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 called mucopolysaccharidosis type II (MPS II) because there are several 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 proteogly-can. 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 iduro-nate-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.