Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a condition that affects many different parts of the body. The condition occurs almost exclusively in boys, although it has been reported in a few girls. It is a progressively debilitating disorder; however, the rate of progression varies among affected individuals.

At birth, individuals with MPS II do not display any features of the condition. Between ages 2 and 4, they develop full lips; large, rounded cheeks; a broad nose; and an enlarged tongue (macroglossia). The vocal cords also enlarge, which results in a deep, hoarse voice. Narrowing of the airway causes frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). As the disorder progresses, individuals need medical assistance to keep their airway open.

Many other organs and tissues are affected in people with MPS II. Individuals with this disorder often have a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), a short neck, an enlarged liver and spleen (hepatosplenomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). People with MPS II usually have thick skin that is not very stretchy. Some affected individuals also have distinctive white skin growths that look like pebbles. Most people with this disorder develop hearing loss. Some individuals with MPS II develop problems with the light-sensitive tissue in the back of the eye (retina) and have reduced vision. Carpal tunnel syndrome commonly occurs in children with this disorder and is characterized by numbness, tingling, and weakness in the hand and fingers. Narrowing of the spinal canal (spinal stenosis) in the neck can compress and damage the spinal cord. The heart is also significantly affected by MPS II, and many individuals develop heart valve problems. Heart valve abnormalities can cause the heart to become enlarged (ventricular hypertrophy) and can eventually lead to abnormalities in the heart's rhythm (arrhythmia) and heart failure.

Children with MPS II grow steadily until about age 5, and then their growth slows and they develop short stature. Individuals with this condition have joint deformities (contractures) that significantly affect mobility. Most people with MPS II also have dysostosis multiplex, which refers to multiple skeletal abnormalities that can be seen on x-rays. Dysostosis multiplex includes a generalized thickening of certain bones, particularly the ribs.

There are two types of MPS II: the neuropathic form, which is more severe, and the non-neuropathic form, which is less severe. While both types affect many different organs and tissues as described above, people with neuropathic MPS II also experience a decline in intellectual function and a more rapid disease progression. Individuals with this form begin to lose basic functional skills (developmentally regress) between the ages of 6 and 8. Their life expectancy is 10 to 20 years. Individuals with non-neuropathic MPS II also have a shortened lifespan, but they typically live into adulthood, and their intelligence is not affected. Heart disease and airway obstruction are major causes of death in people with both types of MPS II.

Variants (also called mutations) in the IDS gene cause MPS II. The IDS gene provides instructions for producing the I2S enzyme, which is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name.

IDS gene variants that cause MPS II reduce or completely eliminate the function of the I2S enzyme. Lack of I2S enzyme activity leads to the accumulation of GAGs within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions that cause molecules to build up inside the lysosomes, including MPS II, are called lysosomal storage disorders.

The accumulation of GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in people with this disorder. Researchers believe that the accumulated GAGs may also interfere with the functions of other proteins inside the lysosomes and disrupt the movement of molecules inside the cell. In addition, buildup in lysosomes may trigger the release of molecules called cytokines that stimulate inflammation and may contribute to the progression of MPS II.

Normal Function

The IDS gene provides instructions for producing an enzyme called iduronate 2-sulfatase (I2S), which is essential for the breakdown of large sugar molecules called glycosaminoglycans (GAGs). Specifically, I2S removes a chemical group known as a sulfate from a molecule called sulfated alpha-L-iduronic acid, which is present in two GAGs called heparan sulfate and dermatan sulfate. I2S is located in lysosomes, which are compartments within cells that digest and recycle different types of molecules.

Health Conditions Related to Genetic Changes

Mucopolysaccharidosis type II

Hundreds of variants (also called mutations) in the IDS gene have been found to cause mucopolysaccharidosis type II (MPS II). Variants that change one DNA building block (nucleotide) are the most common. All the variants that cause MPS II reduce or completely eliminate the function of the I2S enzyme in cells.

There are two types of MPS II: the neuropathic form, which is more severe, and the non-neuropathic form, which is less severe. It is difficult to tell which variants cause each form of the disorder. However, variants that remove large pieces of the gene or rearrange the genetic material, completely eliminating I2S enzyme function, often cause the neuropathic form of the disorder.

Lack of I2S enzyme activity leads to the accumulation of heparan sulfate and dermatan sulfate within lysosomes in cells. The buildup of these GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in people with MPS II. Researchers believe that the accumulated GAGs may also interfere with the functions of other proteins inside the lysosomes and disrupt the movement of molecules inside the cell. In addition, buildup in lysosomes may trigger the release of molecules called cytokines that stimulate inflammation and may contribute to the progression of MPS II.

Other Names for This Gene

• IDS_HUMAN
• iduronate 2-sulfatase (Hunter syndrome)
• iduronate-2-sulfatase

Genomic Location

The IDS gene is found on the X chromosome.

MPS II is a genetic condition that babies typically inherit from their biological mother. Mothers may have the changed gene and not have the condition (a carrier). MPS II can also occur for the first time in a family when the mother is not a carrier (de novo MPS II). Almost all children with MPS II are male.

• MPS II is inherited in an X-linked recessive pattern, which means babies inherit this condition on their X‑chromosome.
  • Baby girls have two X-chromosomes. If they have a nonworking IDS gene on one of the two X-chromosomes, they typically have a working copy of the IDS gene on the other, which is enough to prevent disease.
  • Baby boys only have one X-chromosome. All boys with one nonworking IDS gene (on their only X-chromosome) have MPS II.
• Girls with one working copy and one nonworking copy of the IDS gene are called carriers.
  • Carriers may pass down a nonworking copy of the gene to their children.
• When a boy is diagnosed with MPS II, the mother needs to be tested to find out if she is a carrier. A carrier mother has a 1 in 2 chance of having another son being born with MPS II or having another daughter who is a carrier.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

The timing that MPS II develops and the type of problems it causes vary between different people. Symptoms may appear as early as the first year of life or not until several years of age.

Signs of the condition may include the following:

• Frequent ear infections
• Frequent upper respiratory infections (like cold or flu)
• Chronic or frequent diarrhea
• Large head (macrocephaly)
• Large tongue (macroglossia)
• Large liver and spleen (hepatosplenomegaly)
• Facial features that are different from their parents
• Soft out-pouching around their belly button or groin (umbilical or inguinal hernia)
• Heart problems
• Stiff joints
• Sleep problems
• Hearing loss

Carrier testing for MPS II is available. Testing usually begins with an affected male relative, if one is available for testing, to determine the disease-causing mutation. If there is not living affected male relative, testing possible female carriers involves a type of genetic testing called sequence analysis. This test requires a small blood sample and reads through the genetic code of the IDS gene looking for errors. If a mutation is not found using sequence analysis, then two other tests can be performed to look for mutations that cause MPS II. Genetic testing detects most of the mutations that cause MPS II, but may not detect all mutations that cause this condition Therefore, testing cannot definitively determine that a person is not a carrier for MPS II.

Newborn screening for MPS II requires collecting a small amount of blood from your baby’s heel. Screening measures the activity of the enzyme I2S in your baby’s blood. Screening may also measure GAG levels. Babies with low activity levels of I2S and high levels of GAGs might have MPS II.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for MPS II is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition may happen. Some babies with positive newborn screening results for MPS II have a “pseudodeficiency.” Pseudodeficiency means that a baby’s enzyme levels are low on the screening but are normal in their body. These babies do not have and will never develop MPS II.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about what type of evaluations may be useful to look for problems, and which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Testing may include:

• X-rays
• Ultrasound picture of the heart (echocardiogram)
• Hearing tests

Treatments may include the following:

• Enzyme replacement therapy (ERT)
• Stem cell transplantation
• Physical therapy
• Surgery

Health outcomes for MPS II vary based on a child’s form of the condition. For children with the attenuated form, early and ongoing treatment can lead to healthy growth and development. For children with the severe form, early treatment can prevent or delay some serious symptoms of the condition.