Hunter Syndrome (MPS II) Description

Disease process

The human body depends on a vast array of biochemical reactions to support critical functions, including the production of energy, growth and development, communication within the body, and protection from infection. Another critical function is the breakdown of large biomolecules, which is the underlying problem in Hunter syndrome (MPS II) and related storage disorders.

The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue of the body known as the extracellular matrix. This matrix is made up of a variety of sugars and proteins and helps to form the architectural framework of the body. The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together.

One of the parts of the extracellular matrix is a complex molecule called a proteoglycan. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides, otherwise known as GAG. There are several types of GAG, each found in certain characteristic places in the body (see table below).

GAG	Location in body
Hyaluronic acid	Various connective tissues, skin, cartilage, synovial fluid
Chondroitin sulfate	Cartilage, cornea, bone, skin, arteries
Dermatan sulfate	Skin, blood vessels, heart, heart valves
Heparan sulfate	Lung, arteries, cell surfaces
Heparin	Lung, liver, certain immune system cells
Keratan sulfate	Cartilage, cornea, intervertebral disks

In Hunter syndrome, the problem concerns the breakdown of two GAG: dermatan sulfate and heparan sulfate. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme I2S. In people with Hunter syndrome, this enzyme is either partially or completely inactive.

As a result, GAG build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this buildup continues, it interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. The rate of GAG buildup is not the same for all people with Hunter syndrome, resulting in a wide spectrum of medical problems.

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Signs and symptoms

The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth, but usually start to become noticeable after the first year of life. Often, the first symptoms of Hunter syndrome may include inguinal hernias, ear infections, runny noses, and colds. Since these symptoms are quite common among all infants, they are not likely to lead a doctor to make a diagnosis of Hunter syndrome right away.

As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical manifestations of many children with Hunter syndrome include a distinctive coarseness in their facial features, including a prominent forehead, a nose with a flattened bridge, and an enlarged tongue. For this reason, unrelated children with Hunter syndrome often look alike. They may also have a large head as well as an enlarged abdomen. Many continue to have frequent infections of the ears and respiratory tract.

The continued storage of GAG in cells can lead to organs being affected in important ways. The thickening of the heart valves along with the walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened as well, leading to breathing problems while sleeping (obstructive airway disease). People with Hunter syndrome may also have limited lung capacity due to pulmonary involvement. As the liver and spleen grow larger with time, the belly may become distended, making hernias more noticeable.

All major joints (including the wrists, elbows, shoulders, hips, and knees) may be affected by Hunter syndrome, leading to joint stiffness and limited motion. Progressive involvement of the finger and thumb joints results in decreased ability to pick up small objects. The effects on other joints, such as hips and knees, can make it increasingly difficult to walk normally. If carpal tunnel syndrome develops, a further decrease in hand function can occur. The bones themselves may be affected, resulting in short stature.

In addition, pebbly, ivory-colored skin lesions may be found on the upper arms and legs and upper back of some people with Hunter syndrome. The presence or absence of skin lesions is not helpful, however, in predicting clinical severity in Hunter syndrome.

Finally, the storage of GAG in the brain can lead to delayed development with subsequent mental retardation. The rate and degree of progression may be different for each person with Hunter syndrome.

There is a broad range of severity in the symptoms of Hunter syndrome. It is important to note that though the term mild is used by physicians in comparing people with Hunter syndrome, the effects of even mild disease are quite serious. Two of the most significant areas of variability concern the degree of mental retardation and expected life span. Some people who have Hunter syndrome are not mentally retarded and live into their 20s or 30s; there are occasional reports of people who have lived into their 50s or 60s. The quality of life remains high in a large number of people, and many adults are actively employed. In contrast, others with Hunter syndrome develop severe mental impairment and have life expectancies of 15 years or less.

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Diagnosis

The visible signs and symptoms of Hunter syndrome (MPS II) in younger people are usually the first clues leading to a diagnosis. In general, the time of diagnosis usually occurs from approximately 2 to 4 years of age.

Doctors may use laboratory tests to provide additional evidence that an MPS disorder is present, before making a definitive diagnosis by measuring the I2S enzyme activity. The most commonly used laboratory screening test for an MPS disorder is a urine test for GAG. It is important to note that the urine test for GAG can occasionally be normal and yet the child still may have an MPS disorder.

A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum, white blood cells, or fibroblasts from skin biopsy. In some people with Hunter syndrome, analysis of the I2S gene can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or in chorionic villus tissue.

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Inheritance

Hunter syndrome (MPS II) affects a calculated estimate of 1 in 162,000 live births. Since Hunter syndrome is an inherited disorder (X-linked recessive) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell in the human body has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.

If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; ie, she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. However, during egg and sperm formation, a mutation can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected. Hunter syndrome has been rarely reported to occur in females.

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Management of Hunter syndrome (MPS II)

In managing Hunter syndrome, there are many ways to help enhance your or your child's well-being. One of these is finding the right specialist with experience treating children with special needs. Another is palliative and symptomatic treatments that can help relieve pain and enhance general health. Many organizations provide general information and community and governmental support for families living with the disease (see More resources).

There are several supportive therapies available that may help manage the signs and symptoms of the disorder and treat any resulting complications. Some of the common symptoms and complications are:

• Airway and pulmonary problems
• Infections
• Cardiac complications
• Excessive fluid collection in the area around the brain causing increased pressure
• Hernias
• Join contractures, scoliosis, carpal tunnel syndrome
• Seizures
• Gastrointestinal symptoms; abdominal discomfort; diarrhea

In this section, you’ll find information on how these are commonly treated. If you have any questions about treating your or your loved one’s Hunter syndrome symptoms, please speak to your doctor.

Airway and pulmonary problems

Breathing problems may be treated with oxygen therapy, which may be given as needed during the day or continuously at night while a person with Hunter syndrome is sleeping. The use of breathing devices—such as CPAP (continuous positive airway pressure) or BiPAP (bilevel positive airway pressure)—with or without oxygen in people with sleep apnea may improve sleep and reduce the risk of heart failure caused by low night-time blood oxygen levels.

• CPAP. CPAP (continuous positive airway pressure) uses a face mask, nasal prongs, or an endotracheal tube to assist breathing by pumping air into the airway, keeping the airway open, and increasing lung volume.
• BiPAP. BiPAP (bilevel positive airway pressure) varies the airway pressure to assist breathing and expiration using the same apparatus as CPAP.
• Surgery. Surgery to remove enlarged tonsils and adenoids may ease breathing problems in some people with Hunter syndrome who have obstructive airway disorders and sleep apnea; however, the adenoids may re-enlarge. Some people may require an endotracheal tube or tracheostomy (each of these are methods of placing a tube directly into the airway to aid breathing).
• Anesthesia can be dangerous. When possible, surgical procedures and anesthesia for people with Hunter syndrome should be carried out by surgeons and anesthesiologists experienced in the management of people with MPS. This is because the airway in people with Hunter syndrome is compromised by the presence of accumulated GAG in the membranes of the airway. Also, altered airway anatomy makes intubation difficult.

Infections

Early in childhood, people with Hunter syndrome have frequent ear infections, as do many children without this disease. However, children with Hunter syndrome do not outgrow this condition, as do other children. They continue to have chronic and recurrent ear infections requiring antibiotic treatment.

People with Hunter syndrome usually develop secondary bacterial sinus or middle ear infections after viral infections, such as colds or flu, and therefore may benefit from long-term antibiotic therapy. One complication of long-term antibiotic therapy is that the infecting bacteria can develop resistance to the antibiotics used, making it more difficult to treat future infections.

Tympanostomy tubes (T tubes) may be inserted in the ear for people with recurrent ear infections to improve fluid drainage from the ear, speeding recovery from infection. The presence of tubes also benefits ventilation, and may aid in both healing of ear infections and improving hearing.

Cardiac complications

Heart problems can sometimes be severe in people with Hunter syndrome. The continued accumulation of GAG in the heart can weaken the heart muscle, damage the valves, and narrow the arteries. These complications may lead to high blood pressure, heart failure, and heart attacks. High blood pressure, if present, can be treated with antihypertensive medications. Damaged heart valves may be surgically replaced.

Other symptoms and complications

Other symptoms and complications of Hunter syndrome may be addressed by various surgical procedures and supportive therapies:

• Communicating hydrocephalus (fluid on the brain) can be treated by inserting a shunt or thin tube to drain fluid from the brain when the fluid pressure in the skull is too high
• Hernias may be repaired surgically. Inguinal hernias are always repaired, and may sometimes come back. Umbilical hernias may be repaired if their size causes a problem; they often return after surgical repair
• Other conditions that may be treated surgically include scoliosis, joint contractures, and carpal tunnel syndrome, in which the compressed nerves are freed
• Specific medications can be used to treat seizures, if present
• Hearing aids may be effective for people with either conductive or nerve deafness, or combination deafness
• The use of physical therapy, such as range-of-motion exercises, may preserve the function people have, but would not be expected to restore lost function
• In addition to the surgical treatment mentioned above, carpal tunnel syndrome may also be treated by splinting
• Dietary changes and medications may improve gastrointestinal symptoms in some people with Hunter syndrome

Not all symptoms and complications of Hunter syndrome are able to be addressed with supportive therapies. At times it may be helpful to talk to other families, your physician, nurse, or genetic counselor to identify strategies that may help you improve your quality of life.

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