broken down. In people with Hunter syndrome, this enzyme is partially or completely inactive. As a result, unchanged molecules accumulate in cells. These mucopolysaccharides are stored and interfere with normal cellular functions. The rate of accumulation is not the same for all persons with Hunter syndrome. Variability in the age of onset is thought to be due to lingering amounts of activity by this enzyme.

The cells in which mucopolysaccharides are stored determine the symptoms that develop. When mucopolysaccharides are stored in skin, the proportions of the face change (coarser features than normal and an enlarged head). When they are stored in heart valves and walls, cardiac function progressively declines. If intact mucopolysaccharides are stored in airways of the lung, difficulty in breathing develops due to obstruction of the upper airway. Storage of the molecules in joints decreases mobility and dexterity. Storage in bones results in decreased growth and short stature. As mucopolysaccharides are stored in the brain, levels of mental functioning decline.

There are two variants of Hunter syndrome: a severe form (MPSIIA) and a mild form (MPSIIB). These can be diagnosed early in life and are distinguished on the basis of mental and behavioral differences. External manifestations of the severe form occur between two and four years of age and the mild form later, up to age 10.

Genetic profile

In both variants, the missing enzyme is LSulfoiduronate. Hunter syndrome is X-linked meaning that the I2S gene is located on the X chromosome. The Y chromosome of a male is never affected in Hunter syndrome. Males only have one copy of the I2S gene while females have two. A male who inherits an abnormal I2S gene will develop Hunter syndrome. This can occur in two ways: from a mother who already has the gene (she is a carrier) or from a fresh mutation. Fresh mutations are unusual.

There are four possible genetic configurations. (1) A male can have a normal I2S gene and will be unaffected. (2) A male can have an abnormal I2S gene and will have Hunter syndrome. Should this male reproduce, his sons will not have Hunter syndrome and his daughters will all be carriers. (3) A female can have two normal I2S genes and be unaffected. (4) A female can have one abnormal I2S gene and be a carrier. Should this female reproduce, half of her sons will, on average, have Hunter syndrome. Half of her daughters, on average, will be carriers. It is possible that no sons will have Hunter syndrome or no daughters will be carriers.

Demographics

Several estimates of the incidence of Hunter syndrome have been published. They vary from one in 72,000 male births (Northern Ireland) to one in 150,000 (United States). Because it is carried on the X chromosome, only males can be affected.

Signs and symptoms

Individuals with Hunter syndrome experience a slowing of growth between one and four years of age. They attain an average height of 4-5 feet (122-152 cm). The facial features of persons with Hunter syndrome are coarser than normal. Their heads tend to be large in proportion to their bodies. Over time, their hands tend to become stiff and assume a claw-like appearance. Their teeth are delayed in erupting. Progressive hearing loss eventually leads to deafness. Internal organs such as the liver and spleen are larger than normal. They are quite prone to hernias.

Diagnosis

Hunter syndrome can be identified early in life and is often initially diagnosed by the presence of an enlarged liver and spleen (hepatosplenomegaly), hernias, or joint stiffness. Skeletal changes can be seen with radiographs. Elevated mucopolysaccharide levels in urine focuses the diagnosis to a group of disorders. The concentration of dermatan sulfate and heparan sulfate is 5-25 times higher than in normal urine. Both are present in approximately the same amounts. The diagnosis of Hunter syndrome is confirmed by measuring iduronate-2-sulfatase activity in white blood cells, serum, or skin fibroblasts. Prenatal diagnosis is widely available by measuring the activity of I2S enzyme in amniotic fluid.

Hunter syndrome has many diagnostic characteristics in common with Hurler syndrome . However, there are some distinct differences between the two syndromes. Individuals with Hunter syndrome have clear corneas and tend to have deposits of mucopolysaccharides in the skin. These are characteristically on the back of the hands and elbows (the extensor surfaces) and on the upper surfaces of the shoulders. All are males. These differences are important in diagnosis.

Treatment and management

General support and treatment of specific symptoms are the only treatment options presently available. Iduronate-2-sulfatase can be made using cells that have been genetically engineered. However, as of 2001, the safety and clinical effectiveness of injecting I2S into humans has not been established.

Intrauterine testing of amniotic fluid is reliable. Tests to detect a carrier state are imperfect. There is no cure for Hunter syndrome. The heparan sulfate and dermatan sulfate in urine has no pathological significance.

Prognosis

In the severe form, death usually occurs by age 10-15. Persons with the mild form usually live near-normal lives and have normal intelligence.

Resources

BOOKS

Jones, K. L. "Hunter Syndrome." In Smith's Recognizable Patterns of Human Malformation. Edited by Kenneth L. Jones and Judy Fletcher. 5th ed. Philadelphia: Saunders, 1997, pp. 462-463.

McGovern, Margaret M., and Robert J. Desnick. "Lysosomal storage diseases." In Cecil Textbook of Medicine. Edited by Lee Goldman, et al. 21st ed. Philadelphia: Saunders, 1999, pp. 1104-1108.

Muenzer, Joseph L. "Mucopolysaccharidoses." In Nelson Textbook of Pediatrics. Richard E. Behrman et al., 16th ed. Philadelphia: Saunders, 2000, pp. 420-423.

PERIODICALS

Hunter, C. "A rare disease in two brothers." Proceedings of the Royal Society of Medicine. 1917: 10:104.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, ONT L3R-OM9 Canada. (905) 479-8701 or (800) 667-1846. <http://www.mpssociety.ca>.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR UK. 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (601) 942-0100. Fax: (610) 942-7188. info @mpssociety.org. <http://www.mpssociety.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Society for Mucopolysaccharide Diseases. 46 Woodside Rd., Amersham, Buckinghamshire, HP6 6AJ UK. =44 (01494) 434156. <http://www.mpssociety.co.uk>.